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1
Steen, R. W. J. "The effect of level of protein supplementation on the performance and carcass composition of young bulls given grass silage ad libitum." Animal Science 52, no. 3 (June 1991): 465–75. http://dx.doi.org/10.1017/s0003356100013040.
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ABSTRACTTwo experiments have been carried out to examine the effects of the level of protein supplementation given with grass silage-based diets on the performance and carcass composition of bulls, and to compare diets based on silage and dried forage. The five treatments used consisted of grass silage offered ad libitum and supplemented with 2·5 kg dry matter (DM) of barley-based concentrates containing (1) zero (2) 200 (3) 400 and (4) 600 g soya-bean meal per kg and (5) artificially dried grass and hay supplemented with 3·2 kg concentrate DM. The silages used in both experiments were well preserved, containing on average 200 g DM per kg; 140 g crude protein (CP) per kg DM; 63 g ammonia-nitrogen per kg total N and 731 g digestible organic matter per kg DM. The bulls were of late-maturing breed type and were initially 12 months old and 412 and 405 kg live weight in experiments 1 and 2 respectively. For treatments 1, 2, 4 and 5 in experiment 1 respectively (treatment 3 was not used) total DM intakes were 8·3, 8·3, 81 and 110 (s.e. 0·21) kg/day; CP intakes 1063, 1271, 1664 and 1539g/day; metabolizable energy intakes (MEI) 98, 99, 96 and 87 MJ/day; carcass weights 317, 316, 317 and 316 (s.e. 3·2) kg; carcass saleable meat concentrations 714, 712, 718 and 716 (s.e. 5·8) g/kg and carcass fat trims 73, 81, 73 and 68 (s.e. 3·9) g/kg. In experiment 2 for treatments 1 to 5 respectively total DM intakes were 8·3, 8·5, 8·3, 8·4 and 11·2 (s.e. 0·26) kg/day; CP intakes were 1090, 1329, 1504, 1720 and 1561 g/day; MEI 102, 106, 103, 103 and 94 MJ/day; carcass weights 318, 331, 330, 327 and 321 (s.e. 3·3) kg; carcass saleable meat concentrations 726, 721, 725, 721 and 732 (s.e. 60) g/kg and fat trims 71, 77, 78, 80 and 64 (s.e. 4·5) g/kg. It is concluded that protein supplementation of a silage-based diet did not affect performance or carcass fatness in experiment 1 or carcass fatness in experiment 2, but including 200 or 400 g soya-bean meal per kg concentrate increased performance in experiment 2. Animals given silage produced fatter carcasses than those given dried forage in experiment 2 but not in experiment 1.
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Yurchyshak, I. M., I. O. Kiselyk, N. O. Shurko, and V. L. Novak. "Current issues of application of anti-viral drugs in hematological patients with hepatitis C virus." Infusion & Chemotherapy, no. 3.1 (October 11, 2020): 86–87. http://dx.doi.org/10.32902/2663-0338-2020-3.1-72.
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Objective. To analyze the effectivity of the use of antiviral drugs Sovaldi 400 mg and Harvoni 90/400 mg in hematological patients.
Materials and methods. Under our supervision there were 68 patients: 43 (63 %) male and 25 (37 %) female, age from 23 to 80 years, who were treated with antiviral medications intended to hepatitis C virus (HCV). The drugs had prescribed depending on the genotype of the virus; the degree of liver damage; factors that aggravate the course of the disease and the treatment process; responses and adverse reactions that may occur during the process of taking the drug and the timing of use. The 26 patients with genotypes 1 (3), 1c (4), 2 (4), 3a (14) and 1 patient with atypical genotype Sovaldi 400 mg received. Harvoni 90/400 mg was used for treatment HCV 1b genotype in 41 patients and in 1 patient with an atypical genotype. To all patients were investigation according to the algorithm for the diagnosis and treatment of HCV: general clinical (biochemical and hematological) studies and examinations to determine the genotype of the virus, viral load, the degree of liver fibrosis.
Results and discussion. Given the high infection rate of hematological patients with HCV, which does not allow full treatment, including surgery and chemotherapy, under the program “Treatment of patients with viral hepatitis” antiviral drugs were purchased and treatment was performed in groups of hematological patients. In particular, in patients with the following diagnoses: non-Hodgkin lymphoma (5); myelodysplastic syndromes (1); Hodgkin lymphoma (1); haemophilia A (13) and B (3); leukopenia (3); disaggregation thrombocytopathy (16); immune thrombocytopenic purpura (13); secondary erythrocytosis (5); iron deficiency anemia (5); polycythemia vera (2); chronic lymphocytic leukemia (1). Antiviral therapy was performed according to the clinical protocol for the treatment of viral hepatitis B and C in hematological patients under the supervision of an infectious disease specialist and hematologist. Most patients tolerated treatment satisfactorily and without complications.
Conclusions. In the last years, direct-acting antiviral drugs become the standard of treatment in hematological patients. For today, HCV should not hinder on the basic of full treatment in the hematological patients as most infected patients may receive antiviral therapy.
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McWilliams, Robert R., Michelle R. Mahoney, Benjamin T. Marchello, Aminah Jatoi, Keith D. Krewer, Matthew M. Ames, Daniel Jay Schneider, et al. "Pharmacogenetic dosing by UGT1A1 genotype as first-line therapy for advanced small-bowel adenocarcinoma: A North Central Cancer Treatment Group (NCCTG) trial." Journal of Clinical Oncology 30, no. 4_suppl (February 1, 2012): 314. http://dx.doi.org/10.1200/jco.2012.30.4_suppl.314.
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314 Background: Small bowel adenocarcinoma (SB-ACA) is rare, having little prospective data guiding management. A prior phase I study evaluated UGT1A1 genotype specific dosing of oxaliplatin, irinotecan, and capecitabine. Our prospective, multicenter clinical trial assessing tumor response in pts having metastatic SB-ACA, used a similar dosing strategy. Methods: Genotypes were determined via central lab. Previously untreated pts were dosed by UGT1A1*28 genotypes 6/6, 6/7, and 7/7 receiving 100/85/85 mg/m2 oxaliplatin d1, 150/150/75 mg/m2 irinotecan d1, and 1600/400/200 mg/m2 capecitabine (BID) d2-15 of 21 days. The study design was such that 1 confirmed response in 16 pts expanded enrollment to 33 pts, with 7 required for demonstrating efficacy. Results: 28 pts (13-6/6, 10-6/7, 5-7/7) have been enrolled [75% male, mean age 62.5 (range 41-77)]. Location of primary included: duodenum (63%), jejunum (26%), and ileum (7%), with pts having >1 metastatic site (abdominal-41%, bone-7%, liver-56%, lung-30%, nodal-52%, subcutaneous-4%, other-19%). Gr 3+ treatment related toxicity was not significantly different by genotype (50%-6/6, 44%-6/7, 20%-7/7, p=0.48) and included (pts): diarrhea(5), vomiting(5), leukopenia(5), neutropenia(7), and nausea(6). 57% (13 of 23) pts achieved responses during therapy, with a confirmed response rate of 39% (95% CI 0-58%). 18 have died, with a median follow-up of 8.3 mos (range 0-43). Conclusions: UGT1A1 genotype directed dosing with oxaliplatin, irinotecan, and capecitabine appears to result in prolonged response in this population. Larger studies are needed to determine comparability to CapeOx alone or if response/toxicity differs among genotypes. Supported by NIH Grant CA25224, Sanofi-Aventis, and Pfizer. [Table: see text]
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Paukner, Susanne, David Mariano, Anita F. Das, Gregory J. Moran, Christian Sandrock, Ken B. Waites, and Thomas M. File. "Lefamulin in Patients with Community-Acquired Bacterial Pneumonia Caused by Atypical Respiratory Pathogens: Pooled Results from Two Phase 3 Trials." Antibiotics 10, no. 12 (December 4, 2021): 1489. http://dx.doi.org/10.3390/antibiotics10121489.
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Lefamulin was the first systemic pleuromutilin antibiotic approved for intravenous and oral use in adults with community-acquired bacterial pneumonia based on two phase 3 trials (Lefamulin Evaluation Against Pneumonia [LEAP]-1 and LEAP-2). This pooled analysis evaluated lefamulin efficacy and safety in adults with community-acquired bacterial pneumonia caused by atypical pathogens (Mycoplasma pneumoniae, Legionella pneumophila, and Chlamydia pneumoniae). In LEAP-1, participants received intravenous lefamulin 150 mg every 12 h for 5–7 days or moxifloxacin 400 mg every 24 h for 7 days, with optional intravenous-to-oral switch. In LEAP-2, participants received oral lefamulin 600 mg every 12 h for 5 days or moxifloxacin 400 mg every 24 h for 7 days. Primary outcomes were early clinical response at 96 ± 24 h after first dose and investigator assessment of clinical response at test of cure (5–10 days after last dose). Atypical pathogens were identified in 25.0% (91/364) of lefamulin-treated patients and 25.2% (87/345) of moxifloxacin-treated patients; most were identified by ≥1 standard diagnostic modality (M. pneumoniae 71.2% [52/73]; L. pneumophila 96.9% [63/65]; C. pneumoniae 79.3% [46/58]); the most common standard diagnostic modality was serology. In terms of disease severity, more than 90% of patients had CURB-65 (confusion of new onset, blood urea nitrogen > 19 mg/dL, respiratory rate ≥ 30 breaths/min, blood pressure <90 mm Hg systolic or ≤60 mm Hg diastolic, and age ≥ 65 years) scores of 0–2; approximately 50% of patients had PORT (Pneumonia Outcomes Research Team) risk class of III, and the remaining patients were more likely to have PORT risk class of II or IV versus V. In patients with atypical pathogens, early clinical response (lefamulin 84.4–96.6%; moxifloxacin 90.3–96.8%) and investigator assessment of clinical response at test of cure (lefamulin 74.1–89.7%; moxifloxacin 74.2–97.1%) were high and similar between arms. Treatment-emergent adverse event rates were similar in the lefamulin (34.1% [31/91]) and moxifloxacin (32.2% [28/87]) groups. Limitations to this analysis include its post hoc nature, the small numbers of patients infected with atypical pathogens, the possibility of PCR-based diagnostic methods to identify non-etiologically relevant pathogens, and the possibility that these findings may not be generalizable to all patients. Lefamulin as short-course empiric monotherapy, including 5-day oral therapy, was well tolerated in adults with community-acquired bacterial pneumonia and demonstrated high clinical response rates against atypical pathogens.
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Nursyahra, Muhammad Rizki, and Rizki. "Efektivitas Bokashi Daun Kelapa Sawit (Elaeis guineensis Jacq) Terhadap Produksi Kacang Kedelai (Glycine max (L.) Merr.) di Pasaman Barat." Biotropic : The Journal of Tropical Biology 4, no. 1 (February 29, 2020): 8–14. http://dx.doi.org/10.29080/biotropic.2020.4.1.8-14.
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The low production of soybeans in the West Pasaman district is due to severeal factors, including the lack of community knowledge in soybean farming which results in less productive yields obtained by farmer and the high use of inorganic fertilizers continuously resulting in less productive soil. This study was experimental research using a completely randomized design (CRD). The treatments given were 6 treatments and 5 replications, the treatments used were 15 gram TSP (A treatment) as control treatments, 300 gram bokashi (B treatment), 400 gram bokashi (C treatment), 500 gram bokashi (D treatment), 600 gram bokashi (E treatment), 700 gram bokashi (F treatment). The data obtained were analyzed by analysis of variance and then continued by LSD test at α level of 5%. Observed parameters were the number of planting seeds and weight of 50 seeds per plant. The results of this study indicated that bokashi fertilizer had no significant effect on the number of seeds but it had significant effect on the weight of 50 seeds and the best result was found in B treatment (300 gram bokashi/polybag). This research had environmental conditions with temperatures of 30 – 340 C, environmental humidity of 63 – 80%, wind speeds of 0,2 to 2,8 m/s, and soil pH of 5,4 to 7,0.
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Patel, Vipul R., Sagar Shah, and David Arend. "Histopathologic Outcomes of Robotic Radical Prostatectomy." Scientific World JOURNAL 6 (2006): 2566–72. http://dx.doi.org/10.1100/tsw.2006.397.
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Robotically assisted laparoscopic radical prostatectomy is a minimally invasive alternative for the treatment of prostate cancer. We report the histopathologic and shortterm PSA outcomes of 500 robotic radical prostatectomies. Five hundred patients underwent robotic radical prostatectomy. The procedure was performed via a six trocar transperitoneal technique. Prostatectomy specimens were analyzed for TNM stage, Gleason’s grade, tumor location, volume, specimen weight, seminal vesicle involvement, and margin status. A positive margin was reported if cancer cells were found at the inked specimen margin. PSA data were collected every 3 months for the first year, then every 6 months for a year, then yearly. The average preoperative PSA was 6.9 (1–90) with Gleason’s score of 5 (2%), 6 (52%), 7 (40%), 8 (4%), and 9 (2%); postoperatively, histopathologic analysis showed Gleason's 6 (44%), 7 (42%), 8 (10%), and 9 (4%); 10, 5, 63, 15, 5, and 2% had pathologic stage T2a, T2b, T2c, T3a, T3b, and T4, respectively. Positive margin rate was 9.4% for the entire series. The positive margin rate per 100 cases was: 13% (1–100), 8% (101–200), 13% (201–300), 5% (301–400), and 8% (401–500). By stage, it was 2, 4, and 2.5% for T2a, T2b, T2c tumors; 23% (T3a), 46% (T3b), and 53% (T4a). For organ-confined disease (T2), the margin rate was 2.5% and it was 31% for nonorgan-confined disease. There were a total of 47 positive margins, 26 (56%) posterolateral, 4 (8.5%) apical, 4 (8.5%) bladder neck, 2 (4%) seminal vesicle, and 11 (23%) multifocal. Ninety-five percent of patients (n = 500) have undetectable PSA (<0.1) at average follow-up of 9.7 months. Recurrence has only been seen with nonorgan-confined tumors. Of those patients with a minimum follow-up of 1 year (average 15.7 months), 95% have undetectable PSA (<0.1). Our initial experience with robotic radical prostatectomy is promising. Histopathologic outcomes are acceptable with a low overall, positive margin rate. Shortterm biochemical recurrence-free survival has also been good. We believe that the precise dissection allowed by the advantages of laparoscopic robotic surgery will translate into excellent long-term oncologic outcomes. At this time, the lack of maturity of the PSA data prevent definitive comparison to the open approach.
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Pogliani, Enrico Maria, Fausto Rossini, Isabella Miccolis, Alessandra Ferrarlo, Daniele Perego, Ivana Casaroli, Silvia Bolis, Daniele Fagnani, Milena Brambilla, and Gianmarco Corneo. "Alpha Interferon as Initial Treatment of Essential Thrombocythemia. Analysis after Two Years of Follow-Up." Tumori Journal 81, no. 4 (July 1995): 245–48. http://dx.doi.org/10.1177/030089169508100406.
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Aims and background Recombinant alpha-interferon has been shown to be effective in essential thrombocythemia and in thrombocytosis associated with other myeloproliferative disorders. Patients and methods Twenty-five untreated patients were enrolled in our study from May 1989 to April 1992. Recombinant alpha interferon-2b was administered at an initial dose of 2 megaunits (MU)/m2 three times a week at escalating doses to 5 MU/m2 or the maximum tolerated dose. The mean follow-up for patients still in treatment at the time of this report was 35.9 months (range, 24-63). Results Fourteen patients (56%) had achieved a complete remission by a mean time of 152 days; 6 patients (24%) had achieved a good partial remission by a mean of 180 days. In addition to the favorable effect on platelet count, a marked improvement in clinical symptoms was observed. Treatment had to be discontinued in 9 patients (36%), 5 for toxicity (3 neurologic, 1 anemia and 1 severe hypertriglyceridemia) at a median of 155 days from the beginning of therapy (range, 30-400). Four patients refused to continue therapy because of low tolerance (flu-like syndrome) at mean of 160 days from the beginning of therapy (range, 34-301). Conclusions In our study, lower doses were administered compared with previous short-time trials. The present data show that interferon is an effective alternative to cytostatic agents in long-term treatment of patients with essential thrombocythemia, even when used at lower dosages.
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Demetrio, D., A. Magalhaes, M. Oliveira, R. Santos, and R. Chebel. "11 Invivo-derived embryo pregnancy rates at Maddox Dairy from 2008 to 2018." Reproduction, Fertility and Development 32, no. 2 (2020): 130. http://dx.doi.org/10.1071/rdv32n2ab11.
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Maddox Dairy, located in Riverdale, CA, USA, is a Holstein herd that milks 3500 cows with a 305-day mature-equivalent milk production of 12 800 kg, and they have been producing high genetic animals by embryo transfer (ET) since the early 1980s. Invivo-derived embryos from Holstein donors were transferred fresh (grade 1 or 2) or frozen (grade 1), at morula (4), early blastocyst (5), or blastocyst (6) stage, to virgin heifers (VH, natural oestrus, 13-15 months old) or lactating cows (LC, Presynch-Ovsynch, 86 days in milk, first or second lactation) 6 to 9 days after oestrus. Pregnancy diagnosis was done by transrectal ultrasonography at 32-46 days in VH and by the IDEXX PAG test at 30 days in LC. June, July, August, September, and October were called critical months (first service AI conception rate drops below 44%) and compared with the other months. The data from 32 503 ETs between January 2008 and December 2018 are summarised on Table 1. Pregnancy rates (PR) are lower for LC recipients than for VH. Embryo transfers performed 7 or 8 days after oestrus had higher PR in both types of recipients and embryos, but Day 6 and 9 oestrus are also used with fair results. The season does not seem to affect PR. There is not enough difference in the combination of stage and days from oestrus for invivo-derived embryos. These numbers do not belong to a planned experiment. Several management changes during the years were made, which make it very difficult to apply statistical methods to analyse the data correctly. They are used as a tool to make decisions in an attempt to improve future results. Table 1.Pregnancy rate (PR) of virgin heifers (top) and lactating cows (bottom)-fresh (SH) and frozen (OZ) invivo-derived embryo transfer1 Heat-months SH-ST4 SH-ST5 SH-ST6 SH-All OZ-ST4 OZ-ST5 OZ-ST6 OZ-All PR% n PR% n PR% n PR% n PR% n PR% n PR% n PR% n Heifers 6 d-CM 62 934 66 243 68 69 63 1246 56 473 58 219 62 42 57 734 6 d-OM 62 1623 67 489 69 211 64 2323 56 600 55 296 48 137 55 1033 6 d-T 62 2557 67 732 69 280 63 3569 56 1073 57 515 51 179 56 1767 7 d-CM 64 1506 68 495 67 221 65 2222 60 822 62 340 63 156 61 1318 7 d-OM 66 2723 68 1021 69 510 67 4254 57 1120 59 581 57 231 58 1932 7 d-T 66 4229 68 1516 69 731 67 6476 58 1942 60 921 60 387 59 3250 8 d-CM 65 1348 64 518 67 322 65 2188 59 595 64 258 63 108 61 961 8 d-OM 66 2166 68 886 70 510 67 3562 61 770 60 364 51 130 60 1264 8 d-T 66 3514 67 1404 69 832 66 5750 60 1365 62 622 56 238 60 2225 9 d-CM 60 109 56 43 70 20 60 172 60 5 33 6 50 4 47 15 9 d-OM 58 129 63 57 60 40 60 226 63 16 50 18 75 4 58 38 9 d-T 59 238 60 100 63 60 60 398 62 21 46 24 63 8 55 53 All-CM 64 3897 66 1299 67 632 65 5828 58 1895 61 823 63 310 60 3028 All-OM 65 6641 67 2453 69 1271 66 10 365 58 2506 58 1259 53 502 58 4267 All-T 65 10 538 67 3752 69 1903 66 16 193 58 4401 60 2082 57 812 59 7295 Lactating cows 6 d-CM 54 265 48 86 50 12 53 363 38 141 31 77 50 10 36 228 6 d-OM 49 463 52 203 45 56 50 723 46 101 48 54 59 27 48 182 6 d-T 51 728 51 289 46 68 51 1086 41 242 38 131 57 37 42 410 7 d-CM 54 755 59 274 56 103 55 1137 43 928 48 450 43 192 45 1570 7 d-OM 55 914 66 367 54 109 58 1393 46 1052 45 564 47 353 46 1969 7 d-T 55 1669 63 641 55 212 57 2530 45 1980 46 1014 46 545 45 3539 8 d-CM 63 252 68 82 76 33 65 368 48 219 56 80 42 33 50 332 8 d-OM 61 257 64 161 53 47 61 466 50 191 53 77 56 16 51 284 8 d-T 62 509 65 243 63 80 63 834 49 410 55 157 47 49 50 616 All-CM 56 1272 58 442 60 148 57 1868 44 1288 47 607 43 235 45 2130 All-OM 55 1634 62 731 51 212 56 2582 47 1344 46 695 48 396 47 2435 All-T 55 2906 60 1173 55 360 57 4450 45 2632 47 1302 46 631 46 4565 1ST=stage; CM=critical months (June, July, August, September, and October); OM=other months.
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Freyer, G., M. Debled, J. F. Geay, T. Bachelot, E. Blot, J. Cretin, T. Delozier, et al. "Celecoxib (Ce) + exemestane (Ex) versus placebo + Ex in post-menopausal (PM) metastatic breast cancer (MBC) patients (pts): A double-blind phase III GINECO study." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 565. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.565.
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565 Background: in vitro and in vivo studies suggest that COX-2 inhibitors have proper antitumor effect and could enhance the activity of aromatase inhibitors (AI). Methods: PM first-line MBC pts without previous adjuvant AI were randomized to receive per os until progression either A: Ce (400 mg bid) + Ex (25mg/d) or B: placebo (1 tablet bid) + Ex (25mg/d). PFS was the main end-point. The trial was prematurely stopped (Dec 2004) with 157/342 pts enrolled (A: 74, B: 83 pts) after occurrence of Ce cardio-vascular toxicity in other trials. Results: patient (median age, A:61, B:63 yrs) characteristics were well balanced between A and B (%) : ER and/or PR positive (93, 94), HER2 positive (4, 5), adjuvant chemotherapy (45, 53) or tamoxifen (57, 61), ECOG PS 0–1 (90, 90), visceral (63, 53) or bone involvement (35, 41). Tolerance: compared to placebo (B), pts treated with Ce (A) experienced less gr 2–3 CTCAE: pain (A:52, B:63%), arthralgias (19, 28), asthenia (20, 30), Gr 1–3 insomnia (32, 47), but more hypersentivity reactions (7,0) and oedema (8, 2). Gastro-intestinal toxicity was not increased in A. One episode of paroxystic arythmia occurred in the Ce arm, without complication in a patient with known cardiopathy. Overall response rate was significantly higher in A (35 vs 20%, p=.034). Median PFS in intent-to-treat analysis was similar in A (9.8 months) and B (9.8), but tend to be superior in A (A:12.2, B:9,8, p=.09) in pts who were included at least 3 months before early trial stopping. In addition, PFS was significantly longer in pts treated with Ce +Ex (A: 8.4 months, B: 4.7, p=.019) in the subgroup of pts who developed MBC under Tam or within 12 months after Tam stopping (A: 26, B: 29 pts). Conclusion: The combination of celecoxib and exemestane is promising and should be further explored in MBC with adequate cardiac monitoring. No significant financial relationships to disclose.
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Cassidy-Smith, Tara N., J. Hope Kilgannon, Andrew L. Nyce, Michael E. Chansky, and Brigitte M. Baumann. "Impact of a teaching attending physician on medical student, resident, and faculty perceptions and satisfaction." CJEM 13, no. 04 (July 2011): 259–66. http://dx.doi.org/10.2310/8000.2011.110289.
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ABSTRACT:Objectives:To determine if a dedicated teaching attending for medical student education improves medical student, attending physician, and resident perceptions and satisfaction.Methods:Two dedicated teaching attending physician shifts were added to the clinical schedule each week. A before-after trial compared medical student evaluations from 2000 to 2004 (preteaching attending physician) to medical student evaluations from 2005 to 2006 (teaching attending physician). Attending physician and resident perceptions and satisfaction with the teaching attending physician shifts using a 5-point Likert-type scale (1 = poor to 5 = excellent) were also assessed.Results:Eighty-nine (100%) medical students participated, with 63 preteaching attending physician and 26 teaching attending physician rotation evaluations. The addition of teaching attending physician shifts improved mean medical student satisfaction with bedside teaching (4.1 to 4.5), lecture satisfaction (4.2 to 4.8), preceptor scores (4.3 to 4.8), and perceived usefulness of the rotation (4.5 to 5.0) (allp< 0.05). Thirteen attending physicians (93%) participated in the crosssectional questionnaire. The addition of teaching attending physician shifts improved faculty ratings of their medical student interactions by ≥ 1.5 points for all items (p≤ 0.001). Faculty perceptions of their resident interactions improved for quality of bedside teaching (3.1 to 4.0), their availability to hear resident presentations (3.4 to 4.2), and their supervision of residents (3.4 to 4.1) (p≤ 0.01). Residents (n= 35) noted minor improvements with the timeliness of patient dispositions, faculty bedside teaching, and attending physician availability.Conclusions:The addition of select teaching attending physician shifts had the greatest effect on medical student and faculty perceptions and satisfaction, with some improvements for residents.
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Cortes, Jorge, Susan O'Brien, Dan Jones, Elias Jabbour, Marina Konopleva, Alessandra Ferrajoli, Tapan Kadia, et al. "Efficacy of Nilotinib in Patients (Pts) with Newly Diagnosed, Previously Untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP)." Blood 114, no. 22 (November 20, 2009): 341. http://dx.doi.org/10.1182/blood.v114.22.341.341.
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Abstract Abstract 341 Background: Nilotinib, an oral tyrosine kinase inhibitor with increased selectivity against Bcr-Abl and approximately 30-fold more potent than imatinib, is effective in CML after imatinib failure. We initiated a phase II study to evaluate the efficacy of nilotinib as 1st line therapy in pts with newly diagnosed CML-CP. Aims: To investigate the efficacy and safety of nilotinib as first-line therapy for pts with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with untreated CML-CP within 6 mo from diagnosis were eligible and received nilotinib 400 mg twice daily. A cohort of patients with previously untreated CML in accelerated phase (AP) was also included. Results: Sixty-five pts (61 CP, 4 AP) have been treated for a median of 17 mo (range 1 to 43). The median age was 46 years (range 19 to 86). Among 48 pts who were not in CHR at the start, 47 (98%) achieved CHR (one discontinued after 2 weeks without adverse events). Among 51 pts followed for at least 3 mo, 50 (98%) achieved a complete cytogenetic response (CCyR). MMR has been achieved in 32 (63%) pts, including 12 (24%) with a complete molecular response. The rate of CCyR at different time points (intention-to-treat) for pts in CP compares favorably to that observed in historical controls treated with imatinib 400 mg or 800 mg daily: MMR was achieved by 55% at 12 mo and 53% at 24 mo (corresponding rates with imatinib 400 mg 34 and 55%, and with imatinib 800 mg 58% and 66%, respectively). Grade 3-4 hematologic toxicity (transient) included thrombocytopenia 11%, neutropenia 12%, and anemia 5%. Grade 3-4 non-hematologic adverse events (regardless of causality) included elevation of bilirubin in 8% and lipase in 6%, and non-neutropenic fever in 6%. 24 (37%) pts had transient treatment interruptions and 11 (17%) had dose reductions. The actual median dose is 800 mg daily. Ten pts have discontinued therapy: 4 pts for toxicity, 2 because of transformation to accelerated or blast phase, and 4 for other reasons. 24 mo EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 90%. All patients are alive. Among pts in AP, 3 achieved CCyR (all of them sustained); one patient progressed to blast phase and died. Conclusion: Nilotinib 400 mg twice daily induces a CCyR in nearly all patients as early as 3 mo after the start of therapy and MMR in more than 50% at 12 months with a favorable toxicity profile. Disclosures: Cortes: BMS: Research Funding; Novartis: Research Funding; Wyeth: Research Funding. Off Label Use: Presentation will include use of nilotinib as initial therapy for CML, and indication for which nilotinib is not approved.. O'Brien:Novartis: Research Funding. Jones:Novartis: Research Funding, Speakers Bureau. Jabbour:Novartis: Speakers Bureau; BMS: Speakers Bureau. Borthakur:Novartis: Speakers Bureau. Kantarjian:Novartis: Research Funding; MGI Pharma (Eisai): Research Funding; Genzyme: Research Funding; BMS: Research Funding.
