Journal articles: '004.728.8, 004.75'

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Livingston, Kara, Micaela Karlsen, Gail Rogers, Sai Das, Alice Lichtenstein, Sara Folta, Remco Chang, Christina Economos, Paul Jacques, and Nicola McKeown. "Differences in Eating Behavior Among Followers of Popular Diets Across Categories of Perceived Adherence." Current Developments in Nutrition 5, Supplement_2 (June 2021): 980. http://dx.doi.org/10.1093/cdn/nzab051_024.

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Abstract Objectives To understand how eating behaviors, susceptibility to the food environment, and perceived dietary habit strength differ across self-reported categories of adherence. Methods We used data in a sample (n = 2829) from Adhering to Dietary Approaches for Personal Taste (ADAPT), an online study conducted in self-identified popular diet followers. Adherence was categorized into 3 groups: >95% of the time (high adherers = HA), between 75–95% (moderate adherers = MA); <75% time (lower adherers = LA). The Power of Food Scale (POF) assessed susceptibility to the food environment (availability, presentation, taste), with higher scores indicating food has a higher power over dietary decisions. The Three-Factor Eating Questionnaire captured cognitive restraint (CR), uncontrolled eating (UE), and emotional eating (EE), with higher scores indicating greater response to the specific eating behavior. The Self-Report Habit Index (SRHI) measured perceived habit strength with respect to eating, with a lower score indicating stronger habits. We used ANCOVA adjusting for age, sex, time on diet, and diet group to compare POF, CR, UE, EE, and SRHI outcomes across adherence groups. Results Sixty six percent were HA (n = 1881), 28% MA (n = 787), and 6% LA (n = 161). LA were significantly more susceptible to food availability (mean [95% CI] = 14.9 [13.8–16.1]), presentation (12.1 [11.2–13.1]), and taste (13.4 [12.6–14.2], compared to HA (11 [10.7–11.3], 8 [7.8–8.3],11.6 [11.4–11.9]), respectively. LA indicated significantly greater UE (21 [20.2–21.9]) than HA (17 [16.7–17.4]) and EE (LA = 8 [7.5–8.4] vs. HA = 6.1 [6–6.3]). No significant differences were observed with respect to CR. LA reported weaker SRHI habits (3.4 [3.2–3.6]) compared to HA (1.7 [1.7–1.8]). Differences seen between the LA and MA were similar to those described for HA. Conclusions Our findings show that higher self-reported adherence to dietary patterns is associated with lower susceptibility to negative influences in the food environment, lower uncontrolled and emotional eating, and greater habit strength. Future research should investigate the directionality of the relationship between eating behavior and adherence. Funding Sources USDA Cooperative Agreements 58-8050-9-004 & 58-8050-4-003, General Mills Bell Institute of Health & Nutrition

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Sasaki, Koji, Ildefonso Ismael Rodriguez-Rivera, Hagop M. Kantarjian, Susan O'Brien, Elias Jabbour, Gautam Borthakur, Farhad Ravandi, Michael J. Burke, Patrick A. Zweidler-McKay, and Jorge E. Cortes. "Correlation of Lymphocyte Count with Treatment Response to Tyrosine Kinase Inhibitors in Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase." Blood 124, no. 21 (December 6, 2014): 4538. http://dx.doi.org/10.1182/blood.v124.21.4538.4538.

