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Nengjun, Ben, Oleksandr Labartkava, and Mykhailo Samokhin. "A NEW WELDING MATERIAL FOR REGENERATION IN THE WELDING TECHNOLOGY BASED ON NICKEL. PRINCIPLES OF DOPING OF HIGH-TEMPERATURE NICKEL ALLOYS RESISTANT TO HIGH-TEMPERATURE CORROSION." Science Journal Innovation Technologies Transfer, no. 2019-2 (May 5, 2019): 49–55. http://dx.doi.org/10.36381/iamsti.2.2019.49-55.
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This work involves an analysis of high-chromium high-temperature deformable wieldable nickel alloys for use in GTE repair assemblies. It is shown that the alloys EP868 (VZh98) and Haynes 230 can be used in welded assemblies with an operating temperature of 800-1100 °C. The alloys Nimonic 81, Nimonic 91, IN 935, IN 939, and Nicrotan 2100 GT also have a high potential for use in welded assemblies. They are characterized by a combination of good weldability, high-temperature strength, and resistance to scaling. There have been conducted studies on high-temperature salt corrosion of model nickel alloys. They allowed establishing the patterns of the impact of base metal alloying with chromium, aluminum, titanium, cobalt, tungsten, molybdenum, niobium, tantalum and rare earth metals on the critical temperature of the start of salt corrosion Tcor and the alloy mass loss. It has been established that alloys with a moderate concentration (13-16%) of chromium can possess satisfactory hightemperature corrosion resistance (HTC resistance) under the operating conditions of ship GTE. The HTC resistance of CrAl-Ti alloys improves upon reaching the ratio Ti/Al ˃ 1. Meanwhile, the ratio Ti/Al ˂ 1 promotes the formation of corrosion products with low protective properties. The positive effect of tantalum on the HTC resistance of alloys is manifested at higher test temperatures than that of titanium, and the total content of molybdenum and tungsten in alloys is limited by the condition 8Mo2 – 2W2 = 89. The presence of refractory elements stabilizes the strengthening phase and prevents formation of the ɳ-phase. However, their excess promotes formation of the embrittling topologically close packed (TCP) phases and boundary carbides of an unfavorable morphology. Based on the studies of the HTC resistance, there has been identified a class of model high-temperature corrosionresistant nickel alloys with a moderate or high chromium content (30%), Ti/Al ˃ 1, and a balanced content of refractory and rare-earth elements.
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Kadonsi, Dr Kaziya, and Dr Muzata Kenneth. "Challenges in Indigenizing Mathematics Pedagogies and Practices in Southern Province, Zambia." International Journal of Research and Innovation in Social Science VIII, no. VII (2024): 2847–76. http://dx.doi.org/10.47772/ijriss.2024.807221.
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This study investigates the challenges associated with indigenizing mathematics pedagogies and practices in Zambia, as perceived by teachers. A survey of 55 mathematics teachers identified key obstacles, including limited understanding of indigenous knowledge (9.3%), resource scarcity (8.9%), resistance to change (9.5%), dominance of Western teaching methods (8.8%), and difficulty in identifying appropriate practices (9.9%). Using a sequential exploratory mixed-methods design, quantitative data were collected via structured questionnaires, followed by qualitative data from semi-structured interviews with 15 teachers. Analysis revealed significant challenges: a shortage of culturally relevant teaching materials, language barriers, and inadequate teacher training. The study emphasizes the need for comprehensive professional development programs, culturally relevant teaching materials, curriculum adaptation, and increased community involvement. Recommendations include developing teacher training programs, enhancing the availability of local resources, fostering collaboration among stakeholders, and promoting community engagement. Addressing these challenges requires a multifaceted approach involving educators, policymakers, and communities to create an inclusive and culturally relevant educational system. Future research should explore long-term impacts and interdisciplinary approaches to indigenized education.
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Nelson, Blessie Elizabeth, Mohammed Gouda, Jason Roszik, Mimi L. Hu, Maria Cabanillas, and Vivek Subbiah. "Abstract 4261: Genomic landscape of 2128 thyroid cancers from the aacr genie database: Implications for targeted therapies." Cancer Research 83, no. 7_Supplement (April 4, 2023): 4261. http://dx.doi.org/10.1158/1538-7445.am2023-4261.
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Abstract Background: Understanding molecular biology of thyroid cancer has revolutionized diagnosis, tumor classifications and identifying effective precision oncology therapies. Methods: Using AACR GENIE database v.12, we cataloged genetic and co-occurring alterations in all thyroid cancers. Results: We identified 2128 cases from 153,834 samples where tumor sub-histologies included Papillary Thyroid Cancer (PTC: 55%; 1162), Poorly Differentiated Thyroid Cancer (PDTC: 12%; 262); Medullary Thyroid Cancer (MTC: 12%; 244), Anaplastic Thyroid Cancer (ATC: 10%; 220); Follicular Thyroid Cancer (FTC: 5%; 111); Hurthle Cell Thyroid Cancer (HCTC: 5%; 95); and others (1; 34). Median age at sequencing was 59 years. Gender distribution was higher in female (54%; n=1104) compared to male (46%; n=933). Ethnicities included 73.2% (n=1,493) White, 8.9% (n=178) Asian, and others.Most frequent genomic mutational alterations overall were BRAF (40.8%; 868) [96% (n=845) V600E, 0.6% (n=5) G469A, 0.6% (n=5) V600_K601delinsE, 0.2% (n=2) K601E, 0.2% (n=2) A404Cfs*9, and 2.7% (n=24) others]; TERT (35%; 624); NRAS (11.6%; 247); TP53 (11.6%; 247) and RET (9.3%; 197) genes. There was variability in genomic alterations between sub-histologies (Table 1). There was statistically significant co-occurrence between BRAF and TERT, TERT and TP53, TERT and NRAS alterations (p<0.001). Mutually exclusive alterations were BRAF and NRAS, BRAF and RET, TERT and RET, NRAS and RET, TP53 and RET, and BRAF and TP53 (p<0.001).Copy number alterations (CNA) were observed in 497 samples and were most frequent in CDKN2A, NKX2-1, CDKN2B, NF2, and CRKL genes (16.5%, 16%, 15.5%, 13.1%, and 13%). 362 oncogenic fusions were noted predominantly in CCDC6-RET, RET-NCOA4, ETV6-NTRK3, BRAF-Intragenic (20%, 7.2%, 3%, 1.6%). Conclusion: Genomic profiling identified full breadth of BRAF, RET and NRAS alterations and co-occurring oncogenic driver alterations. This approach may refine use of targeted therapy in thyroid cancer. Table 1. Histology Most frequent Alterations % n PTC BRAF 62.3% 724 TERT 32.7% 332 PDTC TERT 49% 117 NRAS 28.2% 74 MTC RET 71.3% 174 HRAS 7.8% 19 ATC TP53 58.2% 128 TERT 56.7% 106 FTC TERT 41% 27 NRAS 26.1% 29 HCTC TERT 41% 34 TP53 17.9% 17 Citation Format: Blessie Elizabeth Nelson, Mohammed Gouda, Jason Roszik, Mimi L. Hu, Maria Cabanillas, Vivek Subbiah. Genomic landscape of 2128 thyroid cancers from the aacr genie database: Implications for targeted therapies. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4261.
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Weidemann, Sören, Pauline Gagelmann, Natalia Gorbokon, Maximilian Lennartz, Anne Menz, Andreas M. Luebke, Martina Kluth, et al. "Mesothelin Expression in Human Tumors: A Tissue Microarray Study on 12,679 Tumors." Biomedicines 9, no. 4 (April 7, 2021): 397. http://dx.doi.org/10.3390/biomedicines9040397.
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Mesothelin (MSLN) represents an attractive molecule for targeted cancer therapies. To identify tumors that might benefit from such therapies, tissue microarrays including 15,050 tumors from 122 different tumor types and 76 healthy organs were analyzed for MSLN expression by immunohistochemistry. Sixty-six (54%) tumor types showed at least occasional weak staining, including 50 (41%) tumor types with at least one strongly positive sample. Highest prevalence of MSLN positivity had ovarian carcinomas (serous 97%, clear cell 83%, endometrioid 77%, mucinous 71%, carcinosarcoma 65%), pancreatic adenocarcinoma (ductal 75%, ampullary 81%), endometrial carcinomas (clear cell 71%, serous 57%, carcinosarcoma 50%, endometrioid 45%), malignant mesothelioma (69%), and adenocarcinoma of the lung (55%). MSLN was rare in cancers of the breast (7% of 1138), kidney (7% of 807), thyroid gland (1% of 638), soft tissues (0.3% of 931), and prostate (0 of 481). High expression was linked to advanced pathological tumor (pT) stage (p < 0.0001) and metastasis (p < 0.0001) in 1619 colorectal adenocarcinomas, but unrelated to parameters of malignancy in 1072 breast-, 386 ovarian-, 174 lung-, 757 kidney-, 171 endometrial-, 373 gastric-, and 925 bladder carcinomas. In summary, numerous important cancer types with high-level MSLN expression might benefit from future anti-MSLN therapies, but MSLN’s prognostic relevance appears to be limited.
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Rahmadany, Sri Eka, Aza Zakiyatun Nida, Risha Fillah Fithria, and Ayu Shabrina. "UJI IRITASI DAN AKTIVITAS TABIR SURYA SECARA IN VITRO MINYAK BIJI PALA DALAM SISTEM MIKROEMULSI DENGAN VARIASI TWEEN 80-ETANOL." Jurnal Ilmu Farmasi dan Farmasi Klinik 18, no. 2 (February 14, 2022): 47. http://dx.doi.org/10.31942/jiffk.v18i2.5957.
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ABSTRACTNutmeg oil contains of α-pinene that can be used as sunscreen but it is thermolable. It is necessary to form a microemulsion system for nutmeg oil. This study was to determine in vitro SPF value by and irritation index from nutmeg oil in microemulsion system with Tween 80-ethanol as surfactant and cosurfactant. The system were made with 6.4 % of nutmeg oil and Tween 80-ethanol as with concentrations of 45% (F1), 50% (F2), 55% (F3). The nutmeg oil microemulsion was determined SPF value using spectrophotometer UV. The irritation test was done by the patch test method on rabbit skin with 4 groups of negative control, F1, F2, and F3. The skin was observed at 24, 48 and 72 hours. Quantitative data were analyzed using one way Anova while irritation test data were described descriptively. The results of the sunscreen activity on nutmeg oil microemulsion for F1, F2 and F3 were 8,9 ± 0,12; 9,2 ± 0,51; and 9,3 ± 0,32 (p > 0,05). This SPF value were categorized in maximum protection. The primary irritation index values for F1, F2 and F3 were 0,1±1; 0,3±2,5; 0,1±0; so it can be concluded that microemulsion of nutmeg oil were very mildly irritating.Keywords: irritation, microemulsion, nutmeg seed oil, sunscreen activity
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Gugliotta, Luigi, Alessia Tieghi, Gianluca Gaidano, Silvia Franceschetti, Giorgina Specchia, Paola Carluccio, Maria Gabriella Mazzucconi, et al. "The Registro Italiano Trombocitemie (GIMEMA Project): Preliminary Analysis of the First 801 Enrolled Patients." Blood 108, no. 11 (November 16, 2006): 3639. http://dx.doi.org/10.1182/blood.v108.11.3639.3639.
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Abstract Epidemiological, diagnostic, prognostic and therapeutical data were retrospectively obtained by the Italian Registry in over 2000 Essential Thrombocythemia (ET) patients who mainly were diagnosed according to the PVSG criteria and were treated with potentially leukemogenic drugs. The Registro Italiano Trombocitemie (RIT), that is a GIMEMA project, has been activated in order to registry italian ET patients, to improve the diagnosis appropriateness (WHO criteria), to promote the acquisition of biological data, to evaluate the compliance to the therapeutical guidelines of the Italian Society of Hematology (SIE), to monitor in particular the ET patients receiving Interferons alpha and Anagrelide, to evaluate cases of pregnancy, pediatric age and familiarity, to define the prognostic value of the biological factors as JAK2 mutation, clonality, etc, to create a network for activation of new clinical and biological studies. The RIT, co-ordinated by the Hematology Unit of Reggio Emilia, is a web based registry that beside a public area comprehends a database of italian ET patients. The data, with respect of the privacy rules, are object of validation and analysis by various RIT expert subcommittees. Eighty hematological Institutions adhered to the RIT and 801 patients have been registered since June 2005. The ET diagnosis was done according to the PVSG (90%) and WHO (10%) criteria. The patients, 492 females and 309 males, had age <40 yr (19%), 40–60 yr (32%), 60–70 yr (19%), >70 yr (30%), and the median age was 59 years. At diagnosis the platelet count was >1000 ×109/L in 29% of cases (mean 932). Few patients had prior thrombosis (4%; major 2%) and prior hemorrhage (2.6%). Patients at high risk of thrombosis were 55% on considering age >60 yr and/or previous thrombosis and/or PLT count >1500 ×109/L, and 65% on considering the PLT count cut-off of 1000 ×109/L. The patients shown general thrombotic risk factors (70%), disease related symptoms (40%) and splenomegaly (25%). By applying the WHO diagnostic criteria, the picture of true ET was found in 27% of cases. Sixty pregnancies have been reported. Aspirin was administered in 72% of patients and cytoreduction was performed in 62% of them, with use of Hydroxyurea (65%), Anagrelide (10%), Interferons alpha (10%), Pipobroman (4%), Busulfan (2%). A separate analysis for patients treated with Anagrelide and Iterferons alpha is in progress. To improve the diagnostic approach, the RIT has promoted the bone marrow biopsy revision (WHO criteria) and the acquisition of the new biological parameters.
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Zonder, Helene B., Joanne E. Mortimer, Carolyn E. Behrendt, Robin Smith, and Meghan Zomorodi. "Moderate-to-severe symptoms among survivors of early-stage breast cancer." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e19644-e19644. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e19644.
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e19644 Background: This cross-sectional survey describes the prevalence of moderate/severe symptoms among patients in a survivorship clinic. Methods: We administered QoL questionnaires (FACT-B, SF-36, HADS) to pts. treated for stage I-III disease at a survivorship visit. For symptoms reported by at least 18/55 subjects, we identified risk factors using logistic regression. Results: Subjects (n=55) were age 55.9(+8.9) yrs at study, age 52.6(+9.3) at dx, and median 23.7 (range 6.3-157.2) mos. from dx of stage I (30.9%), II (54.5%), or III (14.6%) disease. Systemic treatment included chemotherapy only (20.0%), endocrine therapy only (30.9%), or both therapies (49.1%). Currently, 65.5% were on endocrine therapy. Symptoms experienced “quite a bit” or “very much” during the past wk were: hot flashes (45.5%), joint pain (30.9%), weight gain (30.9%), loss of libido (30.9%), vaginal dryness (27.3%), and night sweats (27.3%). In the past mo., 43.6% accomplished less than they would have liked due to physical health, and 30.9% felt worn out at least “a good bit of the time”. Sleep quality was rated “fairly to very bad” (32.7%), and 25.5% felt fatigued at least half the day during the past week. Vigorous activities were “limited a lot” for 36.4%, and increased with age at dx. Fre-quent hot flashes were associated with age < 50 years (6.40, 1.75-23.35) and being within 1year of dx (10.67, 1.05-108.69). Adjusted for age at dx, poor quality of sleep increased with stage of disease (9.68, 2.25-41.69, per step increase) and was associated with having received endocrine therapy only (9.98, 1.40-71.03) and being within the first year after dx (9.54, 0.76-119.47). Conclusions: Limitation in activities, poor quality of sleep, and symptoms of hormonal suppression are common among survivors of early stage breast cancer. Poor quality sleep and frequent hot flashes appear to decrease in prevalence 1 yr after dx, but other common symptoms do not. A longitudinal cohort study is underway.
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Yurtsever Kum, Nurcan. "Does final intraoperative endoscopic control increase surgical success in conventional septoplasty?" Praxis of Otorhinolaryngology 11, no. 2 (March 28, 2023): 33–37. http://dx.doi.org/10.5606/kbbu.2023.67044.
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Objectives: This study aimed to investigate the effects of the final endoscopic control performed intraoperatively in conventional septoplasty on operative time, residual deviation, and changes in Nasal Obstruction and Septoplasty Effectiveness Scale (NOSE) scores. Patients and Methods: One hundred twenty-five patients who applied with the complaint of nasal obstruction between June 2020 and May 2021 and were found to have isolated nasal septum deviation were evaluated in this prospective study. Patients with comorbidities were excluded from the study. Remaining 80 patients (55 males, 25 females; mean age: 30.1±8.9 years; range, 18 to 58 years) included in this study. The patients were divided into two groups of 40 individuals using the blocked randomization method. In the first group (CS-EC group; 26 male, 14 female; mean age: 31.7±8.3 year; range 18 to 58 year), after conventional septoplasty with head light, additional pathologies were corrected with the conventional method if it was detected by the endoscope. For the second group (CS group; 29 male, 11 female; mean age: 28.6±9.3 year; range 18 to 53 year), only conventional septoplasty was performed. The patients were evaluated with NOSE before and three months after the operation to evaluate the complaint of nasal obstruction. The groups were compared in terms of NOSE scores, operation time, and postoperative residual deviation. Results: The mean operation times in the CS-EC and CS groups were 44.9±9.3 and 39.0±7.7 min, respectively, and this difference was statistically significant (p=0.001). While there was no statistically significant difference between the CS-EC and CS groups in terms of preoperative total NOSE scores (p=0.211), the postoperative total NOSE score was found to be statistically significantly lower in the CS-EC group compared to the CS group (p=0.001). Conclusion: Final intraoperative endoscopic control of the nasal passage in classical septoplasty may be an effective method to detect septal deviations that cannot be adequately evaluated.
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Folprecht, Gunnar, Thomas Gruenberger, Wolf Bechstein, Hans-Rudolf Raab, Juergen Weitz, Florian Lordick, Joerg Thomas Hartmann, et al. "Cetuximab and chemotherapy in the treatment of patients with initially “nonresectable” colorectal (CRC) liver metastases: Long-term follow-up of the CELIM trial." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 3538. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.3538.
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3538 Background: CRC liver metastases can be resected after downsizing with intensive chemotherapy schedules, with a strong correlation between the response and resection rates. Cetuximab plus chemotherapy has been shown to increase the rates of tumor response and resection of liver metastases. (Van Cutsem et al, JCO 2011). Methods: Patients (pts) with technically non-resectable and/or with > 4 liver metastases were randomized to treatment with FOLFOX/cetuximab (arm A) or FOLFIRI/cetuximab (arm B) and evaluated regarding resectability every 2 months. Resection was offered to all patients who became resectable during the study. K-ras and b-raf status were retrospectively evaluated. Data on tumor response and resection were reported earlier (Folprecht et al, Lancet Oncol 2010). Overall and progression free survival were analyzed in December 2012. Results: Between Dec 2004 and March 2008, 56 pts were randomized to arm A, 55 to arm B. For the current analysis, 109 pts were evaluable for overall survival (OS), and 106 patients for PFS. The median OS was 35.7 [95% CI: 27.2-44.2] months (arm A: 35.8 [28.1-43.6], arm B: 29.0 [16.0-41.9], HR 1.03 [0.66-1.61], p=0.9). The median PFS was 10.8 [9.3-12.2] months (Arm A: 11.2 [7.2-15.3], Arm B: 10.5 [8.9-12.2], HR 1.18 [0.79-1.74], p=0.4). Patients with R0 resection had a better OS (median: 53.9 [35.9-71.9] mo) than patients without R0 resection (27.3 [21.1-33.4] mo, p=0.002) and a better PFS (median 15.4 [11.4-19.5] and 8.9 [6.7-11.1] mo in R0 resected and not R0 resected pts, p<0.001). The 5 year survival in R0 resected patients is 46.2% [29.5-62.9%]. Conclusions: This study confirmed a favourable long term survival of patients with initially “nonresectable” CRC liver metastases treated in a multidisciplinary approach of neoadjuvant chemotherapy with cetuximab and subsequent metastasectomy in pts who became resectable. Clinical trial information: NCT00153998. [Table: see text]
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Tan, Ken Wei, Borame Sue Lee Dickens, and Alex R. Cook. "Projected burden of type 2 diabetes mellitus-related complications in Singapore until 2050: a Bayesian evidence synthesis." BMJ Open Diabetes Research & Care 8, no. 1 (March 2020): e000928. http://dx.doi.org/10.1136/bmjdrc-2019-000928.
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ObjectiveWe examined the effects of age, gender, and ethnicity on the risk of acute myocardial infarction, stroke, and end-stage renal disease according to type 2 diabetes mellitus status among adults aged 40–79 in Singapore.MethodsA Bayesian inference framework was used to derive age-specific, gender-specific and ethnicity-specific prevalence of type 2 diabetes mellitus from the 2010 Singapore National Health Survey, and age-standardized gender and ethnicity-specific incidence rates of acute myocardial infarction, stroke and end-stage renal disease from the National Registry of Diseases Office. Population forecasts were used in tandem with incidence rates to project the future chronic disease burden until 2050.ResultsThe highest relative risk of acute myocardial infarction was observed in the youngest age group (aged 40–44), with higher relative risk for women (men: 4.3 (2.7–6.4); women: 16.9 (9.3–28.3)). A similar trend was observed for stroke (men: 6.5 (4.2–9.7); women: 10.7 (6.0–17.4)). For end-stage renal disease, the highest relative risk was for men aged 45–50 (11.8 (8.0–16.9)) and women aged 55–60 (16.4 (10.7–24.0)). The annual incidence of acute myocardial infarction is projected to rise from 9300 (in 2019) to 16 400 (in 2050), the number of strokes from 7300 to 12 800, and the number of end-stage renal disease cases from 1700 to 2700.ConclusionsType 2 diabetes mellitus was associated with an increased risk of complications and is modulated by age and gender. Prevention and early detection of type 2 diabetes mellitus can reduce the increasing burden of secondary complications.
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Lancet, Jeffrey E., Jason Gotlib, Meir Wetzler, Selina Luger, Larry D. Cripe, Martin S. Tallman, Ivana Gojo, et al. "Phase I/II Study of the P-Glycoprotein (Pgp) Inhibitor Zosuquidar Administered by Continuous Infusion (CIV) with Daunorubicin (DNR) and Cytarabine (ARA-C) as Primary Therapy in Older Patients with Pgp-Positive Acute Myeloid Leukemia (AML)." Blood 110, no. 11 (November 16, 2007): 299. http://dx.doi.org/10.1182/blood.v110.11.299.299.