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Clé, Diego V., Elias H. Atta, Danielle S. P. Dias, Carlos B. L. Lima, Mariana M. Bonduel, Gabriela B. Sciuccati, Larissa A. Medeiros, et al. "Repeat Course of Rabbit Antithymocyte Globulin As Salvage Following Initial Therapy with Rabbit Antithymocyte Globulin in Acquired Aplastic Anemia." Blood 124, no. 21 (December 6, 2014): 2944. http://dx.doi.org/10.1182/blood.v124.21.2944.2944.
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Abstract In patients with severe acquired aplastic anemia (AA) not eligible for hematopoietic stem cell transplant (HSCT), immunosuppression with horse antithymocyte globulin (h-ATG) and cyclosporine (CsA) is standard and is associated with a high response rate of about 60-70% at 6 months (Scheinberg et al. N Engl J Med 365: 430, 2011). Patients who are unresponsive to initial h-ATG can be rescued with rabbit ATG (r-ATG) in a third of cases (Scheinberg et al. Br J Haematol 133: 622, 2006). Since 2007, h-ATG is no longer available in most Latin American, Asian and European countries, with rabbit ATG (r-ATG) the only ATG formulation available in these markets. However, the outcome with r-ATG as first therapy in SAA is significantly inferior to that of h-ATG with worst response rate and overall survival (Scheinberg et al. N Engl J Med 365: 430, 2011). The salvage rate for patients who failed initial r-ATG is low with alemtuzumab and horse ATG [Scheinberg et al. Blood 119: 345, 2012; Am J Hematol 89: 467, 2014]. However, the salvage rate of a repeat course of r-ATG after initial r-ATG is unknown. Thus, we conducted a retrospective analysis in marrow failure referral Brazilian and Argentinian centers to address this question. The primary endpoint was hematologic response at 3 and 6 months, which was defined as transfusional independence and no longer meeting criteria for severe AA. Secondary endpoints included relapse, clonal evolution, and overall survival. Since 2005, 37 patients (32 refractory and 5 relapsed; 57% males, median age, 17 years; range 3-63 years) were re-treated with r-ATG (Thymoglobuline¨, Genzyme, Cambridge, MA, USA) with median dose of 3.5 mg/kg/d (range 1.67-5.0) for 5 days and oral cyclosporine adjusted to maintain blood levels between 150 and 400 ng/mL for 6 months. Corticosteroids, usually methylprednisolone, were given for at least 2 weeks to prevent serum sickness and trimethoprim–sulfamethoxazole was administered as Pneumocystis jiroveci prophylaxis. Only patients that completed the 5 day r-ATG course were included in the analysis. Second treatment was administered at a median of 283 days from first r-ATG/CsA (range 118-2379 days). After a median follow-up of 726 days (range 7-2320 days), the overall response rates at 3 and 6 months for initial r-ATG refractory patients was 5/32 (16%) and 7/32 (22%), respectively, and for those who relapsed 60% (3/5) (Table). Among all responders, 2 (20%) relapsed at 170 and 897 days after second treatment. In total, clonal evolutions were observed in 6 patients; 5 in non-responders (4 to monosomy 7; 1 trisomy 8 and 21), and 1 in a responder (myelodysplastic syndrome with normal karyotype). Three non-responders underwent matched-unrelated donor allogeneic HSCT. Twelve patients died, all who were non-responders to repeat r-ATG. Overall survival at 4.1 years (censored at the time of HSCT) was 58% (95% CI, 36-75%) (Figure). Our findings indicate that only a minority of r-ATG refractory AA patients may be successfully rescued with a second course of the same immunosuppression. Similar low salvage rates have been reported with alemtuzumab and h-ATG for those refractory to initial r-ATG. In the aggregate, these data show that: 1) other therapies should be considered for those refractory to initial r-ATG such as alternative donor HSCT, thrombopoietin agonists, or other experimental therapies; 2) the high success rate of initial h-ATG therapies cannot be recapitulated when r-ATG is administered first given the low salvage rate with alemtuzumab, h-ATG and now (current data) with r-ATG; 3) for patients that relapse after first r-ATG treatment, second course r-ATG may be a reasonable option. Table: Hematologic response at 3 and 6 months to second course of rabbit ATG plus cyclosporine Refractory to first r-ATG/CsA(n=32) 95% CI Relapsed to first r-ATG/CsA(n=5) 95% CI At 3 months no. (%) 5 (16) 3-28 3 (60) 17-100 At 6 months no. (%) 7 (22) 8-36 3 (60) 17-100 Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Richardson, Paul G., Constantine S. Mitsiades, Kathleen Colson, Eileen Reilly, Laura McBride, Judy Chiao, Linda Sun, et al. "Final Results of a Phase I Trial of Oral Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) in Patients with Advanced Multiple Myeloma." Blood 110, no. 11 (November 16, 2007): 1179. http://dx.doi.org/10.1182/blood.v110.11.1179.1179.
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Abstract Background: The histone deacetylase inhibitor vorinostat was approved by the United States FDA in October 2006 for the treatment of cutaneous manifestations in patients with cutaneous T-cell lymphoma who have progressive, persistent or recurrent disease on or following 2 systemic therapies. Vorinostat has also demonstrated promising preclinical activity in multiple myeloma. Patients and Methods: A Phase I trial of oral vorinostat 200, 250 or 300 mg bid for 5 days each week of a 4 week cycle or 200, 300, or 400 mg bid for 14 days/3 week cycle until progressive disease or intolerable toxicity was conducted. Patients with measurable, relapsed and/or refractory multiple myeloma with adequate hematologic, hepatic, and renal function were eligible. The objectives were to determine the maximum tolerated dose (MTD) on each of the schedules and assess activity and safety. Results: Thirteen patients (median age, 63 years; median 7 prior systemic therapies) were enrolled. The MTDs were not determined due to early termination of the study due to the decision of the sponsor. One patient (250 mg bid 5 days/week) developed dose-limiting toxicity (DLT) of grade 3 fatigue. There were no other DLTs and the maximum administered doses were 250 mg bid for 5 days each week of a 4-week cycle and 200 mg bid for 14 days/3-week cycle. Common drug-related adverse experiences included fatigue (69%), anorexia (62%), dehydration (46%), diarrhea (46%), and nausea (38%) and were mostly grade ≤ 2. Of 10 evaluable patients, 1 had a minimal response and 9 had stable disease (Table 1). Conclusions: Oral vorinostat was generally well tolerated at 250 mg bid for 5 days each week of a 4 week cycle or 200 mg bid for 14 days/3 week cycle in patients with advanced multiple myeloma. Modest activity was demonstrated in relapsed and/or refractory multiple myeloma and combination studies with other anti-myeloma agents are warranted. Table 1. Clinical outcomes of patients per EBMT Criteria* Allocation Number Age Baseline Myeloma Stage Prior Systemic Therapies Prior Bone Marrow Transplant Baseline β2-microglobulin On-study Duration (days) Best Response EBMT = European Group for Blood and Marrow Transplantation; MR = Minimal Response; ND = Not Determined; NE = Not Evaluable; SD = Stable Disease. *Cohorts 3, 5, and 6 were not initiated. Cohort 1 (200 mg twice daily x 5 days/week) 1001 55 III 12 1 ND 41 NE 1002 47 II 3 1 2.0 254 SD 1003 64 III 4 0 2.6 62 SD Cohort 2 (250 mg twice daily x 5 days/week) 1004 38 I 5 0 1.7 55 SD 1005 74 III 7 1 6.7 240 MR 1006 65 ND 7 2 3.3 74 NE 1007 67 ND 1 0 10.1 118 SD 1008 42 III 5 0 4.7 109 SD 1009 50 III 5 0 1.4 123 SD Cohort 4 (200 mg twice daily x 14 days/3 weeks) 861 69 IIIa 16 1 4.6 56 SD 862 63 IIIa 20 1 3.1 25 NE 863 61 IIIa 10 1 2.7 62 SD 864 71 IIIa 16 1 11.0 155 SD
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Haferlach, Claudia, Susanne Schnittger, Tamara Weiss, Wolfgang Kern, Brunangelo Falini, and Torsten Haferlach. "About 17% of AML with NPM1 mutations Show a Specific Pattern of Chromosome Aberrations but These Cases Do Not Differ Prognostically from AML with NPM1 Mutations Carrying a Normal Karyotype." Blood 112, no. 11 (November 16, 2008): 2527. http://dx.doi.org/10.1182/blood.v112.11.2527.2527.
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Abstract AML with mutated nucleophosmin gene (AML NPM1mut) usually carries a normal karyotype and will be suggested as a provisional entity in the new WHO classification. Thus far, the impact of chromosome aberrations in AML NPM1mut has not been evaluated in detail. Aim of this study was to determine the incidence and prognostic impact of clonal chromosome aberrations in NPM1mut. We further compared this pattern to additional aberrations in AML with recurrent genetic aberrations: t(8;21)(q22;q22), inv(16)(p13q22)/t(16;16)(p13;q22), t(15;17)(q22;q12) and 11q23-abnormalities leading to an MLL-rearrangement. In total 415 AML (de novo AML: 392, s-AML: 11, t-AML: 12) showing an NPM1 mutation were analyzed by chromosome banding analysis. 71 of these showed clonal chromosome aberrations (17.1%; de novo AML: 63 (16.1%), s-AML: 5 (45.5%), t-AML: 3 (25%); de novo AML vs. s-AML: p=0.024). Overall, 111 chromosome aberrations were observed. The most frequent abnormalities were +8 (n=30), −Y (n=10), +4 (n=9), del(9q) (n=5), +21 (n=4), −7 (n=3), +5 (n=2), +10 (n=2), +13 (n=2),+18 (n=2), del(12p) (n=2), del(20q) (n=2), other non-recurrent balanced aberrations (n=6), other non-recurrent unbalanced aberrations (n=32). For comparison 63 AML with t(8;21), 37 cases with inv(16)/t(16;16), 83 patients with t(15;17) and 83 AML showing a 11q23/MLL-rearrangement were evaluated. 44 (69.7%), 13 (35.1%), 39 (47%), and 28 (43.1%) cases showed clonal chromosome aberrations in addition, respectively. Therefore, additional chromosomal aberrations are more frequent in all these subgroups than in the AML NPM1mut. Similar to NPM1mut cases +8 (n=2), −X/Y (n=32), +4 (n=2), and del(9q) (n=10) were observed. The only other recurrent additional aberrations was del(11q) (n=2). In inv(16)/t(16;16) we also found +8 (n=5) and −Y (n=1). The only other recurring additional aberrations were +22 (n=6) and del(7q) (n=2). In AML with t(15;17) recurring additional abnormalities were +8 (n=12), −Y (n=3), del(9q) (n=2), ider(17)(q10) t(15;17) (n=7). AML with 11q23/MLL-rearrangement showed +4 (n=2), +8 (n=8), +13 (n=2), +19 (n=4), +21(n=4), +22 (n=2), −Y (n=1). Thus, chromosome aberration in AML NPM1mut share many overlaps to those in AML with recurrent aberrations. Furthermore, the prognostic impact of chromosome aberrations in AML NPM1mut was evaluated. No difference with respect to overall survival (OS) and event-free survival (EFS) was observed between AML NPM1mut with a normal (n=344) and an aberrant karyotype (n=71) (OS at 2 yrs 78% vs. 81%, p=0.969; EFS at 2 yrs 40% vs. 50%, median EFS 544 days vs. 522 days, p=0.253). The FLT3-ITD status was available in 400 cases. 127 (38%) of 334 cases with a normal karyotype showed a FLT3-ITD, while in only 16 (24%) of 66 cases with an aberrant karyotype a FLT3-ITD was observed (p=0.035). While the negative prognostic impact of additional FLT3-ITD was confirmed in our cohort, the presence of chromosome aberrations did not influence prognosis neither in the FLT3-ITD negative nor in the FLT3-ITD positive subgroup. In addition, 31 patients with AML NPM1mut were analyzed by chromosome banding analysis at diagnosis and at relapse (median time diagnosis to relapse: 301 days (range: 71–986). 22 cases (71%) showed a normal karyotype both at diagnosis and relapse. In 4 cases a normal karyotype was observed at diagnosis and an aberrant karyotype at relapse (del(9q) (n=2), t(2;11) (n=1), inv(12) (n=1)). One case with +8 at diagnosis showed +8 also at relapse. One case with +4 at diagnosis showed +4 and additional aberrations at relapse. In 1 case clonal regression was observed (+21 -> normal). One case with an unbalanced 1;3-translocation at diagnosis showed a der(17;18) (q10;q10) at relapse and one case with −Y at diagnosis showed a del(3p) at relapse. In conclusion: 1. Frequency of additional chromosome aberrations is low in AML NPM1mut as compared to other genetically defined WHO entities. 2. The pattern of additional chromosome aberrations is overlapping between the 5 groups analyzed. 3. Chromosome aberrations observed at diagnosis in AML NPM1mut do not influence prognosis in comparison to AML NPM1mut with normal karyotype. 4. The karyotype is stable in most AML NPM1mut patients at diagnosis and at relapse. These results point to chromosomal aberrations occurring in AML NPM1mut as secondary events and further support inclusion of AML NPM1mut as a provisional entity in the new WHO classification.
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Pérez, J. F., M. Fondevila, J. Balcells, and J. A. Guada. "Composition of liquid-and particle-associated bacteria and their contribution to the rumen outflow." Australian Journal of Agricultural Research 49, no. 5 (1998): 907. http://dx.doi.org/10.1071/a97052.
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A method is described to estimate the composition and rumen outflow of microbes associated with liquid (LAB) and solid (SAB) digesta. Four rumen-cannulated Rasa Aragonesa ewes were given, in random order, the following 4 diets: (1) NaOH-treated barley straw, as a sole diet (700 g/day, TS); (2) NaOH-treated barley straw mixed (50 : 50) with 400 g/day of rolled barley grain (BS); (3) Diet 1 with addition of 8 g/day of urea; and (4) Diet 2 with addition of 16 g/day of urea. Co-EDTA was used as a marker for the liquid phase to estimate rumen outflow of liquid-associated purine bases (PB), and urinary purine derivatives were used as an indirect marker of total duodenal flow of PB. Solid-associated PB were calculated by the difference between both estimates. Urea infusion increased ammonia-N concentration in the rumen fluid from 4·8 to 15·9 mg/100 mL (P < 0· 05) and enhanced dry matter intake of TS diets (from 343±63· 5 to 556±41·2 g/day, P < 0·001). Significant differences were observed in the PB/N ratio of bacteria harvested from the liquid phase compared with that isolated from the solid phase (1·89±0·25 v. 1·66±0·32 mol/mg in LAB and SAB, respectively). Because of the differences observed between the liquid- and solid-associated bacteria, estimated values of bacterial N supply varied depending on which bacterial extract was used as reference. The fractional contribution of LAB and SAB to the postruminal bacteria was significantly influenced by the experimental diets, mainly through variations in the amount of LAB flowing out of the rumen.
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Newell, D. R., A. D. Pearson, K. Balmanno, L. Price, R. A. Wyllie, M. Keir, A. H. Calvert, I. J. Lewis, C. R. Pinkerton, and M. C. Stevens. "Carboplatin pharmacokinetics in children: the development of a pediatric dosing formula. The United Kingdom Children's Cancer Study Group." Journal of Clinical Oncology 11, no. 12 (December 1993): 2314–23. http://dx.doi.org/10.1200/jco.1993.11.12.2314.
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PURPOSE The aim of this study was to define the pharmacokinetics of carboplatin in children and use the data to develop a pediatric dose formula. It was anticipated that renal function would be a major determinant of carboplatin disposition and the relationship between carboplatin clearance and glomerular filtration rate (GFR) was examined in detail. PATIENTS AND METHODS Plasma carboplatin pharmacokinetics were measured as ultrafiltrable platinum in 22 patients (5 to 63 kg) following 200 to 1,000 mg/m2 of carboplatin. GFR was measured by the plasma clearance of chromium 51-edathamil (51Cr-EDTA). RESULTS Carboplatin pharmacokinetics in children were best described in most patients (16 of 22) by a two-compartment model. The dose-normalized area under the plasma carboplatin concentration versus time curve (AUC) ranged from 3.1 to 9.6 mg/mL.min/400 mg/m2 and there was only a weak linear relationship between carboplatin dose and AUC (R2 = .31). There was a significant relationship between absolute carboplatin and 51Cr-EDTA clearances (R2 = .56), but the relationship was weaker (R2 = .28) when both clearances were normalized for body surface area. Carboplatin plasma clearance was predicted by the equation: clearance = GFR (mL/min) + 0.36 x body weight (BW; kg), and a modified form of the adult carboplatin dose formula is proposed: dose (mg) = target AUC x (GFR [mL/min] + [0.36 x BW(kg)]). Two further equations were developed that use the 51Cr-EDTA half-life (t1/2) to calculate the GFR and these may reduce errors resulting from inaccurate measurement of the volume of distribution for 51Cr-EDTA. In patients treated with single-agent carboplatin or carboplatin plus vincristine, there was a significant sigmoidal relationship between AUC and thrombocytopenia (R2 = .56). CONCLUSION GFR-based carboplatin dosing in children should be feasible and will be evaluated prospectively.
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Magamedov, S. S., B. М. Medvedeva, and M. G. Lapteva. "The Utility of Multiparametric MRI or Difffferentiating Adrenal Adenomas from Adrenal Metastases." Journal of oncology: diagnostic radiology and radiotherapy 5, no. 1 (March 16, 2022): 53–64. http://dx.doi.org/10.37174/2587-7593-2022-5-1-53-64.
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Purpose: To evaluate the possibility of multiparametric MRI in the differential diagnosis of benign adrenal adenomas and adrenal metastases.Material and methods: In our study we evaluated 27 adenomas and 13 adrenal metastases using MRI in 35 patients who underwent examination and treatment at the basis of the N.N. Blokhin National Research Center of Oncology during the follow-up period from 2019 to 2021. The following parameters were evaluated: contours, homogeneity (homogeneous and heterogeneous), T2-weighted SI ratio (isointensive, moderately hyperintensive or sharply hyperintensive) relative to muscle and spleen, signal intensity (SI) decrease on chemical-shift MRI, measurement of the chemical-shift SI index, adrenal-to-spleen SI ratio, areas under the ROC curve (AUC) for contrast-enhanced MRI, absolute and relative percentage wash-out. Sensitivity, specificity, and positive and negative predictive values were calculated. DWI with b-values 400 and 800 s/mm2 and ADCs imaging were measured in adrenal lesions.Results: Metastases were subjectively more heterogeneous than adenomas (76.9 % vs 63 % of cases, p = 0.0181). Adenomas had higher T2-weighted SI (average value = 228; range from 91 to 732) than metastases (average value = 331; range from 114 to 581), both quantitatively (p = 0.0326) and subjectively by visual assessment (p = 0.0171).According to the T1-WI out-of-phase data, a more intense MR signal was observed in metastases (average value 162; range from 102 to 242) compared with adenomas (average value = 74; range from 17 to 183) (p < 0.0001), which was confirmed by normalization to muscle (p < 0.0001) and spleen (p = 0.0002). Adrenal metastases were characterized by a significantly lower chemical shift index (average value = 3.8; range from –16.4 to 47.8; p < 0.0001) compared with adenomas (average value 55.4; range from –4.2 to 85.5), and a higher chemical shift index in the ratio adrenal gland/spleen (p = 0.0079). There were no significant difference in the value of ADC-cards of adenomas and adrenal metastases. However, a higher level of SI on DWI at b = 800 s/ mm2 without normalization (p = 0.0262) and with normalization to muscle (p = 0.0064) and spleen (p = 0.0007) was evaluated in metastases, as well as on DWI at b = 400 s/mm2 with normalization for muscle (p = 0.0086) and spleen (p = 0.035). On native T1-WI FS, there was a lower level of SI revealed in adenomas compared to adrenal metastases (p = 0.0025), which was confirmed by normalization to the muscle (p = 0.0028) and spleen (p = 0.0035). In the venous and delayed phases of scanning the SI in adenomas was also lower than in metastases both without normalization (p = 0.0123 and p = 0.007, respectively), and with normalization to the muscle (p = 0.013 and p = 0.0011, respectively) and the spleen (p = 0.0084 and p = 0.0012, respectively). However, the SI in the arterial phase of scanning with and without normalization, the accumulation of MRCS in all phases of MRI scanning, the absolute and relative percentage wash-out of MRCS and the area under the MRCS accumulation curve in the groups had no statistically significant difference.
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Mohan, Meera, Rohan Samant, Larry J. Suva, Corey O. Montgomery, Daisy V. Alapat, Roy Morello, Frits van Rhee, et al. "Re-Mineralization of Large Pelvic Lytic Lesions By CT Imaging in Patients with Multiple Myeloma: The Arkansas Experience." Blood 126, no. 23 (December 3, 2015): 4193. http://dx.doi.org/10.1182/blood.v126.23.4193.4193.
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Abstract INTRODUCTION Profound osteolytic lesions are a hallmark of multiple myeloma (MM) bone disease. Bone destruction is associated with severely unbalanced bone remodeling, secondary to the secretion of osteoclast activating factors and significant osteoblast suppression. Lytic lesions of the pelvis are relatively common in MM patients and contribute to increase morbidity due to the high risk of fracture that frequently demands surgical intervention. Since we observed significant improvements in the pelvic CT of patients following total therapy 4 (TT4) we retrospectively analyzed the appearance on pelvic osteolytic lesions by CT during TT4 treatment for myeloma. METHODS The UAMS Myeloma data base was interrogated to identify patients enrolled on the TT4 trial. TT4 is a protocol designed for low risk MM patients as defined by a baseline plasma cell GEP score < than 0.66. The treatment protocol includes two induction chemotherapy cycles followed by tandem autologous bone marrow transplantation, two consolidation cycles and 3 years of maintenance. During treatment, patients were exposed to alkylating agents, IMIDS and proteasome inhibitor agents as well as bisphosphonates. Baseline pelvic osteolytic lesions with > 1 cm in minimal diameter identified by PET/CT or CT of the pelvis were compared to the most recent radiological study available for the same subject. All identified cases were reviewed by radiology faculty to confirm the baseline and follow-up reported findings. Radiological findings were correlated with disease status, molecular subgroup, PET scanning and MRI. RESULTS Sixty-three (63) patients, with a median age of 62 years, were identified for this analysis. Baseline patient characteristics are shown in Table 1. With a median follow up of 41 months, CT studies indicate that 44% (28/63) of patients with large baseline pelvic lytic lesions achieved re-accumulation of radio-dense mineralized tissue at the lytic site. Sixty-eight percent of such patients reached at least VGPR. The average size of the lytic lesions that re-mineralized was 4.0 cm (minimum 1.3 cm - maximum 10 cm). Baseline GEP-defined molecular subgroups and cytogenetic distribution was not different from the entire patient population of TT4. CONCLUSION This study clearly shows that mineral redeposition in large pelvic lytic lesions of MM patients on TT4 is achievable in a significant proportion of individuals. We observed that the amount of re-mineralization was prominent in pelvic lytic lesions with cortical bone destruction. Since flat bones, such as the pelvis, are formed via intramembranous ossification further investigation of the mechanism responsible for this effect is warranted at skeletal sites with different regenerative capacity. These data also suggest that, contrary to much dogma, MM bone lesions can regain matrix mineralization capacity. Table 1. Baseline Patient Characteristics n/N (%) Male 43/63 (69%) IgA Isotype 11/63 (17.5%) IgD Isotype 1/63 (1.6%) IgG Isotype 36/63 (57.1%) Nonsecretory 1/63 (1.6%) Light Chain Isotype 14/63 (22.2%) LDH > = 190 U/L 8/63 (12.7%) Abnormal Cytogenetics 44/63 (69.8%) GEP CD-1 subgroup 4/64 (6.3%) GEP CD-2 subgroup 17/64 (26.6%) GEP HY subgroup 24/64 (37.5%) GEP LB subgroup 8/64 (12.5%) GEP MF subgroup 1/64 (1.6%) GEP MS subgroup 2/64 (3.1%) GEP PR subgroup 5/64 (7.8%) Disclosures Mohan: University of Arkansas for Medical Sciences: Employment. Samant:University of Arkansas for Medical Sciences: Employment. Suva:University of Arkansas for Medical Sciences: Employment. Montgomery:University of Arkansas for Medical Sciences: Employment. Alapat:University of Arkansas for Medical Sciences: Employment. Morello:University of Arkansas for Medical Sciences: Employment. van Rhee:University of Arkansa for Medical Sciences: Employment. Waheed:University of Arkansas for Medical Sciences: Employment. Thanendrarajan:University of Arkansas for Medical Sciences: Employment. Schinke:University of Arkansas for Medical Sciences: Employment. Heuck:Millenium: Other: Advisory Board; Celgene: Consultancy; Foundation Medicine: Honoraria; Janssen: Other: Advisory Board; University of Arkansas for Medical Sciences: Employment. Jethava:University of Arkansas for Medical Sciences: Employment. Johann:University of Arkansas for Medical Sciences: Employment. Barlogie:University of Arkansas for Medical Sciences: Employment. Davies:University of Arkansas for Medical Sciences: Employment; Celgene: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Onyx: Consultancy. Morgan:CancerNet: Honoraria; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; University of Arkansas for Medical Sciences: Employment; MMRF: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Weismann Institute: Honoraria; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees. Zangari:Novartis: Research Funding; Millennium: Research Funding; Onyx: Research Funding; University of Arkansas for Medical Sciences: Employment.
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Кючуков, Хрісто, and Сава Самуїлов. "Language Use and Identity Among Migrant Roma." East European Journal of Psycholinguistics 6, no. 1 (June 30, 2019): 47–57. http://dx.doi.org/10.29038/eejpl.2019.6.1.hky.
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The paper presents the issue of language use and identity among Muslim Roma youth from Bulgaria, living in Berlin, Germany. Interviews with a structured questionnaire on language use and identity was conducted with Bulgarian Muslim Roma living in Berlin, Germany. The results showed that, in order to be accepted by the German Turks, Bulgarian Muslim Roma youth change their language use and identity from Muslim Roma to a new identity - Bulgarian “Osmanli” Turks. The findings showed that the change of language and identity among young Roma in this study served as strategies for integration and acceptance in the German society.
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Bordoni, R., M. Saleh, S. Khanwani, T. Page, M. Auerbach, F. Steinbaum, and R. Ghalie. "Bexarotene improves median survival (MS) in untreated, advanced NSCLC, when given in combination with carboplatin/paclitaxel." Journal of Clinical Oncology 24, no. 18_suppl (June 20, 2006): 17070. http://dx.doi.org/10.1200/jco.2006.24.18_suppl.17070.
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17070 Background: Bexarotene (bex) is a subclass specific, synthetic rexinoid analogue, that preferentially binds and modulates the expression of RXR subclass of receptors α, β, and γ. It induces concentration-dependent repression of multiple genes (cyclin D1/D3, total EGFR, pEGFR) inhibiting cell growth, angiogenesis, invasion and metastasis, inducing differentiation, and apoptosis in tumor cells. Several phase-I/II trials suggested increased survival in patients with advanced NSCLC. Methods: Stage-IIIB with pleural effusion & Stage-IV chemo-naïve patients, ECOG 0–2, were enrolled and treated with carboplatin IV AUC-6 d-1 and paclitaxel IV 100 mg/m2 d-1, 8, 15, every 28-d for 4 cycles. Pts were randomized using a 1:1 design to bex PO 400 mg/m2/d either concurrent (C) from Day 1 or sequential (S) at the completion of chemo, for up to a year. Results: 56 patients were enrolled; median age 62.3 (range 41–86), 48 TNM Stage IV, 38 males, 50 ECOG PS 0–1. Of 51 pts evaluable for response, 30 (58%) achieved PR (C: 15 and S: 15); 16 (31%) showed SD (C: 8 and S: 8), and 5 (9.5%) had PD (C: 3 and S: 2). Thirty-two (63%) patients have expired as of 12/31/05. Based on ITT, 40 evaluable pts showed a median TTP of 169 days (C: 166.5 and S 172); The MS for the entire group is 342 days (11.42 mo (C: 12.8 and S: 10.53). Currently, 10 pts are still alive between 407 to 1036 days from registration on the trial. The treatment was well tolerated; overall, AEs were reported in 48% of pts in the S arm and 51% in the C arm. The incidence of Gr 3–4 AEs, regardless of the treatment arm, was < 5%. There were no treatment-associated deaths. Conclusions: Our data suggests a better ORR, TTP, and improvement in MS, when bex is added to carboplatin/ paclitaxel, regardless of concurrent or sequential administration, compared with chemo alone. ORR was not compromised by bex administration and in fact it was above average reported for similar phase-II & -III studies. Toxicity is easily managed. [Table: see text]
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Zabotti, A., M. M. Luchetti, C. Selmi, R. Ramonda, R. D. Grembiale, L. Dagna, S. D’angelo, et al. "POS1061 THE ITALIAN PROSPECTIVE SIRENA STUDY: FOCUS ON EARLY PSORIATIC ARTHRITIS COHORT AND GENDER DIFFERENCES." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 809. http://dx.doi.org/10.1136/annrheumdis-2021-eular.607.
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Background:Limited data on early Psoriatic Arthritis (PsA) are available1,2.Objectives:To describe baseline data of PsA patients naive to any DMARDs.Methods:SIRENA study is an Italian, prospective Registry of Spondyloarthritis patients diagnosed according to ASAS criteria and naïve to any DMARDs. Data on demographic and clinical characteristics of PsA cohort were collected and analysed, also by gender.Results:203/350 (58%) subjects included in SIRENA Registry had PsA (mean age 51.9 years) and in 190/203 (94%) CASPAR classification criteria were fulfilled. In 70% of patients the diagnosis was performed within 24 months from symptom onset. At baseline, 194/203 (95.6%) had mainly peripheral manifestations, 74.4% of patients had skin psoriasis, 40% nail psoriasis, 39.3% clinical enthesitis and 25.9% dactylitis. Mean SJC66 and TJC68 were, respectively, 3 and 7.2; mean PhGA was 46.3; 14.7% of patients were in MDA.The higher tender joint count in women (mean TJC68 9.3 in women vs 5.3 in men) resulted in a higher disease activity according to DAPSA (high disease activity: 11.5% women vs 4.1% men), a higher joint VAS score (mean score 47.1 women vs 39.8 men) and a lower prevalence of MDA (8.3% women vs 20% men). We observed a higher prevalence of moderate or severe psoriasis in men (BSA≥3%: 37% men vs 27.8% women) while all PROs collected (PtGA, pain VAS score, sleep VAS score, BASFI, BASDAI, HAQ-DI, WPAI) were worse in women.The most common comorbidities were cardiometabolic (35.5%), endocrine (9.4%), and gastrointestinal disorders (7.4%). Cardiometabolic disorders were more frequently reported by men, endocrine and gastrointestinal disorders by women; depression exclusively by women.Conclusion:This analysis provides real-life data in a cohort of early PsA subjects. Relevant gender differences were observed, with women showing a higher disease activity and more joint pain and men having more severe psoriasis. Women also perceived a worse disease burden.References:[1]Theander E, et al. Ann Rheum Dis 2014; 73:407–413.[2]Nas K, et al. Mod Rheumatol 2017; 27(2):345-349.Table 1.Baseline dataPsAAll patients (n=203)Women (n=98)Men (n=105)Age (years), mean (SD)51.9 (13.1)51.1 (13.2)52.7 (13.0)Men, n (%)105 (51.7)0 (0)105 (100)BMI (kg/m2), mean (SD)25.9 (4.4)25.4 (4.9)26.4 (3.9)BMI categories^, n (%) Obese40 (21.2)20 (22.2)20 (20.2) Overweight44 (23.3)15 (16.7)29 (29.3) Under/normal weight105 (55.6)55 (61.1)50 (50.5)Comorbidities > 5%*, n (%) Cardiometabolic72 (35.5)28 (28.6)44 (41.9) Endocrine disease19 (9.4)15 (15.3)4 (3.8) Gastrointestinal15 (7.4)10 (10.2)5 (4.8) Depression/Anxiety8 (3.9)8 (8.2)0 (0) Hepatic diseases7 (3.5)1 (1.0)6 (5.7)Clinical assessmentCRP (mg/dl), median (min-max)0.40 (0 – 7.12)0.31 (0 - 5.40)0.49 (0 - 7.12)SJC66, mean (SD)3.0 (4.0)3.2 (4.0)2.7 (4.0)TJC68, mean (SD)7.2 (8.8)9.3 (10.3)5.3 (6.6)Dactylitis, n/tot assessed (%)35/135 (25.9)12/63 (19.1)23/72 (31.9)Enthesitis, n/tot assessed (%)66/168 (39.3)39/80 (48.8)27/88 (30.7)Psoriasis skin, n (%)151 (74.4)68 (69.4)83 (79.1)Psoriasis nails, n/tot assessed (%)62/155 (40.0)29/75 (38.7)33/80 (41.3)Fibromyalgia, n (%)6 (3.0)5 (5.2)1 (1.0)VAS, mean (SD) [range: 0-100] PhGA score46.3 (25.8)51.2 (25.4)41.7 (25.4) Joint score43.3 (26.8)47.1 (25.2)39.8 (27.8) Skin score20.3 (24.0)17.8 (23.1)22.6 (24.8)DAPSA, mean (SD)22.3 (14.1)26.8 (15.4)18.7 (11.9)DAPSA categories^, n (%)High disease activity13 (7.4)9 (11.5)4 (4.1)Moderate disease activity83 (47.2)43 (55.1)40 (40.8)Low disease activity71 (40.3)24 (30.8)47 (48.0)Remission9 (5.1)2 (2.6)7 (7.1)MDA°, n (%)23 (14.7)6 (8.3)17 (20.0)BSA categories, n (%) 3-10% (moderate psoriasis)35 (24.6)13 (21.2)22 (27.1) >10% (severe psoriasis)12 (8.5)4 (6.6)8 (9.9)* A patient could report one or more comorbidities. ^The sum does not add up to the total because of some missing values. ° According to Coates et al. (Ann Rheum Dis. 2010;69: 48).Disclosure of Interests:Alen Zabotti: None declared, Michele Maria Luchetti Speakers bureau: Honorary fees for conferences and workshops by Janssen, Abbvie, Novartis, Lilly, Celgene, Pfizer, Carlo Selmi Speakers bureau: Honoraria and/or speaker bureau from AbbVie, Amgen, Celgene, Lilly, Janssen, Novartis, Pfizer, Sanofi-Regeneron, Grant/research support from: Research support from Amgen, Janssen, Novartis, Pfizer, Roberta Ramonda Speakers bureau: Honoraria and speaker fees from Novartis, Abbvie, Pfizer, MSD, Janssen, Rosa Daniela Grembiale: None declared, Lorenzo Dagna Consultant of: Consultation honoraria from Abbvie, Amgen, Biogen, Celltrion, GlaxoSmithKline, Novartis, Pfizer, Roche, Sanofi-Genzyme, and SOBI, Salvatore D’Angelo Speakers bureau: Consulting fees and/or speakers bureau from AbbVie, Biogen, BMS, Celgene, Janssen, Lilly, MSD, Novartis, Pfizer, Sanofi and UCB, Giacomo Cafaro: None declared, Salvatore De Vita: None declared, Mara Felicetti: None declared, Silvia Marelli Employee of: Janssen-Cilag SpA, Daniela Frigerio Employee of: Janssen-Cilag SpA, Ennio Favalli Speakers bureau: Consulting fees and/or speaking engagements from AbbVie, Bristol-Myers Squibb, Lilly, Merck Sharp & Dohme, Pfizer, Galapagos, Sanofi-Genzyme, and UCB.
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Magnus, Dan, Santosh Bhatta, and Julie Mytton. "432 Establishing injury surveillance in emergency departments in Nepal: epidemiology and burden of paediatric injuries." Emergency Medicine Journal 37, no. 12 (November 23, 2020): 825.2–827. http://dx.doi.org/10.1136/emj-2020-rcemabstracts.7.
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Aims/Objectives/BackgroundGlobally, injuries cause more than 5 million deaths annually. Children and young people are a particularly vulnerable group and injuries are the leading cause of death in people aged 5–24 years globally and a leading cause of disability.In most low and middle-income countries where the majority of global child injury burden occurs, systems for routinely collecting injury data are limited. There is a continuing need for better data on childhood injuries and for injury surveillance.The aim of our study was to introduce a hospital-based injury surveillance tool – the first of its kind in Nepal and explore its feasibility. We undertook prospective collection of data on all injuries/trauma presenting to 2 hospital emergency departments to describe the epidemiology of paediatric hospital injury presentations and associated risk factors.Methods/DesignA new injury surveillance system for use in emergency departments in Nepal was designed and used to collect data on patients presenting with injuries. Data were collected prospectively in two hospitals 24 h a day over 12 months (April 2019 - March 2020) by trained data collectors using tablet computers.Abstract 432 Table 1Socio-demographic profile and characteristics of injury among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020 (N=2696)CharacteristicsFrequencyGender Male 1778 Female 918 Age groups 0–4 years 653 5–9 years 866 10–14 years 680 15–17 years 497 Median year (IRQ) 8 (5 – 13) Ethnicity/caste Janajati 1384 Brahmin/Chhetri 892 Dalit 148 Madhesi 146 Muslim 74 Others 50 Unknown 2 Place where injury occurred Home/Compound 1576 Highway/road/street 636 School 233 Recreational area 138 Workplace 76 Other 37 Activities at the time injury occurred Leisure/Play 1889 Travelling (other than to/from school/work) 296 Work 202 Travelling (to/from school/work) 184 Education 42 Organised sports 11 Other 52 Unknown 20 Intent of injury Unintentional 2560 Intentional (self-harm) 61 Intentional (assault) 75 Unintentional (n=2560) Fall 912 Animal or insect related 728 Road traffic injury 356 Injured by a blunt force 201 Stabbed, cut or pierced 176 Fire, burn or scald 65 Poisoning 52 Suffocation/choking 36 Electrocution 12 Drowning and submersion 7 Other 13 Unknown 2 Self-harm (n=61) Poisoning 38 Hanging, strangulation, suffocation 12 Stabbed, cut or pierced 6 Injured by blunt object 4 Other 1 Assault (n=75) Bodily force (physical violence) 43 Injured by blunt object 18 Stabbed, cut or pierced 8 Pushing from a high place 2 Poisoning 2 Sexual assault 1 Other 1 Nature of injury (one most severe) Cuts, bites or open wound 1378 Bruise or superficial injury 383 Fracture 299 Sprain, strain or dislocation 243 Internal injury 124 Head Injury/Concussion 83 Burns 67 Other 115 Unknown 2 Not recorded 2 Severity of injury No apparent injury 125 Minor 1645 Moderate 813 Severe 111 Not recorded 2 Disposition Discharged 2317 Admitted to hospital 164 Transferred to another hospital 179 Died 21 Leave Against Medical Advice (LAMA) 11 Unknown 2 Not recorded 2 Note:Not recorded = missing cases95% CI calculated using one proportion test and normal approximation method in Minitab.Abstract 432 Table 2Distribution of injuries by age-group, sex and mechanism of injury among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Age groups & Sex0 - 4 years5 - 9 years10–14 years15–17 yearsMaleFemaleTotalIntent & mechanismsn (%)n (%)n (%)n (%)n (%)n (%)n (%)Unintentional Fall 239 (26.2) 328 (36.0) 249 (27.3) 96 (10.5) 636 (69.7) 276 (30.3) 912 (100) Animal or insect related 175 (24.0) 260 (35.7) 190 (26.1) 103 (14.1) 470 (64.6) 258 (35.4) 728 (100) Road traffic injury 49 (13.8) 108 (30.3) 86 (24.2) 113 (31.7) 223 (62.6) 133 (37.4) 356 (100) Injured by a blunt force 54 (26.9) 74 (36.8) 49 (24.4) 24 (11.9) 150 (74.6) 51 (25.4) 201 (100) Stabbed, cut or pierced 20 (11.4) 56 (31.8) 49 (27.8) 51 (29.0) 127 (72.2) 49 (27.8) 176 (100) Fire, burn or scald 42 (64.6) 10 (15.4) 9 (13.8) 4 (6.2) 27 (41.5) 38 (58.5) 65 (100) Poisoning 33 (63.5) 6 (11.5) 5 (9.6) 8 (15.4) 26 (50.0) 26 (50.0) 52 (100) Suffocation/choking 24 (66.7) 5 (13.9) 2 (5.6) 5 (13.9) 20 (55.6) 16 (44.4) 36 (100) Electrocution 2 (15.7) 0 (0.0) 3 (25.0) 7 (58.3) 10 (83.3) 2 (16.7) 12 (100) Drowning and submersion 1 (14.3) 1 (14.3) 3 (42.9) 2 (28.6) 3 (42.9) 4 (57.1) 7 (100) Other 6 (46.2) 4 (30.8) 3 (23.1) 0 (0.0) 10 (76.9) 3 (23.1) 13 (100) Unknown 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) 2 (100) Total 647 (25.3) 852 (33.3) 648 (25.3) 413 (16.1) 1702 (66.5) 858 (33.5) 2560 (100) Self-harm Poisoning 0 (0.0) 0 (0.0) 6 (15.8) 32 (84.2) 7 (18.4) 31 (81.6) 38 (100) Hanging 0 (0.0) 0 (0.0) 3 (25.0) 9 (75.0) 4 (33.3) 8 (66.7) 12 (100) Stabbed, cut or pierced 0 (0.0) 0 (0.0) 2 (33.3) 4 (66.7) 1 (16.7) 5 (83.3) 6 (100) Injured by blunt object 0 (0.0) 2 (50.0) 2 (50.0) 0 (0.0) 4 (100) 0 (0.0) 4 (100) Other 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) 1 (100) 0 (0.0) 1 (100) Total 0 (0.0) 2 (3.3) 13 (21.3) 46 (75.4) 17 (27.9) 44 (72.1) 61 (100) Assault Bodily force (physical violence) 3 (7.0) 1 (2.3) 11 (25.6) 28 (65.1) 37 (86.0) 6 (14.0) 43 (100) Injured by blunt object 2 (11.1) 8 (44.4) 4 (22.2) 4 (22.2) 13 (72.2) 5 (27.8) 18 (100) Stabbed, cut or pierced 1 (12.5) 0 (0.0) 2 (25.0) 5 (62.5) 7 (87.5) 1 (12.5) 8 (100) Pushing from a high place 0 (0.0) 1 (50.0) 1 (50.0) 0 (0.0) 1 (50.0) 1 (50.0) 2 (100) Poisoning 0 (0.0) 1 (50.0) 0 (0.0) 1 (50.0) 1 (50.0) 1 (50.0) 2 (100) Sexual assault 0 (0.0) 0 (0.0) 1 (100) 0 (0.0) 0 (0.0) 1 (100) 1 (100) Other 0 (0.0) 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) 1 (100) Total 6 (8.0) 12 (16.0) 19 (25.3) 38 (50.7) 59 (78.7) 16 (21.3) 75 (100) Abstract 432 Table 3Association of injury location, nature and severity with age among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Age groups0 – 4 years5 – 9 years10–14 years15–17 yearsTotalChi-SquareInjury characteristicsn (%)n (%)n (%)n (%)n (%)P valueLocation of injury sustained Home/Compound 537 (34.1) 504 (32.0) 319 (20.2) 216 (13.7) 1576 (100) <0.001 Highway/road/street 85 (13.4) 196 (30.8) 190 (29.9) 165 (25.9) 636 (100) School 15 (6.4) 107 (45.9) 85 (36.5) 26 (11.2) 233 (100) Recreational area 9 (6.5) 44 (31.9) 55 (39.9) 30 (21.7) 138 (100) Workplace 1 (1.3) 4 (5.3) 19 (25.0) 52 (68.4) 76 (100) Other 6 (16.2) 11 (29.7) 12 (32.4) 8 (21.6) 37 (100) Total 653 (24.2) 866 (32.1) 680 (25.2) 497 (18.4) 2696 (100) Nature of injury Cuts, bites or open wound 328 (23.8) 506 (36.7) 314 (22.8) 230 (16.7) 1378 (100) <0.001 Bruise or superficial injury 81 (21.1) 99 (25.8) 118 (30.8) 85 (22.2) 383 (100) Fracture 48 (16.1) 101 (33.8) 112 (37.5) 38 (12.7) 299 (100) Sprain, strain or dislocation 48 (19.8) 78 (32.1) 72 (29.6) 45 (18.5) 243 (100) Internal injury 44 (35.5) 8 (6.5) 18 (14.5) 54 (43.5) 124 (100) Head Injury/Concussion 18 (21.7) 26 (31.3) 18 (21.7) 21 (25.3) 83 (100) Burns 42 (62.7) 9 (13.4) 10 (14.9) 6 (9.0) 67 (100) Other 41 (35.7) 38 (33.0) 18 (15.7) 18 (15.7) 115 (100) Unknown 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Total 652 (24.2) 865 (32.1) 680 (25.2) 497 (18.4) 2694 (100) Severity of injury No apparent injury 39 (31.2) 45 (36.0) 26 (20.8) 15 (12.0) 125 (100) <0.001 Minor 419 (25.5) 535 (32.5) 406 (24.7) 285 (17.3) 1645 (100) Moderate 171 (21.0) 262 (32.2) 225 (27.7) 155 (19.1) 813 (100) Severe 23 (20.7) 23 (20.7) 23 (20.7) 42 (37.8) 111 (100) Total 652 (24.2) 865 (32.1) 680 (25.2) 497 (18.4) 2694 (100) Abstract 432 Table 4Association of injury location, nature and severity with sex among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020SexMaleFemaleTotalChi-SquareInjury characteristicsn (%)n (%)n (%)P valueLocation of injury sustained Home/Compound 979 (62.1) 597 (37.9) 1576 (100) <0.001 Highway/road/street 421 (66.2) 215 (33.8) 636 (100) School 176 (75.5) 57 (24.5) 233 (100) Recreational area 111 (80.4) 27 (19.6) 138 (100) Workplace 62 (81.6) 14 (18.4) 76 (100) Other 29 (78.4) 8 (21.6) 37 (100) Total 1778 (65.9) 918 (34.1) 2696 (100) Nature of injury Cuts, bites or open wound 959 (69.6) 419 (30.4) 1378 (100) <0.001 Bruise or superficial injury 246 (64.2) 137 (35.8) 383 (100) Fracture 200 (66.9) 99 (33.1) 299 (100) Sprain, strain or dislocation 154 (63.4) 89 (36.6) 243 (100) Internal injury 50 (40.3) 74 (59.7) 124 (100) Head Injury/Concussion 59 (71.1) 24 (28.9) 83 (100) Burns 27 (40.3) 40 (59.7) 67 (100) Other 79 (68.7) 36 (31.3) 115 (100) Unknown 2 (100) 0 (0.0) 2 (100) Total 1776 (65.9) 918 (34.1) 2694 (100) Severity of injury No apparent injury 81 (64.8) 44 (35.2) 125 (100) 0.048 Minor 1102 (67.0) 543 (33.0) 1645 (100) Moderate 533 (65.6) 280 (34.4) 813 (100) Severe 60 (54.1) 51 (45.9) 111 (100) Total 1776 (65.9) 918 (34.1) 2694 (100) Abstract 432 Table 5Distribution of injuries by outcome and mechanism of injury among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Outcome of injuryDischargedAdmittedTransferredDiedLAMAUnknownTotalIntent & mechanismsn (%)n (%)n (%)n (%)n (%)n (%)n (%)Unintentional Fall 787 (86.5) 65 (7.1) 53 (5.8) 0 (0.0) 4 (0.4) 1 (0.1) 910 (100) Animal/insect bite/sting 704 (96.7) 3 (0.4) 19 (2.6) 0 (0.0) 1 (0.1) 1 (0.1) 728 (100) Road traffic injury 260 (73.0) 47 (13.2) 44 (12.4) 5 (1.4) 0 (0.0) 0 (0.0) 356 (100) Injured by a blunt force 190 (94.5) 4 (2.0) 6 (3.0) 0 (0.0) 1 (0.5) 0 (0.0) 201 (100) Stabbed, cut or pierced 165 (93.8) 8 (4.5) 3 (1.7) 0 (0.0) 0 (0.0) 0 (0.0) 176 (100) Fire, burn or scald 52 (80.0) 12 (18.5) 1 (1.5) 0 (0.0) 0 (0.0) 0 (0.0) 65 (100) Poisoning 30 (57.7) 4 (7.7) 16 (30.8) 1 (1.9) 1 (1.9) 0 (0.0) 52 (100) Suffocation/choking/asphyxia 24 (66.7) 4 (11.1) 6 (16.7) 1 (2.8) 1 (2.8) 0 (0.0) 36 (100) Electrocution 7 (58.3) 2 (16.7) 2 (16.7) 1 (8.3) 0 (0.0) 0 (0.0) 12 (100) Drowning and submersion 4 (57.1) 0 (0.0) 0 (0.0) 3 (42.9) 0 (0.0) 0 (0.0) 7 (100) Other 12 (92.3) 1 (7.7) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 13 (100) Unknown 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Total 2237 (87.5) 150 (5.9) 150 (5.9) 11 (0.4) 8 (0.3) 2 (0.1) 2558 (100) Self-harm Poisoning 5 (13.2) 8 (21.1) 23 (60.5) 0 (0.0) 2 (5.3) 0 (0.0) 38 (100) Hanging 1 (8.3) 0 (0.0) 1 (8.3) 10 (83.3) 0 (0.0) 0 (0.0) 12 (100) Stabbed, cut or pierced 6 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 6 (100) Injured by blunt object 4 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 4 (100) Other 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) Total 17 (27.9) 8 (13.1) 24 (39.3) 10 (16.4) 2 (3.3) 0 (0.0) 61 (100) Assault Bodily force (physical violence) 34 (79.1) 5 (11.6) 3 (7.0) 0 (0.0) 1 (2.3) 0 (0.0) 43 (100) Injured by blunt object 18 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 18 (100) Stabbed, cut or pierced 6 (75.0) 1 (12.5) 1 (12.5) 0 (0.0) 0 (0.0) 0 (0.0) 8 (100) Pushing from a high place 2 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Poisoning 1 (50) 0 (0.0) 1 (50.0) 0 (0.0) 0 (0.0) 0 (0.0) 2 (100) Sexual assault 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) Other 1 (100) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 0 (0.0) 1 (100) Total 63 (84.0) 6 (8.0) 5 (6.7) 0 (0.0) 1 (1.3) 0 (0.0) 75 (100) Abstract 432 Figure 1Seasonal variation of injuries identified by the injury surveillance system over a year among children attending emergency of hospitals in Makwanpur district, Nepal, April 2019 – March 2020Results/ConclusionsThe total number of ED patients with injury in the study was 10,154.2,696 were patients aged <18 years. Most injuries in children were unintentional and over half of children presenting with injuries were <10 years of age. Falls, animal bites/stings and road traffic injuries accounted for nearly 75% of all injuries with some (drowning, poisonings and burns) under-represented. Over half of injuries were cuts, bites and open wounds. The next most common injury types were superficial injuries (14.2%); fractures (11.1%); sprains/dislocations (9.0%). Child mortality was 1%.This is the biggest prospective injury surveillance study in a low or middle country in recent years and supports the use of injury surveillance in Nepal for reducing child morbidity and mortality through improved data.CHILD PAPER: RESULTS SECTIONTotal number of ED patients: 33046Total number of ED patient with injury: 10154 (adult=7458 & children=2696)8.2% (n=2696) patients with injury were children aged <18 yearsHetauda hospital: 2274 (84.3%)Chure hill hospital: 422 (15.7%)
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Habermann, Thomas M., B. K. Link, M. J. Maurer, J. E. Wooldridge, S. M. Geyer, W. R. Macon, C. Allmer, et al. "The IPI Predicts Outcome in Patients with Diffuse Large B-Cell Lymphoma (DLBCL) Treated with Immunochemotherapy: A Report of the University of Iowa/Mayo Clinic SPORE." Blood 110, no. 11 (November 16, 2007): 1279. http://dx.doi.org/10.1182/blood.v110.11.1279.1279.
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Abstract The International Prognostic Factor Index (IPI) predicts survival in DLBCL in patients treated with chemotherapy. The Revised IPI (R-IPI) has been reported to be a simpler and more accurate predictor of outcome in patients treated with immunochemotherapy (rituximab and anthracycline-based chemotherapy). We evaluated the predictive value of the IPI and the R-IPI in an observational cohort of unselected patients treated with R-CHOP. Consecutive, newly diagnosed patients age 18 years and older with DLBCL were prospectively offered enrollment into our Lymphoma SPORE Registry. Pathology was centrally reviewed, and composite lymphomas and history of concurrent or prior cancers were excluded. All patients were actively followed for progression free progression (PFS) and overall survival (OS). Here we report on patients enrolled from 9/2002 – 6/2006. 229 patients with a median age of 62 years (range 20–93) were evaluated. 56% were >60 years of age, 16% had a performance score ≥2, 54% had an elevated LDH, 19% had >1 extranodal site, and 51% were stage III/IV. During follow-up, there were 63 progressions (28%) and 45 deaths (20%), and the median follow-up time for living patients was 34 months (range 6–61 months). As shown in the table and figure, the IPI and R-IPI were predictive for both PFS and OS (all p<0.001). The predictive ability of the IPI as measured by 3-year concordance index was stronger for the IPI (0.71) compared to the R-IPI (0.67) and the bootstrap 95% confidence interval for the difference (0.01, 0.08) indicates that this difference was statistically significant. While all factors in the IPI were statistically significant (p<0.05) predictors of OS individually, when included in a multivariate model, an elevated LDH (HR=1.5; p = 0.32) and >1 extranodal sites (HR=1.0; p = 0.96) were no longer significant; similar results were obtained for PFS. The IPI remains a strong predictor of PFS and OS in the immunochemotherapy era. Figure Figure Group % Pats 3 Y PFS HR 95% CI 3 Y OS HR 95% CI Standard IPI Low (0,1) 41% 87% 1.0 ref 93% 1.0 ref Low-Int (2) 22% 62% 3.1 (1.4, 6.8) 74% 4.2 (1.6, 11.1) High-Int (3) 21% 60% 3.1 (1.4, 6.8) 77% 3.4 (1.2, 9.7) High (4,5) 15% 39% 7.2 (3.4, 15.2) 47% 10.2 (4.0, 26.5) R-IPI Very good (0) 11% 96% 1.0 ref 100% 1.0 ref Good (1,2) 53% 74% 6.2 (0.8, 46.0) 84% - - Poor (3–5) 36% 52% 13.5 (1.8, 98.9) 65% - -
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Family, Leila, Su-Jau Yang, Zandra Klippel, Yanli Li, John H. Page, Roberto Rodriguez, and Chun Chao. "Risk of Febrile Neutropenia (FN) in Select Myelosuppressive Chemotherapy Regimens." Blood 126, no. 23 (December 3, 2015): 3257. http://dx.doi.org/10.1182/blood.v126.23.3257.3257.