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Background: Pgp expression in AML increases with age and correlates with inferior therapeutic response and survival. Zosuquidar is a potent and highly specific Pgp inhibitor with minimal pharmacokinetic (PK) interaction with conventional xenobiotic antineoplastics. Prolonged Pgp blockade is believed necessary to optimize antineoplastic sensitization in resistant cells in vitro. We previously reported that 72-hour CIV Zosuquidar at 700 mg/d resulted in rapid and sustained Pgp inhibition during the entire period of anthracycline administration in Pgp+ AML (Lancet, et al. ASH 2006). Methods: We report interim results from a Phase I/II trial of 72-hr CIV zosuquidar in older adults with newly diagnosed Pgp+ AML. Primary objective: to determine the response (CR + CRp) rate in Pgp+ patients. Eligibility included ages 55–75, ECOG PS 0-2, adequate end-organ function, and Pgp+ by functional assay. Zosuquidar was initiated 4 hrs prior to the first doses of DNR (45 mg/m2/d x 3d) and ARA-C (100 mg/m2/d CIV x 7d) and continued for 72 hrs. Reinduction with the same dosing schedule was permitted in patients with significant cytoreduction without aplasia. Patients who achieved a CR/CRp received up to 2 cycles of consolidation with the same agents using an abbreviated schedule. Results: 67 patients with Pgp+ AML were enrolled on the study; 80 patients were included in the safety analysis. Sixty-two of the 67 Pgp+ patients received Zosuquidar at 700 mg/day, while 5 received 800 mg/day (during phase I). Median age was 66; M/F was 46/21; cytogenetics: adverse (19), intermediate (29), and unknown/not done (19); de novo/secondary AML: 36/31. Mean percentage of planned Zosuquidar actually administered was 94%. CR/CRp was achieved in 32 of 66 (48%) evaluable Pgp+ patients (CR=25, CRp=7). Fifteen of 31 (48%) patients with secondary AML, and 6 of 19 (32%) with adverse-risk cytogenetics achieved CR/CRp. Eight of 14 (57%) patients age ≥ 70 responded. Induction-related death (< 30 days) occurred in 10% of patients. Other common toxicities included infection/febrile neutropenia (89%), tremor (42%), hallucinations (11%), nausea (52%), and diarrhea (51%). Median times to neutrophil (≥ 1000/μL) and platelet (≥ 100,000/μL) recovery were 34 and 33 days, respectively. With a median followup of 7.5 months, the median overall survival was 8.9 months and the median relapse-free survival was 9.3 months. Conclusions: CIV Zosuquidar 700 mg/d with DNR and ARA-C is well tolerated, with signs of clinical benefit in poor-risk older patients with Pgp+ AML, warranting continued study of this combination. Accrual to the current trial is ongoing.
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Rivas Fuenzalida, Tomás Antonio, Daniel Orizano, Sandra Cuadros, Yisela Quispe-Flores, and Katherine Burgos-Andrade. "BREEDING ECOLOGY, NESTING HABITAT AND THREATS TO A BLACK-AND-CHESTNUT EAGLE SPIZAETUS ISIDORI POPULATION IN THE MONTANE FORESTS OF CENTRAL PERU." Ornitología Neotropical 34, no. 1 (June 29, 2023): 62–70. http://dx.doi.org/10.58843/ornneo.v34i1.1097.
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The Black-and-chestnut Eagle Spizaetus isidori is an endangered and little-known top predator of South American montane forests. To better understand the breeding ecology and threats of this eagle, we studied several pairs between 2017 and 2022 in the central Andes of Peru. We recorded 62 adults, one immature, and 36 juveniles in 36 territories. These territories were in mountainous areas (altitudinal range 690–3,810 m a.s.l.), widely covered by montane forests (43.8–99.7% cover), and secondarily by open land (0.3–56.2% cover), far from urban settlements (1.3–27.1 km). Nesting sites (N = 15) were at medium altitudes (1,330–2,330 m a.s.l.) in steep hillsides or ravines (15–55°), having no preferential cardinal orientation, and relatively close to permanent water courses (20–800 m), open areas (30–930 m) and sites with human activity (120–2,200 m). Nests (N = 15) were placed at the top of tall (28–40 m) and thick-stemmed (DBH range 0.53–1.52 m) emergent trees of nine genera, with Ficus and Juglans being the most used. Incubation and brood-rearing occurred during the dry season (Mar–Nov). The wooded slopes where the eagles nested are being replaced by crops and livestock pastures, causing an estimated loss of 218.2 km2 of forest cover in our study area (5,056 km2) during the last 20 years. We detected human persecution in 55.5% of the territories, resulting in 26 juveniles, four adults, two immatures, and nine unaged eagles killed. Preventing the local extinctions of these eagles will require long-term population monitoring, improving knowledge of its ecology, mitigation of human-eagle conflict, development of education programs, and strengthening of land use inspection.
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Ye, Dingwei, Jun Guo, Jae-Lyun Lee, Ai-Ping Zhou, Yiran Huang, Zhiquan Hu, Cheng Fu, et al. "Sorafenib treatment of Asian patients with advanced renal cell carcinoma (RCC) in daily practice: Subset analysis of the large non-interventional PREDICT study." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): 4628. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.4628.
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4628 Background: Previous studies with sorafenib in Asian patients with advanced RCC were relatively small and used strict entry criteria. Here we investigated safety and efficacy in a large subset of Asian patients in the prospective, non-interventional PREDICT study of sorafenib in routine practice (NCT 00895674). Methods: Patients were eligible based on a diagnosis of advanced RCC and the decision by the investigator to prescribe sorafenib under compliance of the local product label. Tumor status, patients’ performance and physician assessment of efficacy and tolerability were collected up to 12 months. Results: Between Jan 2007 and June 2010, 1092 patients were enrolled in China (n=1033), South Korea (n=55), the Philippines (n=3) and Indonesia (n=1). In the efficacy population (n=909), baseline characteristics were: 71% male; 89% <70 years old; 89% clear cell histology; 78% prior nephrectomy; 56% prior systemic therapy; 16% high MSKCC risk; 35% ECOG PS ≥2; 5% brain metastases. Overall, 19% of patients had ≥1 concomitant disease at baseline; the most frequent concomitant diseases were hypertension (14%) and diabetes (6%). Initial sorafenib dose was 800 mg daily in 97% of patients, of whom 91% were also receiving 800 mg daily as last dose. Median duration of sorafenib treatment was 9.7 months (range 0.2–24.1), and in clinically relevant subgroups was as follows: treatment-naïve, 9.7 months; high MSKCC risk, 9.3 months; brain metastases, 8.4 months; age ≥70 years, 7.6 months; ECOG PS 2, 9.7 months; ECOG PS 3, 6.1 months. At last follow up, 63% of physicians reported good/very good efficacy and 59% good/very good tolerability. Sorafenib was well tolerated; <2% of the safety population (n=1022) reported serious drug-related adverse events (SDRAEs) and only 3% discontinued due to DRAEs. In all, 35% of patients reported a DRAE, with the most frequent being hand-foot skin reaction (21%), diarrhea (7%), rash (7%), alopecia (5%), hypertension (3%). Conclusions: In this large subset of Asian patients with advanced RCC treated in daily practice settings, sorafenib was well tolerated and provided benefit, including in clinically relevant patient subgroups.
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Damião, Inês Perdigão, and Pedro Guilherme Rocha dos Reis. "Percepções dos alunos sobre o desenvolvimento de exposições científicas como estratégia de ativismo (Students 'perceptions about the development of scientific exhibitions as an activism strategy)." Revista Eletrônica de Educação 15 (November 30, 2021): e4911050. http://dx.doi.org/10.14244/198271994911.
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e4911050The current situation of planet Earth reiterates the need for a science education capable of promoting active citizenship, based on scientific knowledge, that can contribute to solving social and environmental problems. This case study, of a qualitative nature, aimed to study the perceptions of Biology and Geology students about the educational potential of developing a scientific exhibition on the theme "Anthropic Occupation and Planning Problems" as a strategy of activism. Twenty-five 11th grade students from a public school outside Lisbon (Portugal) participated in this study. The students developed a scientific exhibition during a three weeks project and, at the end, presented that exhibition to the school community for one week. Data was collected, during the week following to the exhibition, through one questionnaire with open-ended and close-ended items. The results indicate that, in the students' opinion, the strategy used allowed the development of competences in the domains of knowledge, reasoning, communication, attitudes, creativity and activism.ResumoA situação atual do planeta Terra reitera a necessidade de uma educação em ciências capaz de promover uma cidadania ativa fundamentada em conhecimento científico que possa contribuir para a resolução de problemas sociais e ambientais. Neste estudo de caso, de natureza qualitativa, pretendeu-se estudar as percepções de alunos de Biologia e Geologia sobre as potencialidades educativas do desenvolvimento de uma exposição científica sobre a temática “Ocupação Antrópica e Problemas de Ordenamento” como estratégia de ativismo. Participaram 25 alunos de uma turma de 11.º ano de uma escola pública dos arredores de Lisboa, Portugal. Os alunos trabalharam em projeto durante três semanas, para planearem e elaborarem uma exposição científica que, por fim, foi aberta à comunidade escolar durante uma semana. No processo de recolha de dados, realizado na semana após a conclusão da exposição, foi utilizado um questionário constituído por itens de resposta fechada e de resposta aberta. As respostas às questões de resposta aberta foram submetidas a análise de conteúdo de tipo categorial. Relativamente às questões fechadas foram calculadas as percentagens das respostas obtidas em cada um dos níveis da escala. Os resultados obtidos indicam que, na opinião dos alunos, a estratégia utilizada permitiu o desenvolvimento de competências nos domínios do conhecimento, raciocínio, comunicação, atitudes, criatividade e ativismo.Palavras-chave: Ativismo, Exposições Científicas, Educação em Ciências.Keywords: Activism, Scientific exhibitions, Science Education.ReferencesALSOP, Steve; BENCZE, Larry. Activism! Toward a more radical science and technology education. In: Activist science and technology education. Springer, Dordrecht, 2014.APOTHEKER, Jan; BLONDER, Ron; AKAYGUN, Sevil; REIS, Pedro; KAMPSCHULTE, Lorenz; LAHERTO, Antti. Responsible Research and Innovation in secondary school science classrooms: experiences from the project Irresistible. Pure and Applied Chemistry, v. 89, n. 2, 2017.AZINHAGA, Patrícia Fialho; MARQUES, Ana Rita; REIS, Pedro; TINOCA, Lui?s; BAPTISTA, Mo?nica. A construção de exposições científicas: perceções dos alunos sobre as competências desenvolvidas e impacto na motivação e ambiente em sala de aula. Enseñanza de las ciencias, 2017. Disponível em: https://ddd.uab.cat/record/183633?ln=ca" https://ddd.uab.cat/record/183633?ln=ca. Acesso: 21 fev. 2019.BENCZE, J. Lawrence; SPERLING, Erin R. Student teachers as advocates for student-led research-informed socioscientific activism. 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Lisboa: Departamento da Educação Básica, Ministério da Educação (41-66), 2002.GALVÃO, Cecília; FREIRE, Sofia, FARIA, Cláudia, BAPTISTA, Mónica, REIS, Pedro. Avaliação do currículo das ciências físicas e naturais: percursos e interpretações. Avaliação do currículo das ciências físicas e naturais: percursos e interpretações, 2017.GALVÃO, Cecília; NEVES, Adelaide; FREIRE, Ana; LOPES, Ana Maria; SANTOS, Maria da Conceição; VILELA, Maria da Conceição; OLIVEIRA, Maria Teresa. Ciências Físicas e Naturais: Orientações Curriculares 3. Ciclo do Ensino Básico. Lisboa: Ministério da Educação, 2006.GONÇALVES, Teresa Paula Nico Rego. Investigar em educação: Fundamentos e dimensões da investigação qualitativa. In: Investigar em educação: desafios da construção de conhecimento e da formação de investigadores num campo multireferenciado. Lisboa: Faculdade de Ciências e Tecnologia da Universidade Nova de Lisboa, 2010, p. 39-62.GRAY, David. Pesquisa no Mundo Real. Porto Alegre: Penso, 2012.HAWKEY, Roy. Innovation, inspiration, interpretation: museums, science and learning. Ways of Knowing Journal, v. 1, n. 1, p. 23-31, 2001.HODSON, Derek. Going beyond STS: Towards a Curriculum for Sociopolitical Action. Science Education Review, v. 3, n. 1, p. 2-7, 2004.HODSON, Derek. Book Review: Looking to the Future: Building a Curriculum for Social Activism. 2011.HODSON, Derek. Becoming part of the solution: Learning about activism, learning through activism, learning from activism. In: Activist science and technology education. Springer, Dordrecht, 2014. p. 67-98.KARAHAN, Engin. Constructing media artifacts in a social constructivist learning environment to enhance students’ environmental awareness and activism. 2012. Tese de Mestrado.KARAHAN, Engin; ROEHRIG, Gillian. Constructing media artifacts in a social constructivist environment to enhance students’ environmental awareness and activism. 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Disponível em: https://ddd.uab.cat/record/183618?ln=ca.Acesso: 21 fev. 2019.MERRIAM, Sharan. Case study research in education: a qualitative approach. San Francisco: Jossey-Bass, 1988.MORAIS, Carla; PAIVA, João. Simulação digital e actividades experimentais em Físico?Químicas. Estudo piloto sobre o impacto do recurso “Ponto de fusão e ponto de ebulição” no 7. º ano de escolaridade. Sisifo, n. 3, p. 101-112/EN 97-108, 2007.PERRENOUD, Philippe. O que fazer da ambiguidade dos programas escolares orientados para as competências. Pátio. Revista pedagógica, v. 23, p. 8-11, 2002.REIS, Pedro. Da discussão à ação sociopolítica sobre controvérsias sócio-científicas: uma questão de cidadania. Revista ENCITEC, v. 3, n. 1, p. 1-10, 2013.REIS, Pedro. Promoting students’ collective socio-scientific activism: Teachers’ perspectives. In: Activist science and technology education. Springer, Dordrecht, 2014. p. 547-574.REIS, Pedro. Cidadania Ambiental e ativismo juvenil. ENCITEC. Ensino de Ciências e Tecnologia em Revista, v. 11, n. 1, p. 5-24, 2021.REIS, Pedro; MARQUES, Ana Rita. As exposições como estratégia de ação sociopolítica: Cenários do projeto IRRESISTIBLE. As exposições como estratégia de ação sociopolítica: Cenários do projeto IRRESISTIBLE, 2016. Disponível em: http://hdl.handle.net/10451/24686. Acesso: 21 fev. 2019.ROTH, Wolff-Michael. Learning science in/for community. Comunicac?a?o apresentada no Congreso Ensen?anza de las Cie?ncias, Barcelona. Anais. 2001SADLER, Troy D.; DAWSON, Vaille. Socio-scientific issues in science education: Contexts for the promotion of key learning outcomes. In: Second international handbook of science education. Springer, Dordrecht, 2012. p. 799-809.SADLER, Troy D.; FOWLER, Samantha R. A threshold model of content knowledge transfer for socioscientific argumentation. Science Education, v. 90, n. 6, p. 986-1004, 2006.SANTAMARÍA GONZÁLEZ, Fernando. Redes sociales y comunidades educativas. Posibilidades pedagógicas. Telos, v. 76, 2008.SANTAMARÍA GONZÁLEZ, Fernando. Redes sociales educativas. Nuevas tendencias de e-learning y actividades didácticas innovadoras. Madrid: Landeta CEF, 2010.SCHEID, Neusa Maria John; REIS, Pedro. As tecnologias da informação e da comunicação e a promoção da discussão e ação sociopolítica em aulas de ciências naturais em contexto português. Ciência Educação (Bauru), v. 22, n. 1, p. 129-144, 2016.SPERLING, Erin; BENCZE, John Lawrence. “More Than Particle Theory”: Citizenship Through School Science. Canadian journal of science, mathematics and technology education, v. 10, n. 3, p. 255-266, 2010.UNESCO. A cie?ncia para o se?culo XXI: uma nova visa?o e uma base de ac?a?o. Brasi?lia: UNESCO, ABIPTI. 2003.VON AUFSCHNAITER, Claudia; ERDURAN, Sibel; OSBORNE, Jonathan; SIMON, Shirley. Arguing to learn and learning to argue: Case studies of how students' argumentation relates to their scientific knowledge. 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Rocha, Silvana Cruz da, and Marguerite Quoirin. "Calogênese e rizogênese em explantes de mogno (Swietenia macrophylla King) cultivados in vitro." Ciência Florestal 14, no. 1 (March 30, 2005): 91. http://dx.doi.org/10.5902/198050981785.
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A exploração de árvores tropicais realizada de forma indiscriminada, buscando espécies de alto valor econômico, tem levado várias espécies, como o mogno (Swietenia macrophylla King), ao perigo de extinção. O desenvolvimento de uma metodologia de regeneração de gemas, direta ou indireta, poderia auxiliar na obtenção de um grande número de mudas e constituir uma perspectiva à propagação sexuada. Essa última é limitada pelo fato das sementes perderem rapidamente a capacidade germinativa. No presente trabalho, foram utilizados dois tipos de explantes: fragmentos foliares e de raízes de plantas cultivadas in vitro. Após desinfestação, os explantes foram colocados em meio de cultura de Murashige e Skoog (1962) contendo três quartos da concentração de sais, vitaminas do mesmo meio, 30g.L-1 de sacarose, auxina (ácido naftaleno-acético, ANA, 0,11 µM e 0,54 µM), citocinina (cinetina, CIN, 1,2 µM, 2,3 µM, 4,7 µM e 9,3 µM; 6-benziladenina, BA, 2,2 µM, 4,4 µM e 8,8 µM ou 2-isopenteniladenina, 2-iP, 2,5 µM) e 7g.L-1 de ágar. As variáveis testadas foram a concentração e o tipo de regulador de crescimento e a origem dos explantes. A cada 30 dias, os explantes foram avaliados pela contagem do número de explantes formando calos ou raízes e a consistência dos calos. Foram obtidos calos a com base nos dois tipos de explantes. Nos explantes foliares, 90% deles formaram calos em meios de cultura contendo BA 4,4 µM com ANA 0,54 µM e BA 8,9 µM com ANA 0,11 ou 0,54 µM. Nos explantes de raízes, a maior percentagem de explantes com calos foi de 55%, no meio de cultura com BA 2,2 µMe ANA 0,54 µM. Raízes adventícias foram obtidas partindo de calos e do limbo dos explantes foliares, em meios de cultura com CIN e ANA. Não foi observada a formação de gemas adventícias.
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Tamarit-Urias, Juan Carlos, Gerónimo Quiñonez-Barraza, Xavier García-Cuevas, Jonathan Hernández-Ramos, and José Carlos Monárrez-González. "Ecuación dinámica para estimar el crecimiento en diámetro de Pinus montezumae Lamb. en Puebla, México." Madera y Bosques 27, no. 3 (December 23, 2021): e2732180. http://dx.doi.org/10.21829/myb.2021.2732180.
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El diámetro normal tiene correlación alta con otros atributos del árbol y del rodal, por tanto, su modelación es relevante. El objetivo de este trabajo fue desarrollar una ecuación dinámica para estimar, en función de la edad, el crecimiento e incremento en diámetro normal de árboles de Pinus montezumae. Se utilizó una muestra de 81 árboles colectados en la región “Ixta-Popo” de Puebla, México y se aplicó la técnica de análisis trocal. Se evaluó la calidad de ajuste de seis ecuaciones dinámicas expresadas en diferencia algebraica (DA) y en su generalización (DAG). La mejor ecuación fue seleccionada usando criterios estadísticos y análisis gráficos, esta se basó en un modelo de crecimiento de Korf expresado en DAG, que posteriormente se ajustó con el método de variables artificiales y se corrigió la autocorrelación y la heterocedasticidad. Esta ecuación presentó alta precisión y exactitud (RCME = 2.393 cm, sesgo = 0.055 cm); se usó para construir una familia de curvas de crecimiento con base en el índice de diámetro normal (IDn) para determinar el crecimiento corriente y medio anual (ICA e IMA), así como el tiempo de paso (TP) por categoría diamétrica (CD). Para una condición promedio (IDn = 37 cm), el ICAmáx fue de 1 cm año-1 que corresponde a 9.33 cm de Dn y se alcanza a los 14.8 años; el IMAmáx fue de 0.79 cm año-1 que corresponde a 25 cm y sucede a la edad de 31.6 años; el TP promedio fue de 8.09 años para un intervalo de 5 cm a 55 cm con CD de 5 cm. La ecuación desarrollada puede formar parte de sistemas de crecimiento y rendimiento maderable para el manejo sustentable de esta especie en la zona de estudio.
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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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Gerasimova, D., E. Gerasimova, T. Popkova, and A. Melkumyan. "AB0257 IMPACT OF CONVENTIONAL ANTIRHEUMATIC TREATMENT ON CARDIOVASCULAR RISK IN PATIENTS WITH RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 1155.1–1155. http://dx.doi.org/10.1136/annrheumdis-2021-eular.1554.
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Background:Cardiovascular diseases (CVD) are the most common and socially significant comorbidities and the main cause of premature mortality in rheumatoid arthritis (RA). Appropriate RA therapy should not only suppress RA activity, but also reduce CVD risk.Objectives:To evaluate CVD risk and analyze its association with the use of conventional therapy in RA patients (pts).Methods:The study included 100 pts with RA (92 women and 8 men) aged 30 to 60 without established CVD. The median age was 49.5 [44.5;53] years, duration of RA was 144 [60;240] months, DAS28 was 4.4 [3.3;5.3] points. Eighty six RA pts (86%) treated with disease-modifying antirheumatic drugs (DMARDs) (methotrexate, n=55; leflunomide, n=12; hydroxychloroquine, n=8; sulfasalazine, n=11), including 33 pts (33%) in combination with glucocorticoids (GCs). Fourteen pts (14%) received monotherapy with GCs. Pts were divided into three treatment groups: DMARDs group, n=53; GCs group, n=14; DMARDs+GCs group, n=33. CVD risk was calculated with ASSIGN, QRISK3, and ERS-RA scales.Results:No differences were found between the groups when calculating CVD risk using ASSIGN (table 1). Estimated CVD risk by QRISK3 was lower in DMARDs group (4.9 [3.0; 7.7]) than in DMARDs+GCs group (7.1 [4.1; 13.6], p<0.05). High CVD risk on the ERS-RA scale was determined less frequently (13%) and median CVD risk was lower in DMARDs group (4.2 [2.2; 5.4]) than in GCs group (57%; 8.9 [4.8; 11.7], p<0.01) and DMARDs+GCs group (39%; 6.6 [3; 9.3], p<0.05, respectively). In DMARDs group, significant differences in CVD risk by ERS-RA were found in pts treated with hydroxychloroquine (2 [1.4; 5.8]) and leflunomid (6.2 [2.8; 12.3], p<0.05).Conclusion:RA pts treated with DMARDs have a reduced risk for CVD than pts treated with GCs or a combination of DMARDs and GCs. GCs significantly increase CVD risk. To clarify the impact of hydroxychloroquine and leflunomid on CVD risk, a study on a larger number of pts is required.Table 1.The impact of conventional antirheumatic therapy on CVD risk.TreatmentASSIGNQRISK3ERS-RAHigh CVD risk, %median[25-75 percentiles]High CVD risk,%median[25-75 percentiles]High CVD risk,%median[25-75 percentiles]DMARDs, n=53611 [6.5;14]24.9 [3;7.7] v13*v4.2 [2.2;5.4] *vGCs, n=1479.5 [7;13]76.6 [4.4;15.8]57*8.9 [4.8;11.7] *DMARDs+GCs, n=331510 [5;13.5]97.1 [4.1;13.6] v39v6.6 [3;9.3] vNote: * - p<0.01 between pts receiving DMARDs and GCs; v - p<0.05 between pts receiving DMARDs and DMARDs+GCs.Disclosure of Interests:None declared
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Gallienne, Alice, Helene Dreau, Anna Schuh, Chris S. R. Hatton, John Old, and Shirley Henderson. "Nine Novel Mutations in the Erythroid Transcription Factor KLF1 Gene Associated with Increased Fetal Hemoglobin Levels in Adults,." Blood 118, no. 21 (November 18, 2011): 3191. http://dx.doi.org/10.1182/blood.v118.21.3191.3191.