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Abstract Introduction Febrile neutropenia (FN) is a serious adverse effect of myelosuppressive chemotherapy, which often results in hospitalization and chemotherapy dose modification. FN risk depends on patient characteristics and chemotherapy regimen risk. Understanding the FN risk associated with individual chemotherapy regimens can help guide the use of prophylactic granulocyte colony-stimulating factor (G-CSF) and patient monitoring. To this end, the NCCN has classified regimens into high (≥20%), intermediate (10%-20%), or low (<10%) FN risk based primarily on clinical trial data. However, even for the same regimen, the FN risk is often higher in clinical practice than in clinical trials. In this study, we assessed the FN risk associated with several regimens for which FN risk has not been determined or has shown substantial variability outside of a clinical trial setting, using data from Kaiser Permanente Southern California (KPSC), a large, community-based practice. Methods Included were patients diagnosed with incident non-Hodgkin's lymphoma (NHL), breast cancer (BC), or multiple myeloma (MM) between 2008 and 2013 at KPSC who initiated the following chemotherapy regimens: bendamustine ± rituximab for NHL; docetaxel, carboplatin, and trastuzumab (TCH) or docetaxel and cyclophosphamide (TC) for BC; or Q4W lenalidomide 25 mg/dexamethasone for MM. Bendamustine ± rituximab, TCH, and lenalidomide are not classified by NCCN; TC is classified as intermediate FN risk but has shown considerable variability of FN incidence when used in clinical practice. Data on cancer diagnosis, chemotherapy use, G-CSF use, neutrophil count, and infections were obtained from KPSC's electronic medical records to estimate the incidence proportions of FN and grade 3 and 4 neutropenia. FN was defined as (1) hospitalization with absolute neutrophil count (ANC) <1000/µL or (2) hospitalization with primary or secondary diagnosis codes of neutropenia (ICD-9 288.0x) and fever (ICD-9 780.6), diagnosis code for bacterial/fungal infection, or antibiotic use. Grade 3 neutropenia was defined as ANC ≥500/µL to <1000/µL; grade 4 neutropenia as ANC <500/µL. Patients who received prophylactic G-CSF within 5 days of chemotherapy initiation were excluded from analysis. Results Overall, 40 (12%) NHL patients; 149 (24%) and 340 (28%) BC patients who received TCH and TC, respectively; and 0 (0%) MM patients were excluded due to prophylactic G-CSF. Over the first 6 cycles of bendamustine (median 338.4 mg/m2) ± rituximab for NHL patients (n = 307), 7.2% experienced FN, 4.2% grade 3 neutropenia, and 17.6% grade 4 neutropenia. Over the first 6 cycles of TCH for BC patients (n = 462), 24.2% experienced FN, 10.6% grade 3 neutropenia, and 44.6% grade 4 neutropenia. Over the first 6 cycles of TC for BC patients (n = 859), 20.5% experienced FN, 9.5% grade 3 neutropenia, and 37.5% grade 4 neutropenia. Over the first 4 cycles of lenalidomide/dexamethasone for MM patients (n = 186), 3.8% experienced FN, 5.9% grade 3 neutropenia, and 18.3% grade 4 neutropenia (Table 1). Conclusions Using NCCN criteria, bendamustine ± rituximab for NHL and lenalidomide/dexamethasone for MM would be classified as low-FN-risk regimens (<10%). By contrast, BC regimens TCH and TC would be classified as high-FN-risk regimens (>20%) based on our data. These results could help inform prophylactic G-CSF use for the selected regimens in clinical practice. Table 1. Number and Incidence Proportion of Neutropenic Outcomes Overall and by Cycle Cancer: Regimen Cycle Patients n FN Events n (%) Grade 3 Neutropenia Events n (%) Grade 4 Neutropenia Events n (%) NHL: Bendamustine ± rituximab Overall 307 22 (7.2) 13 (4.2) 54 (17.6) 1 307 12 (3.9) 5 (1.6) 28 (9.1) 2 225 3 (1.3) 4 (1.8) 21 (9.3) 3 173 2 (1.2) 4 (2.3) 15 (8.7) 4 130 2 (1.5) 4 (3.1) 10 (7.7) 5 92 4 (4.4) 4 (4.4) 8 (8.7) 6 69 2 (2.9) 2 (2.9) 0 (0) BC: TCH Overall 462 112 (24.2) 49 (10.6) 206 (44.6) 1 462 70 (15.2) 39 (8.4) 138 (29.9) 2 326 13 (4.0) 15 (4.6) 42 (12.9) 3 282 17 (6.0) 9 (3.2) 39 (13.8) 4 247 6 (2.4) 8 (3.2) 31 (12.6) 5 199 4 (2.0) 6 (3.0) 25 (12.6) 6 169 8 (4.7) 3 (1.8) 12 (7.1) BC: TC Overall 859 176 (20.5) 82 (9.5) 322 (37.5) 1 859 126 (14.7) 51 (5.9) 266 (30.9) 2 649 21 (3.2) 42 (6.5) 82 (12.6) 3 571 19 (3.3) 23 (4.0) 62 (10.9) 4 511 14 (2.7) 22 (4.3) 45 (8.8) 5 94 1 (1.1) 3 (3.2) 9 (9.6) 6 84 2 (2.4) 1 (1.2) 2 (2.4) MM: Lenalidomide / dexamethasone Overall 186 7 (3.8) 11 (5.9) 34 (18.3) 1 186 2 (1.1) 8 (4.3) 17 (9.1) 2 101 3 (3.0) 5 (5.0) 14 (13.9) 3 63 2 (3.2) 2 (3.2) 8 (12.7) 4 37 0 (0) 0 (0) 4 (10.8) Disclosures Family: Amgen Inc.: Research Funding. Klippel:Amgen Inc.: Employment, Equity Ownership. Li:Amgen Inc.: Employment, Equity Ownership. Page:Amgen Inc.: Employment, Equity Ownership.
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Lerchenmuller, Christian A., Matthias Groschek, Hendrik Kroening, Burkhard Scheuer, Martina Stauch, Anja Kuhn, Eva Hellebrand, and Ursula Vehling-Kaiser. "Panitumumab (pmab) in patients (pts) with chemorefractory metastatic colorectal cancer (mCRC): Final analysis from a community-based, observational study (VECTOR) in Germany." Journal of Clinical Oncology 31, no. 4_suppl (February 1, 2013): 550. http://dx.doi.org/10.1200/jco.2013.31.4_suppl.550.
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550 Background: Pmab monotherapy significantly improves progression-free survival versus best supportive care in pts with chemorefractory KRAS wild-type (WT) mCRC. This study evaluated the efficacy and safety of pmab in routine clinical practice in Germany. Methods: To ensure a representative sample, eligibility criteria were largely unrestricted. Consenting pts were >18 years old, had histologically confirmed KRAS WT mCRC, >4 weeks pmab therapy, failure of fluoropyrimidine-, oxaliplatin- and irinotecan-containing chemotherapy (CTx) regimens, and women of child-bearing age received contraception. Predefined endpoints were overall response rate (ORR; investigator`s assessment) and skin toxicity (NCI Common Terminology Criteria for Adverse Events v3.0). Results: A total of 428 pts were included in the full analysis set. At the start of pmab therapy, median age was 69 (range 22-89) years, 268 pts (63%) were male and 343 (80%) had an ECOG performance status of 0-1. Overall, 400 pts (93%) had undergone prior surgery and 154 (36%) had received ≥1 cycle of adjuvant CTx. Pts had received a median of 3 cycles (range: 1‑12) of prior CTx for mCRC. The most common regimens were FOLFOX/FOLFIRI ±antibody therapy; 65% of regimens were given with palliative, 32% with curative/palliative and 3% with curative intent. The median pmab dose was 6 mg/kg (range 2.4-7.2) q2w for a median of 8 (range 2‑45) cycles, with 143 pts (33%) receiving >10 cycles. The ORR during pmab therapy was 20% (complete response: n=7 [2%]; partial response: n=77 [18%]); disease control (including stable disease) was achieved in 261 pts (61%). Skin reactions occurred in 324 pts (67%) with 52% experiencing a maximum grade ≥2. Most pts had some type of rash (48% acne, 5% desquamation, 4% hand-foot skin reaction, 1% erythema multiforme). Overall, 21% of pts had other toxicities. Three serious adverse drug reactions (infection/fever; thrombosis/embolism; erythema multiforme) and two grade 1 infusion reactions were reported. Conclusions: In this observational study, pmab monotherapy had efficacy at least as good as was seen in the randomised pmab trial and safety was also similar.
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Goldberg, Stuart L., Nikita Mody-Patel, and E. R. Chen. "Clinical and Economic Consequences of Myelodysplastic Syndromes in the United States: An Analysis of the Medicare Database." Blood 112, no. 11 (November 16, 2008): 636. http://dx.doi.org/10.1182/blood.v112.11.636.636.
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Abstract Background: The myelodysplastic syndromes (MDS) are a heterogeneous group of marrow failure syndromes causing anemia requiring red blood cell transfusions. Since iron overload from chronic transfusions may result in organ damage, it is possible that MDS patients (pts) may develop co-morbid conditions. The aim of this analysis is to describe clinical and economic consequences in newly diagnosed MDS pts followed over a three year period compared to those without MDS in the Medicare population. Methods: The Medicare Standard Analytic File 5% (SAF5%) claims database was used to identify pts with a new primary MDS diagnosis code from Jan-Mar 2003, and followed till Dec 2005 or death. Pts with myeloid leukemia or anemias of known causes in the previous year were excluded. The study timeframe predates the widespread use of “low intensity” treatments to reflect the natural history of MDS with transfusional and growth factor support. Results: Of the 1,713,502 pts in SAF5%, 705 (41 per 100,000) developed MDS in Jan – Mar 2003. Of these 705 cases, 159 had a previous history of unexplained anemia (23%), 43 received prior chemotherapy or radiotherapy (6%), and 503 were de novo (71%). MDS pts were older than the overall SAF5% population (72% vs. 57% were ≥70 years; p<0.0001); male (49% vs. 42%; p=0.0003), and Caucasian (90% vs. 86%; p=0.0164). The diagnosis of MDS was confirmed by bone marrow evaluation in 400 (57%) whereas the MDS diagnostic code was applied by the treating physician based on clinical impression in 43%. During the 3-year follow-up study period, 522 (74%) suffered a cardiac-related event: 142 MIs (20%); 344 CHF (49%); 374 arrhythmias (53%); and 415 less common events (58%). 383 (54%) had no cardiac history in 2002, and among this cohort, 228 (60%) developed cardiac disease. For comparison, of the approximately 1.7 million individuals in Medicare SAF5% database, 726,936 (42.4%) suffered cardiac disease during the 3-year study, significantly less than the MDS cohort (74%; p <0.001). Of the 327 (46%) receiving blood transfusions, 7(2%) were iron chelated. Transfused MDS pts experienced a higher rate of cardiac events; 260 (80%) transfused MDS pts experienced a cardiac event compared with 262 MDS pts (69%) that did not receive transfusions (p=0.002). Diabetes was recorded in 306 (43%) of the 705 MDS pts. Of the 505 pts without a diabetic history, 117 (23%) developed diabetes during the 3 year study. Dyspnea as a diagnostic code was recorded in 359 (51%). Of the 576 pts without a pulmonary history, 261 (45%) developed dyspnea. Hepatic diseases occurred in 13 (1.8%) MDS pts, and were new in 12 (1.7%). Infectious complications occurred in 45%. Deaths occurred in 278 (39%); 63% in the therapy-induced, 40% prior anemia, and 37% de novo groups. During the 3 year study 79% of the MDS pts were hospitalized, 59% had 1 emergency room visit, 45% received growth factor treatments, and 15% chemotherapy. In 2003, median Medicare payment for the MDS pt cohort was $17,556, compared to $1,459 for the total SAF5% Medicare population (mean: $28,023 vs. $6,739; p< 0.001). For the MDS cohort (N=705), median Medicare payments were $34,271 for therapy induced; $17,191 for prior unexplained anemia history, and $16,493 for de novo MDS. In 2004, median Medicare payment for the MDS pt cohort (N=550) was $11,775, compared to $1,633 for the total SAF 5% Medicare population (mean: $22,419 vs. $7,310; p< 0.001). In 2005, median Medicare payment for the MDS pt cohort (N=431) was $9,840, compared to $1,802 for the total SAF 5% Medicare population (mean: $21,533 vs. $7,829; p< 0.001). Conclusions: MDS represents a significant US health concern among Medicare pts, with substantial economic implications. Organ impairment following a diagnosis of MDS is common with transfusion dependent MDS pts. Since chronic anemia can lead to cardiac dysfunction and transfusional iron overload is also known to contribute to cardiac dysfunction, strategies to improve anemia and maintain adequate iron balance through the administration of iron chelation therapy are critical in MDS pts receiving blood transfusions.
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He, Min, Benlong Yang, Jiong Wu, Zhenzhen Liu, Hongjian Yang, Jinhai Tang, Kun Wang, et al. "Abstract P5-18-10: Mecapegfilgrastim for primary prophylaxis of neutropenia in 355 HER2+ breast cancer patients treated with neoadjuvant docetaxel in combination with trastuzumab and/or pyrotinib: Exploratory analysis from randomized, double-blind, phase 3 PHEDRA study." Cancer Research 82, no. 4_Supplement (February 15, 2022): P5–18–10—P5–18–10. http://dx.doi.org/10.1158/1538-7445.sabcs21-p5-18-10.
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Abstract Background: A dose relationship may exist for both antitumor activity and toxicity of docetaxel in breast cancer (BC) patients, while 86% grade 4 neutropenia and 12% febrile neutropenia (FN) were reported when pretreated advanced breast cancer (ABC) patients received 100 mg/m2 docetaxel monotherapy without hematopoietic support. PHEDRA was a randomized, double-blind, multicenter, phase 3 study comparing the efficacy and safety of adding pyrotinib to trastuzumab and docetaxel as neoadjuvant treatment in women with HER2+ early or locally ABC (ClinicalTrials.gov: NCT03588091). We conducted this exploratory analysis to evaluate the effectiveness of mecapegfilgrastim, a long-acting recombinant human granulocyte colony-stimulating factor (rhG-CSF), as primary prophylaxis for neoadjuvant chemotherapy-induced neutropenia in BC patients. Methods: Patients with HER2-positive early or locally ABC were randomly assigned (1:1) to pyrotinib arm receiving 4 neoadjuvant cycles of docetaxel (100 mg/m2 iv d1 q3w), trastuzumab (8 mg/kg iv, cycle 1 d1, then 6 mg/kg d1 q3w), and pyrotinib (400 mg po qd, d1-21, q3w) or placebo arm with placebo, trastuzumab and docetaxel. Per protocol, patients were required to receive a single, 6-mg fixed dose of mecapegfilgrastim on Day 2 of each cycle. Other G-CSF was permitted if mecapegfilgrastim was unavailable at the local center or patients occurred mecapegfilgrastim intolerance. The incidence of neutropenia, FN, time to first neutropenia onset, duration per neutropenia event and cumulative neutropenia duration during neoadjuvant treatment period; and the incidences of grade 3/4 neutropenia, FN and decreased WBC count in Cycle 1 to 4 (C1-4) were presented. The data cutoff date was April 30, 2021. Results: Between July 23, 2018 and January 8, 2021, 355 patients were randomized (pyrotinib arm, n=178; placebo arm, n=177). Among them, 291 (82.0%) patients received a single, 6-mg fixed dose of mecapegfilgrastim in Cycle 1 and 270 (76.1%) patients received mecapegfilgrastim in each of the 4 cycles. Grade 3/4 neutropenia was reported in 33 (18.5%) patients in the pyrotinib arm and 36 (20.3%) patients in the placebo arm. Five (2.8%) patients in the pyrotinib arm and 2 (1.1%) patients in the placebo arm developed FN (5 FN occurred in C1; 2 FN occurred in C2). Median duration of grade 3/4 neutropenia was 3 days in the pyrotinib group and 3 days in the placebo group. Median cumulative duration of grade 3/4 neutropenia was 4 days and 3 days in the pyrotinib group and the placebo group, respectively. Grade 3/4 neutropenia mainly occurred during the first cycle of treatment for both pyrotinib (13.5%) and placebo arm (15.8%), reduced in the second cycle (5.9% vs 4.0%) and thereafter (C3: 1.8% vs 3.4%; C4: 2.4% vs 1.7%). Similar trends were observed for grade 3/4 WBC count decreased in Cycle 1 to 4. No grade 4 infection occurred. Overview of neutropenia, FN and WBC count decreased was summarized in Table 1. Consistent findings were observed in 291 mecapegfilgrastim treated patients. Conclusion: The exploratory analysis demonstrated 6-mg fixed dose of mecapegfilgrastim was effective when administrated as primary prophylaxis for neoadjuvant chemotherapy-induced neutropenia, which could be considered as a new treatment option for its advantage of once-per-cycle dosing and convenient dose management. Table 1.Overview of neutropenia, febrile neutropenia and WBC count decrease during neoadjuvant treatment period.Docetaxel+Trastuzumab+Pyrotinib(N=178)Docetaxel+Trastuzumab+Placebo (N=177)All randomized patients(N=355)Neutropenia, n (%)Any grade57 (32.0)54 (30.5)111 (31.3)Grade 16 (3.4)5 (2.8)11 (3.1)Grade 218 (10.1)13 (7.3)31 (8.7)Grade 315 (8.4)20 (11.3)35 (9.9)Grade 418 (10.1)16 (9.0)34 (9.6)Median time to first onset (IQR), days7 (6-63)6 (6-49)7 (6-53)Median duration per grade 3 or higher neutropenia, days (range)3 (1-16)3 (2-12)3 (1-16)Median cumulative duration of grade 3 or higher neutropenia, days (range)4 (2-16)3 (2-14)3 (2-16)FN, n (%)5 (2.8)2 (1.1)7 (2.0)Grade 3 or higher neutropenia, n (%) *Cycle 124 (13.5)28 (15.8)52 (14.6)Cycle 210 (5.9)7 (4.0)17 (4.9)Cycle 33 (1.8)6 (3.4)9 (2.6)Cycle 44 (2.4)3 (1.7)7 (2.1)Grade 3 or higher FN, n (%) *Cycle 12 (1.1)2 (1.1)4 (1.1)Cycle 22 (1.2)02 (0.6)Cycle 3000Cycle 4000Grade 3 or higher WBC count decreased, n (%) *Cycle 120 (11.2)20 (11.3)40 (11.3)Cycle 28 (4.7)2 (1.1)10 (2.9)Cycle 32 (1.2)1 (0.6)3 (0.9)Cycle 44 (2.4)2 (1.1)6 (1.8)Note: IQR, interquartile range; FN, febrile neutropenia; WBC, white blood cell.*The denominator indicates number of patients with mecapegfilgrastim for prophylaxis use in this cycle. Citation Format: Min He, Benlong Yang, Jiong Wu, Zhenzhen Liu, Hongjian Yang, Jinhai Tang, Kun Wang, Yunjiang Liu, Haibo Wang, Peifen Fu, Shuqun Zhang, Qiang Liu, Zefei Jiang, Shusen Wang, Jian Huang, Chuan Wang, Shu Wang, Yongsheng Wang, Linlin Zhen, Xiaoyu Zhu, Shulin Liu, Ping Yan, Jianjun Zou. Mecapegfilgrastim for primary prophylaxis of neutropenia in 355 HER2+ breast cancer patients treated with neoadjuvant docetaxel in combination with trastuzumab and/or pyrotinib: Exploratory analysis from randomized, double-blind, phase 3 PHEDRA study [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-18-10.
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Tmoyan, N. A., O. I. Afanasieva, M. V. Ezhov, E. A. Klesareva, M. I. Afanasieva, O. A. Razova, T. V. Balakhonova, and S. N. Pokrovsky. "Lipoprotein(а) Level, Apolipoprotein(а) Polymorphism аnd Autoаntibodies Against Lipoprotein(а) in Patients with Stenotic Cаrotid Atherosclerosis." Kardiologiia 59, no. 12 (December 17, 2019): 20–27. http://dx.doi.org/10.18087/cardio.2019.12.n727.
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Аim. Comparative assessment of respiratory indicators according to multifunctional monitoring (PFM) with the recommended standard for a complete polysomnographic study and an assessment of the effect of blood pressure (BP) measurements in PFM on sleep quality. Triаls on the аssociаtion of Lp(а) and cаrotid аtherosclerosis аre limited. The аim of the study wаs to investigаte the аssociаtion of Lp(а), аpolipoprotein(а) [apo(а)] polymorphism аnd аutoаntibodies to Lp(а) with stenotic (≥50%) cаrotid аtherosclerosis in dependence on CHD presence. Materials and methods. The study included 785 pаtients аt the аge from 21 to 92 with dаtа of instrumentаl exаmination of coronаry, cаrotid аnd lower limbs аrteries. Stenotic cаrotid аtherosclerosis wаs diаgnosed in 447 pаtients who were divided into two groups depending on presence (n=344) or аbsence (n=103) of CHD. The control group comprised of 338 pаtients without stenotic аtherosclerosis of coronаry, cаrotid аnd lower limbs аrteries. In the blood serum of pаtients levels of Lp(а), аutoаntibodies to Lp(а) were determined аnd аlso аpo(а) phenotyping wаs conducted. Results. There were more mаles, higher аverаge аge аnd frequency of hypertension, type 2 diаbetes mellitus, smoking, Lp(а) concentrаtion (mediаn [interquаrtile rаnge]): 30 [11; 63] vs. 14 [5; 30] mg/dl, p<0.01) in the group with stenotic cаrotid аtherosclerosis in compаrison with control group. Besides, Lp(а) level wаs higher in CHD subgroup thаn in pаtients with stenotic cаrotid аtherosclerosis without CHD: 32 [12; 72] vs. 24 [8; 50] mg/dl, respectively, p=0.01. Elevаted (≥30 mg/dl) Lp(а) level, low moleculаr weight аpolipoprotein(а) [(LMW аpo(а)] phenotype were аssociаted with stenotic cаrotid аtherosclerosis (odds rаtio (OR) 2.9; 95% confidence intervаl (CI) 2.1–4.0, p<0.01 аnd OR 2.3; 95% CI 1.6–3.4, p<0.01, respectively). Logistic regression аnаlysis showed independent аssociаtion of elevаted Lp(а) level аnd LMW аpo(а) phenotype with stenotic cаrotid аtherosclerosis both in the presence аnd absence of CHD. The level of IgM аutoаntibodies to Lp(а) wаs higher in control group thаn in pаtients with stenotic cаrotid аtherosclerosis, p=0.02. Conclusion The level of Lp(a) ≥30 mg/dl and low molecular weight phenotype of aprotein(a) are predictors of stenotic atherosclerosis CA, regardless of the presence of coronary heart disease and other risk factors, while a reverse relationship was found between the level of autoantibodies of the IgM class against Lp(a) and the severity of atherosclerosis CA.
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Haugeberg, G., A. Kavanaugh, and B. Michelsen. "AB0783 THE IMPACT OF SKIN ITCHING ON HEALTH RELATED QUALITY OF LIFE IN PSORIATIC ARTHRITIS OUTPATIENT CLINIC PATIENTS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1689.1–1690. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1088.
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Background:In psoriatic arthritis (PsA) both skin and musculoskeletal involvement can contribute to reduce health related quality of life (HRQoL) (1). Although itch is considered an important symptom in psoriasis, less is known about its extent and potential impact on HRQoL in PsA.Objectives:The aim of the study was to assess the prevalence of itchy, sore, painful or stinging skin in PsA patients and also to explore the impact of these symptoms on overall HRQoL and skin related HRQoL.Methods:PsA patients were consecutively recruited from a rheumatology outpatient clinic. Data collection included variables listed in the table. Patients also answered the question: “Over the last week, how itchy, sore, painful or stinging has your skin been? With answer alternatives: Not at all (score 0), a little (score 1), a lot (score 2) and very much (score 3)”. For analysis the variable was dichotomized; ‘Not at all’ and ‘a little’ were scored as ‘not itching’, and ‘a lot’ and ‘very much’ were scored as ‘itching’. HRQoL was assessed using the 15D questionnaire and skin HRQoL using the Dermatology Life Quality Index (DLQI). Categorical variables are presented as numbers and (%) and continuous variables as mean with (SD). An association with 15D and DLQI was explored using univariate and multivariate linear regression analysis.Results:Among 125 PsA patients (63 men and 63 women), means age was 52.2 years, BMI 28.3 kg/m2, disease duration 8.9 years; 15.2% were smokers. The number and percentage (%) of PsA patients reporting their skin to be itchy, sore, painful or stinging was as follows: Not at all 25 (20.0%), a little 71 (56.8%), a lot 23 (18.4%) and very much 6 patients (4.8%). The table shows data for all PsA patients and for patients defined to have no itching or having itching skin.Total (n=125)No itching (n=96)Itching (n=29)PAge (SD), years52.2 (10.1)52.3 (10.1)51.6 (10.2)0.73Women, n (%)62 (49.6%)49 (51.0%)13 (44.8%)0.56BMI (SD), kg/m228.3 (4.3)28.0 (4.0)29.4 (4.9)0.12Smoking, n (%)19 (15.2%)14 (14.6%)5 (17.2%)0.73Dis.dur. (SD), years8.9 (6.7)9.1 (6.7)8.0 (6.9)0.42CRP (SD), mg /L4.8 (8.5)4.4 (8.5)6.1 (8.5)0.37TJC68 (SD)9.70 (11.07)9.21 (10.32)11.39 (13.41)0.36SJC66 (SD)0.57 (0.99)0.56 (1.00)0.61 (0.96)0.84MASES (SD)2.9 (3.1)2.5 (2.9)4.0 (3.7)0.02IGA (SD), (VAS 0-100)14.0 (11.7)12.9 (10.2)17.8 (15.4)0.12PGA (SD), (VAS 0-100)35.3 (24.2)30.5 (22.6)50.9 (22.8)<0.01Pain (SD), (VAS 0-100)33.4 (23.4)28.6 (21.3)49.1 (23.6)<0.01Fatigue (SD), (VAS 0-100)45.1 (32.0)40.3 (31.7)61.0 (28.1)<0.01MHAQ (SD), (0-3)0.40 (0.35)0.35 (0.32)0.58 (0.39)<0.01PASI (SD), (0-72)2.4 (3.5)1.9 (3.2)4.1 (4.1)0.01DLQI (SD), (0-30)3.5 (3.6)2.2 (2.3)7.9 (3.9)<0.0115D (SD), (0-1)0.84 (0.09)0.86 (0.09)0.80 (0.08)<0.01bDMARDs, n (%)43 (34.7%)33 (34.7%)10 (34.5%)0.98csDMARDs, n (%)73 (58.4%)61 (63.5%)12 (41.4)0.03Dis.dur.: disease durationIn univariate analysis itching was found to be associated with impaired HRQoL assessed by 15D but not in adjusted analysis. In a regression model adjusting for age, gender, BMI and including variables with p<0.2 in univariate analysis (MASES enthesitis score, investigator [IGA] and patients global assessment [PGA], fatigue, pain, MHAQ, Psoriasis Area Severity Index [PASI] score and itching and treatment), only female gender, PASI score and itching were independently associated with reduced skin HRQoL.Conclusion:Skin itching was frequently reported in our PsA patients (20-25%) and was also found to be associated with impaired HRQoL, in particular for skin HRQoL (DLQI). The association was independent of the extent of skin involvement (PASI). More needs to be understood about subjective skin symptoms such as itch in order to improve HRQoL in PsA.References:[1]Kavanaugh A, et al. Ann Rheum Dis 2019;9:1215-9Disclosure of Interests:Glenn Haugeberg: None declared, Arthur Kavanaugh Grant/research support from: Abbott, Amgen, AstraZeneca, BMS, Celgene Corporation, Centocor-Janssen, Pfizer, Roche, UCB – grant/research support, Brigitte Michelsen Grant/research support from: Research support from Novartis, Consultant of: Consulting fees Novartis
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Gugliotta, Gabriele, Fausto Castagnetti, Massimo Breccia, Alessandra Iurlo, Mariella D'Adda, Fabio Stagno, Luciano Levato, et al. "Outcome of 472 Chronic Myeloid Leukemia Patients Treated with Frontline Nilotinib: A Gimema CML WP Analysis." Blood 132, Supplement 1 (November 29, 2018): 458. http://dx.doi.org/10.1182/blood-2018-99-119182.
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Abstract BACKGROUND: In chronic phase (CP) chronic myeloid leukemia (CML) nilotinib showed better efficacy compared to imatinib. The higher rates of deep molecular response with nilotinib may translate in more patients (pts) eligible for treatment discontinuation. On the other hand, cardiovascular toxicity may limit nilotinib use in selected groups of pts (e.g. elderly pts). AIM: To investigate the efficacy and safety, overall and according to age, of first-line treatment with nilotinib in CML pts. METHODS: We analyzed response rates, events and outcome of 472 pts ≥ 18 y of age with CP CML, enrolled in clinical trials of the GIMEMA CML WP with nilotinib frontline. Pts were treated with: nilotinib 300 mg BID (n=276); nilotinib 400 mg BID (n=73); rotation of nilotinib 400 mg BID / imatinib 400 mg OD (3-month periods for each drug)(n=123). The median follow-up was 36 (3-82) months. Pts were further analyzed considering 3 age groups: 18-39 y (98 pts); 40-59 y (217 pts); and ≥ 60 y (157 pts). Definitions: Major molecular response (MR3): BCR-ABL≤0.1% (IS), with > 10.000 ABL copies; MR4: BCR-ABL≤0.01% (IS), with > 10.000 ABL copies. Events: permanent discontinuation of nilotinib for any reason, including adverse events, progression to accelerated/blast phase (AP/BP), or deaths. Arterial thrombotic events (ATEs): peripheral arterial obstructive disease, acute coronary syndrome, chronic ischemic heart disease, significant carotid stenosis and ischemic stroke, or other significant ischemic events. RESULTS: Overall, the cumulative incidences of MR3 by 12, 24, and 36 months were 75, 88, and 93%, respectively. The cumulative incidences of MR4 by 12, 24, and 36 months were 38, 63, and 76%, respectively. Events leading to permanent nilotinib discontinuation occurred in 132 (27.9%) pts. ATEs occurred in 33 (7% of pts) ATEs, corresponding to 19.7 ATEs/1000 pt-y. Fifteen (3.1%) pts progressed to AP/BP. Overall, 23 (4.9%) pts died, 11 of them after progression to AP/BP. The estimated 5-year OS was 93%. The sub-analysis according to age showed that: MR3 and MR4 rates were similar across the 3 age groups (cumulative incidences of MR4 by 24 months were 55, 62, and 70% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively; p=0.25). Progressions to AP/BP were: 6.1% in pts 18-39 y, 2.8% in pts 40-59 y, and 1.9% in pts ≥ 60 y. ATEs were: 0 in pts 18-39y, 4.1% (11.7/1000 pt-years) in pts 40-59 y, and 15.3% (41.3/1000 pt-years) in pts ≥ 60 y (no difference in ATEs was found between pts 60-69 y and those ≥ 70 y). The 5-y OS was 91, 97, and 89% in pts 18-39 y, 40-59 y, and ≥ 60 y, respectively (p=0.065). Death was always leukemia-related in pts 18-39 y (100%), while it was mainly leukemia-unrelated (75%) in pts ≥ 60 y. SUMMARY/CONCLUSION: Nilotinib as first-line treatment of newly diagnosed CP CML pts showed high rates of deep molecular responses, few progressions to AP/BP, and a high OS. Deep molecular response were similar in all age groups; as expected, ATEs were more frequent in pts > 60 y. These data suggest that: in pts > 60 y, the high efficacy of nilotinib should be weighed against its potential toxicity; in pts < 60 years, nilotinib may be a very good choice, with high efficacy and low toxicity. Disclosures Gugliotta: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria; Bristol-Myers Squibb: Honoraria. Castagnetti:Bristol Myers Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Breccia:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria; Incyte: Honoraria. Levato:Novartis: Other: Advisory board. Abruzzese:Pfizer: Consultancy; Ariad: Consultancy; Novartis: Research Funding; BMS: Consultancy. Soverini:Bristol Myers Squibb: Consultancy; Incyte Biosciences: Consultancy; Novartis: Consultancy. Foà:NOVARTIS: Speakers Bureau; JANSSEN: Other: ADVISORY BOARD, Speakers Bureau; CELTRION: Other: ADVISORY BOARD; INCYTE: Other: ADVISORY BOARD; CELGENE: Other: ADVISORY BOARD, Speakers Bureau; ABBVIE: Other: ADVISORY BOARD, Speakers Bureau; ROCHE: Other: ADVISORY BOARD, Speakers Bureau; GILEAD: Speakers Bureau; AMGEN: Other: ADVISORY BOARD. Cavo:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Pane:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau; AMGEN: Speakers Bureau.
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Lyons, Roger M., Sharon T. Wilks, David J. Friedman, Shelby A. Young, and Gail Brown. "Oral Ezatiostat HCl (Telintra), a Glutathione Analog Prodrug GSTP1-1 Inhibitor, for Treatment of Patients with Myeloid Growth Factor-Resistant Idiopathic Chronic Neutropenia (ICN)." Blood 120, no. 21 (November 16, 2012): 4394. http://dx.doi.org/10.1182/blood.v120.21.4394.4394.
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Abstract Abstract 4394 Introduction: Idiopathic chronic neutropenia (ICN) is a group of diseases characterized by low circulating neutrophils, recurrent fevers, mucosal inflammation, and systemic infections. The risk of complications is inversely proportional to the absolute neutrophil count (ANC), with the most severe occurring with ANC of < 0.5 × 109/L. Most patients respond to daily s.c. administration of granulocyte colony stimulating factors (G-CSF); however, some patients do not respond. Patients undergoing G-CSF therapy also often have bone and muscle pain, thrombocytopenia and splenomegaly, complicating therapy. Ezatiostat, a glutathione S-transferase (GST) inhibitor that activates Jun kinase, promoting growth and maturation of hematopoietic progenitors, is an investigational agent in development for treatment of ICN. This report describes 4 patients with longstanding ICN who responded to ezatiostat, all of whom prior to treatment had frequent hospitalizations for sepsis, prolonged courses of antibiotics and poor response to myeloid growth factors. Methods: Patients (pts) with severe ICN and inadequate ANC response to G-CSF were enrolled in this phase 2 trial. After initial starting dose of 2000 mg in divided doses twice daily (b.i.d.) dose-equilibration over 4 weeks, pts were treated with ezatiostat daily for 3 weeks followed by 1 week off. Treatment was given until lack of ANC response or unacceptable toxicity. Clinical benefit was determined by ANC response, infection-free periods, antibiotic use and hospitalizations for infections. Results: Four female pts, age range 23–63, with median ANC of 200 (50–400) were enrolled. Patient 1 is 62 y.o. with longstanding history of infections and treatment with G-CSF. Before entering study, she had recurrent ear, labial, left thigh, pulmonary and sinus infections despite growth factor treatment, to which she had severe reactions. Baseline white blood cell (WBC)/ANC ratio was 2.2/0.7. WBC/ANC improved with ezatiostat for 4 mo to 3.62/1.71 and infections resolved. Patient 2, a 63 y.o. with ICN for 26 years, had a median baseline WBC/ANC on G-CSF treatment of 3.1/.180 and a history of multiple hospital admissions for sepsis, non-healing perineal and decubitus ulcers, and recurrent high fevers within 4 days of cessation of parenteral antibiotics, necessitating resumption. Post-ezatiostat treatment median ANC was 3.1 (range 1.6–3.75) with a persistent infection-free period of over 22 mo with no hospitalizations or antibiotic therapy required. Patient 3, a 23 y.o. with ICN since age 10, initially responded to G-CSF but stopped responding despite injections b.i.d., and ANC never rose above 1000. Her last hospitalization was for methicillin-resistant staphylococcus aureus skin infection, upper respiratory infection with cervical adenopathy, and oral ulcers. She had infections every 3 months and baseline WBC/ANC of 1.4/0.13. She had minimal response over 4 mo of observation, with highest values 2.65/0.92 and median ANC of 0.40, but had no further bacterial infection or use of G-CSF. Patient 4, a 39 y.o. with ICN of 10 years' duration, had severe bone pain with G-CSF and responses were brief (1–2days). Previously, she had hospital admissions and emergency room visits 4–5 times a year and was ill 2–3 times a week with recurrent urinary tract infections, pneumonias (4–5 times per year), oral ulcers, sinus and gastrointestinal infections, furuncles, and infection after dental work. Baseline WBC/ANC was 1.23/0.20. Currently, her WBC/ANC is 1.50/0.26. While ANC did not increase, infection rate decreased and she had no ER visits or admissions for over 5 mo. She responded to a single 300 mcg dose of of G-CSF with an ANC of 1.0 for a week, suggesting re-sensitization to G-CSF. Most common ezatiostat-related adverse events were grade 1 nausea, abnormal urine/stool odor, and dysgeusia. Conclusions: Ezatiostat, a novel GSTP1-1 inhibitor and jun kinase modulator as treatment of patients with ICN and grade 4 neutropenia not responsive to myeloid growth factors, results in a durable ANC response and clinically significant reductions in serious infections. Results suggest a potential role for ezatiostat as an oral therapy alternative or adjunct to G-CSF in the treatment of ICN in patients who are not responsive to G-CSF. Response to this targeted therapy may also give insight into the pathophysiology of ICN and further study is warranted. Disclosures: Lyons: Telik, Inc.: Research Funding. Wilks:Telik, Inc.: Research Funding. Friedman:Telik, Inc.: Research Funding. Young:Telik, Inc.: Employment, Equity Ownership. Brown:Telik, Inc.: Employment, Equity Ownership.
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Diamantopoulos, Panagiotis Theodorou, Konstantinos Zervakis, Athanasios G. Galanopoulos, Panagiotis Bakarakos, Vasiliki Papadopoulou, Theodoros Iliakis, Fani Kalala, et al. "Decrease in Transfusion Needs in Patients with Higher-Risk Myelodysplastic Syndrome and Acute Myeloid Leukemia Treated with 5-Azacytidine. a Retrospective Study." Blood 124, no. 21 (December 6, 2014): 5608. http://dx.doi.org/10.1182/blood.v124.21.5608.5608.
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Abstract Introduction The hypomethylating agent 5-azacytidine (AZA) has been the standard of care for higher risk Myelodysplastic Syndromes (MDS) for the last few years. Its efficacy has been proven in large clinical trials, and its safety has been shown to be superior to that of conventional treatments. We have conducted a retrospective study about the efficacy and safety of 5-azacytidine, as reported and analyzed in our center. Patients and Methods Forty four consecutive patients with MDS or Acute Myeloid Leukemia (AML) with 20-30% bone marrow blasts that were treated with AZA during the last 63 months were included in the study. The clinical and laboratory characteristics of the patients were recorded, and the efficacy and safety data were analyzed. Results The epidemiologic and hematologic characteristics of the patients are shown in Table 1. The median overall survival was 13 months (1-101) and there was no primary treatment failure (Table 2). Serious adverse events consisted mostly of neutropenic infections (blood stream and pneumonia) (Table 3). Discussion Treatment with AZA offered a favorable (complete and partial) response in 34.1% of the patients, and an overall survival of 13 months, with generally predictable toxicities, although hospitalization was frequently inevitable during the first treatment cycles, when supportive treatment was a significant part of the management. A valuable observation is that there was a considerable decrease in the patients’ transfusion needs following treatment (p<0.0001). Our results are consistent with the results of other clinical trials and point out the need for investigational 5-azacytidine combinations. Table 1. Epidemiologic and hematologic characteristics. Male: Female ratio 30:14 (2.1 : 1) Age, Median (Range) 73 (54-81) WHO classification of MDS/AML, N (%) RAEB-I RAEB-II RCMD-RS RCMD RARS CMML AML 9 (20.5) 18 (40.9) 2 (4.5) 3 (6.7) 1 (2.3) 4 (9.1) 7 (15.9) IPSS classification, N (%) Low Intermediate-1 Intermediate-2 High Not Applicable (AML) 0 (0) 3 (6.8) 29 (65.9) 5 (11.4) 7 (15.9) Complete Blood Count Parameters, Median (Range) Hemoglobin (g/dL) Absolute Neutrophil Count (x109/L) Platelet count (x109/L) 8.55 (4.5 - 12.5) 1.08 (0.0 – 16.3) 80.0 (2 – 820) Transfusion dependence, N (%) 39 (88.6) Transfusions per month, Median (Range) 3 (0 – 7) Table 2. Efficacy data AZA cycles, Median (Range) 5 (1-22) Actual AZA dose (mg/m2/cycle), Median (Range) 75 (59-75) Actual cycle duration (days), Median (Range) 28 (28-40) Dose reductions due to sustained neutropenia, N (%) 6 (13.6) Temporary AZA interruption, N (%) 26 (59.1) Reason Sustained cytopenia 10/26 (38.5) Neutropenic Infection 15/26 (57.7) Hemorrhagic Complication 1/26 (3.8) Permanent AZA discontinuation, N (%) 23/44 (52.3) Reason AML transformation 17/23 (73.9) Recurrent or severe infection 4/23 (17.4) Pyoderma gangrenosum 1/23 (4.3) Allogeneic Bone Marrow Transplantation 1/23 (4.3) AZA cycles till response (according to the IWG criteria), Median (Range) 4 (1 – 7) Response (IWG criteria), N (%) Complete response Partial response Stable disease Failure 7 (15.9) 8 (18.2) 29 (65.9) 0 (0) Overall survival (months), Median (Range) 13 (1 – 101) Post treatment transfusion dependence, N (%) 34 (77.3) Transfusions per month (post-treatment), Median (Range) 1 (0 – 5) Death rate, N (%) 29/44 (65.9) Cause of death, N (%) Infection Hemorrhage Cardiac dysrhythmia 24/29 (82.8) 3/29 (10.3) 2/29 (6.9) Table 3. Safety data Clinical adverse events, N (%) 29/44 (65.9) Neutropenic Infections 26/29 (89.7) Bloodstream Infection 9/26 (34.6) Lower respiratory infection 10/26 (38.5) Neutropenic Fever 8/26 (30.1) Septic shock 2/26 (7.7) Hemorrhagic events 2/29 (6.7) Cerebral hemorrhage (Grade 5) 1/2 (50.0) Epistaxis (Grade 3) 1/2 (50.0) Other (pyoderma gangrenosum) 1/29 (3.4) Laboratory incidents1, N (%) 44/44 (100) All grades Grades 3/4 Neutropenia 36/44 (81.8) 34/44 (77.3) Anemia 44/44 (100) 24/44 (54.5) Thrombocytopenia 31/44 (70.5) 21/44 (47.7) Supportive treatment (during AZA administration), N (%) GCSF administration 16/44 (36.4) Erythropoietin administration 7/44 (15.9) Red blood cell transfusions 39/44 (88.6) Red blood cell transfusions (units/cycle), Median (range) 3 (0-7) Pooled random donor platelet transfusions 17 (38.6) 1According to the CTCAE Version 4.0 Disclosures No relevant conflicts of interest to declare.
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Kulagin, Aleksandr, Olesya Klimova, Tatiana Rudakova, Irina Golubovskaya, Maria Ivanova, Anna Smirnova, Alexandra Lapina, et al. "Benefits and Limitations of Long-Term Eculizumab Treatment for Paroxysmal Nocturnal Hemoglobinuria (PNH): Real-World Data from Large Cohort Study in Russia." Blood 132, Supplement 1 (November 29, 2018): 2589. http://dx.doi.org/10.1182/blood-2018-99-120139.
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Abstract Background: Anticomplement C5 therapy with eculizumab is the standard of treatment of patients (pts) with active hemolytic PNH. However, there are few data on long-term complement inhibition efficacy and current PNH prognosis from real-world clinical practice. Objectives: The aim of this study was to evaluate long-term eculizumab efficacy and PNH outcomes in the large cohort in Russia. Methods: As of August 1, 2018, a total of 354 pts with hemolytic PNH were observed in the I.P. Pavlov First St. Petersburg State Medical University in cooperation with the local hematological service in 75 regions of Russia (n=344), as well as in Belarus, Kazakhstan, Kyrgyzstan, Ukraine, Tajikistan (n=10) (Table 1). The analysis was conducted in the whole cohort and separately in the prospective phase after November 2011 with the eculizumab availability in Russia. We analyzed indications and access to anticomplement C5 therapy according to National guidelines (2014), frequency and causes of discontinuation of therapy, cumulative incidence of independence from transfusions with allo-HSCT as competing risk, frequency of breakthrough hemolysis (BTH) and intensive extravascular hemolysis, overall survival (OS) and causes of mortality. Results: According to the current National guidelines (2014), 323 pts had at least one indication for therapy with eculizumab: thrombosis (n=89, 25 %), transfusion-dependent hemolytic anemia (n=261, 74 %), acute kidney injury (AKI, n=69, 19 %), chronic kidney disease (CKD, n=244/304, 80 %) including CKD stage ≥ 2 (n=66/304, 22 %), pulmonary hypertension (n=66/265, 25 %) and pregnancy (n=22). Due to differences in regional support for rare diseases, only 204 (63%) pts had access to therapy with eculizumab. In addition, 19 pts received novel anti-C5 agent in clinical trial and were excluded from analysis. Allogeneic HSCT was performed in 24 pts, including 2 cases of MDS/AML evolved from AA/PNH and 17 cases of severe AA/PNH with eculizumab bridging in the prospective phase. With the median duration of eculizumab therapy of 3.4 years (0.2-6.1) the independence from RBC transfusions (TI) was achieved in 109 of 154 initially transfused pts (71 %) with a cumulative incidence of 61 % (95 % CI, 52-68) and 69 % (95 % CI, 60-76) after 12 and 24 months of therapy respectively. The median hemoglobin level at last follow-up were 6.6 (4.0-9.7), 10.5 (range, 7.1-15.4) and 12.1 g/dl (8.9-14.0) in patients who did not reach the TI, who reached the TI and were never transfused, respectively (p =0.0001). BTH was documented in 36 of 184 evaluated pts (20 %), including 16 and 20 cases with and without obvious triggers respectively. Intensive extravascular hemolysis with bilirubin level > 2xULN persisted in 31 % pts. Temporary or permanent discontinuation of eculizumab treatment occurred in 58 pts due to death (n=11), allogeneic BMT (n=17), spontaneous clone reduction (n = 4), absence of new indications 6 months after delivery (n=4), and terminating access to treatment (n=22). All pts of the latter group developed a relapse of intensive intravascular hemolysis, which in 3 cases was complicated by AKI (n=1), stroke (n=1) and myocardial infarction (n=1). OS was assessed in the prospective phase after 2011. A total of 24/203 (12 %) pts died which resulted in 5-year OS of 87% (CI 95 %, 81-92). Treatment with eculizumab significantly improved OS (Fig.1). The 5-year OS rate was 91% (CI 95 %, 85-98) in pts treated with eculizumab and 74 % (CI 95 %, 63-85) in never-treated pts (p=0.0003). There were significant differences in the causes of death between pts receiving and not receiving eculizumab: related to thrombosis 1/7 (14 %) vs 9/17 (53 %), AA and MDS 4/7 (57%) vs 5/17 (29 %). Conclusions: The results of the study show both the high efficacy and limitations of treatment with eculizumab for PNH in real-world practice. Prospectively confirmed significant improvement of the overall survival on eculizumab stress the need for faster and wider access to costly therapy. Nevertherless, a number of limitations, including BTH and extravascular hemolysis, lack of control of bone marrow failure and further clonal evolution, determine the relevance of next-generation complement inhibitors and risk-adjusted allogeneic HSCT as a curative option. Disclosures Kulagin: Alexion Pharmaceuticals, Inc: Consultancy, Honoraria.
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Falchi, Lorenzo, Michael J. Keating, Susan Lerner, Xuemei Wang, Sara S. Strom, William G. Wierda, and Alessandra Ferrajoli. "Other Cancers in Patients with Chronic Lymphocytic Leukemia Requiring Therapy: Association with Prognostic Factors and Impact On Survival." Blood 120, no. 21 (November 16, 2012): 3896. http://dx.doi.org/10.1182/blood.v120.21.3896.3896.
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Abstract Abstract 3896 Chronic lymphocytic leukemia (CLL) is associated with an increased incidence of other cancers (OC). Potential risk factors for OC in CLL include immune disturbances, shared risk factors, genetic predisposition and chemotherapy. While reports on OC in patients with CLL have been typically descriptive in nature, detailed information regarding the clinical features of OC, relationship with the time of diagnosis of CLL, patient characteristics, prognostic factors and survival have been missing. We report an analysis of OC in pts with CLL requiring therapy, with a post therapy observation time of 5 years or longer. We reviewed our database and selected pts with CLL seen at our center who underwent treatment and who have a follow-up of at least 5 years after therapy. We studied pts with an OC either before or after the diagnosis and/or treatment of CLL and compared them with patients without OC. Richter's transformation of CLL was not considered an OC in this analysis. A total of 1,364 pts with CLL referred between 1963 and 2007 with a median follow up time of 8.2 years (range 5–28) were studied. Among these, we identified 324 pts (24%) with OC. Sixty-eight pts were diagnosed with >1 OC [2 OC (62 pts), 3 OC (4 pts) or 4 OC (2 pts)], for a total of 400 individual OC. Of the 324 pts with OC, OC preceded the diagnosis of CLL in 117 pts (36%), with a median time from OC to CLL of 80 (0–455) months, OC occurred after the diagnosis of CLL but before treatment in 49 pts (15%), with median time from CLL to OC of 22 (0–131) months. OC occurred after treatment of CLL in 158 pts (49%), with a median time from treatment to OC of 94 (0–304) months. The type, frequency and timing of OC are summarized in table 1. Clinical characteristics and traditional prognostic factors were not significantly different between pts with and without OC, with the exception of age, as pts with OC are older than pts without OC at the time of referral (median age: 60 vs 55 years, p<.0001). We next analyzed the distribution of the newer prognostic parameters in these two groups. Fifty-three % of pts with OC had unmutated IGHV genes, 65% were ZAP70+, 22% CD38+, 8% had del17p, 27% del11q, 22% +12, 20% negative FISH, and 23% del13q. Sixty-one % of pts without OC had unmutated IGHV genes, 58% were ZAP70+, 26% CD38+, 6% had del17p, 17% del11q, 22% +12, 26% negative FISH, and 29% del13q. A trend toward significance (p.07) for a higher incidence of del11q was observed in pts with OC. At the time of this analysis 536 (39%) pts have died and 828 (61%) are alive. One hundred seventy six/324 (54%) pts with OC are alive, vs 652/1040 (63%) pts without OC (p<.007). Median overall survival (OS) has not been reached in either pt group at a median follow up of 95 (61–284) months for pts with OC and 98 (61–340) months for pts without OC. Causes of death were: progression of CLL (99), CLL-related complications (121), OC (43), complications of stem cell transplant (16), events unrelated to CLL (39) and unknown causes (218). In pts with OC, the OC itself was the cause of death in 37%. Other causes of death were CLL/CLL-related complications in 44%, complications of stem cell transplant in 8%, and events unrelated to CLL in 11%. In contrast, in pts without OC CLL/CLL-related complications accounted for 83% of deaths, complications of stem cell transplant for 4%, and events unrelated to CLL for 13%. In conclusion, in pts with CLL requiring therapy and with post therapy follow up of >5 years, the incidence of OC is 24%. Among pts with OC, there is a trend for higher number of pts with del11q. In pts with OC, OC itself is a major cause of death, while the vast majority of deaths among pts without OC are caused by CLL or CLL-related complications. Table 1. Distribution of OC (1364 pts). Site of OC 1st case Total cases OC prior/at CLL OC after CLL After diagnosis After treatment NMSC1 124 144 41 26 77 PROSTATE 43 54 18 7 29 MELANOMA 26 34 16 2 16 BREAST 23 26 14 2 10 MDS/AML2 16 18 0 0 18 LUNG 14 21 0 1 20 NEUROENDOCRINE 3 6 1 0 5 HEAD AND NECK 12 16 3 2 11 UROTHELIAL CELL CANCERS 11 12 7 2 3 GI3 (including pancreas and liver) 10 18 4 3 11 KIDNEY 10 11 4 3 4 NHL4 and MM5 8 12 0 0 12 TESTIS/OVARY 6 6 4 0 2 THYROID 6 7 5 1 1 SARCOMAS 4 5 4 0 1 UTERUS 2 3 3 0 0 OTHERS6 6 7 3 0 4 TOTALS 324 400 127 49 224 1 non-melanoma skin cancers; 2 myelodysplastic syndrome/acute myeloid leukemia; 3 gastrointestinal; 4 non-Hodgkin's lymphoma; 5 multiple myeloma; 6 includes: brain, nasopharyngeal, penis carcinoma, mesothelioma, unknown primary. Disclosures: No relevant conflicts of interest to declare.
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Acevedo, Jose, Gheorghe Doros, Raphael Szalat, John Mark Sloan, Shayna Sarosiek, and Vaishali Sanchorawala. "Clinical Characteristics, Treatment Regimens and Survival in Elderly Patients with AL Amyloidosis in a Tertiary Referral Center." Blood 134, Supplement_1 (November 13, 2019): 5447. http://dx.doi.org/10.1182/blood-2019-124980.