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Abstract Abstract 3191 Hereditary persistence of fetal hemoglobin (HPFH) is a benign condition defined as an increased proportion of fetal hemoglobin which persists beyond infancy. HPFH has been identified in a wide range of ethnic groups but is more common in populations with a high prevalence of hemoglobinopathies and thalassemias. This is thought to be due to selective pressure resulting from the ameliorating effect which HPFH can have in some of these disorders. Consequently, although it can occur as a single entity it is often observed as a co-existing condition in a variety of hemoglobin disorders. Although several well established genetic factors have been identified that can cause the HPFH phenotype, they only account for <50% of the Hb F variance observed in adults. More recently, mutations in the erythroid transcription gene KLF1 have been found to be associated with a HPFH phenotype in a single family from Malta (Borg et.al. Nat Genet. 2010; 42(9): 801–805) and in a single family from Sardinia (Satta et.al. Haematologica 2010; 96(5):767–70). We therefore decided to investigate whether KLF1 mutations could be associated with increased Hb F levels observed in patients referred to our laboratory for hemoglobinopathy investigation. 130 adult patient samples with an elevated Hb F level above 1.5% (range 1.5 – 25%) were studied for KLF1 mutations. 55 of these samples had co-existing alpha thalassemia trait, 6 were carriers for sickle cell trait, 28 were beta thalassemia carriers and 41 had no evidence of any other hemoglobinopathy. The results showed that 8% of the cohort had a mutation in the KLF1 gene. 10 different mutations which were predicted to be deleterious (PolyPhen-2 and SIFT) were identified in 10 patients, 8 of which are previously unreported (c.159_169 del GAAGTCTGAGG, c.901C→T, c.902G→A, c.939G→T, c.1001C→A, c.913+1G→A, c.526_527Ins CGGCGCC, c.152T→G). No deleterious KLF1 mutations were identified in a matched cohort of 101 samples referred for hemoglobinopathy investigation that had normal Hb F levels (<1.0%), strongly suggesting that the KLF1 mutations are associated with a HPFH phenotype. In addition, 35 sickle cell disease patients with Hb F levels greater than 10% were investigated. One further unreported deleterious KLF1 mutation (c.914–4_914–1 del CTAG) was found in a sickle cell disease patient with a Hb F level of 20.3%. Interestingly this patient appeared to have a particularly mild phenotype and maintained a hemoglobin level of 12.7g/dl. The KLF1 mutations were predominantly found in individuals of African, Indian and Southeast Asian descent, indicating that KLF1 mutations could be a widespread cause of HPFH in malarial regions where hemogobinopathies are common, possibly making a significant contribution to Hb F variance in these populations. All the mutations identified were heterozygous, with only one case of compound heterozygosity, suggesting that haploinsufficiency for KLF1 may be sufficient to increase Hb F levels. This in turn provides further in-vivo evidence that controlled reduction of KLF1 gene expression could activate fetal hemoglobin expression and provide a potential therapeutic target. Disclosures: No relevant conflicts of interest to declare.
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Montcuquet, Nicolas, Sylvain Perruche, Benjamin Shipman, Aliette Marandin-Decock, Francis Bonnefoy, Philippe Saas, Eric Robinet, and Pierre Tiberghien. "Infusion of Ex-Vivo Expanded Donor T Cells To Improve Graft-Derived T-Cell Reconstitution after Allogeneic Hematopoietic Stem Cell Transplantation." Blood 110, no. 11 (November 16, 2007): 3261. http://dx.doi.org/10.1182/blood.v110.11.3261.3261.
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Abstract Limitations resulting from the reduced availability of related donors have been solved by the development of haplo-identical transplantation or by the use of cord blood as an alternative source of hematopoietic stem cells (HSC) to the bone marrow or peripheral blood. However, these kinds of transplantation remain associated with an impaired immune reconstitution, leading to an increased risk of infection and require an efficient modulation of post-transplant alloreactivity. In this setting, we and others demonstrated the possibility to control the alloreactivity by suicide gene transfer into donor T cells after ex-vivo T-cell culture. Such ex vivo culture was associated with the acquisition of a memory-like phenotype and with a decreased alloreactivity of gene-modified T cells, leading to an impaired potential of GvHD induction in murine models of allogeneic bone marrow transplantation (BMT). Chen and al. (Blood 2004) showed in an allogeneic BMT murine models that memory T cells were less alloreactive than naive T cells, leading to a less severe GvHD, but improved the immune reconstitution as compared with mice transplanted with bone marrow cells (BMC) only. By analogy with these results, we investigated the potential of ex-vivo expanded T cells (consisting of Con-A-activated splenocytes cultured ex vivo for 12 days in the presence of 500 UI/ml IL-2) to improve immune reconstitution without inducing GvHD. As compared with recipients of T-cell-depleted (TCD) BMC only, the administration of 106ex-vivo-expanded splenocytes (T) from CD45.1 C57Bl/6 mice together with 106 TCD-BMC from CD45.2 C57Bl/6 donors into 8 Gy-irradiated Balb/c allogeneic recipients significantly increased survival of transplanted mice at day 45 (58.3% vs 23.4% for BMC + T vs BMC only; p=0.0012, log rank test). Improved survival was associated with accelerated lymphoid and myeloid reconstitution as evidenced by day 15 lymphocyte and granulocyte blood counts: 212 (median) [range: 15–991]) vs 135 [14–632] lymphocytes/μl (p=0.0220) and 802 [6–5648] vs 114 [5–2411] granulocytes/μl (p=0.0006) for BMC + T (n=61) vs BMC only (n= 55). Importantly, FACS analysis demonstrated that enhanced lymphoid and myeloid reconstitution induced by ex-vivo expanded donor T-cells was due to enhanced donor bone-marrow-derived cells (lymphocyte and granulocyte blood counts: 129 [0–932] vs 11 [0–603] lymphocytes/μl (p=0.0014) and 801 [2–5637] vs 114 [2–2409] granulocytes/μl (p=0.0007) for BMC + T vs BMC only) and not ex-vivo expanded donor cells or residual recipient cells. Within the lymphoid compartment, enhanced reconstitution was observed mainly for CD3+CD8+ cells. Co-infusion of ex-vivo expanded donor T-cells did not induce GvHD (no GvHD-induced mortality or weight loss) while co-infusion of fresh splenocytes from CD45.1 C57Bl/6 mice induced severe GvHD (p<0.001 vs BMC only). Our results establish that ex-vivo expanded donor T-cells have a graft-facilitating effect and that they could be considered as a new cell therapy product allowing improving immune reconstitution after hematopoietic stem cell transplantation. Mechanisms involved in this graft-facilitating effect of ex-vivo expanded donor T cells remain to be elucidated.
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Kawada, Tatsuya, Satoshi Watanabe, Riyan Achmad Budiman, Keiji Yashiro, Kazuhisa Sato, Toshiyuki Hashida, Yuta Kimura, et al. "(High-Temperature Energy, Materials, & Processes Division Subhash Singhal Award) From Electrochemical to Mechanical Modeling of SOFCs and Their Experimental Validation." ECS Meeting Abstracts MA2023-01, no. 54 (August 28, 2023): 7. http://dx.doi.org/10.1149/ma2023-01547mtgabs.
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Due to the asymmetric structure with multiple materials, SOFCs are subjected to various modes of mechanical stress, resulting in a risk of failure. Of particular importance are thermal and chemical strains, which depend on the micro- and macroscopic distribution of electrochemical reaction sites. Therefore, SOFC modeling must include electrochemistry, mass and charge transport, thermo-fluid dynamics, and structural analysis. In addition, appropriate experiments must be performed to validate the modeling results. This research group is working to develop a comprehensive environment for modeling and validation in order to evaluate the mechanical reliability of SOFCs. Electrochemical modeling of cathode was made based on the defect chemistry and mass transport of (La,Sr)CoO3 (LSC) and (La,Sr)(Co,Fe)O3 (LSCF). An empirical equation for the surface reaction of the porous electrode was determined by electrochemical analysis of a dense film electrode taking into account the difference between the dense film and porous electrodes [1]. Anode reaction rate on a unit length of triple phase boundary of Ni-YSZ-gas was determined using circular Ni model electrodes of various size [2]. Evaluation of 3D oxygen potential distribution inside the constituent oxides was made using an in-house code called SIMUDEL where mixed ionic/electronic conduction and oxygen nonstoichiometry were taken into consideration [3,4]. It was combined with commercial software to make structural analysis. Mechanical properties used for calculation were obtained from measurements by the resonance method and the small punch method or collected from the literature. Non-linear stress-strain behaviors were observed with Ni-YSZ cermet [5] and inelastic behaviors were found in most nonstoichiometric oxide materials. Large ferro-elasticity emerged in the LSC and LSCF [6] and in Sc stabilized ZrO2 electrolyte at elevated temperatures. Chemical strain in vacancy formation was formulated with a linear function of the defect concentration as an independent factor from the thermal expansion. In the structural analysis, it was treated as the additional temperature change of the local material. Volume change of Ni-YSZ cermet on red-ox operation was a difficult factor to formulate because of its complex dependence on composition, temperature, and atmosphere. As expected, Ni-YSZ showed expansion when oxidized, but under certain conditions at an intermediate temperature range, it rather contracted on oxidation [7]. In reality, the calculated stress distribution does not always match the actual behavior of the cell since there often are unconsidered factors. Thus, experimental validation is essential. For this purpose, we have developed methods for in-situ or operando measurements of cell shape and the residual stress. Long-focus laser profilometer was used to measure the warping of a planar cell during heating, operating, and cooling operations. For the change in the diameter of a tubular cell, the laser projection type dimension meter was employed. Residual stress measurements were made with a handy X-ray analyzer (μ-X360s, Pulstec Industrial. Co. Ltd.) combined with a newly developed one- or two-chamber cell holder [8,9]. Anode-supported cells from multiple sources were analyzed, showing different stress histories in red-ox operations depending on the microstructure of the anode support layer. Currently, we are developing a protocol for testing robustness of planar SOFCs. Here, temperature distribution is intentionally applied on a cell with segmented heater allays on the top and the bottom of the cell. Severe condition tests will be performed, and the results will be analyzed with the above-mentioned simulation. Acknowledgement This study was supported by the New Energy and Industrial Technology Development Organization (NEDO) . [1] T. Kawada, Current Opinion in Electrochemistry, 21, 274-282 (2020) DOI: 10.1016/j.coelec.2020.03.016 [2] M. Takeda, Master’s thesis, Graduate School of Environmental Studies, Tohoku University (2016) : M. Takeda, et al. Submitted to J. Electrochem. Soc. [3] K. Terada, et. al., ECS Trans. 35(2 part2), 923-933 DOI: 10.1149/1.3570073 [4] M. Sato, et. al., Trans. Jpn. Soc. Comp. Eng. Sci. 2017, 14 (2017) DOI: 10.11421/jsces.2017.20170004 [5] S. Watanabe et al., J. Mater. Sci. 55, 8679-8693 (2020) DOI: 10.1007/s10853-020-04624-4 [6] Y. Kimura et al., J. Electrochem. Soc. 161(11), F3079- F3083 (2014) DOI: 10.1149/2.0131411jes [7] Y. Morishita et al. , ECS Trans., 91(1) 1979-1984 (2019). DOI: 10.1149/09101.1979ecst [8] K. Yashiro et al., submitted to J. Power Sources [9] K. Oshima et al.,ECS Trans. 103(1), 1251-1260 (2021) DOI: 10.1149/10301.1251ecst
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Ali, Myzoon, Kathryn VandenBerg, Linda J. Williams, Louise R. Williams, Masahiro Abo, Frank Becker, Audrey Bowen, et al. "Predictors of Poststroke Aphasia Recovery." Stroke 52, no. 5 (May 2021): 1778–87. http://dx.doi.org/10.1161/strokeaha.120.031162.
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Background and Purpose: The factors associated with recovery of language domains after stroke remain uncertain. We described recovery of overall-language-ability, auditory comprehension, naming, and functional-communication across participants’ age, sex, and aphasia chronicity in a large, multilingual, international aphasia dataset. Methods: Individual participant data meta-analysis of systematically sourced aphasia datasets described overall-language ability using the Western Aphasia Battery Aphasia-Quotient; auditory comprehension by Aachen Aphasia Test (AAT) Token Test; naming by Boston Naming Test and functional-communication by AAT Spontaneous-Speech Communication subscale. Multivariable analyses regressed absolute score-changes from baseline across language domains onto covariates identified a priori in randomized controlled trials and all study types. Change-from-baseline scores were presented as estimates of means and 95% CIs. Heterogeneity was described using relative variance. Risk of bias was considered at dataset and meta-analysis level. Results: Assessments at baseline (median=43.6 weeks poststroke; interquartile range [4–165.1]) and first-follow-up (median=10 weeks from baseline; interquartile range [3–26]) were available for n=943 on overall-language ability, n=1056 on auditory comprehension, n=791 on naming and n=974 on functional-communication. Younger age (<55 years, +15.4 Western Aphasia Battery Aphasia-Quotient points [CI, 10.0–20.9], +6.1 correct on AAT Token Test [CI, 3.2–8.9]; +9.3 Boston Naming Test points [CI, 4.7–13.9]; +0.8 AAT Spontaneous-Speech Communication subscale points [CI, 0.5–1.0]) and enrollment <1 month post-onset (+19.1 Western Aphasia Battery Aphasia-Quotient points [CI, 13.9–24.4]; +5.3 correct on AAT Token Test [CI, 1.7–8.8]; +11.1 Boston Naming Test points [CI, 5.7–16.5]; and +1.1 AAT Spontaneous-Speech Communication subscale point [CI, 0.7–1.4]) conferred the greatest absolute change-from-baseline across each language domain. Improvements in language scores from baseline diminished with increasing age and aphasia chronicity. Data exhibited no significant statistical heterogeneity. Risk-of-bias was low to moderate-low. Conclusions: Earlier intervention for poststroke aphasia was crucial to maximize language recovery across a range of language domains, although recovery continued to be observed to a lesser extent beyond 6 months poststroke.
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Chatzivassiliou, E. K., V. Giavachtsia, A. H. Mehraban, K. Hoedjes, and D. Peters. "Identification and Incidence of Iris yellow spot virus, a New Pathogen in Onion and Leek in Greece." Plant Disease 93, no. 7 (July 2009): 761. http://dx.doi.org/10.1094/pdis-93-7-0761a.
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Iris yellow spot virus (IYSV; genus Tospovirus, family Bunyaviridae) is an emerging and serious pathogen affecting several Allium spp. worldwide (2). The virus causes straw-colored, chlorotic or necrotic lesions that coalesce, occasionally resulting in an extensive necrosis on onion (A. cepa L.) leaves. From February to June 2008, 530 onion and 439 leek (A. porum L.) leaf samples showing a variety of lesions were collected from different areas of Greece. All plants sampled were infested with Thrips tabaci Lindeman, the sole thrips species identified as the vector of this virus. Samples were analyzed by double-antibody sandwich (DAS)-ELISA using polyclonal antibodies against the N protein of IYSV (Laboratory of Virology, Wageningen Agricultural University). A higher percentage of onion samples than leek samples were infected, with IYSV detected in 36, 44, 23.7, 61.7, 10, 55, 15.3, and 9.4% of onion samples from the prefectures of Evros, Heraklion, Kavala, Magnissia, Pella, Rodopi, Thessaloniki, and Viotia, respectively, and in 5, 0, 0, 9.3, and 13% of leek samples from Evros, Heraklion, Magnissia, Pella, and Thessaloniki, respectively. No leek samples were tested from Kavala, Rodopi, and Viotia. Sap extracts from some positive samples were mechanically inoculated onto Nicotiana benthamiana leaves, and infected plants developed typical IYSV symptoms and were positive in DAS-ELISA, confirming transmission from the field samples. Viral RNA was extracted from ELISA-positive onion and leek samples and an ~800-bp amplicon was obtained from both hosts by reverse-transcription (RT)-PCR and N-gene primers derived from IYSV (IY1: 5′-CCCGAGGATCCATGGCTACCGTTAGGG-3′ and IY2: 5′-CCCGAGGATCCAAATTAATTATATCTATCTTTCTTGG-3′) (1). These amplicons were cloned and sequenced (GenBank Accession No. FJ785835) and nucleotide sequence comparisons showed a 98 to 99% identity with a Dutch isolate of IYSV (GenBank Accession No AF001387). The virus was transmitted among onion seedlings in the laboratory using a leek population of T. tabaci. Infected seedlings, as determined by DAS-ELISA, developed symptoms similar to those observed in the field samples. To our knowledge, this is the first report of IYSV in Greece; however, the virus seems already to be very well established. References: (1) I. Cortez et al. Phytopathology 88:1276, 1998. (2) D. Gent et al. Plant. Dis. 90:1468, 2006.
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Kazama, Tomiei, Kazuyuki Ikeda, and Koji Morita. "Reduction by Fentanyl of the Cp50Values of Propofol and Hemodynamic Responses to Various Noxious Stimuli." Anesthesiology 87, no. 2 (August 1, 1997): 213–27. http://dx.doi.org/10.1097/00000542-199708000-00007.
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Background Propofol and fentanyl infusion rates should be varied according to the patient's responsiveness to stimulation to maintain satisfactory anesthetic and operative conditions. However, somatic and autonomic responses to various noxious stimuli have not been investigated systematically for intravenous propofol and fentanyl anesthesia. Methods Propofol and fentanyl were administered via computer-assisted continuous infusion to provide stable concentrations and to allow equilibration between plasma-blood and effect-site concentrations. The propofol concentrations needed to suppress eye opening to verbal command and motor responses after 50-Hz electric tetanic stimulation, laryngoscopy, tracheal intubation, and skin incision in 50% or 95% of patients (Cp50 and Cp95) were determined at fentanyl concentrations of 0.0, 1.0, 2.0, 3.0, and 4.0 ng/ml in 133 patients undergoing lower abdominal surgery. The ability of propofol with fentanyl to suppress hemodynamic reactions in response to various noxious stimuli also was evaluated by measuring arterial blood pressure and heart rate before and after stimulation. Results The various Cp50 values for propofol alone (no fentanyl) for the various stimuli increased in the following order: Cp50loss of consciousness, 4.4 microg/ml (range, 3.8-5.0); Cp50tetanus, 9.3 microg/ml (range, 8.3-10.4); Cp50laryngoscopy, 9.8 microg/ml (range, 8.9-10.8); Cp50skin incision, 10.0 microg/ml (range, 8.1-12.2); and Cp50intubation, 17.4 microg/ml (range, 15.1-20.1; 95% confidence interval). The reduction of Cp50loss of consciousness, with fentanyl was minimal; 11% at 1 ng/ml of fentanyl and 17% at 3 ng/ml of fentanyl. A plasma fentanyl concentration of 1 ng/ml (3 ng/ml) resulted in a 31-34% (50-55%) reduction of the propofol Cp50s for tetanus, laryngoscopy, intubation, and skin incision. Propofol alone depresses prestimulation blood pressure but had no influence on the magnitude blood pressure or heart rate increase to stimulation. Propofol used with fentanyl attenuated the systolic blood pressure increases to various noxious stimuli in a dose-dependent fashion. Conclusions The authors successfully defined the propofol concentration required for various stimuli. Tracheal intubation was the strongest stimulus. The absence of somatic reactions for propofol does not guarantee hemodynamic stability without fentanyl. Propofol with fentanyl was able to suppress motor and hemodynamic reactions to various noxious stimuli.
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Medina, A., M. Calle, R. Eraso, L. Hernandez, J. S. Peinado Acevedo, M. Velasquez, A. Vanegas, D. Jaramillo Arroyave, and C. Muñoz. "FRI0468 SYSTEMIC AND CUTANEOUS POLYARTERITIS NODOSA IN COLOMBIAN PEDIATRIC PATIENTS: CUTANEOUS POLYARTERITIS IS NOT SO BENIGN." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 831.3–831. http://dx.doi.org/10.1136/annrheumdis-2020-eular.6512.
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Background:Polyarteritis nodosa (PAN) is the third most frequent vasculitis in pediatrics, Cutaneous PAN (CPAN) being more common that Systemic PAN (SPAN). CPAN is frequently described as a benign disease. In children, PAN onset is frequent between 9 and 11 years of age, with no sex differences, and its clinical features may be nonspecific.Objectives:To characterize pediatric patients who were diagnosed with CPAN and SPAN and to compare their clinical features, treatments, and outcome.Methods:A descriptive study was conducted in two centers from Medellin- Colombia, using retrospective data from January 2010 to December 2019. Patients under 18 years of age classified as PAN according to EULAR/PRINTO/PRES(1) criteria were included. CPAN patients were defined according to EULAR/PRES definition (2). Data from medical records were registered, and were expressed in median and ranges and mean and standard deviation (SD) according to their distribution. A univariate analysis was carried out by comparing signs, symptoms, and treatment between CPAN and SPAN, and ap-value < 0,05was considered as significant.Results:Twenty patients were included. The median age at diagnosis was ten years. 60% were boys. The median follow-up period was 27 months. CPAN was diagnosed in 11 (55%) and SPAN in 9 patients (45%). The most frequent symptoms were cutaneous manifestations (95%), fever (60%) and Calf Pain (55%). Mucosal ulcers were described in four patients; 3 of them were defined as CPAN. Lingual necrosis was present in two CPAN, and peripheral nervous system involvement was found in one SPAN and two CPAN patients in skin affected with lesions; even though, no significant statistical differences between CPAN and SPAN were found in constitutional, cutaneous, muscle-skeletal symptoms, and acute phase reactants. Arteriographic anomalies as hepatic and renal microaneurysms, carotidal aneurysms without aortic involvement, and renal infarction were found in one patient each. Skin Biopsy was performed in 18 patients, being compatible with PAN in 16. All PAN patients (CPAN and SPAN) required treatment with glucocorticoids. None of the patients died during the follow-up period.Conclusion:In this Colombian pediatric cohort of PAN patients, the disease was more common in boys than girls, and CPAN was more frequent than SPAN, as already been described. As is evident in this cohort, although CPAN has been considered a benign disease, these patients may be severely ill, requiring glucocorticoid treatment. Pediatric CPAN patients should be strictly followed with particular attention to identify systemic involvement, considering that constitutional, cutaneous, and muscle-skeletal features may be very similar between CPAN and SPAN.References:[1]Ozen S, Pistorio A, Iusan S, et al. EULAR/PRINTO/PRES criteria for Henoch-Schönlein purpura, childhood polyarteritis nodosa, childhood Wegener granulomatosis and childhood Takayasu arteritis: Ankara 2008. Part II: Final classification criteria. Ann Rheum Dis. 2010 May;69(5):798–806.[2]Ozen S, Ruperto N, Dillon M, et al. EULAR/PReS endorsed consensus criteria for the classification of childhood vasculitides. Ann Rheum Dis. 2006;65(7):936–41.Disclosure of Interests:None declared
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Magro, Elena, Rosa Gonzalo-Daganzo, Trinidad Martin-Donaire, Rocio Sanchez, Nuria Panadero, Rafael Cabrera, Carmen Regidor, et al. "Single Unit Cord Blood Transplant Supported by Third Party Highly Purified Mobilized Hematopoietic Stem Cells: Immune Reconstitution Studies." Blood 108, no. 11 (November 16, 2006): 311. http://dx.doi.org/10.1182/blood.v108.11.311.311.