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Background AL amyloidosis is the most common form of systemic amyloidosis, characterized by an associated plasma cell dyscrasia leading to extracellular fibril deposition causing organ dysfunction. In these patients there is a fine balance between treatment toxicities and tolerability due to frailty and presence of multiorgan involvement. This balance is increasingly recognized in the elderly but treatment and outcomes have not been systematically studied, where co-morbidities and frailty may compound morbidity and mortality. Methods A retrospective analysis of all patients 70 years or older who were evaluated at the Boston University (BU) Amyloidosis Center from 2000 until 2018 was performed to determine demographics, clinical characteristics, treatments and outcome measures. Kaplan Meier method was used to perform an overall survival (OS) of all patients from the time of diagnosis. Further analysis of OS was performed based on whether treatment was received before or after 2010 (when proteasome inhibitors were incorporated in the treatment algorithm for AL amyloidosis), whether administered treatment regimens consisted of proteasome inhibitors (PI), and whether or not treatment with high dose melphalan and stem cell transplantation (HDM/SCT) was received. Results A total of 342 patients with AL amyloidosis who were older than 70 years of age at the time of diagnosis had their initial evaluation at BU Amyloidosis Center from 2000 to 2018. There were 215 (63%) men. The median age was 74 years (range, 70 - 90), and 55 (16%) were older than 80 years of age. The majority of patients were Caucasians (90%). The median number of organs involved by AL amyloidosis was 2 (range, 1- 7). The most common organ involvement was renal in 229 patients (68.3%), followed by cardiac in 167 patients (48.8%), and neurologic in 98 (29.2%). The majority of patients had renal stage II disease and BU cardiac stage II disease. Of the 342 patients, 223 (65%) received systemic treatment, the remainder (35%) received only supportive treatment. The median number of chemotherapy regimens administered was 1 (range 1-5), 116 patients (52%) received one regimen, 81 (36.1%) received two regimens, 35 (15.6%) patients received more than three treatment regimens. Of the 342 patients, 32 (9.4%) received treatment with HDM/SCT. The median age of patients undergoing HDM/SCT was 71 years (range, 70-75). The median overall survival was 3.4 years (95% CI 2.9-4.1) with a median follow-up of 2.6 years (range, 0.02-15.2). The median OS of patients treated with PI based therapy was 6.0 years vs 3.7 years for those not treated with PI based regimens (p=0.01) (Figure 1). The median OS of patients was 6.8 years for patients treated with HDM/SCT and 4.0 years for those not receiving HDM/SCT (p=0.08). Moreover, the median OS of patients diagnosed prior to 2010 was 3.4 years which is similar to 3.9 years for those diagnosed after 2010 (p=0.07). Conclusion In summary, the presentation of elderly patients with systemic AL amyloidosis is similar to that of younger patients in general. There are a higher proportion of patients with advanced cardiac and renal stage disease, perhaps reflecting delay in diagnosis. Compared to supportive care, overall survival in those receiving a PI based therapy is better with respect to survival, although this may reflect selection bias. In addition, HDM/SCT can be offered to highly selected patients with age older than 70 years. Prospective studies in older patients with novel agents with a better toxicity profile and ease of administration may allow a greater proportion of patients to benefit from treatment. Figure 1 Disclosures Sloan: Merck: Other: endpoint review commitee; Stemline: Consultancy; Abbvie: Other: Endpoint Review Committee. Sarosiek:Acrotech: Research Funding. Sanchorawala:Proclara: Consultancy, Honoraria; Caelum: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Celgene: Research Funding; Takeda: Research Funding.
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Jurado Quijano, G., L. Fernández de la Fuente Bursón, B. Hernández-Cruz, P. Muñoz Reinoso, V. Merino Bohóquez, and J. J. Pérez Venegas. "AB0213 SAVING GLUCOCORTICOIDS AFTER RITUXIMAB TREATMENT IN PATIENTS WITH REUMATOID ARTHRITIS. ANALYSIS OF A COMMON CLINICAL PRACTICE COHORT." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1132.3–1133. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1362.
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Background:Rituximab (RTX) is a monoclonal antibody against the CD20 B cell antigen that has been used successfully in recent years for the treatment of rheumatoid arthritis (RA). It is an effective drug that reaches survival rates of 60% at 5 years of treatment as reflected in the British experience. However, survival in Spanish patients is unknown.Objectives:To study the survival of RTX treatment and the characteristics of patients with RA treated with the drug since its commercialization in Spain.Methods:Observational, retrospective and analytical study of a cohort of patients with RA treated with at least one dose of RTX. We reviewed the medical records of all patients with RA from January 2007 to June 2017. A total of 178 previous defined variables were collected, highlighting data about treatment (use of RTX, associated conventional synthetic disease modifying drugs [FAMEsc], doses of corticosteroids [GC] used) and activity indices. Descriptive statistics were performed (median and the 25th and 75th percentiles are shown). The comparative analysis was done with χ2 and U of Mann Whitney for categorical variables and paired sign rank test or Student’s t for continuous. Survival Kaplan Mayer curves were constructed. The study was carried out in accordance with the standards of our Clinical Research Ethics Committee.Results:A total of 54 patients were analyzed. 74% (n = 40) of them were women, the age was 61.2 years (51.0 - 67.4). 74% (n = 40) presented some type of relevant comorbidity. Its RA was FR + in 96% (n = 52) and ACCP + in 78% (n = 42) of the cases, with an evolution time of 9.3 years (3.5-19, 2), and with radiographic erosions in up to 63% (n = 34). At the time of the start of the RTX, 100% of the patients (n = 54) received some FAMEsc, and 33 (61%) were treated with prednisone; the daily dose of prednisone was 9 (6-12) mg. The baseline DAS28-VSG was 5 (4.1 - 6.0). The duration of the follow-up was 56.6 (29.3-92.1) months. Patients received a mean of 5 (1-6) cycles of RTX at a dose of 1000 mg on days 0 and 15 in most cases. The final DAS28-VSG was 2.6 (2.1 - 4.0), p = 0.00001 compared to baseline. The delta between baseline and final DAS was -2.36 (-0.55 - -3.1). At the end of the RTX treatment, the EULAR response rate was good in 64% (n = 25), reaching remission in 17 (31%) of the patients, and moderate response in 21% (n = 8) of them (Figure 1). Only 2 (4%) patients were treated with GCC at the end of the follow-up, p<0,00001 compared to baseline. The daily dose of PDN at the end of follow-up was 6 mg in a case and 12 mg in the other, p=00001 compared to baseline. At the end of the follow-up 24%of the patients (n = 13) changed or discontinued the drug: 9 changed due to secondary failure, 2 suspended due to adverse events, 1 due to death due to prior neoplastic process and 1 due to complete disease remission. Survival at 1, 2, 3, 4, 5, 6 and 7 years was 92%, 92%, 82% 78%, 75%, 75% and 65% respectively; with a mean survival rate of 90 months (Figure 1).Conclusion:The results of our analysis show that patients with RA undergoing RTX treatment have adequate control of disease activity and drug survival rates, like published data. RTX treatment allowed stopped GCC treatment in 31 cases (90%).References:[1]Oldroyd AGS, et al. Rheumatology (Oxford). 2018 Jun 1;57(6):1089-1096.Disclosure of Interests:Gonzalo Jurado Quijano: None declared, Lola Fernández de la Fuente Bursón: None declared, Blanca Hernández-Cruz Speakers bureau: Sociedad Española de Reumatología, Abbvie, Roche, Bristol, MSD, Lilly, Pfizer, Amgen, Sanofi, Consultant of: Abbvie, Lilly, Sanofi, STADA, UCB, Amgen, Grant/research support from: Fundación para la Investigación Sevilla, Junta de Andalucía, Fundación Andaluza de Reumatología, Paloma Muñoz Reinoso: None declared, Vicente Merino Bohóquez: None declared, José Javier Pérez Venegas: None declared
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Dacosta Byfield, Stacey, Nicole Engel-Nitz, Timothy Bancroft, Amy J. Anderson, Carolina Reyes, Arliene Ravelo, Sarika Ogale, May Chen, and Matthew J. Matasar. "Differences in Patients with Progressive Versus Non-Progressive AML, CLL, or NHL: Implications for Proposed Bundled Payment Strategies." Blood 126, no. 23 (December 3, 2015): 4528. http://dx.doi.org/10.1182/blood.v126.23.4528.4528.
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Abstract Background: Increasingly, payers are redefining how payments for cancer care are structured. Demonstration programs and policy proposals by insurers and oncology organizations have bundled payments for various services, including chemotherapy. The impact of such payment policies may vary for patients (pts) with hematologic malignancies given their widely varying disease severity. Progression of disease (PD), and costs associated with it, may stress bundled payment programs, particularly if such programs do not accurately assess risk of progression across the insured cohort. To inform this ongoing development of new payment strategies for pts with hematologic malignancy, this study compared patterns of care in pts with AML, CLL or other forms of NHL who do, or do not, experience PD. Methods: This retrospective studyused medical and pharmacy claims from a large national US health plan to identify commercially insured and Medicare Advantage (MA) pts age ≥18 years from 1/2007 - 8/2014 with ≥2 medical claims for AML (ICD-9-CM code 205.0x), CLL ( ICD-9-CM code 204.1x), or other NHL (ICD-9-CM codes 200.xx, 202.0x-202.2x, 202.4x, 202.7x-202.9x, 203.8x, 204.8x-204.9x, 273.3x). Pts required ≥1 claim for systemic anti-cancer therapy (SACT); the first observed claim was the index date. Continuous enrollment (CE) in the health plan for 6 months (mths) prior to (baseline period) and ≥6 mths after index date (variable follow-up period) was required; pts with <6 mths of follow-up due to death were included. Pts with baseline SACT or additional primary malignancies were excluded. Line of therapy (LOT) periods were defined. The 1st LOT (LOT1) started on index date; regimens included all drugs received in the first 45 days. LOT1 ended at the earliest of: start of a new drug, ≥60-day gap in initial regimen, death or end of CE or study period. LOT2 started with a SACT after LOT1 end. PD was defined as: start of LOT2, receipt of hospice care (based on procedure or revenue codes) or death (based on Social Security Administration death data). Results: Among 667 AML, 1354 CLL and 9399 NHL pts who met study criteria, 70%, 45%, and 46% respectively had PD during the study period. Mean (median) time in mths to PD was 6.6 (4.2) for AML, 12.8 (9.2) for CLL and 10.0 (7.1) for NHL. Descriptive results are shown in the Table. Compared to pts without PD during the study period, pts who progressed were MA pts, older and had shorter initial LOTs. The most common initial therapy varied across PD cohorts. Among pts with PD, the AML cohort had the highest percentage of death and evidence of hospice care. Conclusion: Characteristics and treatment patterns varied for pts with PD versus non-PD AML, CLL and NHL. Understanding the variability across patient groups will aid in the development of new bundled payment policies and help providers determine whether and in which payment systems to participate. Table 1. AML CLL NHL PD N=464 No PD N=203 PD N=604 No PD N=750 PD N=4291 No PD N=5108 Age, yrs mean (SD), median^# 60 (17), 62 58 (17), 59 71 (11), 72 67 (11), 67 64 (14), 65 60 (16), 62 Baseline Quan-Charlson comorbidity score mean (SD), median# 3.1 (1.6), 2 3.1 (1.6), 2 2.8 (1.3), 2 2.7 (1.2), 2 3.4 (2.0), 3 3.3 (1.9), 2 Male, N (%)# 271 (58) 115 (57) 366 (61) 490 (65) 2480 (58) 2832 (55) Insurance, N (%)*^# Commercial 300 (65) 148 (73) 284 (47) 428 (57) 2,723 (63) 3489 (68) MA 164 (35) 55 (27) 320 (53) 322 (43) 1568 (37) 1619 (32) Stem Cell Transplant, N (%) 105 (23) 61 (30) 11 (2) 5 (1) 443 (10) 169 (3) Length of follow-up, mths, mean (SD), median ^# 17.6 (17.1), 12.1 19.9 (15.5), 14.4 28.6 (21.4), 23.7 22.4 (15.9), 17.2 28.2 (21.5), 22.3 27.2 (19.9), 20.9 Length of LOT1, mths, mean (SD), median *^# 3.8 (4.3), 2.5 5.4 (6.5), 3.5 3.6 (4.0), 2.8 4.8 (4.0), 4.3 4.1 (3.6), 3.6 5.2 (5.1), 4.5 Monotherapy in LOT1*^# 322 (69) 158 (78) 371 (61) 272 (36) 1623 (38) 1254 (25) Biologic in LOT*^# 136 (29) 38 (19) 384 (64) 603 (80) 3523 (82) 4066 (80) Most common LOT1 regimens (%)┼ 1st aza (19) cyt (17) R (24) FCR (23) R (26) RCHOP (39) 2nd dec (15) dec (17) chl (19) BR (21) RCHOP (25) R (14) 3rd cyt (9) aza (17) FCR (12) R (16) RCVP (9) BR (7) Hospice, N (%) 124 (27) - 74 (12) - 664 (15) - Died, N (%) 204 (44) - 177 (29) - 1040 (24) - *^# p<0.05 for AML, CLL and NHL progression cohorts respectively ┼no testing Aza-azacitadine, B-bendamustine, C-cyclophosphamide, chl-chlorambucil, cyt-cytarabine, dec-decitabine, F-fludarabine, R-rituximab, V-vincristine RCHOP=R,C,V,doxorubicin±prednisone RCVP=R,C,V±prednisone Disclosures Dacosta Byfield: Optum: Employment. Engel-Nitz:United Health Group: Equity Ownership; Optum: Employment. Bancroft:Optum: Employment; United Health Group: Equity Ownership. Anderson:Optum: Employment; United Helath Group: Equity Ownership. Reyes:Genentech: Employment; Roche: Equity Ownership. Ravelo:Roche: Equity Ownership; Genentech, Inc.: Employment. Ogale:Roche: Equity Ownership; Genentech, Inc.: Employment.
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Mueller, Niklas, Daniel Wicklein, Gregor Eisenwort, Juliana Schwaab, Mohamad Jawhar, Alexandra Boehm, Harald Herrmann, et al. "Identification of CD44 As a RAS-MEK-Regulated Invasion Receptor That Is Overexpressed in Neoplastic Mast Cells and Triggers Disease Expansion in Advanced Systemic Mastocytosis." Blood 128, no. 22 (December 2, 2016): 1955. http://dx.doi.org/10.1182/blood.v128.22.1955.1955.
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Abstract CD44, also known as Hermes antigen, is a multifunctional invasion receptor that mediates homing and expansion of normal and neoplastic stem- and progenitor cells in various organs including the bone marrow (BM). Mast cells (MC) and their progenitors also express CD44. However, little is known about the impact and regulation of CD44 in neoplastic cells in systemic mastocytosis (SM). We examined the expression, regulation, and functional role of CD44 in neoplastic cells in SM. As assessed by multi-color flow cytometry, CD34+/CD38- stem cells (SC), CD34+/CD38+ progenitor cells (PC), and KIT+/CD34- MC invariably expressed CD44 in all SM variants, including patients with indolent SM (ISM, 11/11), SM with associated hematologic neoplasm (SM-AHN, 7/7), aggressive SM (ASM, 3/3), and MC leukemia (MCL, 8/8). Expression of CD44 on SC, PC, and MC increased significantly with the aggressiveness of SM. Moreover, soluble CD44 levels measured in the sera of patients with SM by ELISA were found to correlate with the WHO type of SM. In particular, significantly higher levels of soluble CD44 were measured in advanced SM compared to ISM, cutaneous mastocytosis (CM), or healthy controls (p<0.05). In addition, all human MC lines examined, including HMC-1.1, HMC-1.2, ROSAKIT WT, ROSAKIT D816V, MCPV-1.1, MCPV-1.2, MCPV-1.3, and MCPV-1.4 expressed cytoplasmic and cell surface CD44. To study the mechanisms underlying CD44 expression on MC, we applied various targeted drugs. Incubation with the demethylating agents decitabine (0.1-5 µM) or 5-azacytidine (0.1-5 µM) for 96 hours resulted in a dose-dependent upregulation of CD44 surface expression compared to baseline levels (100%) in all MC lines examined (decitabine, 5 µM: 210±50% in HMC-1.1, 294±76% in HMC-1.2, 236±56% in ROSAKIT WT, 210±54% in ROSAKIT D816V, 242±47% in MCPV-1.1, 179±23% in MCPV-1.2, 207±17% in MCPV-1.3, and 152±5% in MCPV-1.4 cells, p<0.05; 5-azacytidine, 5 µM: 355±104% in HMC-1.1, 429±105% in HMC-1.2, 412±135% in ROSAKIT WT, 292±136% in ROSAKIT D816V, 365±55% in MCPV-1.1, 345±106% in MCPV-1.2, 325±87% in MCPV-1.3, and 278±38% in MCPV-1.4 cells, p<0.05). In contrast, incubation with the MEK-inhibitor refametinib (RDEA119) (0.1-5 µM) or the STAT5 blocker pimozide (2.5-10 µM) for 48 hours resulted in a dose-dependent downregulation of CD44 surface expression compared to baseline levels (100%) in all MC lines examined (refametinib, 2.5 µM: 71±9% in HMC-1.1, 82±3% in HMC-1.2, 33±13% in ROSAKIT WT, 31±3% in ROSAKIT D816V, 62±6% in MCPV-1.1, 82±13% in MCPV-1.2, 84±5% in MCPV-1.3, and 87±1% in MCPV-1.4 cells, p<0.05; pimozide, 7.5 µM: 59±7% HMC-1.1, 68±3% in HMC-1.2, 62±16% in ROSAKIT WT, and 80±3% in ROSAKIT D816V, 62±5% in MCPV-1.1, 72±4% in MCPV-1.2, 73±4% in MCPV-1.3, and 63±9% in MCPV-1.4 cells, p<0.05). These data suggest that the RAS/MEK pathway and the STAT5 pathway are involved in expression of CD44 in neoplastic MC. In order to confirm this hypothesis we transduced HMC-1.2 cells and ROSAKIT WT cells with KRASWT or oncogenic KRASG12V. In all transduced cell lines, KRAS overexpression resulted in upregulation of CD44 surface expression compared to empty vector (100%) (HMC-1.2: 143±17% with KRASWT, 249±53% with KRASG12V, p<0.05; ROSAKIT WT: 170±13% with KRASWT, 403±64% with KRASG12V, p<0.05). As expected, refametinib was found to suppress RAS-induced CD44 expression in these cells. To study the functional role of CD44 in neoplastic MC, we employed a mouse xenotransplantation model using severe combined immunodeficient (SCID) mice, HMC-1.2 cells, and shRNA against CD44. In this model, the shRNA-induced knock-down of CD44 in HMC-1.2 cells resulted in reduced MC expansion, reduced tumor formation, delayed ulceration, and prolonged survival compared to cells transduced with control shRNA (median survival in the CD44 shRNA group: 110 days vs 97 days in the control group, p<0.05). The formation of lung metastasis, quantified by human Alu-sequence-specific qPCR, was found to be particularly decreased (15-fold) in the CD44 knock-down group compared to control mice. In conclusion, CD44 is expressed in neoplastic MC as well as in neoplastic stem- and progenitor cells in patients with advanced SM. Our data also suggest that CD44 is an important mediator of evolution and of malignant spread of neoplastic MC into various organs in SM. Future studies will show whether CD44 can serve as a therapeutic target in patients with advanced SM. Disclosures Hoermann: Gilead: Research Funding; Novartis: Honoraria; Amgen: Honoraria; Ariad: Honoraria. Sperr:Novartis: Honoraria; Amgen: Honoraria, Research Funding. Arock:Agensys, Inc: Research Funding. Valent:Ariad: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria; Deciphera Pharmaceuticals: Research Funding; Celgene: Honoraria, Research Funding.
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Hutcheson, Laurie B., Janice Axelrod, Colleen L. Fitzwater, Maxine S. Jochelson, Gitte H. Joergensen, Theresa Langdon, Julia K. Levine, Otto Metzger, Mason Mitchell-Daniels, and Barbara F. Neilsen. "Abstract P3-15-03: Imaging and invasive lobular carcinoma: A survey study conducted by the lobular breast cancer alliance." Cancer Research 82, no. 4_Supplement (February 15, 2022): P3–15–03—P3–15–03. http://dx.doi.org/10.1158/1538-7445.sabcs21-p3-15-03.
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Abstract Background: The Lobular Breast Cancer Alliance (LBCA) is an advocacy organization guided by an expert advisory board. Since it launched in 2017, LBCA has been committed to raising awareness of the distinct aspects of invasive lobular carcinoma (ILC) and promoting ILC research. While ILC is the second most common histological breast cancer type representing 15% of breast cancer diagnoses in the United States annually, it is understudied compared to the more common invasive ductal carcinoma (IDC). ILC tumor cell density and lack of desmoplastic stromal reaction can pose challenges to detection by physical examination and mammography. Many studies have shown decreased accuracy of breast imaging tools for ILC, and those with ILC are often diagnosed at later stages and require more extensive surgery. We sought to hear from members of the LBCA community with ILC about their experiences with detection of their tumors. Methods: LBCA conducted an anonymous survey online. A link to the survey on the SurveyMonkey platform was made available for two weeks in June. It was sent to LBCA newsletter subscribers and posted to the LBCA website and ILC social media groups. The survey questions included stage and size of tumors at initial diagnosis and after surgery, and questions related to imaging for advanced ILC. It specifically asked whether and what type of mammogram initially detected the ILC. Results: Within 24 hours over 1,000 people responded, and a total of 1,476 people previously diagnosed with ILC responded by survey close. The majority of participants, 1,052 (72%), were from the US, followed by participants from 35 additional countries. 170 (12%) reported having metastatic ILC. 1,035 (70%) of respondents were under 60 at diagnosis. Of respondents reporting tumor size and stage, 936 (67%) of respondents indicated having a tumor larger than 2cm at diagnosis, and 897 (63%) reported stage 2 or higher, including 73 (5%) reporting stage 4 at initial diagnosis. In the subset of participants initially diagnosed with stage 2 or higher, 410 (46%) of respondents reported the tumor was not detected by mammogram. In the subset of participants who noticed changes in their breasts prior to the diagnosis, 521 (79%) had tumors larger than 2cm, and 490 (74%) were diagnosed at stage 2 or higher. Of the 1,241 respondents who had no preoperative therapy, 531 (43%) had tumors larger than initially seen on imaging and/or 321 (26%) had more tumors than initially found on imaging. Discussion: To the best of our knowledge this represents the largest survey seeking to understand patients’ experience with imaging to diagnose or visualize ILC. The results from this community survey of patients diagnosed with invasive lobular carcinoma confirmed patients’ perceptions of mammography as an imperfect screening tool to detect ILC. Of note were the findings that mammography failed to visualize 46% of ILC cases at stage 2 or higher, and the majority of respondents had tumors diagnosed/detected at stage 2 or higher and at sizes greater than 2cm. Moreover, participants often reported that the actual tumor size on the final pathology specimen was larger than seen on diagnostic imaging, and a significant number of respondents were diagnosed de novo metastatic. In summary, our findings affirm patients’ perception about the limitations of diagnostic and monitoring imaging of ILC. Our impressively large response also demonstrates the urgent need from patients’ perspectives for more research on better methods for detecting and monitoring ILC to improve outcomes for patients diagnosed with lobular disease. Citation Format: Laurie B Hutcheson, Janice Axelrod, Colleen L Fitzwater, Maxine S Jochelson, Gitte H Joergensen, Theresa Langdon, Julia K Levine, Otto Metzger, Mason Mitchell-Daniels, Barbara F Neilsen. Imaging and invasive lobular carcinoma: A survey study conducted by the lobular breast cancer alliance [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P3-15-03.
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Jakubowiak, Andrzej, Tara Kendall, Ammar Al-Zoubi, Yasser Khaled, Shin Mineishi, Christine Brozo, Erica Campagnaro, Moshe Talpaz, and Mark S. Kaminski. "Initial Treatment with Bortezomib (Velcade®), Doxil®, and Dexamethasone (VDD) Is Superior to Thalidomide and Dexamethasone (TD) as Initial Therapy Prior to Autologous Stem Cell Transplantation (ASCT) for Multiple Myeloma (MM)." Blood 112, no. 11 (November 16, 2008): 3713. http://dx.doi.org/10.1182/blood.v112.11.3713.3713.
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Abstract A number of novel combinations used in initial therapy of myeloma show improved overall response (OS) and complete and near complete response (CR/nCR) rates. However, it is not clear if improved responses impact the results after the subsequent ASCT and the overall outcome of MM therapy. To address this issue, we performed a retrospective analysis of patients with symptomatic myeloma who were initially treated with TD (N= 31) or VDD (N =30) followed by ASCT, as part of 2 consecutive clinical studies conducted at the University of Michigan Cancer Center. From July 2003 to May 2005, 31 pts were enrolled in a phase II study of treatment of newly diagnosed myeloma with initial therapy using three 5-week cycles of TD. Thalidomide was given daily starting at 50 mg/d up to 400 mg/d and dexamethasone at 40 mg on days 1–4, 9–12, and 17–20. The outcomes were compared with 30 pts who were enrolled from July 2005 to January 2007 in a phase II trial of initial therapy with six 3-week cycles of VDD regimen. VDD included Velcade at 1.3 mg/m2 on days 1, 4, 8, and 11, Doxil at 30 mg/m2 on day 4, and Dexamethasone at 40 mg on days 1–4 in the first 10 pts and 40 mg (cycle 1) then 20 mg (cycle 2–6) Dexamethasone on days of Velcade and the day after in the remaining patients. There were no significant differences in eligibility criteria between both studies. The characteristics of pts in the TD vs. VDD trial were as follows: median age 57 (26–65) vs. 58 (38–71), stage III in 23 vs. 27 pts, ch13 del in 12 vs. 13 pts, and median beta2-microglobulin 3.1 vs. 4.6. Best response to initial therapy (≥PR by modified EBMT criteria) was observed in 80% of pts treated with TD vs. 93% with VDD, CR/nCR in 10% treated with TD vs. 40% with VDD, ≥ very good partial response (VGPR) in 29% treated with TD vs. 63% with VDD (P < 0.01). Grade 3–4 toxicities related to TD included DVT/PE in 5 pts, constipation in 2, CHF in 2, and diabetes in 2. Three pts were removed from the TD study due to toxicities, and 1 died of unexplained cause. Grade 3–4 toxicities during VDD therapy included 4 pts with fatigue, 2 with DVT/PE, 2 with hand-foot syndrome, 1 with pneumonia. There was no death on VDD therapy. In the TD group, 27/27 patients collected median 8.8 × 106 CD34+ cell/kg and 27 completed at least a single ASCT (21 tandem, 6 single). In VDD group, 30/30 collected median 7.5 × 106 CD34+ cell/kg and 28 completed at least a single ASCT (17 tandem, 12 single, 1 single then reduced intensity allo). For pts initially treated with TD, 74 % achieved ≥PR, 48% ≥VGPR and 29% CR/nCR at 3 months after the completion of ASCT. For patients initially treated with VDD, response rates at 3 months post transplant were significantly better with ≥PR in 87%, ≥VGPR in 77%, and CR/nCR in 57% of pts (P ≤ 0.01). After a median follow-up of 49.75 (TD) and 23.8 (VDD) months, progression-free survival (PFS) is 27 months in TD group and not reached in VDD group, with 2 year PFS 53% in TD group and 83% in VDD group (P < 0.01). OS is not reached in both groups with 2 year OS slightly better (NS) in VDD (92%) compared to TD (85%). Based on these observations, it appears that high CR/nCR and VGPR rates in response to initial treatment with VDD persist post transplant, resulting in an improved probability of longer progression-free survival and possibly overall survival. Updated survival curves will be presented at the meeting.
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Murchison, D., and W. H. Griffith. "High-voltage-activated calcium currents in basal forebrain neurons during aging." Journal of Neurophysiology 76, no. 1 (July 1, 1996): 158–74. http://dx.doi.org/10.1152/jn.1996.76.1.158.