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Abstract Background and Objectives: Following cord blood transplants (CBT) there is a period of severe and often prolonged immune deficiency that results in long term susceptibility to infections. Immune reconstitution is an important factor for long term survival. We analyzed the immune reconstitution of adult recipients of a single unit CBTs supported by a low number of third party donor highly purified mobilized hematopoietic stem cells (dual CB/TPD transplants), as previously described (Magro et al. Haematologica2006;91:640–8). This strategy results in transient double chimerism of CB and TPD cells and early granulocyte recovery, initially of TPD predominance. Complete CB chimerism is regularly achieved within 100 days.The objective of this study is to evaluate immune reconstitution in this CBT. Patients and Methods: Data were obtained from 19 patients between July 2004 and July 2006. Data collection was initiated at different intervals (from day −7 to +720, quartiles Q1=35, Q2=90 and Q3=210). Samples were obtained on days +15, +35, +55, +90 and monthly thereafter up to two years. By four-color flow cytometric immunophenotyping we analyzed the subsets of peripheral blood lymphocytes: CD3+/CD4+ (T helper/inducer), CD3+/CD8+ (T suppressor/cytotoxic), NK cells (CD3−/CD56+/CD16+) and B cells, as well as cells with naïve, memory and effector T-cell immunophenotypes. TREC bearing cells were analyzed by quantitative PCR in sorted CD4+ and CD8+ T cells collected from 3 months post-transplant onwards. Results: CD56+ cells recovered early after transplantation, with median absolute number counts (ANC) of 69 (range 18–307), 170 (0–366) and 159 (32–531) cells/uL in days +15, +35 and +55 samples [normal controls 153 (71–438)], representing the largest subset within the first two months (decreasing proportions of 60%, 50% and 40%, respectively). ANC of CD4 and CD8 T cells remained low for several months, progressively increasing to reach normal ranges at different intervals. Naïve CD4 and CD8 cells (CD45RO−/CD27+) start to be detected by immunophenotyping after three months post-transplantation with median ANC of 17 (12–79) and 12 (5–103) cells/uL respectively and increasing thereafter [normal controls 860 (552–1072) and 331 (227–521)]. By the end of the first year values of T cell subsets were: CD4+, 823 (16–1123) cells/uL [normal controls 872 (470–1093)]; CD8 934 (56–1174) [normal controls 371 (208–808)], with persisting predominance of the naive phenotypes and proportions of memory phenotypes slowly increasing. B cells became detectable around day +90 with median ANC of 249 (0–1934) cells/uL, rapidly reaching values within the normal range [275 (133–684)]. Transient acute GVHD was developed by six of the 19 patients. All showed a transient drop in absolute numbers of NK, T and B cells. Chimerism analysis showed initial transient double chimerism of CB and TPD cells. Complete CB chimerism was achieved between days +15 and +94 (median, +35). Results of chimerism of lymphocyte subsets and TREC are not yet available. Conclusions: Following dual CB/TPD transplants we have observed early recovery of NK and B-cells and slow development of T cells subsets and of non-naive immunophenotypes.
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Saillard, Colombe, Frederique Rousseau, Maud Cecile, Cecile Braticevic, Anne Etienne, Jerome Rey, Evelyne D'Incan, Christophe Zemmour, Norbert Vey, and Aude Charbonnier. "Evaluation of a Standardized Geriatric Assessment at Diagnosis in a Prospective Cohort of Elderly Patients with Newly Diagnosed Acute Myeloid Leukemia." Blood 132, Supplement 1 (November 29, 2018): 2671. http://dx.doi.org/10.1182/blood-2018-99-116400.
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Abstract Introduction: Acute myeloid leukemia (AML) in the elderly is a therapeutic challenge, and global evaluation of comorbidity, performance status, fitness and frailty is crucial for therapeutic decision of treatment intensity. Accurately predicting risks and benefits of available therapies is particularly difficult, as it relies on subjective criteria, no geriatric scores being validated so far. The aim of this study was to evaluate the impact of a standardized geriatric assessment at diagnosis in a prospective cohort of newly diagnosed AML in elderly patients, and to investigate correlations between geriatric scores and overall survival. Methods: All patients aged ≥ 70 years with newly diagnosed AML were prospectively included in this cohort. They all benefited from an exhaustive geriatric assessment in addition to standard AML workup, including ADL, IADL, ECOG, comorbidities, nutritional status (assessed by BMI and mini-MNA), cognitive impairment (mini-COG, mini-GDS), quality of life (QLQ-C30), functional scales (physical, role, emotional, cognitive and social functioning), symptom scales (fatigue, nausea and vomiting, pain, dyspnea, insomnia, appetite loss, constipation, diarrhea, financial difficulties) and frailty criteria (physical activity, energy visual scale, mobility, nutrition). Patients were treated according to international guidelines, with intensive chemotherapy, hypomethylating agents, subcutaneous low-dose cytarabine, palliative oral chemotherapy or best supportive care only, according to physician choice. The impact of geriatric scores on 6-months overall survival was analyzed. Results: Between 2010 and 2015, 94 patients were enrolled, including 61.7% of males and 38.3% of females. Median age was 75.5 years (70-96). Initial median leucocytes, neutrophils, hemoglobin, and platelets counts were respectively 4.7 G/L (0.4-174), 1.3 G/L (0.1-5.4), 9.3 g/dL (5.3-13.2), 51 G/L (5-520). Median bone marrow blasts percentage was 55% (20-96). Cytogenetics was favorable, intermediate and adverse in 18%, 62% and 20% respectively. Intensive chemotherapy was chosen in 57.4% of patients, and low intensity or palliative approach in 42.6% of patients. Patients spent a median of 30.5 days in hospital (0-119), received a median of 12 (0-44) red blood cells units and 2 (0-33) platelets units. Global geriatric assessment of patients is reported in Table 1. By univariate analysis, prognostic factors associated with a reduced survival were high dementia risk (HR=3.63, 95% CI=1.4-9.3, p=0.004), high ECOG score (HR=2.1, 95% CI=1.1-4, p=0.02) and high risk of denutrition (HR=3.43, 95% CI=1.33-8.9, p=0.007), while intensive chemotherapy was associated with a better outcome (HR=0.45, 95% CI=0.2-0.9, p=0.014). Multivariate analysis identified high risk of denutrition as independently associated with reduced survival (HR=3.08, 95% CI=1.17-8.11, p=0.02). Intensive chemotherapy treatment tended to impact prognosis but was not statistically significant (HR=0.54, 95% CI=0.27-1.01, p=0.08). Conclusions: In a prospective cohort of newly diagnosed AML elderly patients, an exhaustive standardized geriatric assessment at diagnosis identified high risk patients for mortality. The most relevant prognostic factor was nutritional status, which correlated with overall survival. Other geriatric scores and scales did not impact prognosis, which highlights the difficulty of global evaluation in this population. Patients treated with intensive chemotherapy tended to have a better outcome. Disclosures No relevant conflicts of interest to declare.
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Kallmann, Boris A., Klaus Tiel-Wilck, Jennifer S. Kullmann, Ulrich Engelmann, and Andrew Chan. "Real-life outcomes of teriflunomide treatment in patients with relapsing multiple sclerosis: TAURUS-MS observational study." Therapeutic Advances in Neurological Disorders 12 (January 2019): 175628641983507. http://dx.doi.org/10.1177/1756286419835077.
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Background: Teriflunomide is a once-daily oral immunomodulatory agent approved for the treatment of relapsing–remitting multiple sclerosis (MS). We aimed to obtain data on the effectiveness, tolerability, and subject satisfaction with teriflunomide (Aubagio®) under clinical practice conditions in unselected MS patients. Methods: This work was a non-interventional, prospective, longitudinal, observational study in 307 sites in Germany. Results: A total of 1128 patients were eligible for the efficacy analysis [67.5% female; mean age (± standard deviation) 44.9 ± 9.7 years, range 20–73 years]. Time since first MS symptoms was 10.6 ± 8.2 years, and time since MS diagnosis was 8.9 ± 7.6 years. Expanded Disability Status Scale (EDSS) score at inclusion was 2.3 ± 1.5 (70.4% with score < 3.5). The mean observation period was 16.3 ± 9.1 months. A total of 75.2% had received previous disease-modifying therapies (DMTs) at any time. Of these patients, 504 (44.7%) received no DMT within 6 months of study entry, 593 patients (52.6%) had DMT discontinued prior to study entry [glatiramer acetate in 10.6%, subcutaneous interferon-beta 1a (IFNβ-1a) in 9.3%, intramuscular IFNβ-1a or IFNβ-1b in 6.6% each, azathioprine oral in 0.4%, other in 7.3%, last medication not known in 12.0%]. The mean annualized relapse rate decreased from 0.87 in the 24 months prior to study entry to 0.35 in the 24 months after study entry ( n = 468; p ⩽ 0.001). EDSS and Fatigue Severity Scale remained stable. In patients who received previous MS treatments, Treatment Satisfaction Questionnaire (TSQM-9) values (maximum = 100), for the observation at 24 months improved by 8.1 points for effectiveness, 17.0 points for convenience, and 15.3 points for global satisfaction ( p ⩽ 0.001 each, compared with study entry). In the safety cohort ( n = 1139), the proportion of patients with adverse events (AEs) of any severity was 35.8%, and with serious events 13.0%. The most frequently reported AEs were diarrhea ( n = 55), followed by MS relapse ( n = 48), hair thinning ( n = 38), and viral upper respiratory tract infection ( n = 31). Conclusions: Relapse rate was halved during the observation period in comparison with the same time period before study entry. Patient satisfaction with teriflunomide was high in this real-world observation of patients, the majority of whom switched from other DMTs. The safety and tolerability profile of teriflunomide was similar to that reported in previous clinical trials.
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Rovo, Alicia, Thomas Daikeler, Joerg Halter, Dominik Heim, Jan Dirk Studt, Michael Medinger, Caroline Arber, et al. "Late Altered Organ Function in Long Term Survivors after Allogeneic HSCT: A Paired Comparison with Their Identical Sibling Donor." Blood 112, no. 11 (November 16, 2008): 4298. http://dx.doi.org/10.1182/blood.v112.11.4298.4298.
Full textAbstract:
Abstract Long term prognosis following allogeneic hematopoetic cell transplantation (HSCT) has greatly improved over the last decades. Therefore, interest of the general health status has become a major topic in the surveillance of long term survivors. To assess health status in very long term survivors (>10 years follow-up) we conducted a prospective, single center cross-sectional study, evaluating simultaneously 44 recipients and their respective sibling donors. A comprehensive clinical and biological examination was performed. We compared here in a paired analysis the results of routine clinical chemistry tests between recipients and their respective donor (table 1). At the time of this study, recipients and donors had a median age of 44.3 (24–63) and 43.4 (22–61) years respectively, and a median time of 17.5 (11–26) years since HSCT; 22/44 (50%) recipients had chronic graft-versus-host disease (cGVHD). Performance status demonstrated that 81/88 (92%) participants had a Karnofsky Score of 100%, reflecting the overall good clinical condition of both, recipients and donors (p>0.10). However, clinical chemistry tests of the recipients were systematically abnormal, with increased C-reactive protein (CRP), liver tests, lipids, von Willebrand factor antigen (vWF), creatinine, and decreased albumin, and glomerular filtration rate (GFR), compared with the donors (p<0.05; table 1). In the recipients, increased CRP, creatinine, vWF and decreased GFR were associated with chronic GvHD (p<0.05). For the other parameters no correlation with transplant related factors were found. Furthermore, we defined a scoring system to detect organ dysfunctions. All values out of range were allocated with one point. Included parameters were: high CRP, decreased GFR, low albumin, increased vWF, abnormal liver tests and dyslipidemia We compared recipients/donors with a score of ≥2 to those with a score below this value. An abnormal score was observed in 28/44 (64%), recipients, and in 7/44 (16%) donors (p<0.0001). More recipients with cGVHD had an abnormal score (13/22; 59%) compared to recipients without (5/22; 23%; p= 0.014). In conclusion, using a unique design comparing recipients with their respective donor, we demonstrate that an altered organ function may exist in clinically healthy very long term survivors. In part, this altered organ function is attributed to cGVHD reflected by an ongoing inflammatory process even in patients off immunosuppression. The clinical significance of the altered organ function not explained by cGVHD needs to be further investigated. Table 1: Clinical chemistry parameters: comparison between long-term survivors and their respective donor (with and without GvHD). Parameter Donors N 44 Recipients P-values donors versus recipients All N 44 with GVHD N 22 without GVHD N 22 All recipients with/without GVHD C-Reactive Protein (CRP) 1.0 (0.5–38.1) 3.7 (0.5–79.2) 4.5 (0.9–79.2) 1.2 (0.5–11.0) 0.034 0.001/0.125 Creatinine 66 (45–93) 79 (44–206) 88 (55–206) 77 (44–103) 0.0001 <0.0001/0.007 Glomerular Filtration Rate (GFR) 107 (72–144) 82 (30–141) 77 (30–124) 95 (66–141) <0.0001 <0.0001/0.034 Albumin 41 (29–46) 40 (31–45) 38 (31–43) 40 (32–45) 0.009 0.021/0.361 Bilirubine 9.5 (5–29) 8.0 (5–20) 8.0 (5–17) 7.0 (5–20) 0.020 0.213/0.053 ASAT 22 (16–64) 27.5 (15–65) 26 (20–65) 28 (15–44) 0.0004 0.002/0.013 ALAT 22 (10–101) 25.5 (12–72) 27 (12–70) 23 (12–72) 0.037 0.030/0.161 Gamma-GT 18 (9–140) 31 (10–319) 30 (11–319) 32 (10–91) 0.0003 0.002/0.005 Alkaline Phosphatase 56 (32–155) 69 (39–222) 70 (39–222) 68 (41–120) 0.003 0.016/0.034 Triglicerides 1.0 (0.45–3.9) 1.5 (0.53–8.9) 1.5 (0.53–8.9) 1.6 (0.69–3.7) 0.011 0.208/0.007 Cholesterol 4.7 (3.1–9.3) 5.1 (2.7–7.8) 5.0 (2.7–7.8) 5.3 (3.7–6.4) 0.118 0.407/0.058 HDL-cholesterol 1.6 (1.0–3.2) 1.5 (0.6–2.5) 1.5 (0.6–2.5) 1.5 (1.0–2.2) 0.037 0.213/0.124 Chol/HDL-chol. Ratio 2.9 (1.7–8.6) 3.2 (1.8–8.7) 3.1 (1.8–8.7) 3.4 (1.8–5.7) 0.022 0.094/0.047 LDL-cholesterol 2.4 (1.4–7.7) 2.8 (1.07–4.8) 2.7 (1.1–4.8) 2.9 (1.1–3.9) 0.126 0.284/0.145 Von Willebrand factor Antigen (vWF) 97.5 (55–188) 126 (51–296) 139 (51–296) 108 (51–235) 0.006 0.002/0.173
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Pleyer, Lisa, Reinhard Stauder, Sonja Burgstaller, Martin Schreder, Christoph Tinchon, Michael Pfeilstocker, Susanne Steinkirchner, et al. "Report on Response and Overall Survival of 128 Unselected, Consecutive AML Patients From the Austrian Azacitidine Registry (AAR) of the AGMT-Study Group." Blood 118, no. 21 (November 18, 2011): 4266. http://dx.doi.org/10.1182/blood.v118.21.4266.4266.
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Abstract Abstract 4266 Twelve participating centers in Austria included 257 unselected, consecutive patients with MDS, CMML or AML, who received azacitidine (AZA) between 02/2007 and 07/2011, in the nationwide Austrian Azacitidine Registry (AAR) of the AGMT-study group. This registry was approved by the national Ethics Committee and includes 128 patients with AML of all FAB-subtypes, as well as de novo AML (39%), t-AML, MDS-AML and post-CMPD-AML. This registry comprises a large number of patients with >30% bone marrow blasts (83/128) (currently off-label indication for AZA), as well as myeloproliferative AML (35/128), as defined by presence of >10.000 WBC/μ l at diagnosis. The AAR includes a high proportion of very old AML patients (median age 73a, 20% 75–79a, 24% >80a). Although the PS was generally low (22% ECOG-0, 47% ECOG-1), AML patients suffered from coronary artery disease (n=29), renal insufficiency (n=26), diabetes mellitus (n=21), a prior/concomitant solid tumor (n=17), COPD (n=14) and/or mild liver disease (n=13), respectively. Only 40% of all AML-patients included were treatment-naïve, whereas the rest was pretreated with G-CSF (12%), ESA (9%), ICT (3%) revlimid or thalidomide (6%), other agents (11%) and/or intensive chemotherapy (47%), respectively. Thus, this registry more accurately reflects a real-life treatment scenario, than most clinical trials that have strict inclusion/exclusion criteria. In the 93 patients in whom pre-AZA cytogenetics were performed, 56.9%, 25.8% and 17.2% could be grouped into IPSS good, intermediate and poor risk categories, respectively. Of these, 43 patients had MDS-specific cytogenetic aberrations (5q-, +8, -7, -7q, -Y and -20q). Most AZA-cycles were applied s.c. (89%), whereas 11% were applied i.v. Median and mean number of AZA-cycles was 4.0 and 5.6 (range 1–24), respectively. 60% of patients predominantly received the FDA-approved d1-7 schedule, whereas the non-approved alternative schedules 5-2-2, d1-5 and ‘others’ were most often given in 17%, 16% and 7% of patients, respectively. The FDA-approved target dose (75mg/m2 over 7 days) was achieved in 58% of all cycles and in 61% of patients, respectively. Longitudinal repetitive analysis of serum GOT, GPT, bilirubin and creatinine over up to 24 cycles shows no relevant variation or worsening tendency of these parameters during treatment with AZA, including patients with reduced baseline renal and/or hepatic function. Reasons for termination of treatment were death for any reason (26%), disease progression or relapse (27%), no response (6%), toxicity (7%), recurrent infectious complications (2%) and other reasons (23%). Adverse events will be presented in detail (number, grade, duration, hospitalization rate, effects on AZA (dose reductions/treatment pause/termination)). Any kind of hematologic improvement (HI) was noted in 38% of patients. When looking at each lineage separately, 21/128 had HI-ery, 23/128 HI-PLT and 24/128 HI-neutrophils. 35/85 patients who were RBC-TD and 19/55 patients who were PLT-TD prior to AZA-treatment achieved transfusion independence (TI). In patients, in whom (repetitive) bone marrow analyses were performed for response evaluation (n= 56), the following best marrow responses were observed: CR (19.6%), marrow CR (7.1%), PR (33.9%), SD (30.4%) and primary PD (8.9%). At the time of writing, 35 patients had received ≤2 cycles. This number largely accounts for the patients in whom no bone marrow response evaluation was performed. The OR rate observed prior to 07/2011 was 38% (CR + marrow CR + PR + HI). When limiting response analysis to patients who received ≥2 AZA cycles, which is required for achievement of hematologic response by the IWG-criteria, ORR was 57%. The median OS was 9.5mo (95%CI 8.15–10.9). In univariate analyses, ECOG >=2 (p=.0026), circulating blasts (9.3 vs. 24.8mo; p=.0014), IPSS poor risk cytogenetics (p=.0037) and failure to achieve any HI (8.6 vs. 22.4mo; p=.0001), significantly negatively impacted OS. Prior treatment with G-CSF and/or ESA, age >80a, WBC >10G/l, BM blasts >30%, LDH >225U/l, number of cytopenic lineages as well as RBC-TD and/or PLT-TD at baseline, did not significantly impact OS (p>0.05) (detailed statistics will be presented). In conclusion, in this population of partly heavily pretreated very old patients with AML, AZA was well tolerated and yielded substantial clinical and hematological benefit, irrelevant of baseline BM blast or PB WBC count. Disclosures: Pleyer: Celgene: Research Funding. Off Label Use: Azacitidine for treatment of AML including patients with >30% bone marrow blasts. Egle:AOP Orphan Pharmaceuticals AG: Research Funding. Fridrik:Cephalon: Research Funding. Greil:AOP Orphan Pharmaceuticals AG: Research Funding.
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Bisovskaya, Yulia, Matthias Pinter, Werner Scheithauer, and Markus Peck-Radosavljevic. "Comparative outcome of sorafenib treatment in central Europe and Russia." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e14681-e14681. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e14681.