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1. Both conventional whole cell and perforated-patch voltage-clamp recordings were made of high-voltage-activated (HVA) calcium (Ca2+) channel currents in acutely dissociated medical septum and nucleus of the diagonal band neurons from young (1-3.5 mo) and aged (19-26.5 mo) Fischer 344 rats. Barium (Ba2+) was used as the charge carrier to minimize secondary Ca(2+)-induced conductances and Ca(2+)-induced inactivation. 2. When HVA currents generated by voltage ramps from a holding potential (Vh) of-60 mV were recorded within minutes after whole cell formation, no change in peak current density was observed between young (-44.7 +/- 2.5 pA/pF, mean +/- SE, n = 93) and aged (-44.2 +/- 2.1 pA/pF, n = 86) cells. However, currents recorded later with voltage step protocols revealed a reduction in peak current amplitudes and a trend toward larger peak current densities in aged cells. From a Vh of -60 mV and with steps to -10 mV, current densities were -21.5 +/- 1.9 pA/pF in young cells (n = 55) and -25.0 +/- 2.0 pA/pF in aged cells (n = 44). The differences in current densities recorded by the two protocols were explained by nonspecific current rundown and the development of a slow (min) inactivation process. Slow inactivation was different from conventional rundown of HVA currents because it was reversible with the use of perforated-patch recordings. 3. Perforated-patch recordings were used to characterize slow inactivation. There was significantly less slow inactivation in aged cells. When voltage steps (200 ms in duration, from -80 to -10 mV) were delivered at 12-s intervals, slow inactivation reduced the current after 15 min to 63 +/- 7% of control in young cells and 86 +/- 4% in aged cells (P = 0.028). When voltage steps were delivered at 20-s intervals, the current at the 15th step decreased to 93.4 +/- 1.5% of control in aged cells, compared with 86.6 +/- 1.6% in young (P = 0.007). There was less slow inactivation with increased intervals between voltage steps and with shorter step durations. There was also less inactivation with reduced concentration of charge carrier, indicating a current-dependent component to slow inactivation. Additionally, a voltage-dependent component was evident, because slow inactivation was increased at depolarized VhS. 4. Perforated-patch recordings were used to study at least four pharmacologically distinct fractions of HVA currents in both young and aged cells. Nifedipine (10 microM) blocked 16.9 +/- 2.8% and 23.6 +/- 2.5% of the HVA currents in young and aged cells, respectively. omega-Conotoxin GVIA (500 nM) blocked 53.2 +/- 5.8% in young and 53.6 +/- 2.9% in aged cells. In young cells, omega-agatoxin IVA (200-400 nM) blocked 28.4 +/- 2.2% of the HVA current, and it blocked 29.9 +/- 2.8% in aged cells. A fraction of the current (young cells: 13.8 +/- 2.2%; aged cells: 11.4 +/- 1.6%) was resistant to a combination of all three antagonists. Cadmium (100 microM) completely blocked the remaining HVA current. No significant age-related differences in the HVA current fractions were observed. 5. The HVA current density, current-voltage relationship, and voltage-dependent activation were unchanged with age. However, slow inactivation of HVA currents was reduced in aged cells. The age-related difference in HVA Ca2+ currents reported here suggests a possible mechanism by which Ca2+ homeostasis may be altered in aged neurons.
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Gubar, E. E., Y. L. Korsakova, E. Yu Loginova, T. V. Korotaeva, E. A. Vasilenko, A. A. Vasilenko, N. A. Kuznetsova, I. M. Patkikeeva, and E. L. Nasonov. "Nail disease in psoriatic arthritis. Data from the Russian Psoriatic Arthritis Registry." Rheumatology Science and Practice 59, no. 5 (October 31, 2021): 563–70. http://dx.doi.org/10.47360/1995-4484-2021-563-570.
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Objective of the study – to compare, in real clinical practice, according to the data of the Russian Psoriatic Arthritis Registry, characteristics of two groups of psoriatic arthritis (PsA) patients: with and without nail psoriasis.Material and methods. 588 PsA patients (277 males and 311 females) with PsA according to CASPAR criteria were included in the Russian Psoriatic Arthritis Registry. Patients’ age was 48.6±0.5 years, disease duration – 7.0±0.3 years. Patients underwent standard clinical examination of PsA activity. Disease activity measures evaluated in this study included DAPSA (Disease Activity in Psoriatic Arthritis), BASDAI (Bath Ankylosing Spondylitis Disease Activity Index) and ASDAS-СRP (Ankylosing Spondylitis Disease Activity Score). Enthesitis was measured using LEI (Leeds Enthesitis Index) index. Dactylitis was detected, the number of digits with acute dactylitis was defined. Skin lesion severity was evaluated in terms of BSA (Body Surface Area) affected, and PASI (Psoriasis Area Severity Index); PASI was calculated in case BSA > 3%. The criteria of minimal disease activity (MDA) had been used to assess the treatment efficiency. MDA was achieved if a patient met ≥5 of the 7 following categories: tender joint count (TJC) ≤1, swollen joint count (SJC) ≤1, PASI≤1 or BSA≤3%, patient pain VAS ≤15, patient global activity (PGA) VAS ≤20, Health Assessment Questionnaire Disability Index (HAQ) ≤0.5, and tender entheseal points ≤1. Patients were split into two groups: those with nail psoriasis (group 1), and those without nail psoriasis (group 2).Results. 312 (53.1%) patients had nail psoriasis and 276 (46.9%) did not. Patients’ age in group 1 was 45.7±11.9 years, in group 2 – 48.8±13.2 years (р>0.05). PsA duration in groups 1 and 2 did not differ, it was 7.1±6.6 and 7.0±6.2 years respectively (р>0.05). Higher proportions of patients with nail psoriasis were male, disabled from working and chronic smokers compared to patients without nail psoriasis: 51.9% vs 44.1% (р=0.013), 37.20% vs 26.40% (р<0.01) and 18.9% vs 8.7% (р<0.01) respectively. Patients with nail psoriasis had more severe erosive peripheral arthritis compared to patients without nail psoriasis. Median TJC was 8 [4–15] vs 5 [2–12] (р=0.002), SJC – 5 [1–9] vs 2 [0–7] (р=0.003), and erosive radiographic arthritis of feet was found in 45.0% vs 31.2% of patients (р=0.003) respectively. Group 1 patients had higher disease activity measured by DAPSA – 25 [15–39] vs 20 [12–33] (p=0.001) and ASDAS-CRP – 3.1 [2.2–4.0] vs 2.8 [1.8–3.5] (р=0.004), compared to group 2 patients. Patients with nail psoriasis had higher frequency of heel enthesitis and dactylitis; axial disease was diagnosed more often among them, compared to patients without nail psoriasis. Heel enthesitis was detected in 53 (17.0%) vs 28 (10.1%; р=0.016), dactylitis – in 76 (24.4%) vs 46 (16.7%; р=0.022), spondylitis – in 109 (35.0%) vs 73 (26.4%; р=0.025) patients respectively. Patients in group 1 had worse skin psoriasis than in group 2. Patients with nail psoriasis significantly more often had moderate and severe skin psoriasis according to BSA, compared to patients without nail psoriasis (39.9% vs 26.1% and 14.8 vs 1.1% respectively; р<0.01 for both comparisons); group 2 patients significantly more often had limited skin psoriasis compared to group 1 patients – in 72.8% vs 45.3% of cases respectively (р<0.01). Median PASI index in groups 1 and 2 was 6 [2–14] vs 3 [1–6] respectively (р<0.01). Group 1 patients gave worse assessment of their disease than group 2 patients; median PGA was 50 [40–70] mm vs 50 [30–65] mm VAS respectively (р=0.044). Less patients with nail psoriasis compared to patients without nail psoriasis had achieved MDA throughout the whole study. At the first visit MDA was detected in 3% vs 9% (р=0.006) of patients, at the second – in 12% vs 27% (р<0.001), at the third – in 14% vs 28% (р=0.011), at the fourth – in 17% vs 38% (р<0.001) and at the fifth in 27% vs 52% (р=0.004) of patients respectively. Patients with and without nail psoriasis were given equivalent therapy with diseasemodifying antirheumatic drugs (DMARDs) and biological agents (bDMARDs). DMARDs were given to 78.2% and 80.1% of patients respectively (р>0.05), it was mostly methotrexate (MTX); MTX was used in 66.0% and 64.1% of cases respectively (р>0.05). bDMARDs were prescribed to 22.1% and 28.3% (р>0.05) of patients, including tumour necrosis factor (TNF) inhibitors – in 67% and 63% of cases, interleukin (IL) inhibitors – in 33% and 37% of cases (р>0.05 for both comparisons). Taking into account the similar disease duration and equivalent therapy in both groups, it could be concluded that patients with nail psoriasis achieved MDA less frequently due to greater disease severity.Conclusion. Nail involvement is identified in more than half (53%) of PsA patients of the Russian Psoriatic Arthritis Registry. Nail psoriasis is associated with significantly worse disease status as measured by severe peripheral arthritis, enthesitis, dactylitis, spondylitis and skin lesions; higher frequency of erosive arthritis was detected in this category of patients. Patients with nail psoriasis had achieved MDA less frequently compared to patients without nail psoriasis. Nail involvement is associated with worse response to therapy and patients’ disability. These data emphasize the importance of accurate diagnostics of nail psoriasis and optimization of treatment approach, including “targeted” therapy.
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Takeda, June, Kenichi Yoshida, Tetsuichi Yoshizato, Yuichi Shiraishi, Yusuke Okuno, Ayana Kon, Keisuke Kataoka, et al. "Analysis of Genomic Predispositions to Sporadic Myeloid Neoplasms Mediated By DDX41 in Japan." Blood 132, Supplement 1 (November 29, 2018): 4371. http://dx.doi.org/10.1182/blood-2018-99-117664.
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Abstract Germline mutations of DEAD-box helicase 41 (DDX41) have recently been implicated in adult-onset myeloid neoplasms, including myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML). However, with their prevalence being largely based on the studies from Caucasian populations, the prevalence of DDX41 pathogenic variants in other ethnicities and their risks for myeloid neoplasms have not been fully investigated. Moreover, the clinicopathological features of DDX41-mutated myeloid neoplasms and their genetic profiles have not been elucidated either. To address these issues, we investigated germline DDX41 variants among a large cohort of Japanese patients (n=1,609) with sporadic myeloid neoplasms including MDS (n=1,102), myelodysplastic/myeloproliferative neoplasms (n=14), myeloproliferative neoplasms (MPN) (n=31), secondary AML derived from these myeloid neoplasms (sAML) (n=47), and de novo AML (n=410), as well as Japanese healthy controls (n=17,186) using targeted deep sequencing, whole exome sequencing, and/or whole genome sequencing, though which pathogenic germline DDX41 variants and their clinical, pathological, and genetic features were investigated. Risk of detected germline variant for myeloid neoplasms was evaluated by comparing their frequencies between patients and healthy individuals. The germline origin of candidate risk alleles was confirmed using buccal mucosa samples. We identified 4 germline variants that were significantly enriched in the patient cohort (n=58, 3.6 %) compared to healthy controls (n=42, 0.2%) (OR=15; 95%CI: 10.2-22.8), including two truncating variants, p.A500fs (OR=14; 95%CI: 8.7-24.4), p.E7X (OR=12.6; 95%CI: 2.1-86), and two missense alleles, p.Y259C (OR=15; 95%CI: 4.1-60), and p.S363del (OR=11; 95%CI: 3.4-35). Four additional truncating and splice-site variants, Y279X (n=1), R124fs (n=1), c.571+2T>G (n=2), and c.298+1G>T (n=1), were also considered as risk alleles, although a small number of each variant precluded an accurate estimation of enrichment in the patient cohort. Overall, as many as 63 (3.9%) patients harbored one of these variants, where each variant allele was invariably heterozygous. Of note, none of these 8 risk variants have been reported in the Caucasian population. To further evaluate the pathogenic role of these DDX41 germline variants, clinical features and somatic genetic events were investigated. The median age at diagnosis did not significantly differ between patients with and without DDX41 variants (60 and 56 years old in variant carrier and in non-carrier, respectively), suggesting that DDX41-mediated myeloid leukemogenesis shows an age-dependence similar to that in other sporadic cases. Compared with DDX41-unmutated cases, DDX41-mutated cases showed a higher male predominance (52/11 and 987/559, respectively; OR=2.7; 95%CI: 1.4-5.1) and were more likely to have an initial diagnosis of MDS rather than de novo AML (55/8 and 1,094/402, respectively; OR=2.5; 95%CI: 1.2-5.4). Patients with germline DDX41 mutations had a median of 1 (0-5) somatic mutations. Somatic DDX41 mutations were found in 43 (2.6%) cases, a majority of which harbored a germline DDX41 risk variants (32/63 (52%) and 11/1,549 (0.7%), respectively; OR=143; 95%CI: 67-311). Other targets of somatic mutations in risk allele-positive cases included ASXL1 (n=9), DNMT3A (n=6), TP53 (n=5), and JAK2 (n=4), for which no significant correlation was observed between risk allele-positive and negative cases. Abnormal cytogenetics and copy number abnormalities were detected in 30 (48%) of the patients with DDX41 risk alleles, none of which were significantly in the risk allele-positive cases. In conclusion, we identified DDX41 germline risk variants among the Japanese population. Germline DDX41 variants were seen in a substantial fraction of Japanese patients with sporadic myeloid neoplasms. Found in the general Japanese population at very low frequencies, these risk alleles account for the largest germline risk for myeloid neoplasms. Somatic DDX41 mutations were common with a prominent mutational hotspot, almost exclusive found in patients with DDX41 risk alleles. Given the high prevalence of DDX41 germline variants and the late onset of associated MDS and sAML, their detection may help better manage patients and carriers who carried DDX41 risk alleles, even when no family history is known. Figure. Figure. Disclosures Ishiyama: Alexion Pharmaceuticals, Inc.: Honoraria. Chiba:Bristol Myers Squibb, Astellas Pharma, Kyowa Hakko Kirin: Research Funding. Asou:Chugai Pharmaceutical Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding; Asahi Kasei Pharma Co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; SRL Inc.: Consultancy; Yakult Honsha Co., Ltd.: Speakers Bureau; Kyowa Hakko Kirin Co., Ltd.: Speakers Bureau. Naoe:Otsuka Pharmaceutical Co., Ltd.: Research Funding; Toyama Chemical Co., Ltd.: Research Funding; Nippon Shinyaku Co., Ltd.: Research Funding; Pfizer Japan Inc.: Research Funding; Astellas Pharma Inc.: Research Funding; Fujifilm Corporation: Patents & Royalties, Research Funding. Usuki:Otsuka Pharmaceutical Co., Ltd.: Research Funding; GlaxoSmithKline K.K.: Research Funding; Kyowa Hakko Kirin Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding; Sanofi K.K.: Research Funding; Shire Japan: Research Funding; SymBio Pharmaceuticals Limited.: Research Funding; Celgene Corporation: Research Funding, Speakers Bureau; Daiichi Sankyo: Research Funding; Sumitomo Dainippon Pharma: Research Funding, Speakers Bureau; Boehringer-Ingelheim Japan: Research Funding; Pfizer Japan: Research Funding, Speakers Bureau; Janssen Pharmaceutical K.K: Research Funding; Novartis: Speakers Bureau; Ono Pharmaceutical: Speakers Bureau; Takeda Pharmaceutical: Speakers Bureau; Chugai Pharmaceutical: Speakers Bureau; Nippon Shinyaku: Speakers Bureau; Mochida Pharmaceutical: Speakers Bureau; MSD K.K.: Speakers Bureau. Miyawaki:Novartis Pharma KK: Consultancy; Otsuka Pharmaceutical Co., Ltd.: Consultancy; Astellas Pharma Inc.: Consultancy.
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Haferlach, Torsten, Ulrike Bacher, Tamara Alpermann, Wolfgang Kern, Alexander Kohlmann, Susanne Schnittger, and Claudia Haferlach. "Further Insights Into The Molecular Landscape Of De Novo Acute Myeloid Leukemia (AML) Investigating 1,291 Patients." Blood 122, no. 21 (November 15, 2013): 607. http://dx.doi.org/10.1182/blood.v122.21.607.607.
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Abstract Background The Cancer Genome Atlas Research Network (TCGA) published a hallmark sequencing study on molecular mutations in 200 fully characterized adult de novo AML (NEJM 2013). According to their data AML harbor in average 13 mutations in the coding region of the genome of which 5 are in genes known to be recurrently mutated in AML. Further, detailed data on co-occurrence and mutual exclusiveness of molecular mutations was presented. However, given the heterogeneity of AML a cohort of 200 AML might not be fully representative. Aims 1. Compare the published mutation frequency to our cohort 2. Evaluate, whether the mutation frequencies vary with age. 3. Determine the number of additional mutations in genetically defined AML subgroups 4. Analyze the co-occurrence of molecular mutations. Patients and Methods 1,291 adult de novo AML (700 m/591 f; median: 68 yrs; 18-100 yrs) were analyzed for mutations by different PCR assays and next-generation sequencing including the 11 most frequently mutated genes reported by TCGA (FLT3-ITD/-TKD, NPM1, DNMT3A, IDH1, IDH2, TET2, RUNX1, TP53, NRAS, CEPBA, WT1) and also ASXL1, KRAS, MLL-PTD (that had been found at lower frequencies by TCGA), and CBL. Cytogenetics was performed in all cases. Results Mutations were found in NPM1: n=410/1,189 (34.5%), DNMT3A: n=105/340 (30.9%), TET2: n=104/349 (29.8%), FLT3-ITD: n=305/1,231 (24.8%), RUNX1: n=201/1,045 (19.2%), IDH2: n=154/938 (16.4%), ASXL1: n=157/1,000 (15.7%), TP53: n=97/743 (13.1%), NRAS: n=101/842 (12.0%), IDH1: n=93/1,053 (8.8%), FLT3-TKD: n=94/1,132 (8.3%), MLL-PTD: 98/1,181 (8.3%), CEPBA: n=84/1,105 (7.6%) (double-mut: n=38; single-mut: n=46), KRAS: n=38/552 (6.9%), WT1: n=58/918 (6.3%), and CBL: 8/352 (2.3%). These mutation frequencies are comparable to those reported by TCGA. Only ASXL1 mutations were less frequently observed by TCGA (2.5%). The following mutations were more frequent in pts <60 yrs: FLT3-ITD (P=0.003), NPM1mut and WT1mut (P<0.001 for both). In contrast, ASXL1, RUNX1 (P<0.001, each) and TET2mut (P=0.005) were more frequent in pts ≥60yrs. A total of 802 pts were investigated for at least 9 markers (ASXL1, FLT3-ITD, FLT3-TKD, CEBPA, MLL-PTD, IDH1, IDH2, NPM1, RUNX1): The median number of molecular mutations was 2 (range, 0-5; mean±SD, 1.6±0.9). The lowest number of additional mutations was observed in pts with RUNX1-RUNX1T1 (0.3±0.6) and reciprocal MLL rearrangements (mean±SD, 0.4±0.6) followed by CBFB-MYH11 (0.6±0.8), NPM1 (0.9±0.7), CEPBAmut (0.9±1.0), and MLL-PTD (1.2±0.7). In concordance with TCGA results, a significant coincidence of ASXL1mut with IDH2mut and RUNX1mut was found. A total of 335 pts was screened for FLT3-ITD, DNMT3Amut, and NPM1mut in parallel and there was a high coincidence: 27/335 (8.1%) with all 3 mutations and further 63 (18.8%) with 2 out of 3; all combinations P<0.001, each). Beyond the observations within the TCGA study, we found additional positive correlations such as IDH1mut to DNMT3A (P=0.004) and as well to NPM1mut (P=<0.001), and FLT3-ITD to MLL-PTD (P=0.010) as well as to WT1mut (p=0.001). Furthermore, according to the TCGA data, the following mutations were mutually exclusive: TP53mut to NPM1mut and to FLT3-ITD (P<0.001, each), and in addition RUNX1mut to NPM1mut (P<0.001). However, we could not confirm the mutual exclusiveness of RUNX1mut and FLT3-ITD as 21.0% of RUNX1mut AML also showed FLT3-ITD. Beyond the TCGA data, we found the following mutations to show significant negative correlations: MLL translocations were significantly negatively correlated with FLT3-ITD, NPM1, DNMT3A, IDH2, and RUNX1mut, as well were RUNX1-RUNX1T1 rearrangements with FLT3-ITD, NPM1, and IDH2mut, and CBFB-MYH11 rearrangements with FLT3-ITD and NPM1mut. Conclusions 1) Investigation of a large cohort of de novo AML largely confirmed the mutation frequencies of the TCGA data, but revealed a higher frequency of ASXL1mut. 2) In addition, we depicted new patterns of positive and negative correlations of genetic alterations. 3) This further emphasizes the variety of pathways of leukemogenesis in de novo AML requiring additional analyses to delineate the prognostic impact of different marker combinations and their impact on treatment decisions. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Bacher:MLL Munich Leukemia Laboratory: Employment. Alpermann:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Kohlmann:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Haferlach, Torsten, Manja Meggendorfer, Susanne Schnittger, Annette Fasan, Wolfgang Kern, and Claudia Haferlach. "Clinical Impact of Minimal Residual Disease (MRD) Monitoring in AML with PM-Rara, CBFB-MYH11, and RUNX1-RUNX1T1: A Study on 600 Patients." Blood 126, no. 23 (December 3, 2015): 228. http://dx.doi.org/10.1182/blood.v126.23.228.228.
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Abstract Introduction: The cure rate in AML is dependent on patient´s (pts) age and performance, cytogenetics, early blast clearance and sustainable first complete remission. Investigation of minimal residual disease (MRD) is possible by multiparameter flow cytometry and molecular techniques. Recent findings have further depicted a broad spectrum of molecular markers in AML in 99% of pts (TCGA, NEJM, 2013). This broadens the portfolio of targets for MRD assessment and will hopefully help to better individualize treatment strategies. We here focused - as a paradigm - on the three hallmarks for molecular MRD studies in AML. Aims: To better define the clinical impact and to suggest strategies for MRD monitoring in AML with PML-RARA, CBFB-MYH11, and RUNX1-RUNX1T1. Patients and Methods: Between 2005 und 2015 we at diagnosis investigated 321 PML-RARA, 134 CBFB-MYH11, and 145 RUNX1-RUNX1T1 AML pts. Individual follow-up time points during their course of disease were studied in 2657, 1047, and 890 samples, respectively. Thus, the combined number of investigated samples is 4,594. Molecular techniques applied comprised quantitative real-time PCR and nested PCR. Median age in PML-RARA was 52 years (yrs) (2-86 yrs), in CBFB-MYH11 53 yrs (21-81 yrs), and in RUNX1-RUNX1T1 52 yrs (10-83 yrs). Median time between 2 investigations was 3.0 months (mo) in PML-RARA, 2.1 mo in CBFB-MYH11, and 2.8 mo in RUNX1-RUNX1T1 pts (range for all 0.1-40.4 mo), respectively. All pts were treated with standard protocols according to genotype and age. Allogeneic bone marrow or stem cell transplantation was performed in 85 pts (14%). Results: 294/321 pts (92%) with PML-RARA achieved complete molecular remission (CMR) after a median of 2.9 mo (range: 0.8-9.7 mo). In contrast, in CBFB-MYH11 CMR was reached in 89/134 pts (66%) after a median of 7.4 mo (range: 1.6-16.8 mo), and in RUNX1-RUNX1T1 CMR was reached in 75/145 pts (51%) after a median of 4.7 mo (range: 1.0-11.5 mo). Of note, some of the CBFB-MYH11 pts never reached CMR, always showing low level signals. 95% (278/294) of PML-RARA pts that achieved CMR stayed in first CMR and did not relapse within a median follow-up of 32.6 mo (range: 1.2-134.5 mo). 5% (16/294) relapsed at a median interval after CMR of 8.1 mo. However, a second CMR was reached in 12/16 pts after relapse. Five of these 12 pts suffered from second relapses, whereof 4 pts achieved a third CMR. Third relapses occurred in 2/4 pts. 69/89 (78%) of pts with CBFB-MYH11 stayed in first CMR and never relapsed during a median follow-up of 10.4 mo (range: 1.6-47.1 mo). 20/89 relapsed after 4.0 mo of CMR, whereof 11 achieved second CMR. 3/11 relapsed again. 63/75 (84%) of pts with RUNX1-RUNX1T1 stayed in first CMR and never relapsed during a median follow-up of 10.1 mo (range: 1.0-65.8 mo). However, 12/75 relapsed after a median time of CMR of 5.3 mo. 4/12 achieved another CMR. In 85 patients (10 PML-RARA, 42 CBFB-MYH11, and 33 RUNX1-RUNX1T1) allogeneic bone marrow or stem cell transplantation (Tx) was performed, and 72/85 (85%) were rescued by Tx. However, two patients each with PML-RARA and RUNX1-RUNX1T1 relapsed, respectively, and 9 in CBFB-MYH11 positive AML after Tx. Patients did not experience first relapse later than 50.3 mo in CMR in PML-RARA, later than 30.7 mo in CBFB-MYH11, and later than 35.7 mo in RUNX1-RUNX1T1. Additionally, keeping periods between two MRD samplings at a maximum of 3 mo allowed the detection of nearly all cases of first relapse due to the molecular hint. Addressing the sensitivity levels of the assays applied to bone marrow (BM) versus peripheral blood (pB) samples showed a 1.4 fold higher sensitivity for BM samples (median copies of reference gene, 13,204 vs 9,240). Due to the comparable sensitivities pB can be investigated until a first hint of relapse, followed by BM sampling for confirmation. Conclusions: 1) MRD by molecular techniques reliably defines pts risks in AML with PML-RARA, CBFB-MYH11, and RUNX1-RUNX1T1, respectively. 2) Clinical decisions are reliable within screening intervals of 3 mo using pB. 3) Relapses in first CMR are not detected later than 50.3 mo in PML-RARA, 30.7 mo in CBFB-MYH11, and 35.7 mo in RUNX1-RUNX1T1 AML, respectively. 4) Pts after relapse can be rescued by transplantation in the majority of cases. 5) As the availability of other molecular markers in AML has dramatically increased, more individualized treatment strategies based on specific MRD monitoring are achievable in nearly every patient in the near future. Disclosures Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Meggendorfer:MLL Munich Leukemia Laboratory: Employment. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Fasan:MLL Munich Leukemia Laboratory: Employment. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Cheah, Chan Yoon, Martin Hutchings, Kirsty Rady, Kerry J. Savage, Musa F. Alzahrani, Laurie H. Sehn, Sally Barrington, et al. "The Absolute Number of Extranodal Sites Detected By PET-CT Is a Powerful Predictor of Secondary Central Nervous System Involvement in Patients with Diffuse Large B-Cell Lymphoma Treated with R-CHOP." Blood 126, no. 23 (December 3, 2015): 3905. http://dx.doi.org/10.1182/blood.v126.23.3905.3905.