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e14681 Background: Sorafenib is the standard treatment for advanced stage HCC. Here we compare outcomes in 2 cohorts of HCC patients from two large oncologic referral centers in Russia (R) and Austria (A). Methods: 69 pts (19 f/50 m) with HCC (BCLC A/B/C/D 1/30/38/0) in R and 148 pts (27 f/121 m; n. s. between cohorts) with HCC (BCLC A/B/C/D 0/26/104/18) in A were treated with standard dose of sorafenib 400 mg bid until progression or death between 2006 and 01/2012. Dose reductions were due to side effects. Survival was evaluated using Kaplan-Meier analysis and compared by log-rank test. Prognostic factors evaluated were pretreatment BCLC stage, Child-Pugh stage, and etiology of liver disease (viral/non-viral). Results: BCLC-staging distribution was significantly different between R and A centers with more patients in advanced st BCLC-C in A (A 70% vs. R 55%, p<0.0001). Patients also had more advanced stage liver disease in A (Child-Pugh stage A/B/C = 52/37/11%) compared to R (A/B/C = 85/15/0%; p<0.0001). Overall survival in A (median 7.4 mo; 95% CI 5.5 – 9.3) compared to R (median 9 mo; 95% CI 7.6 – 10.4) was not significantly different between the two cohorts (p=0.144). When analyzed according to BCLC-stage (B and C), survival in st B pts (A 11.2 vs. R 11.0; p=0.286) as well as st C pts (A 8.9 vs. R 6.4; p=0.62) was not different between the two cohorts. When evaluated according to severity of liver disease (non-cirrhotics/Child-Pugh A and Child-Pugh B), survival in non-cirrhotics/Child-Pugh A patients (A 11.3 mo vs. R 9.0 mo; p=0.746) and Child-Pugh B patients (A 5.5 mo vs. R 3.3 mo; p=0.481) was again not different between these two cohorts. Patients with viral etiology were more common in R (48%) than in A (34%) but not significantly so (p=0.06). Survival in patients with viral (A 10.2 mo vs. R 8.7 mo; p=0.644 ) or non-viral etiology of chronic liver disease (A 6.7 mo vs. R 9.7 mo; p=0.089) was also not significantly different. Conclusions: Overall survival and survival in various subgroups analyzed was not significantly different between the two cohorts. Sorafenib treatment in Russia compared to European Institutions seems to offer a comparable benefit for patients with intermediate/advanced stage HCC, independent of severity or etiology of the underlying liver disease.
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Offer, J. E., and N. W. Offer. "Calcium hydroxide treatment of malt distillers' grains 2. Effects on apparent digestibilityin vivo, intake and performance in sheep." Animal Science 55, no. 2 (October 1992): 209–18. http://dx.doi.org/10.1017/s0003356100037478.
Full textAbstract:
AbstractThe effects of calcium hydroxide (Ca(OH)2)treatment of malt distillers' grains (MDG) on apparent digestibilityin vivo, food intake and lamb performance were measured in three experiments. Experiment 1 measured effects on intake and apparent digestibility of wet MDG either untreated (C), mineralized with a high-calcium mineral (M), Ca(OH)2treated at ambient temperature (L) or at 70°C for 72 h (LH) and offeredad libitumto mature wether sheep (approx. 75 kg live weight). Dry matter (DM) intakes for MDG were 1251,1585,1838 and 1889 (s.e. 93) g/day for C, M, L and LH respectively when given with 780 g DM per day of a standard complete diet (diet A). Corresponding values for whole diet organic matter (OM) apparent digestibility when MDG was given at a fixed rate (1250 g DM per day) with a standard diet (660 g DM per day diet A) were 049, 049, 0·58 and 0·60 (s.e. 0·008) respectively. Experiment 2 compared mineralized wet MDG (M) with a prototype dried food made from Ca(OH)2-treatedensiled MDG (neutralized with NaOH before treatment) held at 60°C for 18 h before drying (NID) and a proprietary lamb finishing compound (PC). The supplements were offered at an increasing rate (350 g DM per day to 1200 g DM per day) to 30 Blackface lambs of approximately 31 kg initial live weight, penned in pairs, and givenad libitumaccess to hay and water. Mean DM intakes (g DM per day) to day 60 for supplements were 925, 750 and 934 (s.e. 19) and for hay were 258, 200 and 311 (s.e. 17) for NID, M and PC respectively. Corresponding values for live-weight gain (g/day) were 136, 123 and 130 (s.e. 11); for condition score (day 59) were 3·9, 3·6 and 4·0 (s.e. 0·06) and for number of lambs finished at day 60 were 8, 2 and 10. Experiment 3 evaluated the apparent digestibility and effects on rumen function of NID, M and PC fed at a fixed rate with chopped hay (804 g DM per day supplement + 396 g DM per day hay) to rumen fistulated wethers (approx. live weight 70 kg). Apparent digestibility values for OM were 0·63, 0·53 and 0·65 (s.e. 0·015) and for neutral-detergent fibre were 0·69, 0·55 and 0·57 (s.e. 0·037) for NID, M and PC respectively. Rumen pH, volatile fatty acid concentrations or hay digestibility in sacco were not significantly affected by supplement. Ca(OH)2treatment greatly improved the nutritional characteristics of MDG giving substantial improvements in apparent digestibility, intake and performance.
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Negrao, Marcelo V., Wen-Hsing Wu, Colin R. Lindsay, Rafael Caparica, Vincent Prêtre, Yehrim Kang, Nydia Caro, Anna Farago, Fen Ye, and Gilberto de Castro. "Abstract 918: Real-world clinical characteristics and treatment (tx) outcomes by co-mutation status in patients (pts) with KRAS G12C-mutated non-small cell lung cancer (NSCLC)." Cancer Research 83, no. 7_Supplement (April 4, 2023): 918. http://dx.doi.org/10.1158/1538-7445.am2023-918.
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Abstract Background: KRAS mutations occur in ~30% of NSCLC and KRAS G12C is the most common subtype (~40%). Co-mutations can impact NSCLC prognosis and tx response. Methods: This retrospective study used the nationwide (US-based) de-identified Flatiron Health-Foundation Medicine clinico-genomic database (FH-FMI CGDB; January 1, 2011 to March 31, 2022). De-identified data originated from ~280 US cancer clinics (~800 sites of care). This study is based on tissue-based assay (FoundationOne CDx). Pts were aged ≥18 years; had KRAS G12C-mutated, advanced/metastatic NSCLC, and had received ≥1 line of tx, with 1L tx initiated after October 1, 2016. Pts were categorized by presence (m) or absence (wt) of single co-mutations in STK11, KEAP1, or TP53; pts with EGFR, ALK, ROS1, BRAF, MET, or NTRK alterations were excluded. Key endpoints included overall survival (OS) and real-world progression-free survival (rwPFS). Statistical methods included a univariate Cox hazard model. Results: Among 847 pts with KRAS G12C-mutated NSCLC, co-mutations of STK11 were seen in 24%, KEAP1 in 14%, and TP53 in 51%. Based on non-missing records (82%), low tumor mutational burden (<10 mut/Mb) was more frequent in the STK11m vs wt group (72% vs 55%; p<0.001), not significantly different in the KEAP1m vs wt group (53% vs 60%; p=0.145), and less frequent in pts with TP53m vs wt (50% vs 69%; p<0.001). Negative PD-L1 status (<1%) was more frequent in pts with STK11 (50% vs 18%; p<0.001) or KEAP1 (41% vs 23%; p<0.001) mutations, and less frequent in pts with TP53 mutations (15% vs 37%; p<0.001). STK11 or KEAP1 co-mutations were associated with shorter rwPFS and OS, particularly in pts treated with immunotherapy (IO)-based 1L tx (Table 1). TP53 status did not significantly impact pt outcomes in the 1L setting. Conclusions: In this real-world analysis, STK11 or KEAP1 co-mutations were associated with PD-L1-negative tumors and poor outcomes with IO-based tx in KRAS G12C-mutated NSCLC. Table 1. rwPFS and OS by co-mutation status, and OS by 1L treatment and co-mutation status rwPFS and OS by co-mutation status rwPFS All (N=846) STK11m (n=206) STK11wt (n=640) KEAP1m (n=121) KEAP1wt (n=725) TP53m (n=429) TP53wt (n=417) Median, months (95% CI) 5.0 (4.5-5.7) 4.0 (3.1-4.9) 5.6 (4.9-6.2) 3.8 (2.7-4.8) 5.6 (4.7-6.2) 5.3 (4.6-6.1) 4.7 (4.0-5.7) HR (95% CI); p value - 1.38 (1.16-1.64); <0.001 1.46 (1.18-1.80); <0.001 0.87 (0.75-1.01); 0.07 OS All (N=847) STK11m (n=206) STK11wt (n=641) KEAP1m (n=121) KEAP1wt (n=726) TP53m (n=429) TP53wt (n=418) Median, months (95% CI) 11.9 (10.2-14.3) 9.4 (7.2-13.8) 12.4 (10.8-15.0) 7.6 (5.4-9.4) 13.5 (11.0-15.1) 11.0 (9.2-14.4) 12.7 (10.4-15.3) HR (95% CI); p value - 1.40 (1.15-1.70); <0.001 1.59 (1.26-2.00); <0.001 0.98 (0.83-1.17); 0.85 OS by 1L treatment and co-mutation status IO + chemotherapy STK11m (n=106) STK11wt (n=228) KEAP1m (n=53) KEAP1wt (n=281) TP53m (n=162) TP53wt (n=172) Median, months (95% CI) 6.9 (4.5-9.4) 11.3 (9.0-14.8) 7.9 (4.5-10.3) 10.2 (7.7-12.9) 9.3 (6.6-11.9) 10.9 (7.2-14.0) HR (95% CI); p value 1.75 (1.33-2.31); <0.0001 1.60 (1.13-2.26); 0.01 1.04 (0.80-1.36); 0.75 IO monotherapy STK11m (n=33) STK11wt (n=181) KEAP1m (n=29) KEAP1wt (n=185) TP53m (n=111) TP53wt (n=103) Median, months (95% CI) 9.7 (2.8-16.9) 16.1 (10.7-23.3) 5.7 (3.9-14.3) 16.6 (10.8-23.0) 15.1 (9.1-22.4) 14.6 (8.9-23.0) HR (95% CI); p value 1.54 (0.97-2.46); 0.07 1.81 (1.12-2.90); 0.01 0.96 (0.68-1.37); 0.83 Chemotherapy only STK11m (n=56) STK11wt (n=188) KEAP1m (n=28) KEAP1wt (n=216) TP53m (n=130) TP53wt (n=114) Median, months (95% CI) 18.6 (10.2-22.8) 13.5 (9.5-15.3) 7.8 (5.0-17.4) 14.5 (11.1-16.3) 12.0 (8.9-16.0) 15.0 (11.1-19.5) HR (95% CI); p value 0.84 (0.57-1.25); 0.40 1.31 (0.82-2.10); 0.26 1.12 (0.81-1.54); 0.49 CI, confidence interval; HR, hazard ratio. Citation Format: Marcelo V. Negrao, Wen-Hsing Wu, Colin R. Lindsay, Rafael Caparica, Vincent Prêtre, Yehrim Kang, Nydia Caro, Anna Farago, Fen Ye, Gilberto de Castro Jr. Real-world clinical characteristics and treatment (tx) outcomes by co-mutation status in patients (pts) with KRAS G12C-mutated non-small cell lung cancer (NSCLC) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 918.
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Ngongo, Nadine Mayasi, Gilles Darcis, Hippolyte Situakibanza Nanituna, Marcel Mbula Mambimbi, Nathalie Maes, Murielle Longokolo Mashi, Ben Bepouka Izizag, Michel Moutschen, and François Lepira Bompeka. "Longitudinal analysis of sociodemographic, clinical and therapeutic factors of HIV-infected individuals in Kinshasa at antiretroviral therapy initiation during 2006-2017." PLOS ONE 16, no. 11 (November 5, 2021): e0259073. http://dx.doi.org/10.1371/journal.pone.0259073.
Full textAbstract:
Background The benefits of antiretroviral therapy (ART) underpin the recommendations for the early detection of HIV infection and ART initiation. Late initiation (LI) of antiretroviral therapy compromises the benefits of ART both individually and in the community. Indeed, it promotes the transmission of infection and higher HIV-related morbidity and mortality with complicated and costly clinical management. This study aims to analyze the evolutionary trends in the median CD4 count, the median time to initiation of ART, the proportion of patients with advanced HIV disease at the initiation of ART between 2006 and 2017 and their factors. Methods and findings HIV-positive adults (≥ 16 years old) who initiated ART between January 1, 2006 and December 31, 2017 in 25 HIV care facilities in Kinshasa, the capital of DRC, were eligible. The data were processed anonymously. LI is defined as CD4≤350 cells/μl and/or WHO clinical stage III or IV and advanced HIV disease (AHD), as CD4≤200 cells/μl and/or stage WHO clinic IV. Factors associated with advanced HIV disease at ART initiation were analyzed, irrespective of year of enrollment in HIV care, using logistic regression models. A total of 7278 patients (55% admitted after 2013) with an average age of 40.9 years were included. The majority were composed of women (71%), highly educated women (68%) and married or widowed women (61%). The median CD4 was 213 cells/μl, 76.7% of patients had CD4≤350 cells/μl, 46.1% had CD4≤200 cells/μl, and 59% of patients were at WHO clinical stages 3 or 4. Men had a more advanced clinical stage (p <0.046) and immunosuppression (p<0.0007) than women. Overall, 70% of patients started ART late, and 25% had AHD. Between 2006 and 2017, the median CD4 count increased from 190 cells/μl to 331 cells/μl (p<0.0001), and the proportions of patients with LI and AHD decreased from 76% to 47% (p< 0.0001) and from 18.7% to 8.9% (p<0.0001), respectively. The median time to initiation of ART after screening for HIV infection decreased from 40 to zero months (p<0.0001), and the proportion of time to initiation of ART in the month increased from 39 to 93.3% (p<0.0001) in the same period. The probability of LI of ART was higher in married couples (OR: 1.7; 95% CI: 1.3–2.3) (p<0.0007) and lower in patients with higher education (OR: 0.74; 95% CI: 0.64–0.86) (p<0.0001). Conclusion Despite increasingly rapid treatment, the proportions of LI and AHD remain high. New approaches to early detection, the first condition for early ART and a key to ending the HIV epidemic, such as home and work HIV testing, HIV self-testing and screening at the point of service, must be implemented.
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Leite Msc Phd, Fernanda, Sara Almeida Ferreira, and Ângela Leite. "Quality of Oral Anticoagulation with Vitamin K Antagonists and Direct Oral Anticoagulants in ‘real-World’ Patients: Lessons from a Five Years Audit Study." Blood 142, Supplement 1 (November 28, 2023): 5551. http://dx.doi.org/10.1182/blood-2023-188834.
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Background: Even with the introduction of direct oral anticoagulants (DOACs), anticoagulation clinics (ACs) stand with a key role in monitoring. Indeed, routine evaluation by health care professionals is recommended as it is with vitamin K antagonists (VKA) with adjustments in practices of anticoagulation management services. Quality of oral anticoagulation (QOA) is associated to better clinical outcomes in those patients with indications for such therapy. It is well established that patients receiving VKA therapy, maintenance of an international normalized ratio (INR) in the therapeutic range is essential for treatment efficacy and safety. It has been reported that ACs should aim for a time in therapeutic range (TTR) between 70-80% to optimize benefit and minimize the risk of adverse events. So far, QOA for DOACs is not fully established. Aim: Since few clinical data are available considering the new era of ACs, this study aims to describe actual trends and QOA of an AC at a large academic medical hospital. Methodology: We retrospectively analyzed 23275 appointments of 5 consecutive years (May 2018 to May 2023), corresponding to 930 patients that are regularly followed up at an outpatient AC of a central hospital under anticoagulation for at least 8 weeks. TTR (≥70%) determined by Rosendaal method was used for patients under AVK and for those individuals in DOACs, QOA was considered the presence of therapeutic plasma levels of the drugs after the European Heart Rhythm Association 2021 in, at least, one determination. Patients were divided according to target INR in 3 groups: Group 1 with target INR 2-3, including 809 patients mean age 65±18 years (mean±SD), majority (36.6%) with atrial fibrillation (AF); Group 2 with target INR 2.5-3.5, including 92 patients with mean age 70±11 years, majority (85.9%) with mechanical heart valves; Group 3 with target INR 3-4, including 29 patients with mean age 63±15 years, majority (55.5%) with antiphospholipid syndrome. Seventy patients were under DOACs (apixaban in 74.3%), with mean age of 71±17 years, majority (62.9%) with non-valvular AF, were included in Group 1 and all individuals were under direct inhibitors of factor Xa. Descriptive statistics (mean, standard deviation, minimum, maximum, chi-square), inferential statistics (t-test, A-Nova and effect sizes) tests were performed. Results: The 930 patient population, 52.2% female, mean age of 65±18 years and 87% in Group 1, showed a mortality of 17%. The mean recall interval between appointments was superior to 90 days in 94% of the population. The individuals who died in comparison with the survivors showed higher frequency of AF (54.1%) [ χ 2= 47.099; p<.001; φ=.225], were from Group 1 (93%) [ χ 2= 6.641; p=.036; φ=.085], male (59.2%) [ χ 2= 10.103; p=.001; φ=-.104] and older [76±12 vs .63±18 years (p<.001), respectively]. No differences were noticed in mortality between AVK and DOACs [ χ 2= 1.828; p=.401; φ=-.044], even DOAC patients being older than AVK patients (71±17 vs 65±17; p=.005), respectively. QOA associated with mortality being the individuals who died with higher frequency of no QOA (21.9% vs 13.9%) [ χ 2= 8.126; p=.004; φ=-.101] respectively. The individuals on AVK from Group 1 corresponding to 86% of total population showed a mean TTR of 76%, patients from Group 2 had a TTR of 72% and patients in Group 3 had TTR of 55%. From the individuals under DOACs, only 30% had at least one determination of plasma levels of the drug and all but one showed therapeutic levels. Comparatively with our previous studies related to the periods of 2006-2012 and 2012-2018, we noticed a significant decrease in patient population / appointments size (2087/ 61988) (1587/ 37931),(p <.001) with an increase of TTR in Group 1 (1927/1430 patients) (83% /72%) and Group 2 (120/125 patients) (74% / 69%) but a TTR decrease in Group 3 (40 / 32 patients) (54% / 60%) (p <.001). respectively. Mortality in the 2012- 2018 period was 18%. Conclusions and Discussion: The trends of decreasing the number of anticoagulated patients at our AC with an overall good quality of monitoring but with a low percentage of individuals under DOACs suggests that the majority of anticoagulated population is on these drugs without routine follow up in opposition to the recent recommendations. Our study underlines the importance of the quality of anticoagulation monitoring on mortality that was no different from the previous years before SARS-CoV- 2 pandemic nor between AVK and DOACs.
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Saqib, Muhammad, Jaewoon Hong, Aniqa Anjum, Keith Duncan, and Eric D. Wachsman. "Transitioning Low-Temperature GDC Socs: Lab to Commercialization Scale." ECS Meeting Abstracts MA2024-01, no. 37 (August 9, 2024): 2259. http://dx.doi.org/10.1149/ma2024-01372259mtgabs.
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Solid oxide fuel cells (SOFCs) electrochemically convert hydrogen and oxygen into electricity, heat, and water with high efficiency (~55%) [1], while in reverse operation, water and electricity are converted to hydrogen and oxygen in solid oxide electrolysis cells (SOECs). Appropriately designed solid oxide cells (SOCs) can operate in both SOFC and SOEC mode. Conventional SOCs typically demand elevated operating temperatures (800-1000°C), resulting in higher cost and accelerated degradation issues. Lowering operating temperatures below 600°C reduces thermal stresses, shortens start-up times, and broadens applications [2]. Ce1-xGdxO2-δ (GDC), due to its superior oxygen ion conductivity at reduced temperatures, has lower ohmic losses than competing electrolyte materials. Thus, our 1.2 cm diameter circular anode supported GDC cell with 0.31 cm2 active area exhibits exceptional power densities, reaching approximately 3 watt per square centimeter at 650°C. Through optimal design, these cells exhibit exceptional performances in fuel cell mode, significantly enhancing efficiency and effectiveness when operating as an electrolyzer for fuel generation. This advance in performance is a result of mitigating the leakage current issues typical of ceria-based electrolytes through precise engineering of the cathodic microstructure and surface chemistry modification [3]. The transition from lab-scale to large-scale commercialization (with active areas of 16 cm² &; 81 cm²) presents significant challenges such as tailoring material properties for large-cell versus button-cell synthesis while maintaining high performance levels. In this work we explore the challenges encountered during the scaling-up process. We report on fabrication strategies employed to achieve cell flatness, maintain high efficiency, ensure cost-effectiveness, and achieve long-term stability. Specifically, we have fabricated graded anode-supported cells [4] by developing an innovative lamination strategy involving tapes oriented perpendicular to each other. This approach notably contributed to achieving superior electrolyte densification and resulted in significantly flatter (low curvature values) with respect to both horizontal and vertical axes in cartesian coordinate space. When compared to the flatness values of 10x10 cm2 commercially available cells, our cells demonstrated remarkably flatter curvatures as shown in figure 1. This characteristic has proven highly beneficial for stack assembly, minimizing issues such as cell cracking and reducing sealing-related problems. By optimizing the cathode scaffold and infiltration process on larger area cells through a spray-coating machine, scaling up challenges are effectively mitigated compared to the button cell approach, where scaffold preparation and infiltration were performed using blade coating and a hand pipette, respectively. This approach effectively tackles electronic conduction issues in ceria-based electrolytes, leading to higher Open Circuit Voltages (OCVs) in fuel cell mode and increased efficiencies in reversible mode. References: D. Wachsman, and K. T. Lee, Science, 334, 935 (2011). Q. Minh, Journal of the American Ceramics Society, 76, 563 (1993). A. Robinson, Y. L. Huang, S. A. Horlick, J. Obenland, N. Robinson, J. E. Gritton, A. M. Hussain, E. D. Wachsman, Advanced Functional Materials, (In press). Ostrovskiy, M. Saqib, J. Hong and E. D. Wachsman, The Electrochemical Society, MA2023-01, 132 (2023). Figure 1
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Haferlach, Torsten, Ulrike Bacher, Tamara Alpermann, Claudia Haferlach, Wolfgang Kern, and Susanne Schnittger. "Rising Percentages of Blasts Are Associated with Continuously Increasing Frequencies of FLT3-ITD and NPM1 Mutations In AML and In Addition Depend on Combinations of These Markers: Analysis of 805 Cases with Normal Karyotype AML." Blood 116, no. 21 (November 19, 2010): 1043. http://dx.doi.org/10.1182/blood.v116.21.1043.1043.