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Abstract Background Central nervous system (CNS) relapse in patients with diffuse large B-cell lymphoma (DLBCL) is an infrequent but devastating complication. The German Risk model which includes the 5 IPI risk factors plus involvement of the kidneys has been validated in 2 large independent cohorts (Schmitz, ICML 2013; Savage, ASH 2014; El-Galaly, ICML 2015). In this model, the presence of >1 extranodal site of involvement contributes only 1 point. However, the precise impact of the extent of extranodal disease in PET-CT staged patients is unknown. Patients and Methods We identified patients with newly diagnosed DLBCL presenting to hospitals in Denmark, Canada, the United Kingdom and Australia through systematic searches of national/local lymphoma registries. Inclusion criteria were: staging included PET-CT, primary treatment with R-CHOP or similar regimen ± CNS prophylaxis. Patients treated with high-dose regimens (such as R-HyperCVAD) and those with CNS involvement at diagnosis were excluded. Medical records and PET-CT reports were reviewed for clinical information and outcome. Multiple lesions in one organ or set of paired organs/ tissue were counted as a single extranodal site, and the spleen and Waldeyer's ring were not included as extranodal sites. Time to CNS relapse was determined using the method of Kaplan and Meier, with univariate analysis of absolute number of extranodal sites associated with CNS relapse performed using competing risk regression with death before CNS relapse as competing risk. Multivariate analyses (adjusted for elevated LDH, age>60 y and performance status>1) were performed using Cox proportional hazards to identify the specific increase in risk attributable to the absolute number of extranodal sites of involvement. Involvement of the kidney/adrenals and advanced disease stage were not included in the adjustment because of their intrinsic relationship to number of extranodal sites. Results 1,536 patients meeting the above criteria were included, with the following characteristics: median age 65 y (range 17-92), 63% stage III/IV, 39% B symptoms, 50% elevated LDH, 15% performance status >1 and 39%, 36%, 15%, 6% and 3% had 0, 1, 2, 3 and 4+ extranodal sites of involvement, respectively. 79% received no specific CNS-directed prophylaxis; 8% received intrathecal chemotherapy alone, 5% received systemic high-dose anti-metabolites and 8% received both intrathecal and systemic. After a median follow-up of 41 (interquartile range 28-61) months, 62 (4%) patients developed CNS relapse at a median of 9 (range 4-78) months from initial diagnosis. The 3-y incidence of CNS relapse, unadjusted and adjusted hazard ratios for CNS relapse according to number of extranodal sites of involvement are presented in Table 1. The competing risk regression analysis for CNS relapse using absolute number of extranodal sites of involvement is displayed in Figure 1; >2 vs 2 or fewer extranodal sites was associated with markedly increased risk of CNS progression (P <0.0001). Conclusions In patients with newly diagnosed DLBCL staged with PET-CT and treated with R-CHOP, the presence of 3 or more extranodal sites of involvement is associated with markedly increased CNS relapse risk, even when adjusting for other variables. This finding may reflect the greater sensitivity of PET-CT for detection of extranodal disease compared with CT alone. This population would be suitable for prospective studies evaluating the efficacy of prophylaxis strategies and predictive biomarker studies. Table 1. Risk of CNS relapse according to number of extranodal sites at initial diagnosis. *adjusted for LDH, age>60 y and performance status >1 Number of extranodal sites n (%) 3-year incidence % (95%CI) Unadjusted hazard ratio HR (95% CI) Adjusted hazard ratio* HR (95% CI) 0 602 (39) 1.7 (0.9-3.5) 1.0 (ref) 1.0 (ref) 1 559 (36) 4.0 (2.5-6.4) 3.0 (1.3-6.7) 3.1 (1.3-7.2) 2 230 (15) 4.8 (2.4-9.4) 3.4 (1.3-8.5) 2.8 (1.0-7.5) 3 92 (6) 12.8 (6.6-24.0) 8.1 (3.1-20.9) 6.3 (2.2-17.6) 4+ 53 (3) 32.1 (20.1-48.8) 22.0 (9.0-53.6) 17.2 (6.5-45.8) Figure 1. Competing risk regression analysis depicting cumulative incidence of CNS relapse according to absolute number of extranodal sites of involvement. Figure 1. Competing risk regression analysis depicting cumulative incidence of CNS relapse according to absolute number of extranodal sites of involvement. Disclosures Hutchings: Takeda: Research Funding. Connors:Roche: Research Funding; Seattle Genetics: Research Funding. Seymour:Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Research Funding; Phebra: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Infinity: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Genentech, Inc.: Membership on an entity's Board of Directors or advisory committees. Villa:Roche: Research Funding.
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Suttorp, Meinolf, Christian Thiede, Josefine T. Tauer, Silja Roettgers, Petr Sedlacek, and Jochen Harbott. "Chronic Myeloid Leukemia in Pediatrics — First Results From Study CML-PAED II." Blood 114, no. 22 (November 20, 2009): 342. http://dx.doi.org/10.1182/blood.v114.22.342.342.
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Abstract Abstract 342 Background: Chronic myeloid leukemia (CML) is a rare malignancy in pediatrics. In this decade -like in adults- imatinib meyslate (IMA) has been established also as first line treatment for children with CML while allogeneic stem cell transplantation (SCT) as treatment option is postponed for those cases becoming intolerant or refractory to tyrosine kinase inhibitor (TKI) treatment. However, results from controlled trials in children are lacking so far. We here report an analysis of pediatric data from patients (pts) with newly diagnosed Philadelphia-chromosome positive (Ph+) CML on up-front treatment with IMA. Pts and Methods: According to protocol CML-PAED II pediatric pts with confirmed diagnosis of Ph+ CML were treated in CP with IMA 300 mg/sqm once daily, while in accelerated phase (AP) or in blastic phase (BC) the dose was increased to 400 mg/sqm and 500 mg/sqm (bis daily), respectively. Initial and long-term clinical and laboratory data, treatment response and side effects were reported to the study center on standardized forms by the treating physician. Specimen from peripheral blood (pB) and bone marrow (BM) were assessed by cytogenetics and by quantitative RT-PCR for BCR-ABL transcript rates in central laboratories for standardized monitoring in three months intervals. Results: From 1. Jan 2004 until 31. Mrch 2009 a total of 51 pts (21 female, 30 male; median age: 10.6 yrs [range:1-20 yrs]) were registered: 10 pts with ongoing IMA treatment were recruited and analyzed retrospectively while 41 pts were enrolled prospectively from centers in Austria (n=1), Czech Rep. (n=6), Germany (n=40), Italy (n=1), Netherlands (n=1), Slovak Rep. (n=2). Stages of disease were: CP n=47; AP n=1; BC n=3 (two myeloid). Those four pts diagnosed in AP and BC underwent early SCT. Observed side effects in the whole group included: nausea (n=9), muscle pain (n=7), edema (n=3), rhabdomyolysis (n=1, short interruption of IMA), reduced blood cell count (n=2, short interruption of IMA in one pt), biochemical alterations in bone metabolism [for details see: N Engl J Med 2006;354:2006] (n = 8), impaired longitudinal growth (n=1, [Haematologica 2009;94:1177]). Two pts experienced intolerance (muscle pain) or toxicity (hepatic), respectively, therefore stopped IMA and were put on dasatinib after 4 and 10 months, respectively. Having achieved complete cytogenetic response (CyR) and 2 log-fold reduction of BCR-ABL transcript rate, one pt opted for SCT from her HLA-identical brother after 15 mo of treatment. Response rates in advanced stages of CML were as follows: in BC (n=3) two pts became hematological responders (HR), one pt exhibited partial HR. The only one pt diagnosed in AC exhibited partial CyR but complete HR. A landmark analysis in pts entering CML-paed II in CP exhibited that 2/42 pts (5%) had no complete HR at month 3; 2/28 (7%) had no complete CyR at month 12, and 2/19 (15%) pts achieved no major molecular response (MMR, defined as >0.1% BCR-ABL [Blood 2006;108:28–37]) at month 18 after start of IMA. Each two of those four patients with incomplete response (one pt with no CyR at month 12, one pt with no MMR at month 18) underwent SCT from a sibling donor and the other two pts stopped IMA and were put on dasatinib. With a median follow-up of 19 months (range: 0-63 months) all 47 pts diagnosed in CP are alive. Of note none of the six pts (median age at diagnosis: 5 yrs; range 1–13 years) treated by imatinib meanwhile for >36 months have opted for SCT. Conclusion: Keeping in mind that the number of pediatric pts is still small, IMA treatment for children and adolescents with CML in CP is associated -like in adults- with high treatment response rates. Refractoriness to IMA is uncommon and side effects seem tolerable, as only 10% of the total cohort stopped imatinib and were put on 2nd generation TKI. However, disturbances of bone metabolism and longitudinal growth impairment may be of special concern in this not yet outgrown cohort [N Engl J Med 2006;354:2006, Blood 2008;111:2538; Haematologica 2008;93:1101; Lancet 2008;372:111; Int J Hematol; 2009;89:251; Haematologica 2009;94:1177]. Only 3/47 pts not diagnosed in advanced phases of CML so far underwent SCT thus underlining that also in pediatrics SCT has been shifted to a second-line strategy for high-risk patients and those who failed therapy with IMA. Disclosures: Suttorp: Novartis : Research Funding. Thiede:Novartis: Research Funding.
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Bahlis, Nizar, Rachid Baz, Simon Harrison, Hang Quach, Shir-Jing Ho, Annette Juul Vangsted, Philippe Moreau, et al. "First Analysis from a Phase 1/2 Study of Venetoclax in Combination with Daratumumab and Dexamethasone, +/- Bortezomib, in Patients with Relapsed/Refractory Multiple Myeloma." Blood 134, Supplement_1 (November 13, 2019): 925. http://dx.doi.org/10.1182/blood-2019-124407.
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Background: Novel and more effective therapies for multiple myeloma (MM) have led to increasing overall survival, but most patients (pts) will eventually relapse or become refractory (RR). The proteasome inhibitor (PI) bortezomib (V), the anti-CD38 antibody daratumumab (D), and dexamethasone (d) are key agents for combination therapy in first-line and RR settings. Venetoclax (Ven) is a highly selective, potent, oral BCL-2 inhibitor that induces apoptosis in BCL-2-dependent MM cells in vitro. Encouraging clinical efficacy has been observed with Ven monotherapy in t(11;14) pts, and with VenV in pts irrespective of disease genetic background. In view of MM intraclonal heterogeneity, the addition of D to Ven +/- PI is postulated to further enhance antitumor activity of Ven-based regimens in RRMM. Methods: M15-654 (NCT03314181) is an ongoing Phase 1/2, nonrandomized, multicenter study of combination therapy consisting of VenDd +/- V in pts with RRMM. The primary objective is to evaluate the safety, tolerability, and preliminary efficacy of VenDd +/- V. In Part 1, VenDd was evaluated in t(11;14) MM pts who received ≥1 prior line of therapy that included a PI and an immunomodulatory drug (IMiD). In Part 2, VenDVd was evaluated in MM pts irrespective of t(11;14) status who were non-refractory to PIs and received 1 - 3 prior lines of therapy. Each regimen was evaluated in a dose escalation and expansion phase. In each part, Ven dose escalation was initiated at 400 mg daily (QD) and escalated to 800 mg QD if acceptable safety and tolerability were observed. Escalation cohorts had ≥3 pts, and escalation decisions were based on a Bayesian optimal interval design and the number of pts with a dose limiting toxicity (DLT). In Part 1, cycles (C) were 28-day: Ven QD + D 16 mg/kg intravenous (IV) (C1, 2: Days 1, 8, 15, 22; C3 - 6: Days 1, 15; C7+: Day 1) + d 40 mg total weekly. In Part 2, C1 - 8 were 21-day, C9+ were 28-day: Ven QD + D 16 mg/kg IV (C1 - 3: Days 1, 8, 15; C4+: Day 1) + V 1.3 mg/m2 subcutaneous (C1 - 8, Days 1, 4, 8, 11) + d 20 mg (C1 - 3: Days 1, 2, 4, 5, 8, 9, 11, 12, 15; C4 - 8, Days 1, 2, 4, 5, 8, 9, 11, 12) and 40 mg weekly for C9+. Results: As of 13 May 2019, 48 pts were enrolled. Of 24 t(11;14) pts treated in Part 1 with VenDd, median age was 63 (range, 51 - 76), median prior lines of therapy was 2.5 (range, 1 - 8), 14 (58%) had ISS II/III disease, and 24 (100%) received both prior PI and IMiD (46% refractory to PI, 71% refractory to IMiD, 42% double refractory). Of 24 pts treated in Part 2 with VenDVd, median age was 64 (range, 41 - 80), median prior lines of therapy was 1 (range, 1 - 3), 14 (58%) had ISS II/III disease, and 6 (25%) were t(11;14). Twenty-two (92%) pts received prior PI, 17 (71%) received prior IMiD (33% refractory), and 15 (63%) received prior PI + IMiD. The most common adverse events (AEs; VenDd/VenDVd) were fatigue (54%/21%), diarrhea (50%/42%), nausea (33%/38%), insomnia (29%/42%), cough (21%/8%), headache (21%/4%), upper respiratory tract infection (21%/17%), constipation (8%/33%), infusion related reaction (8%/33%), peripheral neuropathy (4%/25%), and dyspepsia (4%/21%). Grade 3/4 AEs were seen in 63%/54% of pts. The most common Grade 3/4 AEs in pts receiving VenDd were neutropenia (13%), fatigue, hyperglycemia, and hypertension (8% each); in pts receiving VenDVd, the most common were insomnia (17%), diarrhea, and thrombocytopenia (8% each). There were 6 pts with infection-related Grade 3/4 AEs (3 VenDd, 3 VenDVd). No AEs of tumor lysis syndrome were observed. Eleven pts had a serious AE (5 VenDd, 6 VenDVd), the most common being pyrexia in 3 pts. One pt treated with VenDd had a DLT of febrile neutropenia, and 1 pt treated with VenDVd died due to progressive disease. No infection-related deaths were seen. Pharmacokinetic analyses demonstrated that addition of D and V did not impact Ven exposure. Median time on study is 3.6 months (m; 8.1 m escalation, 2.8 m expansion) in the VenDd arm and 3.1 m (5.8 m escalation, 2.4 m expansion) in the VenDVd arm. The objective response rate (ORR) was 92% and 88% in pts receiving VenDd and VenDVd, respectively (Table). Conclusions: This first analysis of pts treated with VenDd +/- V demonstrate a tolerable safety profile with encouraging efficacy, notably among t(11;14) pts treated with VenDd who had an ORR of 92%. No new safety signals were observed. Although the study is currently on partial clinical hold, enrolled pts continue to be followed. Analysis will be updated at presentation. Disclosures Bahlis: Amgen: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Baz:Bristol-Myers Squibb: Research Funding; AbbVie: Research Funding; Merck: Research Funding; Sanofi: Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Harrison:Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; GSK: Consultancy, Research Funding; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: investigator on studies, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Quach:Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees. Ho:Celgene: Membership on an entity's Board of Directors or advisory committees. Vangsted:Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Jansen: Honoraria. Moreau:Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria. Gibbs:BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Salem:AbbVie: Employment, Other: Stock/stock options. Ross:AbbVie: Employment, Other: Stock/stock options. Pesko:AbbVie: Employment, Other: Stock/stock options. Westrup:AbbVie: Employment, Other: Stock/stock options. Vue:AbbVie: Employment, Other: Stock/stock options. Maciag:AbbVie: Employment, Other: Stock/stock options. Bueno:AbbVie: Employment, Other: Stock/stock options. Kaufman:Takeda: Consultancy; Amgen: Consultancy; AbbVie: Consultancy; Winship Cancer Institute of Emory University: Employment; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy; Karyopharm: Membership on an entity's Board of Directors or advisory committees; TG Therapeutics: Consultancy; Janssen: Honoraria; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy. OffLabel Disclosure: Venetoclax is a BCL-2 inhibitor that is FDA-approved in some indications. This presentation will focus on venetoclax for treatment of multiple myeloma, which is not an approved indication.
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Alegre, Adrian, Merche Gironella, Juan Miguel Bergua, Esther Gonzalez, Fernando Escalante, Alfon Soler, Antonia Sampol, et al. "Observational Prospective Registry for the Assessment of the Clinical Impact of Starting Anti-Myeloma Treatment at Biological Relapse." Blood 124, no. 21 (December 6, 2014): 4765. http://dx.doi.org/10.1182/blood.v124.21.4765.4765.
Full textAbstract:
Abstract Introduction: Despite the great medical advances associated with the introduction of thalidomide, bortezomib (BORT), and lenalidomide (LEN) for the treatment of multiple myeloma (MM), it remains an incurable disease. Most patients (pts) show disease progression, consistent with the clinical evolution of MM, and only a low percentage achieve long-term responses and extended progression-free survival (PFS). The heterogeneous nature of MM in both the clinical and biological setting is reflected in the heterogeneity of MM relapses. The International Myeloma Workshop Consensus Panel (Rajkumar, Blood 2011) states that treatment (Tx) shall begin either at clinical relapse with symptoms (clinR), or in the event of asymptomatic relapse with significant paraprotein relapse, biological relapse (BR). The purpose of this Spanish registry is to describe MM relapse patterns comparing the impact of Tx decisions in pts who meet the criteria for biological relapse (BR) according to IMWG criteria with those in whom Tx was delayed until clinical relapse (clinR). Here, the preliminary results of this study are presented. Methods: MM pts in (or previous to) first or second BR who have achieved ≥ PR since their last Tx are eligible for inclusion in this observational prospective registry at the time BR is detected. Evaluations performed at least bi-monthly are mandatory. A total of 41 Spanish sites participated in the registry following approval from their independent ethics committees, with 410 pts expected to be included, without physician’s decision of prescribing Tx affecting the inclusion. The main objective of the registry is to assess the time to progression (TTP) from the start of anti-MM Tx at the onset of asymptomatic BR vs. the start of Tx at the time of clinR. Secondary objectives are to describe demographics of BR; to assess the median time elapsing from BR to clinR; to assess overall response rate (ORR), event-free survival (EFS), PFS, overall survival (OS) at BR and at clinR (if appropriate); to asses safety and quality of life (QoL) using 2 validated questionnaires (European Organisation for Research and Treatment of Cancer [EORTC] QLQ-C30 and QLQ-MY24); to document the tolerability profile of the Tx; and to describe the use of associated resources. Here, we summarize baseline characteristics and preliminary results from 83 pts (out of 126 registered pts) who had basal data in the registry at the time of this report. Results: Overall, 79% of pts presented with a BR and 21% were in a bi-monthly watchful waiting follow up. The mean age of pts was 67 years, 53% were female, 57% were in first relapse, 43% and 27% had an ECOG performance status (PS) of 0 and 1, respectively, while the ECOG PS was unknown in 30% of pts at the time of this report. In total, 30% of pts had ISS stage I, 26% had ISS stage II, and 22% had ISS stage III, while ISS stage data were not available or unknown for 12% and 10% of pts, respectively. MM types were IgG Κ (37% of pts), IgG λ (23%), IgA Κ (13%), IgA λ (9%), and type was unknown in 17% of pts. 28% of IgG/IgA MM types were Bence-Jones. Cytogenetic risk assessments were available in 66% of pts. Among those pts with a BR, 51% received active Tx without waiting for a ClinR. First-line Tx was BORT-based in 70% of pts. Overall, 55% of pts had undergone autologous stem cell transplantation, 15% had received consolidation Tx and 34% had received maintenance Tx. After first-line Tx, 17% of pts achieved a stringent complete response (sCR), 31% achieved a CR, 24% achieved a very good partial response (VGPR), and 10% achieved a PR. The median time to BR was 24.53 months. Most (63%) pts who registered after second relapse received LEN-based Tx. Conclusions: To our knowledge, this is the first prospective study in MM to evaluate BR as well as the effects of Tx based on the decision to start Tx at BR vs. clinR. In this preliminary cohort, the physicians’ decision to start active Tx at BR, before the onset of clinR in 50% of cases, was noteworthy. Further follow-up is needed to identify the differences between these two strategies. Updated clinical results will be presented at the meeting. MM-BR Study, Spanish Myeloma Group-GEM/PETHEMA Bibliography Alegre A, et al. Haematologica. 2002;87:609-14. Brioli A, et al. Blood. 2014;123:3414-9. Fernández de Larrea C, et al. Bone Marrow Transplant. 2014;49:223-7. Lenhoff S, et al. Haematologica. 2006;91:1228-33. Rajkumar SV, et al. Blood. 2011;117:4691-5. Zamarin D, et al. Bone Marrow Transplant. 2013;48:419-24. Disclosures Alegre: Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jansen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Lahuerta:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Ruiz:Celgene: Celgene Stock options as part of the employee's compensation plan Other, Employment. Vilanova:Celgene: Contracted by Celgene Other.
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Gossec, L., D. D. Gladman, E. Mcdearmon-Blondell, P. Sewerin, C. T. Ritchlin, D. Feng, A. Lertratanakul, et al. "AB0550 EFFICACY OF UPADACITINIB IN PATIENTS WITH ACTIVE PSORIATIC ARTHRITIS AND A LOW OR HIGH SWOLLEN JOINT COUNT: A SUBGROUP ANALYSIS OF 2 PHASE 3 STUDIES (SELECT-PsA 1 AND SELECT-PsA 2)." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1308.2–1309. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2127.
Full textAbstract:
Background:Although most patients with psoriatic arthritis (PsA) enrolled in clinical trials have polyarticular arthritis, patients in clinical practice may present with oligoarthritis. Data on the efficacy of Janus kinase inhibitors in patients with PsA with low joint counts are limited.Objectives:To evaluate the efficacy of upadacitinib (UPA) in subgroups of patients with PsA with a low (baseline swollen joint count [SJC] <5) or high (SJC ≥5) SJC (LSJ or HSJ).Methods:Data were pooled across the SELECT-PsA 11 (non-biologic disease-modifying antirheumatic drug [non-bDMARD] inadequate response [IR] or intolerance) and SELECT-PsA 22 (bDMARD IR or intolerance) trials, which both enrolled patients with ≥3 involved joints (SJC ≥3 and tender joint count [TJC] ≥3). Subgroup analysis was performed for patients with LSJ or HSJ treated with UPA 15 mg once daily (QD) or placebo (PBO). Efficacy endpoints included minimal disease activity (MDA), very low disease activity (VLDA), Psoriatic Arthritis Disease Activity Score (PASDAS) low disease activity (LDA; ≤3.2), PASDAS remission (≤1.9), and 20/50/70% improvement in American College of Rheumatology (ACR) criteria (ACR20/50/70), all at Week 24, and Psoriasis Area Severity Index (PASI) 75 and static Investigator Global Assessment of Psoriasis (sIGA) 0/1 at Week 16.Results:At baseline, patients with HSJ (n=1060) had similar demographic characteristics but tended to have higher overall disease activity than patients with LSJ across multiple disease domains (n=215; Table 1). UPA efficacy appeared comparable in patients with LSJ and HSJ, with similar proportions of patients achieving composite (MDA, VLDA, PASDAS LDA, and PASDAS remission) measures at Week 24, and skin endpoints (PASI 75 and sIGA 0/1) at Week 16 (Figure 1). At Week 24, 60.0/36.8/22.1% of patients with LSJ receiving UPA 15 mg achieved ACR20/50/70 vs 40.0/17.5/5.8% in the PBO group; rates were 70.3/49.7/26.2% (UPA 15 mg) and 36.1/15.3/3.3% (PBO) in those with HSJ.Table 1.Baseline characteristicsPBOUPA 15 mg QDTotalLSJn=120HSJn=515LSJn=95HSJn=545LSJn=215HSJn=1060Female, n (%)65 (54.2)266 (51.7)49 (51.6)302 (55.4)114 (53.0)568 (53.6)Age (years), mean (SD)52.2 (12.7)51.5 (12.0)52.0 (10.6)52.0 (12.4)52.1 (11.8)51.8 (12.2)Duration since PsA symptoms (years), mean (SD)10.5 (9.2)11.1 (10.2)9.8 (8.2)10.3 (8.9)10.2 (8.7)10.7 (9.6)BMI, mean (SD)29.7 (6.3)31.1 (7.2)29.8 (6.2)30.7 (6.9)29.7 (6.2)30.9 (7.0)Prior failed bDMARDs, n (%)03 (2.5)15 (2.9)1 (1.1)15 (2.8)4 (1.9)30 (2.8)122 (18.3)113 (21.9)22 (23.2)104 (19.1)44 (20.5)217 (20.5)24 (3.3)31 (6.0)7 (7.4)28 (5.1)11 (5.1)59 (5.6)≥34 (3.3)20 (3.9)7 (7.4)27 (5.0)11 (5.1)47 (4.4)Use of ≥1 non-bDMARD atbaseline, n (%)87 (72.5)360 (69.9)63 (66.3)388 (71.2)150 (69.8)748 (70.6)Dactylitis (LDI >0), n (%)21 (17.5)169 (32.8)15 (15.8)176 (32.3)36 (16.7)345 (32.5)Enthesitis (LEI >0), n (%)60 (50.0)325 (63.1)60 (63.2)343 (62.9)120 (55.8)668 (63.0)TJC68, mean (SD)12.5 (11.3)23.9 (15.8)14.6 (13.5)23.1 (15.8)13.4 (12.3)23.5 (15.8)SJC66, mean (SD)3.5 (0.5)13.2 (8.3)3.6 (0.5)12.9 (9.0)3.6 (0.5)13.0 (8.7)HAQ-DI, mean (SD)1.0 (0.6)1.2 (0.7)0.9 (0.6)1.2 (0.6)0.9 (0.6)1.2 (0.7)hs-CRP > ULN (mg/L), n (%)82 (68.3)363 (70.5)62 (65.3)388 (71.2)144 (67.0)751 (70.8)BSA-Ps, median (range)3.0 (0.1–70.0)4.0 (0.1–95.0)2.0 (0.1–80.0)3.0 (0.1–97.0)3.0 (0.1–80.0)3.0 (0.1–97.0)BSA-Ps ≥ 3%, n (%)57 (47.5)285 (55.3)44 (46.3)300 (55.0)101 (47.0)585 (55.2)PASI (baseline BSA-Ps ≥ 3%), mean (SD)7.7 (7.5)12.1 (11.9)8.2 (7.0)10.2 (10.0)7.9 (7.2)11.1 (11.0)PASI (baseline BSA-Ps ≥ 3%), median (range)5.3 (0.1–39.4)7.9 (0.3–64.8)6.5 (0.2–35.4)6.8 (0.1–70.8)6.0 (0.1–39.4)7.3 (0.1–70.8)Conclusion:UPA efficacy was generally similar in patients with PsA with LSJ or HSJ, with both patient groups showing improvements in composite clinical endpoints and skin responses vs PBO.References:[1]McInnes I, et al. Ann Rheum Dis 2020;79(Suppl. 1):16–17;[2]Mease PJ, et al. Ann Rheum Dis 2020; Epub ahead of print.Acknowledgements:AbbVie funded this study; contributed to its design; participated in data collection, analysis, and interpretation of the data; and participated in the writing, review, and approval of the abstract. No honoraria or payments were made for authorship. Medical writing support was provided by Grant Kirkpatrick, MSc of 2 the Nth (Cheshire, UK), and was funded by AbbVie.Disclosure of Interests:Laure Gossec Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB, Dafna D Gladman Consultant of: AbbVie, Amgen, Bristol-Myers Squibb, Celgene, Eli Lilly, Galapagos, Gilead, Janssen, Novartis, Pfizer, and UCB, Grant/research support from: AbbVie, Amgen, Celgene, Eli Lilly, Novartis, Pfizer, and UCB, Erin McDearmon-Blondell Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Philipp Sewerin Consultant of: AbbVie, Amgen, Axiom Health, Biogen, Bristol-Myers Squibb, Celgene, Chugai, Deutscher Psoriasis Bund, Eli Lilly, Fresenius Kabi, Gilead, Hexal, Janssen, Johnson & Johnson, Medi-login, Mediri, Novartis, Onkowissen, Pfizer, Roche, Rheumazentrum Rhein-Ruhr, Sanofi, Swedish Orphan Biovitrum, and UCB, Grant/research support from: AbbVie, Amgen, Biogen, Bristol-Myers Squibb, Bundesministerium fuer Bildung und Forschung, Deutsche Forschungsgesellschaft, Deutscher Psoriasis Bund, Eli Lilly, Fresenius Kabi, Gilead, Hexal, Janssen, Novartis, Pfizer, Rheumazentrum Rhein-Ruhr, Roche, Sanofi, and UCB, Christopher T. Ritchlin Consultant of: AbbVie, Amgen, Celgene, Eli Lilly, Janssen, Novartis, Pfizer, Sun, and UCB, Grant/research support from: AbbVie, Amgen, and UCB, Dai Feng Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, Apinya Lertratanakul Shareholder of: May own stock or options in AbbVie, Employee of: AbbVie, R Ranza Consultant of: AbbVie, Eli Lilly, Janssen, Novartis, and Pfizer, Grant/research support from: AbbVie, Janssen, Novartis, and Pfizer, Lai-Shan Tam Consultant of: AbbVie, Boehringer Ingelheim, Eli Lilly, Janssen, Pfizer, and Sanofi, Grant/research support from: Amgen, Boehringer Ingelheim, GSK, Janssen, Novartis, and Pfizer, Antonio Marchesoni Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Janssen, MSD, Novartis, Pfizer, and UCB, Laura C Coates: None declared., Peter Nash Consultant of: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB, Grant/research support from: AbbVie, Bristol-Myers Squibb, Celgene, Eli Lilly, Gilead, Janssen, MSD, Novartis, Pfizer, Roche, Sanofi, and UCB.