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Abstract Abstract 1043 Introduction: FLT3-ITD is supposed to function as driver mutation in acute myeloid leukemia (AML), e.g. higher WBC counts are found in FLT3-ITD mutated (FLT3+) cases. Also for NPM1 mutations (NPM1+) higher blast proportions were described. As both mutations can be concomitantly found we investigated correlations and the biological background of these aspects. Patients/Methods: We analyzed 805 pts (m/410; f/395; median, 66.6 yrs; 20.0–93.3 yrs) with de novo normal karyotype AML for FLT3+ and NPM1+ and by bone marrow (BM) cytomorphology. Blast definition and classification was done according to FAB and WHO criteria on May Giemsa Gruenwald, MPO, and NSE stained BM aspirates. The FLT3-ITD status and the FLT3-ITD mutant/wildtype ratio were analyzed by fragment analysis (genescan); the NPM1+ status was investigated by melting-curve based PCR assay. Results: The overall mutation rate for FLT3+ was 219/805 (27.2%), for NPM1+ 391/805 (48.6%). Mean WBC count was higher in FLT3+ cases when compared to the FLT3- (69.0 × 109/l vs. 25.7 × 109/l; p<0.001). The 2-year survival rate was best in the NPM1+/FLT3- pts (n=240; 82.3%) when compared to all other subgroups (NPM1+/FLT3-ITD+: n=151; 55.2%; NPM1-/FLT3+: n=68; 40.5%; NPM1-/FLT3-: n=346; 62.1%; p=0.003). This demonstrates the universal validity of our data set. Frequencies of both FLT3-ITD or NPM1 mutated cases were increasing by blast percentages per decade from 20% to 100%: For the FLT3+: blasts 20–29%: 15/108 (12.2% of cases); 30–39%: 7/91 (7.7%); 40–49: 11/69 (15.9%); 50–59%: 14/80 (17.5%); 60–69%: 25/102 (24.5%); 70–79%: 34/114 (29.8%); 80–89%: 55/123 (44.7%); 90–100%: 58/103 (56.3%) (p<0.001). For NPM1+: blasts 20–29%: 38/123 (30.9% of cases); 30–39%: 31/91 (34.1%); 40–49: 20/69 (29.0%); 50–59%: 36/80 (45.0%); 60–69%: 51/102 (50.0%); 70–79%: 62/114 (54.4%); 80–89%: 83/123 (67.5%); 90–100%: 70/103 (68.0%) (p<0.001). Subsequently, we separated the whole cohort according to the threshold 40% BM blasts: 2 yrs survival rate was significantly lower in pts with ≥40% of blasts (n=591; 63.4%) when compared to those with <40% (n=214; 77.5%; p=0.004). Patients with ≥40% of blasts showed significant higher rates of NPM1+/FLT3+ (blasts <40%: 13/214; 6.1% vs. ≥40%: 138/591; 23.4%; p<0.001) and NPM1-/FLT3+ (blasts <40%: 9/214; 4.2% vs. ≥40%: 59/591; 10%; p=0.009). NPM1-/FLT3- cases were less frequent in cases with ≥40% of blasts (blasts <40%: 136/214 NPM1-/FLT3-; 63.6% vs. blasts ≥40%: 210/591; 35.5%; p<0.001). Focusing on the blast levels in the different molecular subgroups, cases with 90–100% blasts were most frequent in the NPM1+/FLT3+ (double mutated) subgroup (45/151; 29.8%). In the NPM1+/FLT3- and the NPM1-/FLT3+ subgroups, cases with 80–89% of blasts were most frequent (43/240; 17.9%; and 15/68; 22.1%, respectively). In contrast, the NPM1-/FLT3- pts were most frequently from the 20–29% blast category (79/346; 22.8%) (p<0.001 for comparison of all subgroups). A higher FLT3-ITD-mutant/wildtype ratio was correlated with a higher proportion of BM blasts (Spearman; p<0.001). In univariate analysis for prognostically relevant parameters, OS was significantly related to age (p<0.001; RR=1.36 per 10 years of increase), WBC (p<0.001; RR=1.06 per 10×109/l), blasts <40% (p=0.005; RR=2.29), the NPM1+/FLT3- subgroup (p≤0.001; RR=0.40), and a FLT3mut/wildtype ratio ≤0.5 (p=0.024; RR=1.78). No significance was found for gender, Hb, thrombocytes, and FAB subtypes. In multivariate analysis, age (p<0.001), WBC (p=0.003), blasts <40% (p=0.008) and the NPM1+/FLT3- status (p=0.002) retained prognostic significance. Conclusion: The frequencies of the FLT3+ and the NPM1+ cases are continuously increasing in parallel to increasing blast percentages in normal karyotype AML. Thresholds of 40% of blasts are suitable to discriminate different prognostic groups which can be related to significantly higher frequencies of NPM1+/FLT3+ and NPM1-/FLT3+ in patients with higher blast proportions. Therefore, both molecular markers apparently contribute to blast proliferation in normal karyotype AML. Combinations of these markers are also relevant since blasts were highest in the double NPM1/FLT3-mutated cases and lowest in the NPM1-/FLT3- cases in our study. Disclosures: Haferlach: MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Haferlach:MLL Munich Leukemia Laboratory: Employment, Equity Ownership, Research Funding. Kern:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership.
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Zaaroor, Menashe, Alon Sinai, Dorith Goldsher, Ayelet Eran, Maria Nassar, and Ilana Schlesinger. "Magnetic resonance–guided focused ultrasound thalamotomy for tremor: a report of 30 Parkinson's disease and essential tremor cases." Journal of Neurosurgery 128, no. 1 (January 2018): 202–10. http://dx.doi.org/10.3171/2016.10.jns16758.
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OBJECTIVEThalamotomy of the ventral intermediate nucleus (VIM) is effective in alleviating medication-resistant tremor in patients with essential tremor (ET) and Parkinson's disease (PD). MR-guided focused ultrasound (MRgFUS) is an innovative technology that enables noninvasive thalamotomy via thermal ablation.METHODSPatients with severe medication-resistant tremor underwent unilateral VIM thalamotomy using MRgFUS. Effects on tremor were evaluated using the Clinical Rating Scale for Tremor (CRST) in patients with ET and by the motor part of the Unified Parkinson's Disease Rating Scale (UPDRS) in patients with PD and ET-PD (defined as patients with ET who developed PD many years later). Quality of life in ET was measured by the Quality of Life in Essential Tremor (QUEST) questionnaire and in PD by the PD Questionnaire (PDQ-39).RESULTSThirty patients underwent MRgFUS, including 18 with ET, 9 with PD, and 3 with ET-PD. The mean age of the study population was 68.9 ± 8.3 years (range 46–87 years) with a mean disease duration of 12.1 ± 8.9 years (range 2–30 years). MRgFUS created a lesion at the planned target in all patients, resulting in cessation of tremor in the treated hand immediately following treatment. At 1 month posttreatment, the mean CRST score of the patients with ET decreased from 40.7 ± 11.6 to 9.3 ± 7.1 (p < 0.001) and was 8.2 ± 5.0 six months after treatment (p < 0.001, compared with baseline). Average QUEST scores decreased from 44.8 ± 12.9 to 13.1 ± 13.2 (p < 0.001) and was 12.3 ± 7.2 six months after treatment (p < 0.001). In patients with PD, the mean score of the motor part of the UPDRS decreased from 24.9 ± 8.0 to 16.4 ± 11.1 (p = 0.042) at 1 month and was 13.4 ± 9.2 six months after treatment (p = 0.009, compared with baseline). The mean PDQ-39 score decreased from 38.6 ± 16.8 to 26.1 ± 7.2 (p = 0.036) and was 20.6 ± 8.8 six months after treatment (p = 0.008). During follow-up of 6–24 months (mean 11.5 ± 7.2 months, median 12.0 months), tremor reappeared in 6 of the patients (2 with ET, 2 with PD, and 2 with ET-PD), to a lesser degree than before the procedure in 5. Adverse events that transiently occurred during sonication included headache (n = 11), short-lasting vertigo (n = 14) and dizziness (n = 4), nausea (n = 3), burning scalp sensation (n = 3), vomiting (n = 2) and lip paresthesia (n = 2). Adverse events that lasted after the procedure included gait ataxia (n = 5), unsteady feeling (n = 4), taste disturbances (n = 4), asthenia (n = 4), and hand ataxia (n = 3). No adverse event lasted beyond 3 months. Patients underwent on average 21.0 ± 6.9 sonications (range 14–45 sonications) with an average maximal sonication time of 16.0 ± 3.0 seconds (range 13–24 seconds). The mean maximal energy reached was 12,500 ± 4274 J (range 5850–23,040 J) with a mean maximal temperature of 56.5° ± 2.2°C (range 55°–60°C).CONCLUSIONSMRgFUS VIM thalamotomy to relieve medication-resistant tremor was safe and effective in patients with ET, PD, and ET-PD. Current results emphasize the superior adverse events profile of MRgFUS over other surgical approaches for treating tremor with similar efficacy. Large randomized studies are needed to assess prolonged efficacy and safety.
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Marchetti, Monia, Carlo Aprile, Carla Greco, and Giovanni Barosi. "99mTc-BW250/183 Bone Marrow Immunoscintigraphy Is Correlated to Clinical and Biologic Features of Myelofibrosis with Myeloid Metaplasia." Blood 106, no. 11 (November 16, 2005): 4944. http://dx.doi.org/10.1182/blood.v106.11.4944.4944.
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Abstract BACKGROUND: Myelofibrosis with myeloid metaplasia (MMM) is a rare chronic myeloproliferative disease characterized by both myeloproliferative and myelodepletive features: myeloproliferation typically includes enhanced spontaneous mobilization of hematopoietic progenitor cells (HPC) from the bone marrow (BM) and their homing into extramedullary sites (mainly spleen); myelodepletion results from exhaustion of both BM and extramedullary hemopoiesis. AIMS: To investigate the extent and distribution of hematopoiesis in MMM patients and to capture its relationship with BM fibrosis, HPC mobilization and clinical severity. METHODS: Immunoscintigraphy employing a dual-head camera was performed 120–260 minutes (median 180 minutes) after administration of 553–830 MBq (median 700 MBq) 99mTc-BW250/183, corresponding to 0.3–0.5 mg. Hematopoietic function in the central compartment (sacrum) was described by “subtypes” (normal, increased or decreased) and by the sacrum-to-soft tissue uptake ratio (UR) (Huic at el, J Nucl Med 1997). The degree of peripheral BM displacement (limbs) was described through 5 “types” (I to V) (Huic at el, J Nucl Med 1997). RESULTS: Twenty-three MMM patients (13 males, median age 55 years) were studied. Eleven patients showed a reduced uptake by the central BM compartment: they had a higher WHO fibrosis grade (p=0.008), lower hemoglobin values (p=0.012) and lower platelet counts (p=0.007) than patients with a preserved central compartment. Patients with an exhausted central compartment at immunoscintigraphy also showed a significantly higher mobilization of HPC into peripheral blood, as documented by higher values of the following parameters: CD34+ count (0.86% vs 0.12%; p=0.029), immature myeloid cells or blasts (9.5% versus 0.3%; p=0.005), spleen size (9.3 vs 2.4 centimeters from costal arc; p=0.007). Among the patients with a depressed central compartment, those who also lost peripheral BM function (type V) showed a more severe myelodepletion and more intense HPC mobilization. On the opposite side, among the 12 patients with a preserved central compartment, the 8 ones with a mild peripheral BM displacement (type I–II) showed absent or mild fibrosis (WHO 0-1), elevated platelet counts, normal to high hemoglobin values, minimally enlarged spleens and no hints of increased HPC mobilization (CD34+ <0.1%; no blasts; <=1% immature myeloid cells). From these data it appears that progressive fibrosis and exhaustion of central BM is accompanied by a gradual displacement of hemopoiesis into the peripheral bone compartment and the spleen and by derangement of HPC trafficking. CONCLUSIONS: BM immunoscintigraphy accurately tracks MMM clinical features and may help staging MMM patients, understanding MMM biology and targeting therapies Clinical and immunoscintigraphy parameters (means and ANOVA p values) Type I-III II–IV V p § Barosi et al, Leuk Lymph 2002 Subtype not reduced reduced reduced UR 9.39 2.53 1.22 0.041 Fibrosis (grade) 1.0 2.0 2.7 0.001 Hb (g/dl) 13.5 11.1 9.6 0.023 PLT *10(9) 613 283 86 0.04 WBC *10(9) 8.9 6.2 6.9 0.059 Spleen (cm) 1.9 7.6 10.5 0.011 Immature myeloid cells (%) 0.3 3.6 9.7 0.0005 Blast cells (%) 0.0 0.2 3.8 0.048 CD34+ cells (%/μl) 0.1 / 6.4 0.4 / 22.1 1.3 / 155.5 0.009 / 0.12 LDH (UI/l) 566 956 1381 0.014 Severity Score§ 2.4 3.0 3.8 0.036 Disease duration (mo) 43 30 74 0.45
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Shroff, Rachna T., Katherine A. Guthrie, Aaron James Scott, Mitesh J. Borad, Laura Williams Goff, Khalid Matin, Amit Mahipal, et al. "SWOG 1815: A phase III randomized trial of gemcitabine, cisplatin, and nab-paclitaxel versus gemcitabine and cisplatin in newly diagnosed, advanced biliary tract cancers." Journal of Clinical Oncology 41, no. 4_suppl (February 1, 2023): LBA490. http://dx.doi.org/10.1200/jco.2023.41.4_suppl.lba490.
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LBA490 Background: Biliary tract cancers (BTCs) are a heterogeneous group of malignancies with a dismal prognosis. Gemcitabine-based regimens are the standard of care in advanced disease, but median overall survival (OS) is roughly 12 months. The addition of albumin-bound paclitaxel to gemcitabine and cisplatin (GAP) demonstrated promising efficacy in a 60 patient, single-arm phase II study (Shroff et al, JAMA Oncol 2019), with observed median OS of 19.2 months. Methods: SWOG 1815 is a randomized, open-label, phase III trial comparing GAP to gemcitabine/cisplatin (GC). The study included newly diagnosed advanced BTC patients (pts), randomized 2:1 to GAP vs. GC. GAP included gemcitabine at 800 mg/m2, cisplatin at 25 mg/m2 and albumin-bound paclitaxel at 100 mg/m2 on days 1 and 8 of a 21-day cycle. GC included standard dosing of gemcitabine at 1000 mg/m2 and cisplatin at 25 mg/m2 on days 1 and 8 of a 21-day cycle. Pts were treated until progression. The primary endpoint was overall survival (OS) with a target hazard ratio of 0.7 with 90% power and a 1-sided alpha of 0.025; randomization was stratified by disease site (intrahepatic cholangiocarcinoma [CCA] vs gallbladder adenocarcinoma [GBC] vs extrahepatic CCA), disease stage (locally advanced vs metastatic), and Zubrod PS 0 vs 1. Results: Of 441 eligible pts randomized, 55% were female. 67% of patients had intrahepatic CCA, 16% had GBC and 17% had extrahepatic CCA. Most pts had metastases (73%). Median OS with GAP vs. GC was 14 vs. 12.7 mo respectively (HR 0.93, 95% CI 0.74-1.19, p=0.58), ORR (confirmed and unconfirmed) 34% vs 25% (p=0.11) and median PFS 8.2 vs 6.4 mo (HR 0.92, 95% CI 0.72-1.16, p=0.47), respectively. Grade 3 and 4 treatment related adverse events (TRAEs) in ≥10% of pts for GAP and GC were anemia, neutropenia, and thrombocytopenia. GAP had more ≥ grade 3 hematologic AEs compared to the GC arm (60% vs. 45%, p=0.003). Discontinuation due to toxicity was at 24% vs 19% (p=0.26) with GAP vs GC. In exploratory subset analyses, GAP vs GC improved OS in pts with locally advanced disease (medians 19.2 vs 13.7 mo; HR 0.67, 95% CI 0.42-1.06, p=0.09) and in GBC pts (medians 17.0 vs 9.3 mo; HR 0.74, 95% CI 0.41-1.35, p=0.33). ORR for GAP vs GC in GBC was 50% vs 24% (p=0.09) and for locally advanced disease 28 vs 21% p=0.74. Conclusions: SWOG 1815 did not result in a statistically significant improvement in median OS with GAP vs. GC. The GAP regimen had higher rates of TRAEs without a statistically significant difference in discontinuation rates. Pts with locally advanced disease and GBC may benefit from the use of GAP. Further analyses are ongoing to understand potential benefit of GAP in subsets of BTC pts. Funding: NIH/National Cancer Institute grants CA180888, CA180819, CA180820, CA180821, and CA180868; and in part by Celgene Corporation, Summit, NJ (subsidiary of Bristol Myer Squibb). Clinical trial information: NCT#03768414 .
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Ali, I., M. T. Ghaffar, N. Harrington, S. Mansoor, C. Silke, M. O’sullivan, and B. Whelan. "FRI0029 EFFECTIVENESS OF A NURSE LED TREAT TO TARGET (T2T) MODEL IN ACHIEVING REMISSION FOR EARLY RHEUMATOID ARTHRITIS PATIENTS IN A REAL-WORLD SETTING." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 587. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1899.
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Background:Rheumatoid Arthritis (RA) is a chronic, inflammatory and systemic autoimmune disease, affecting multiple joints particularly small joints in hands and feet.1For the past two decades, there has been significant change in approach for the diagnosis and treatment of RA. Now early diagnosis and aggressive management of RA is considered key role for preventing permanent damage to joints.2Treat to Target (T2T) strategy has been proven to be very effective in achieving pre-decided outcome either clinical remission (CR) or low disease activity(LDA).3Objectives:To assess the outcome of nurse led T2T strategy in Early RA patients within first 2 years of treatment.Methods:This was Observational Prospective Study, based on data collected in our ANP led Early Inflammatory Arthritis clinic. All patients diagnosed with inflammatory arthritis were managed following a T2T protocol. Every patient had predefined target set according to co-morbidities, preexisting osteoarthritis and duration of disease. Patients were followed up at varying intervals depending on clinical need until the steroid free target was achieved or for up to 2 years. Clinical Disease Activity Index (CDAI) tool was used to assess disease activity.Data collected included age, gender, diagnosis, Rheumatoid factor and/or Anti CCP positivity, erosions on x ray at the time of diagnosis and Health Assessment Questionnaire (HAQ-DI). For this analysis, only patients meeting the 2010 ACR/EULAR criteria4for the diagnosis of RA were included.The primary analysis in this study was the proportion of patients who achieved CR or LDA using different DMARDs used alone or in combination and the clinical determinants of this outcome.Results:Out of 417 patients with Early Inflammatory Arthritis, 300 met criteria for RA. 27 were lost to follow up (3 deaths) and 44 remained on the T2T pathway. For the 229 patients completing the pathway, mean age was 43.25 years (SD 9.405), Female gender 146 (63.75%), Anti CCP positive in 160 (69.86%), Rheumatoid Factor (RF) positive in 154 (67.24%), Both RF and Anti CCP positive 141 (61.57%), CDAI at baseline was 22.65 (SD 22.19) and Mean HAQ-DI at presentation 1.19 (SD 0.629). There were 18.34% (42) of patients who had erosive changes on x-ray at presentation.). Outcome of T2T strategy showed that 151 (65.93%) achieved clinical remission and 78(34.06%) achieved low disease activityConclusion:Remission in patients who were less than 40 years of age was 100% as opposed to 49% above the age of 40 years. This difference was found to be statistically significant with a p value of <0.05 (Table 1).Table 1.Treat to target outcomes with analysed variables.Group CharactersRemissionn (%)Low disease activity n (%)TotalP valueFemale92 (63.01)54 (36.99)1460.215Male59 (71.08)24 (28.92)83RF +103 (66.88)51 (33.12)1540.666RF -48 (64)27 (36)75CCP +105 (65.63)55 (34.37)1600.760CCP -44 (67.79)21 (32.31)65< 40 years76 (100)0 (0)760.000>40 years75 (49.02)78 (50.98)153Further to this, Methotrexate monotherapy was the dominant DMARD used to achieve remission and/or low disease activity in more than 50 % of the RA patients (Figure 1).References:[1]Lee DM, Weinblatt ME. Rheumatoid arthritis. Lancet. 2001 Sep 15;358(9285):903-11.[2]Heidari B. Rheumatoid Arthritis: Early diagnosis and treatment outcomes. Caspian J Intern Med. 2011;2(1):161–170.[3]Brinkmann GH, Norvang V, Norli ES, Grovle L, Haugen AJ, Lexberg AS, et al. Treat to target strategy in early rheumatoid arthritis versus routine care - A comparative clinical practice study. Semin Arthritis Rheum. 2019;48(5):808-14.[4]Kay J, Upchurch KS. ACR/EULAR 2010 rheumatoid arthritis classification criteria. Rheumatology (Oxford). 2012;51 Suppl 6:vi5-9.Disclosure of Interests:None declared
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Kalwak, Krzysztof, Joanna Owoc-Lempach, Ewa Gorczynska, Marek Ussowicz, Dominik Turkiewicz, Dorota Wojcik, Agnieszka Dyla, and Alicja Chybicka. "High Numbers of CD34+ Cells/kg and CD3+ Cells/kg Have No Negative Impact on the Incidence of Severe GvHD and Survival in a Large Series of Children Undergoing Unmanipulated Allogeneic HCT from Matched or Mismatched Unrelated Donors." Blood 108, no. 11 (November 16, 2006): 5390. http://dx.doi.org/10.1182/blood.v108.11.5390.5390.
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Abstract The aim of the study was to analyze the correlation between the number of transplanted CD34+ cells and CD3+ cells and the incidence of severe Graft versus Host Disease (GvHD) in children undergoing allogeneic hematopoietic cell transplantation from HLA-matched or mismatched unrelated donors. 115 patients (median age 11.4, range 0.7 – 31.6; ALL n=41, AML n=22, CML n=21, MDS/JMML n=10, NHL/HD n=4, SAA/FA n=13, SCID/WAS n=4) underwent unmanipulated allogeneic BMT (n=34) or PBSCT (n=81) from unrelated donors between 1999 and 2005. There were 88 matched- and 27 mismatched donor-recipient pairs, respectively (acc. to ALL SZT - BFM 2003 protocol). Among 88 matched pairs, 51 were 10 out of 10 HLA-allele matched (High Resolution Class I and II typed), whereas in another 37 cases 9 out of 10 alleles were matched. In the mismatched group there were 22 pairs with a 8 out of 10 allele-match and 5 pairs with 7 out of 10 allele-match, respectively. No single DRB1* mismatch was accepted. A distinct correlation between the degree of HLA-match and the risk of grades III-IV aGvHD was found (p=0.05), which occurred in 11 out of 27 pts in the mismatched group (40.7%) and in 19 out of 88 pts in the matched group (21.6%). No difference between the 2 groups was observed with regard to the incidence of extensive cGvHD. No correlation was found between the number of transplanted CD34+ cells/kg or CD3+ cells/kg and the incidence of aGvHD grades III–IV or extensive cGvHD. Median numbers of transplanted CD34+ cells/kg and CD3+ cells/kg were 7.7 × 106 (10.9 × 106) and 2.6 × 108 (3.3 × 108) respectively in the group of patients with grades III–IV aGvHD (extensive cGvHD) and 9.3 × 106 (8.8 × 106) and 3.4 × 108 (3.1 × 108) respectively in the group without these complications. Pts in the mismatched group were given slightly higher numbers of CD3+ cells/kg (4.9 vs 3.0 × 108 in the matched group) and similar numbers of CD34+ cells/kg (median 8.1 vs 8.9 × 106 in the matched group). Despite a higher incidence of severe aGvHD in the mismatched group, probability of 5-year survival was in contrast slightly better in the mismatched group (pS = 0.59 vs pS = 0.48 in the matched group, p=NS). Seventeen from 27 pts in the mismatched group remain alive (62.9%). Median follow-up of all 63 surviving pts (55%) is 21 months (range 6 – 69). Neither degree of HLA match, nor the source of stem cells (PB vs BM), nor number of transplanted CD34 (less or more than 8 × 106/kg) or CD3 cells/kg had an impact on survival. In conclusion, there seems to be no correlation between the numbers of transplanted CD34+ cells/kg and/or CD3+ cells/kg and the incidence of severe GvHD in the unrelated donor setting in children. It is safe and feasible to perform allogeneic transplants from unrelated mismatched donors, provided a detailed selection of more than 1 HLA-allele-mismatched donors is performed. This conclusion remains in contrast with the ALL SZT-BFM 2003 protocol, which requires extensive T-cell depletion in case of mismatched donor-recipient pairs. High number of transplanted CD34+ cells seems to be a positive factor influencing engraftment and survival in this constellation. There seems to be not necessary to limit the number of transplanted CD34+ cells to 6 or 8 × 106/kg, which had been previously suggested by studies performed in Europe or USA in adults.
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Shrestha, Rajesh, Nathaniel M. Cook, and Adam J. Olszewski. "Race-Specific Features and Treatment Patterns of Nodular Lymphocyte-Predominant Hodgkin Lymphoma (NLPHL) in the United States: Analysis of the National Cancer Data Base." Blood 124, no. 21 (December 6, 2014): 2594. http://dx.doi.org/10.1182/blood.v124.21.2594.2594.
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Abstract Background: NLPHL is a rare, biologically distinct subtype of Hodgkin lymphoma (HL) characterized by late recurrences and risk of transformation to non-Hodgkin histology. The incidence of NLPHL is markedly increased among black patients (pts), but they were not distinguished in prior studies, and data are lacking about specific features in this group. Relative benefits of various treatment modalities in early-stage NLPHL are also controversial. Radiation therapy (RT) is endorsed by guidelines, but one large study suggested a survival advantage of combined modality therapy (CMT) over historical controls treated with RT alone (Savage et al., Blood 2011:118:4585). The objective of this study was to compare clinical features of NLPHL in black and other pts, and to describe treatment patterns and survival using the National Cancer Data Basea registry capturing over 70% of incident cancers in the United States (US). Methods: We identified NLPHL and classical HL cases diagnosed between 1998 and 2011, with survival data available for the 1998-2006 cohort. Receipt of chemotherapy (ChT), RT or CMT as initial course of treatment was recorded. Stage was categorized as limited (Ann Arbor I, IIA) or advanced (IIB, III, IV). Overall survival (OS) was the primary outcome and was compared using log-rank tests stratified by stage, sex and age group. Trends were assessed using log-linear regression. All confidence intervals (CI) were set at 95%. Results: Among the NLPHL pts (N=2,656), 23% were of black race (N=602), compared with 10% of classical HL cases (N=66,369). Most NLPHL pts presented with limited stage disease (66%), without any difference between races (P=0.79). Stage migration was evident between 1998 and 2003 with the proportion of stage III/IV cases increasing by 13.2% per year (CI, 3.3-24.0, P=0.008). The male-to-female ratio was 1.0 (CI, 0.9-1.2) in black pts, whereas pronounced male predominance was present in others (ratio 2.5, CI, 2.2-2.7). Black pts were also on average younger (median age 42 years, versus 45 for others, P=0.0001), and their NLPHL more often originated from the axillary nodes (25%, versus 17% for other races, P=0.0003). Median follow-up was 7.1 years. OS at 7 years was 90.1% (CI, 87.7-92.1) for limited- and 80.1% (CI, 75.6-83.8) for advanced-stage NLPHL, with no difference between the races (P=0.15, Fig. A). In limited disease, RT alone was used in 55%, 31% and 27% of pts with stage IA, IB and IIA, respectively, while CMT was used in 21%, 33% and 35%, and ChT alone in 12%, 24% and 31%, respectively. Black pts were more likely to have no treatment recorded (P<0.0001), but the proportions of various modalities was otherwise the same (P=0.76). The difference in OS between the treatments was not significant, with 7-year OS of 93.3% (CI, 88.8-96.1) after CMT, 90.0% (CI, 85.7-92.9) after RT, and 86.5% (CI, 79.5-91.2) after ChT alone (P=0.12, Fig. B). There was a significant trend towards decreased utilization of RT over time (on average by 1.6% per year, P=0.0002). In advanced NLPHL, 71% of patients were treated with ChT alone, 15% with CMT, 3% with RT alone and 11% had no recorded treatment. A significant trend towards less RT was again evident (8.9% per year, P<0.0001). Conclusions: The specific gender, age and primary site distribution in black pts with NLPHL suggests an inherited susceptibility, possibly mediated by immune or endocrine factors. Survival outcomes are not different from other races. In early-stage NLPHL, various treatment modalities are not associated with significant OS differences, although survival is numerically highest with CMT. Because of stage migration coinciding with the introduction of positron emission tomography, stage-based survival comparisons with cohorts from 1990's may be biased. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.
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Mease, P. J., A. M. Orbai, B. Parikh, C. Gaillez, X. Meng, and C. T. Ritchlin. "POS1022 RELATIONSHIPS BETWEEN INHIBITION OF RADIOGRAPHIC PROGRESSION AND ACHIEVEMENT OF LOW DISEASE ACTIVITY OR REMISSION AND THEIR CORE COMPONENTS IN PATIENTS WITH PSORIATIC ARTHRITIS TREATED WITH SECUKINUMAB IN FUTURE 5 DURING THE FIRST 24 WEEKS." Annals of the Rheumatic Diseases 81, Suppl 1 (May 23, 2022): 822. http://dx.doi.org/10.1136/annrheumdis-2022-eular.1167.
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BackgroundPatients with active psoriatic arthritis (PsA) experience inflammation that may result in structural damage and disability. In the phase 3 FUTURE 5 study, treatment with secukinumab (SEC) inhibited radiographic progression and led to sustained remission and low disease activity (LDA) through Week 104.1,2ObjectivesThis post hoc analysis of FUTURE 5 explored relationships between radiographic progression status and achievement of LDA or remission in patients treated with SEC.MethodsPatients were randomized 2:2:2:3 to receive SEC 300 mg with loading dose (LD), 150 mg LD, SEC 150 mg without LD, or placebo (PBO) at Baseline, Weeks 1, 2, 3, 4, and every 4 weeks thereafter until Week 24. In this post hoc analysis, patients were grouped by radiographic progression status at Week 24 (non-radiographic progressors: change from baseline in modified total Sharp score [mTSS] ≤0.0; radiographic progressors: change from baseline in mTSS >0.0). Efficacy (achievement of Minimal Disease Activity [MDA] or Very Low Disease Activity [VLDA] and their individual components, and Disease Activity Index for Psoriatic Arthritis [DAPSA] LDA or remission) was assessed at Week 24.ResultsOf 933 patients with available data, 675 (72.3%) were classified as non-radiographic progressors and 258 (27.7%) were radiographic progressors at Week 24. Non-progressors at Week 24 were more likely than progressors to achieve DAPSA LDA and remission at Week 24 across all treatment arms (Figure 1A). In addition, non-progressors were more likely to achieve MDA and VLDA at Week 24 than progressors across all treatment arms (Figure 1B). Similar trends were observed for all of the individual MDA/VLDA criteria at Week 24 among patients treated with SEC 300 mg or SEC 150 mg LD (Table 1). Notably, non-progressors were more likely to achieve improvements in physical function, pain, and patient global assessment of disease activity than progressors across all treatment arms.Table 1.Proportion of Patients Achieving MDA/VLDA Components at Week 24 Grouped by Radiographic Progression Status at Week 24Week 24 non-progressorsWeek 24 progressorsOutcome, n/N (%)SEC 300 mg n = 166SEC 150 mg n = 150SEC 150 mg NL n = 159PBO n = 200SEC 300 mg n = 51SEC 150 mg n = 63SEC 150 mg NL n = 51PBO n = 93TJC78 ≤152/161 (32.3)46/146 (31.5)37/150 (24.7)38/196 (19.4)15/50 (30.0)13/62 (21.0)13/49 (26.5)11/90 (12.2)SJC76 ≤1105/160 (65.6)85/146 (58.2)83/150 (55.3)88/196 (44.9)32/50 (64.0)28/62 (45.2)20/49 (40.8)30/90 (33.3)PASI ≤1 or BSA ≤3%99/128 (77.3)90/128 (70.3)69/109 (63.3)64/153 (41.8)29/38 (76.3)27/47 (57.4)28/40 (70.0)26/70 (37.1)Patient pain VAS ≤1557/144 (39.6)50/133 (37.6)50/141 (35.5)33/179 (18.4)14/42 (33.3)15/60 (25.0)13/43 (30.2)7/82 (8.5)PtGA VAS ≤2063/145 (43.4)47/125 (37.6)50/135 (37.0)39/173 (22.5)13/41 (31.7)14/61 (23.0)13/41 (31.7)7/81 (8.6)HAQ-DI ≤0.572/135 (53.3)55/118 (46.6)54/122 (44.3)47/158 (29.7)13/39 (33.3)18/58 (31.0)17/39 (43.6)19/77 (24.7)Tender entheseal points ≤170/87 (80.5)44/63 (69.8)42/76 (55.3)45/88 (51.1)13/18 (72.2)17/31 (54.8)11/19 (57.9)23/38 (60.5)BSA, body surface area; HAQ-DI, Health Assessment Questionnaire Disability Index; MDA, Minimal Disease Activity; NL, no loading dose; PASI, Psoriasis Area and Severity Index; PBO, placebo; PtGA, patient global assessment of disease activity; SEC, secukinumab; SJC, swollen joint count; TJC, tender joint count; VAS, visual analog scale; VLDA, Very Low Disease Activity.ConclusionPatients who did not have radiographic progression over 6 months of SEC treatment were more likely to achieve LDA or remission and improvement in physical function at Week 24. Additional analyses will explore relationships between radiographic progression and additional clinical and patient-reported outcomes over longer time periods.References[1]Mease P, et al. RMD Open. 2021;7:e001600.[2]Coates LC, et al. Ann Rheum Dis. 2021;80:803-4.AcknowledgementsThis study was funded by Novartis Pharmaceuticals Corporation. Medical writing support was provided by Eric Deutsch, PhD, CMPP, of Health Interactions, Inc, and was funded by Novartis Pharmaceuticals Corporation. This abstract was developed in accordance with Good Publication Practice (GPP3) guidelines. Authors had full control of the content and made the final decision on all aspects of this publication.Disclosure of InterestsPhilip J Mease Speakers bureau: AbbVie, Amgen, Janssen, Eli Lilly, Novartis, Pfizer, and UCB, Consultant of: AbbVie, Amgen, Boehringer Ingelheim, Bristol Myers Squibb, Celgene, Galapagos, Gilead, GlaxoSmithKline, Janssen, Eli Lilly, Novartis, Pfizer, Sun Pharma, and UCB, Grant/research support from: AbbVie, Amgen, Bristol Myers Squibb, Celgene, Gilead, Janssen, Eli Lilly, Novartis, Pfizer, Sun Pharma, and UCB, Ana-Maria Orbai Consultant of: Bristol Myers Squibb, Janssen, Lilly, Novartis, Pfizer, and UCB, Grant/research support from: To Johns Hopkins University from AbbVie, Amgen, Celgene, Horizon, Janssen, Lilly, and Novartis, Bhumik Parikh Employee of: Novartis Pharmaceuticals Corporation, Corine Gaillez Employee of: Novartis Pharma AG, Xiangyi Meng Employee of: Novartis Pharmaceuticals Corporation, Christopher T. Ritchlin Consultant of: AbbVie, Amgen, Eli Lilly, Janssen, Pfizer, Novartis, Gilead, and UCB
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Niyazov, Alexander, Monika Izano, Colden Johanson, Sheetal Walters, Anna Berry, Bhakti Arondekar, A. Douglas Laird, Lillian Shahied Arruda, and Henry Kaplan. "Abstract P2-09-05: Germline BRCA1/2 mutation testing in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC): A real-world study in the Syapse Learning Health Network (LHN)." Cancer Research 82, no. 4_Supplement (February 15, 2022): P2–09–05—P2–09–05. http://dx.doi.org/10.1158/1538-7445.sabcs21-p2-09-05.
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Abstract Background: Germline (g)BRCA1/2 mutations represent approximately 5% of metastatic breast cancer. Poly ADP-ribose polymerase inhibitors (PARPi) have shown improved clinical outcomes, a manageable toxicity profile, and favorable patient (pt)-reported outcomes versus chemotherapy in pts with gBRCA1/2 mutated HER2- locally advanced or metastatic breast cancer. With the advent of PARPi, clinical guidelines have broadened eligibility criteria for gBRCA1/2 testing. However, limited information is available on the impact of the COVID-19 pandemic on gBRCA1/2 testing rates. We assessed trends and factors associated with gBRCA1/2 testing in pts with HER2- ABC before and during the COVID-19 pandemic. Methods: This retrospective study included pts from the Syapse LHN, a longitudinal database of pts with cancer cared for in community-based, integrated care delivery networks in 25 states in the United States. Pts were eligible for gBRCA1/2 testing from initial ABC diagnosis until death or date of last contact with the participating health system. Information on gBRCA1/2 testing was obtained from scaled sources and further curated by Certified Tumor Registrars. Logistic regression evaluated the associations between age at diagnosis, family history of relevant cancer, race/ethnicity, median household income, health system, and diagnosis year with gBRCA1/2 testing among HER2- ABCs; models included hormone receptor status. Results: The study population included 1769 pts with HER2- ABC, including 577 pts with triple negative ABC initially diagnosed from 2010: 96% were women, 69% were non-Hispanic White, and 94% had an estimated median household income >$30,000 USD; median age at initial diagnosis was 61 years. The percentage of pts ever gBRCA1/2-tested among those eligible increased over time: 26%, 28%, and 31% by end of 2018, 2019, and 2020, respectively. Similarly, the percentages of new testing among eligible but not previously tested pts increased from 2018-March 2020, decreased from April-September 2020, and trended upwards thereafter (Table 1). In logistic regression models combining data from pre- and post-COVID-19 periods, family history of relevant cancer (odds ratio [OR]=1.9; 95% CI, 1.5-2.4), younger age at diagnosis (>65 reference; <45: OR=12.8, 95% CI, 8.9-18.3; 45-54: OR=6.7, 95% CI, 4.9-9.3; 55-64: OR=2.0, 95% CI, 1.5-2.8), and diagnosis year of 2013 or later (OR=1.9, 95% CI, 1.4-2.6) were significantly associated with increased odds of gBRCA1/2 testing. Positive hormone receptor status (OR=0.5; 95% CI, 0.4-0.6) and Hispanic ethnicity (OR=0.5; 95% CI, 0.3-0.9) were significantly associated with reduced odds; associations with non-Hispanic Black ethnicity did not reach statistical significance (OR=0.8; 95% CI, 0.6-1.1). Conclusion: Following the expanded eligibility criteria for gBRCA1/2 testing, testing rates increased from 2018 to 2019 and decreased only slightly during the national COVID-19 lockdown. Age at diagnosis, family history, diagnosis year, ethnicity, and hormone receptor status impacted the odds of testing. Given that gBRCA1/2 mutations are actionable, focused efforts should be developed to resume the pre-pandemic trajectory of gBRCA1/2 mutation testing. Funding: Pfizer Inc Table 1.Percentages of Newly gBRCA1/2-Tested Pts with HER2- ABC Who Were Eligible for Testing Anytime During the Time Period and Not Previously TestedTime Period2018, % (n/N)2019, % (n/N)2020, % (n/NJanuary-March2.3 (10/427)2.7 (14/512)4.3 (23/537)April-June2.9 (13/447)3.4 (18/536)2.8 (14/495)July-September4.3 (20/468)4.7 (27/569)2.5 (13/517)October-December1.9 (9/478)3.1 (17/548)3.5 (16/456)Total8.4 (52/622)10.0 (76/757)8.8 (66/747)A pt diagnosed in February and tested in April of 2018 would be included in the denominator (N) for January-March and April-June of 2018 and in the numerator (n) for April-June of 2018. Citation Format: Alexander Niyazov, Monika Izano, Colden Johanson, Sheetal Walters, Anna Berry, Bhakti Arondekar, A. Douglas Laird, Lillian Shahied Arruda, Henry Kaplan. Germline BRCA1/2 mutation testing in human epidermal growth factor receptor 2 (HER2)-negative advanced breast cancer (ABC): A real-world study in the Syapse Learning Health Network (LHN) [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 P2-09-05.
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García-Gutiérrez, Valentín, Dragana Milojkovic, María Luisa Martín Mateos, Simone Claudiani, Concepcion Boque, Luis Felipe Casado, Gloria González, et al. "Safety and Efficacy of Bosutinib in Fourth Line Therapy of Chronic Myeloid Leukemia Patients." Blood 126, no. 23 (December 3, 2015): 2786. http://dx.doi.org/10.1182/blood.v126.23.2786.2786.
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Abstract BACKGROUND: Despite the excellent prognostic of chronic myeloid leukemia (CML) patients since the introduction of tyrosine kinase inhibitors (TKIs), approximately 50% of patients that are treated with TKIs will discontinue first line treatment due to lack of efficacy or intolerance. Once patients need a second line treatment, a considerable proportion of patients will need third or even fourth line therapy during further evolution. At this moment, there is a lack of data about real benefit of this group of patients. We have recently published our experience of 30 CML patients treated with bosutinib in 4th line. We present an update of the study where we have increased the number of patients, and the follow-up. The aim of this study is to present safety and efficacy data CML chronic phase patients treated with bosutinib in 4th line. METHODS: We have collected data from 59 CML patients treated with bosutinib in 4th line after resistance or intolerance to IM, NI and DA. 51 patients have been treated under the Spanish compassionate use program (36 centers) and 10 patients were treated in a single institution from United Kingdom. Median age of patients at diagnosis was 53 years. The percentage of low, intermediate and high risk Sokal groups were 47%, 37% and 16%. Median time TKIs exposure before bosutinib was 9 years. The most common indication (30/59) was intolerant to DA and NI. Patients' dispositions and main line characteristics are shown in table 1. RESULTS: Median follow-up was 14.3 months. All patients started bosutinib at 500mg/d, median dose of was 450mg/d. Overall probabilities to either achieve or maintain previous response were 96% (57/59), 62% (37/59), 40% (24/59) and 17% (10/59) for complete hematological response (CHR), complete cytogenetic response (CCyR), major molecular response (MMR) and MR4.5 respectively. However, probabilities to obtain responses (in patients without response evaluated at baseline) were 27% (7/26), 26% (12/45) and 12% (7/55) for CCyR, MMR and MR4.5. As expected, probabilities to obtain CCyR were lower for patients resistant to DA and NI patients than for patients intolerant to DA and NI (8% VS 44%). Event free survival (EFS) and progression free survival (PFS) probabilities were 50% and 83% by 27 month. Treatment was discontinued in 20/58 (34%), most frequent reasons being adverse events 9/59(15%), lack of efficacy 5/59 (8.5%), disease progression 2/59 (3.4%) and death 1/59 (1.7%). Two patients discontinued due to stem cell transplantation. The adverse events that led to treatment discontinuation were pleural effusion (3), diarrhea (2), rash, renal impairment, auricular fibrillation and liver enzyme elevation one patient each. Overall, bosutinib was well tolerated. Grade 3-4 hematological toxicities were 3%, 6% and 6% for anemia, thromboctytopenia and neutropenia. Most common non hematological side effects were diarrhea (39%, nauseas 13% and liver alterations 14% and pleural effusion 14%. CONCLUSIONS: Little is known about the therapeutic role of Bosutinib in 4th line. The series presented here is, to our knowledge, the largest being presented. Bosutinib seems to be an appropriate treatment option for patients resistant or intolerant to three prior TKIs. Table 1. IM+NI-I+DA-R (N=4) IM+NI-R+DA-R (N=18) IM+NI-I+DA-I (N=30) IM+NI-R+DA-I (N=7) Total (N=59) Sex, N (%) Male 2 (50) 11 (61.1) 16 (53.3) 2 (28.6) 31 (52.5) Median age of diagnosis, yr (range) 57.32 (50-64) 49.19 (23-73) 54.95 (21-89) 48.87 (26-68) 53.15 (21-89) Median age of Bosutinib initiation, yr (range) 69.13 (61-70) 62.27 (39-79) 64.85 (25-90) 64.79(35-74) 63.7 (25-9) Median follow up, months (range) 18.5(7.8-34.1) 8.4(1.22-36.1) 16.3(0.5-34.7) 23.4(3.3-28.9) 14.3(0.7-36.1) SOKAL Index at diagnosis, N (%) High 2(50.0) 4 (23.5) 1 (4.3) 1 (20) 8 (16.3) Intermediate 1 (25.0) 5 (29.4) 10(43.5) 2 (40) 18 (36.7) Low 1 (25.0) 8 (47.1) 12 (52.2) 2 (40) 23 (46.9) Median Time from first TKI to BOS, (yr, range) 10.3 (4.8-11.9) 9.3 (2.0-11.4) 8.8 (0.7-13.6) 8.2 (5.1-12.3) 8.8 (0.7-13.6) Median duration of prior therapy, months (range) Imatinib 38.8 (11.8-69.8) 32.6 (6.3-96.8) 26.2 (1.6-102.6) 23.1 (8.3-66.8) 28.8 (1.6-102.6) Dasatinib 21.5 (12.6-75) 21.8 (7.7-69) 31.4 (0.4-87.1) 23.7 (10.3-53.6) 23.44 (0.4-87.1) Nilotinib 19.1 (2.1-46.2) 16.7 (5-65.6) 8.9 (0.2-58.5) 30.9 (6.9-49.3) 14.3 (0.2-65.6) BOS: bosutinib, IM, imatinib; DA, dasatinib; NI, nilotinib, I: Intolerance, R: Resistant, Yr: year Disclosures García-Gutiérrez: Ariad: Consultancy; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Milojkovic:Novartis: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; Ariad: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Boque:Novartis: Honoraria; BMS: Honoraria; Celgene: Honoraria. Casado:Novartis: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Jiménez:Pfizer: Consultancy, Honoraria. Giraldo:Pfizer: Consultancy. Steegmann:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau; Pfizer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Ariad: Consultancy, Honoraria, Research Funding, Speakers Bureau.
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Leung, Nelson, Shaji Kumar, Angela Dispenzieri, Martha Lacy, Francis Buadi, David Dingli, William J. Hogan, Dennis Gastineau, and Morie Gertz. "Comparison of Troponin T and N-Terminal-Pro-Brain Natriuretic Peptides In Two Models of Treatment Related Mortality In AL Amyloidosis Patients Following Autologous Stem Cell Transplantation." Blood 116, no. 21 (November 19, 2010): 3572. http://dx.doi.org/10.1182/blood.v116.21.3572.3572.
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Abstract Abstract 3572 High dose melphalan and autologous stem cell transplantation (ASCT) is an effective treatment for light chain amyloidosis (AL) but high treatment related mortality (TRM) limits its use. Both cardiac troponin T (cTnT) and N-terminal-pro-brain natriuretic peptide (NT-pro-BNP) are sensitive predictors of high risk patients. Aim of this study is to compare two models of TRM, one using cTnT and the other BNP. Patients who underwent ASCT between 7/1996 and 7/2009 at the Mayo Clinic were analyzed retrospectively. Variables were chosen for ease of measurement and reproducibility thus echocardiographic parameters were excluded. Each additional risk factor must contribute to a significant increase in TRM. Also, since NT-pro-BNP and cTnT are already highly associated with mortality, the other risk factors must be independent predictors. Univariate analysis revealed serum albumin, B-2-microglobulin, cTnT, NT-pro-BNP, and uric acid were associated with TRM while age, sex, alkaline phosphatase, serum creatinine, CRP, proteinuria were not (Table 1). Multivariate analysis showed albumin and uric acid were independent risk factors to cTnT and NT-pro-BNP (Table 2). Of the 412 patients, 347 (8.9% TRM) could be evaluated by the cTnT, albumin and uric acid (TAU) model and 282 (9.2%) TRM could be evaluated by the NT-pro-BNP, albumin, uric acid (BAU) model. Both models showed increasing TRM with additional risk factors beyond 1 risk factor (Table 3 and 4). Albumin and uric acid were found to be significant contributors in both models. Patients with elevated cTnT alone had a 0% TRM vs 23.4% if they had 1 additional risk factor, p = 0.03. Similarly, TRM was 3.7% in patients with elevated NT-pro-BNP alone but 18.0% if they had 1 other risk factor, p = 0.05. NT-pro-BNP and cTnT could not be used in the same model because cTnT becomes non-significant. Both models were superior to visceral organ involvement which had TRM of 5.3% with 1, 9.2% with 2 and 16.7% with 3 organ involvement. Both models were also predictive of overall survival (Figure 1 and Figure 1b). Our results show that these models show that albumin and uric acid with either cTnT or NT-pro-BNP can accurately predict TRM in AL patients undergoing ASCT. Multivariate analysis shows that the NT-pro-BNP containing model may be superior since cTnT loses it significance when added to the model. Our results suggest these models could be very helpful in identifying high risk patients not suitable for ASCT. Figure 1a Overall survival evaluated by Kaplan-Meier method on 347 patients using the TAU model. Mortality increased significantly with the number of risk factors, p < 0.001. Solid line represents patients with 0 risk factors, dotted line represents patients with 1 risk factor, dashed line represents those with 2 risk factors and dotted dashed line represent those with 3 risk factors. Figure 1a. Overall survival evaluated by Kaplan-Meier method on 347 patients using the TAU model. Mortality increased significantly with the number of risk factors, p < 0.001. Solid line represents patients with 0 risk factors, dotted line represents patients with 1 risk factor, dashed line represents those with 2 risk factors and dotted dashed line represent those with 3 risk factors. Figure 1b Overall survival evaluated by Kaplan-Meier method on 282 patients using the BAU model. Overall survival was significantly longer in patients with less risk factors, p < 0.001. Solid line represents patients with 0 risk factors, dotted line represents patients with 1 risk factor, dashed line represents those with 2 risk factors and dotted dashed line represent those with 3 risk factors. Figure 1b. Overall survival evaluated by Kaplan-Meier method on 282 patients using the BAU model. Overall survival was significantly longer in patients with less risk factors, p < 0.001. Solid line represents patients with 0 risk factors, dotted line represents patients with 1 risk factor, dashed line represents those with 2 risk factors and dotted dashed line represent those with 3 risk factors. Table 1. Patient characteristics Control TRM p-value N 318 29 Age 58 (25–73) 55 (35–75) 0.54 Sex (male) 58.2% 72.4% 0.13 Albumin (g/dl) 2.7 (0.8–4.4) 2.2 (0.8–3.7) 0.02 Alkaline phosphatase (U/L) 89 (28–1014) 86 (31–1394) 0.22 b2m (mg/ml) 2.6 (1.0–35.1) 3.2 (1.3–15.2) 0.007 NT-pro-BNP (pg/ml) 564 (12–35000) 1661 (21–35001) 0.03 CRP (mg/L) 0.3 (0.01–16.6) 0.3 (0.05–3.2) 0.34 cTnT (ng/ml) 0.01 (0–1.0) 0.03 (0.01–0.22) <0.001 Scr (mg/dl) 1.1 (0.4–12) 1.2 (0.8–2.3) 0.09 Proteinuria (g/d) 3.4 (0.01–35.4) 5.1 (0.1–20.5) 0.10 Uric acid (mg/dl) 6.2 (1–14.8) 7.5 (3.7–13.2) 0.02 Organ Involvement 1 94.7% 5.3% 0.04 2 90.7% 9.3% 3 83.3% 16.7% Table 2. Multivariate analysis using proportional hazard model cutoffs >Risk Ratio >p-value Model TAU cTnT 0.04 ng/ml 2.78 0.01 Albumin 3.3 g/dl 3.11 0.03 Uric acid 8.5 mg/dl 2.69 0.02 Model BAU NT-pro-BNP 1270 pg/ml 3.77 0.003 Albumin 3.3 g/dl 3.53 0.04 Uric acid 8.5 mg/dl 3.11 0.03 Table 3. Model of cTnT, albumin and uric acid TAU Risk Factors n TRM p-value Risk Ratio 0 69 2.9% 1 205 5.9% 0.33 2 61 16.4% 0.009 2.98 3 12 41.7% 0.05 8.52 Table 4. Model of NT-pro-BNP, albumin and uric acid BAU Risk Factors >n >TRM >p-value >Risk Ratio 0 28 0% 1 161 5.6% 0.20 2 82 14.6% 0.02 2.7 3 11 45.5% 0.01 10.8 Disclosures: Kumar: Celgene: Consultancy, Research Funding; Millennium: Research Funding; Merck: Consultancy, Research Funding; Novartis: Research Funding; Genzyme: Consultancy, Research Funding; Cephalon: Research Funding. Dispenzieri:Celgene: Honoraria, Research Funding; Binding Site: Honoraria. Lacy:Celgene: Research Funding.
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Kwiatkowski, Janet L., Alexis A. Thompson, John E. J. Rasko, Suradej Hongeng, Gary J. Schiller, Usanarat Anurathapan, Marina Cavazzana, et al. "Long-Term Clinical Outcomes of Lentiglobin Gene Therapy for Transfusion-Dependent β-Thalassemia in the Northstar (HGB-204) Study." Blood 134, Supplement_1 (November 13, 2019): 4628. http://dx.doi.org/10.1182/blood-2019-125807.
Full textAbstract:
Background Patients with transfusion-dependent β-thalassemia (TDT) may experience transfusional iron overload and end-organ damage. While potentially curative, allogeneic hematopoietic stem cell (HSC) transplantation is limited by transplant-related risks and donor availability. Transplantation of autologous CD34+ cells encoding a βA-T87Q-globin gene (LentiGlobin gene therapy for β-thalassemia) may overcome some of these limitations. βA-T87Q-globin is incorporated into adult hemoglobin (Hb), forming gene therapy-derived HbAT87Q, which can be distinguished from other Hb species. The phase 1/2 Northstar study (HGB-204; NCT01745120) using the original manufacturing process evaluated the safety and efficacy of LentiGlobin in adolescents and adults with TDT (≥100 mL/kg/yr of red blood cells [RBCs] or ≥8 RBC transfusions/yr) and non-β0/β0 or β0/β0 genotypes. Methods HSCs were mobilized with G-CSF and plerixafor and collected via apheresis. CD34+ cells were transduced with BB305 lentiviral vector. After busulfan myeloablation, patients were infused with transduced cells. Primary efficacy endpoints were sustained production of ≥2 g/dL HbAT87Q between months 18 and 24 and transfusion independence (TI; weighted average Hb ≥9 g/dL without RBC transfusions for ≥12 months). Patients were monitored for 2 years and subsequently enrolled in the 13-year long-term follow-up study, LTF-303 (NCT02633943). Results are shown as median (min ‒ max) unless otherwise indicated. Results Eighteen patients were treated (age: 20 [12 - 35] yrs) and followed for 40.7 (29.3 - 53.8) months as of 13 December 2018. In the 2 years prior to enrollment, patients had an annualized transfusion volume of 169.0 (124.0 - 273.0) mL/kg/yr and pre-transfusion weighted mean nadir Hb of 9.3 (7.0 - 10.1) g/dL. Neutrophil and platelet engraftment occurred at 18.5 (14 - 30) and 39.5 (19 - 191) days, respectively. No patient had graft failure. Grade ≥3 non-hematologic adverse events (AEs) reported in ≥25% of patients after infusion were stomatitis, febrile neutropenia, and pharyngeal inflammation. No replication-competent lentivirus or death has been reported. The vector integration site profile in all 18 patients has remained polyclonal. The number of unique integration sites (UIS) identified was 1646 (190 - 2888), 1677 (151 - 6935), 2484 (984 - 5511), 1773 (1260 - 2693) at Months 12 (n=18), 24 (n=18), 36 (n=11), 48 (n=4), respectively. The highest mean (SD) frequency of any UIS in patients across all visits was 11.5% (5.8%). No oncogenesis has been reported. In Northstar, 16/18 (89%) patients achieved the primary endpoint of ≥2 g/dL HbAT87Q between months 18 and 24. Eight of 10 (80%) patients with non-β0/β0 genotypes achieved and maintained TI; current duration of TI was 38 (21.2 - 45.3) months (Figure 1). The weighted average total Hb during TI was 10.3 (9.1 - 13.2) g/dL. Total Hb and HbAT87Q remained stable over time. Total Hb in patients with non-β0/β0 genotypes who achieved TI was 10.3, 10.4, 10.6, and 11.1 g/dL at Months 12 (n=8), 24 (n=8), 36 (n=7), 48 (n=3), respectively. Transfusion volumes were reduced by 73% and 43% in the 2 patients still receiving transfusions. Three of 8 (38%) patients with β0/β0 genotypes achieved TI with a current duration of 16.4 (16.1 - 20.8) months. Weighted average total Hb during TI was 9.9 (9.5 - 10.1) g/dL and HbAT87Q was 8.0 - 8.9 g/dL at last visit. One additional patient was transfusion-free for 13.7 months; however, total Hb was <9 g/dL. The 4 other patients had a transfusion volume reduction of 53% (10% - 72%). Patients who achieved TI resumed iron chelation 13 (2 - 15) months after infusion and all remain on iron chelation as of last follow-up. Serum ferritin and liver iron content (LIC) (Figure 2A, 2B) were reduced in patients who achieved TI by 55% (16 - 78%) and 56% (38 - 83%) from screening to Month 48 (n=4), respectively. Of these 4 patients who had a Month 48 visit, LIC values were 0.8 - 7.1 mg/g at Month 48 compared to 4.8 - 11.5 mg/g at screening. In patients who achieved TI, cardiac T2* ranged from 27.0 - 39.0 msec at screening and 31.4 - 57.6 msec at last visit. Summary With up to 4.5 years of follow-up after LentiGlobin gene therapy, generally stable HbAT87Q levels and durable TI were observed in 8/10 and 3/8 patients with TDT and non-β0/β0 and β0/β0 genotypes, respectively. Iron burden has improved over time in patients who achieved TI. The safety profile of LentiGlobin remains consistent with myeloablative conditioning. Disclosures Kwiatkowski: Imara: Consultancy; Agios: Consultancy; bluebird bio, Inc.: Consultancy, Research Funding; Terumo: Research Funding; Apopharma: Research Funding; Novartis: Research Funding; Celgene: Consultancy. Thompson:bluebird bio, Inc.: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Baxalta: Research Funding. Rasko:GSK: Honoraria; bluebird bio: Honoraria; Imago: Consultancy; Novartis: Honoraria; Cynata: Honoraria; Spark: Honoraria; Takeda: Honoraria; NHMRC Mitochondrial Donation Expert Working Committee: Other: Advisory Committee; Gilead: Honoraria; Cure The Future Foundation: Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; Genea: Equity Ownership; Rarecyte: Consultancy, Equity Ownership; Gene Technology Technical Advisory, Australian Government: Other: Advisory committee; Celgene: Honoraria; Advisory Committee on Biologics, Australian Government: Other: Advisory Committee; Australian Cancer Research Scientific Advisory Board: Membership on an entity's Board of Directors or advisory committees; FSHD Global Research Foundation: Membership on an entity's Board of Directors or advisory committees. Schiller:Amgen: Other, Research Funding; Agios: Research Funding, Speakers Bureau; Astellas: Research Funding; Biomed Valley Discoveries: Research Funding; Bristol Myer Squibb: Research Funding; Celgene: Research Funding, Speakers Bureau; Constellation Pharmaceutical: Research Funding; Daiichi Sankyo: Research Funding; Eli Lilly and Company: Research Funding; FujiFilm: Research Funding; Genzyme: Research Funding; Gilead: Research Funding; Incyte: Research Funding; J&J: Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Karyopharm: Research Funding; Novartis: Research Funding; Onconova: Research Funding; Pfizer Pharmaceuticals: Equity Ownership, Research Funding; Sangamo Therapeutics: Research Funding. Cavazzana:Smartimmune: Other: Founder of Smartimmune. Ho:Celgene: Other: investigator meeting travel costs; Janssen: Other: investigator meeting travel costs; Novartis: Other: investigator meeting travel costs; La Jolla: Other: investigator meeting travel costs. Schmidt:German Cancer Research Center, Heidelberg, Germany: Employment; GeneWerk GmbH, Heidelberg, Gemrany: Equity Ownership. Vichinsky:Agios: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; GBT: Consultancy, Research Funding; bluebird bio: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Deary:bluebird bio, Inc.: Employment, Equity Ownership. Chen:bluebird bio, Inc.: Consultancy. Petrusich:bluebird bio, Inc.: Employment, Equity Ownership. Walters:Editas Medicine: Consultancy; TruCode: Consultancy; AllCells, Inc: Consultancy.
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Ndari, Susianty selaras, Chandrawaty Chandrawaty, Imam Mujtaba, and Mafaza Conita Ananto. "Children's Outdoor Activities and Parenting Style in Children's Social Skill." JPUD - Jurnal Pendidikan Usia Dini 13, no. 2 (November 30, 2019): 217–31. http://dx.doi.org/10.21009/jpud.132.02.
Full textAbstract:
Physical activity is very important for early childhood, especially outdoor activities that add a lot of new experiences. This study aims to check the relationship of children's outdoor activities and parenting styles and children's social skills. The participants are 125 parents of early childhood who attend kindergarten. The research method is a descriptive study using the relational screening model. The results showed that there was a relationship between outside play and parenting style on the social skills of children in their childhood. Democratic parenting styles are found to promote children's social skills, while authoritative parenting styles have a negative correlation with interpersonal skills, the ability to express verbally, self-control, listening skills, emotional management and adaptation to change. In the sub-dimensions of anger management and adaptation to changing skills is a significant difference between authoritative parenting styles and not permissive parenting with children's social skills.
Keywords: Early Childhood Social skills, Outdoor Activities, Parenting Styles
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Kumar, Shaji, Simon J. Harrison, Michele Cavo, Javier de la Rubia, Rakesh Popat, Cristina J. Gasparetto, Vania Hungria, et al. "Final Overall Survival Results from BELLINI, a Phase 3 Study of Venetoclax or Placebo in Combination with Bortezomib and Dexamethasone in Relapsed/Refractory Multiple Myeloma." Blood 138, Supplement 1 (November 5, 2021): 84. http://dx.doi.org/10.1182/blood-2021-145757.
Full textAbstract:
Abstract Background: Multiple myeloma (MM) is a heterogenous cancer of terminally differentiated plasma cells that typically express elevated levels of antiapoptotic proteins, such as BCL-2. Venetoclax (Ven), a highly selective, potent, oral BCL-2 inhibitor, induces apoptosis in MM cells, and when combined with bortezomib and dexamethasone showed promising efficacy in patients (pts) with relapsed/refractory MM (RRMM; Moreau et al. Blood. 2017;130:2392-2400). The Phase 3 BELLINI study primary analysis showed significantly improved response rates and progression-free survival (PFS) in pts with RRMM treated with Ven added to bortezomib and dexamethasone versus placebo (Pbo); however, increased mortality was observed in the Ven group (Kumar et al. Lancet Oncol. 2020;21:1630-1642). At the initial data cutoff (November 26, 2018), the PFS hazard ratio (HR) was 0.63 (95% CI, 0.44-0.90) and overall survival (OS) HR was 2.03 (95% CI, 1.04-3.95). Pts with t(11;14) translocation or high BCL2 expression showed improved responses and PFS without increased mortality. Here, we present updated safety and efficacy data from the prespecified final OS analysis. Methods: BELLINI (NCT02755597) is a Phase 3, randomized, double-blind, multicenter study of Ven or Pbo combined with bortezomib and dexamethasone in pts with RRMM who had received 1-3 prior lines of therapy and were either sensitive or naïve to proteasome inhibitors. Pts were randomized 2:1 to receive Ven 800 mg/day or Pbo plus bortezomib and dexamethasone. Cycles 1-8 were 21-day cycles with bortezomib 1.3 mg/m 2 on Days 1, 4, 8, and 11 and dexamethasone 20 mg on Days 1, 2, 4, 5, 8, 9, 11, and 12. Cycles 9 and beyond were 35-day cycles with bortezomib 1.3 mg/m 2 on Days 1, 8, 15, and 22 and dexamethasone 20 mg on Days 1, 2, 8, 9, 15, 16, 22, and 23. The primary endpoint was PFS assessed by independent review committee. Key secondary endpoints included overall response rate and OS. BCL2 expression was measured by quantitative polymerase chain reaction with the cutoff for high BCL2 determined using bootstrapping and aggregating thresholds from trees. Results: Of 291 randomized pts (194 to Ven and 97 to Pbo), 33 pts were receiving ongoing treatment (28 with Ven and 5 with Pbo) as of the final OS analysis data cutoff (March 15, 2021). At a median follow-up of 45.6 months, there were 78 (40%) deaths in the Ven arm versus 36 (37%) in the Pbo arm. Updated PFS and OS among all pts and those with t(11;14) or high BCL2 expression are shown in the Table. Among all pts, the median PFS per investigator was 23.4 months in the Ven arm versus 11.4 months in the Pbo arm (HR, 0.58 [95% CI, 0.43-0.78]). In pts with t(11;14), the median PFS was 36.8 months in the Ven arm versus 9.3 months in the Pbo arm (HR, 0.12 [95% CI, 0.03-0.44]). In pts with high BCL2, the median PFS was 30.1 months in the Ven arm versus 9.9 months in the Pbo arm (HR, 0.37 [95% CI, 0.21-0.64]). Median OS was not reached in the Ven or Pbo arm among all pts (HR, 1.19 [95% CI, 0.80-1.77]), pts with t(11;14) (HR, 0.61 [95% CI, 0.16-2.32]), pts with high BCL2 (HR, 0.70 [95% CI, 0.32-1.51]), and pts with t(11;14) or high BCL2 (HR, 0.82 [95% CI, 0.40-1.70]). The most common treatment-emergent adverse events (AEs) with Ven (versus Pbo) were diarrhea (60% versus 50%), nausea (38% versus 23%), and constipation (35% versus 31%). The most common Grade 3/4 AEs (Ven versus Pbo) were thrombocytopenia (16% versus 30%), neutropenia (23% versus 8%), pneumonia (19% versus 13%), anemia (16% versus 15%), and diarrhea (15% versus 11%). Serious AEs occurred in 57% of Ven- and 55% of Pbo-treated pts, with serious infections and infestations occurring in 35% and 29% of pts, respectively. Overall, 26% of pts in the Ven arm and 11% of pts in the Pbo arm experienced an AE leading to Ven or Pbo discontinuation. AEs led to 12 deaths in the Ven arm, with 9 of these deaths due to serious infection; an AE led to 1 death in the Pbo arm. A total of 16 (6%) treatment-emergent deaths occurred (14 [7%] with Ven and 2 [2%] with Pbo), with 3 of these deaths due to disease progression (2 [1%] with Ven and 1 [1%] with Pbo). Conclusion: In the final OS analysis, the addition of Ven to bortezomib and dexamethasone showed significantly improved PFS but resulted in increased mortality versus Pbo in the total population. Consistent with results from previous analyses, Ven added to bortezomib and dexamethasone showed the greatest PFS improvement in pts with t(11;14) or high BCL2, with a favorable benefit-risk profile. Figure 1 Figure 1. Disclosures Kumar: Beigene: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bluebird Bio: Consultancy; Merck: Research Funding; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Tenebio: Research Funding; BMS: Consultancy, Research Funding; Antengene: Consultancy, Honoraria; Roche-Genentech: Consultancy, Research Funding; Novartis: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding. Harrison: Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; Terumo BCT: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Cavo: Novartis: Honoraria; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Adaptive Biotechnologies: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. de la Rubia: Ablynx/Sanofi: Consultancy; Amgen, Bristol Myers Squibb,: Honoraria, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Celgene, Takeda, Janssen, Sanofi: Honoraria; AbbVie: Consultancy; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations; GSK: Consultancy; Takeda: Consultancy; Sanofi: Membership on an entity's Board of Directors or advisory committees. Popat: Abbvie, Takeda, Janssen, and Celgene: Consultancy; AbbVie, BMS, Janssen, Oncopeptides, and Amgen: Honoraria; Takeda: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; GlaxoSmithKline: Consultancy, Honoraria, Research Funding; Janssen and BMS: Other: travel expenses. Gasparetto: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Karyopharm Therapeutics Inc.: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Oncopeptite: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, 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; BMS: Consultancy; Connect Registry: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding, Speakers Bureau. Hungria: Sanofi: Honoraria, Other: Support for attending meetings/travel ; Takeda: Honoraria; Abbvie: Honoraria; Amgen, BMS, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings/travel . Salwender: Oncopeptides: Honoraria; GlaxoSmithKline: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Sanofi: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Takeda: Honoraria; Pfizer: Honoraria; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Chugai: Honoraria; AbbVie: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Janssen-Cilag: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Bristol-Myers Squibb/Celgene: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Suzuki: Japanese Red Cross Medical Center: Current Employment; Janssen: Honoraria; AbbVie: Honoraria; Sanofi: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Research Funding; ONO: Honoraria; Novartis: Honoraria. Kim: Seoul National University Hospital: Current Employment. Onishi: Roche: Current Employment, Current equity holder in publicly-traded company; Genentech: Current Employment. Ku: Roche: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Genentech: Current Employment, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Pothacamury: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Sehgal: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Masud: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Ross: AbbVie: Current Employment, Current equity holder in publicly-traded company, Current holder of individual stocks in a privately-held company. Dobkowska: AbbVie: Current Employment, Current equity holder in publicly-traded company, Other: TRAVEL, ACCOMMODATIONS, EXPENSES; Pharmacyclics: Current Employment. Moreau: Celgene BMS: Honoraria; Amgen: Honoraria; Abbvie: Honoraria; Janssen: Honoraria; Sanofi: Honoraria; Oncopeptides: Honoraria.