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Abstract Background: Total lymphocyte count (TLC) has been shown to correlate with outcomes in patients (pts) with acute leukemia. The clinical correlation to TLC in pts with chronic myeloid leukemia in chronic phase (CML-CP) who were treated with a tyrosine-kinase inhibitor (TKI) is unclear. Methods: Lymphocyte data in pts with newly diagnosed CML-CP who were enrolled in consecutive or parallel clinical trials with front-line imatinib (IM), nilotinib (Nilo), or dasatinib (Dasa) were collected at the time of diagnosis, and 3 and 6 months (M) after the start of TKI. Relative lymphocytrosis (RLC) was defined as lymphocyte >150% at 3 or 6M compared with baseline at diagnosis. Absolute lymphocytosis (ALC) was defined as lymphocyte > 4,000 /µL at 3 or 6M after the start of TKI. Pts were assessed for response, overall survival (OS), event-free survival (EFS), transformation-free survival (TFS), and failure-free survival (FFS) based on ALC and RLC. The Kaplan-Meier method was used to calculate OS, EFS, TFS, and FFS. A log-rank test and Cox regression were used for univariate (UVA) and multivariate analysis (MVA), respectively. Results: A total of 483 pts were enrolled in this study: 271 in IM, 105 in Nilo, and 107 in Dasa. Patient characteristics and outcomes are summarized in Table 1. Median age at diagnosis was 48 years, and median follow-up was 85M and ongoing (5-154+). Time from diagnosis to start of TKI, Sokal risk score, and ALC at baseline between groups did not differ clinically. Of 481 pts, 93 (19%) developed RLC at 3 or 6M; IM, 38 (14%); Nilo, 23 (22%); Dasa, 32 (30%) (p= .001). ALC at 3 or 6M was observed in 15 (3%); IM, 3 (1%); Nilo, 1 (1%); Dasa, 11 (10%) (p<.001). Overall, cumulative incidence of complete cytogenetic response (CCyR) at 6M, major molecular response (MMR) at 12M, molecular response with 4.5 log reduction by IS (MR4.5) at 24M did not differ significantly between RLC and non-RLC (3 or 6M), or between ALC and non-ALC (3 or 6M). 5-y TFS, EFS and OS in ALC group were significantly worse than those in non-ALC group (p= .002, p=.016, p=.008, respectively). By UVA and MVA related to OS, age [p <.001; Hazard ratio (HR), 1.062; 95% confidence interval (95%CI), 1.036-1.089], presence of ALC at 3 or 6M [p = .028; HR, 10.948; 95%CI, 1.297-92.415], absence of MMR at 24M [p=.016; HR, 2.263; 95%CI, 1.165-4.393] were identified as adverse prognostic factors for OS. Conclusion: The presence of ALC ≥4,000/µL at 3 or 6M of TKI therapies is rare but is adversely associated with overall survival. Table 1. Patient Characteristics and Outcomes (N=483)a Overall [n= 481] IM [n= 271] Nilo [n= 105] Dasa [n= 107] Age, (year) 48 (15-85) 48 (15-85) 49 (17-82) 48 (16-83) Sokal Risk, No. (%) Low 334 (69) 175 (65) 79 (75) 80 (75) Intermediate 114 (24) 74 (27) 18 (17) 22 (21) High 32 (7) 20 (7) 8 (8) 4 (4) Time from diagnosis to start of TKI, (M) 0.9 (0-12.6) 1.0 (0-12.6) 0.5 (0-5.6) 0.7 (0.1-7.8) ALC at baseline, (/109L) 2.5 (0-86.6) 2.4 (0-16.7) 2.6 (0.4-9.2) 2.7 (0.3-86.6) Incidence of Relative Lymphocytosis, No. (%) At 3M 65 (14) 25 (9) 16 (15) 24 (22) At 6M 76 (16) 32 (12) 20 (19) 24 (22) Overall 93 (19) 38 (14) 23 (22) 32 (30) Incidence of Absolute Lymphocytosis, No. (%) At 3M 8 (2) 1 (0) 0 7 (7) At 6M 11 (2) 3 (1) 1 (1) 7 (7) Overall 15 (3) 3 (1) 1 (1) 11 (10) Outcomes of RLC and ALC at any time in each group, +/- (%/%) (p) <10% BCR-ABL/ABL at 3M RLC 36/40 (.596) 22/44 (.213) 50/37 (.280) 31/38 (.537) ALC 38/39 (.952) 0/42 (.394) 100/39 (.214) 36/35 (.952) Cumulative CCyR at 6M RLC 75/75 (.288) 50/66 (.063) 96/90 (.413) 90/87 (.628) ALC 67/75 (.711) 33/64 (.276) 0/92 (.001) 82/89 (.599) Cumulative MMR at 12M RLC 67/74 (.406) 53/70 (.030) 83/82 (.921) 72/74 (.903) ALC 60/73 (.488) 33/68 (.197) 0/83 (.033) 73/74 (.745) Cumulative MR4.5 at 24M RLC 46/52 (.564) 37/50 (.139) 57/55 (.889) 50/57 (.729) ALC 33/52 (.332) 33/48 (.610) 0/56 (.264) 36/57 (.252) 5-y FFS RLC 61/71 (.133) 56/69 (.167) 62/70 (.710) 61/74 (.285) ALC 50/69 (.076) 0/68 (<.001) 0/70 (<.001) 71/70 (.974) 5-y TFS RLC 90/93 (.369) 88/93 (.597) 91/88 (.115) 91/99 (.213) ALC 72/93 (.002) 67/93 (.014) 0/90 (<.001) 80/97 (.121) 5-y EFS RLC 80/86 (.213) 71/83 (.154) 84/87 (.450) 86/93 (.486) ALC 64/85 (.016) 33/82 (<.001) 0/87 (<.001) 80/92 (.574) 5-y OS RLC 89/93 (.068) 81/94 (.007) 100/84 (.126) 96/99 (.207) ALC 82/93 (.008) 67/93 (.001) 100/88 (.847) 83/99 (.040) a Two in IM and 1 in Dasa were not evaluable due to lack of differential data at 3 and 6M. Figure 1. OS in Pts with ALC Figure 1. OS in Pts with ALC Disclosures O'Brien: Amgen, Celgene, GSK: Consultancy; CLL Global Research Foundation: Membership on an entity's Board of Directors or advisory committees; Emergent, Genentech, Gilead, Infinity, Pharmacyclics, Spectrum: Consultancy, Research Funding; MorphoSys, Acerta, TG Therapeutics: Research Funding.

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Stilgenbauer, Stephan, Thorsten Zenz, Dirk Winkler, Andreas Bühler, Silja Groner, Raymonde Busch, Manfred Hensel, et al. "Subcutaneous Alemtuzumab (Campath) in Fludarabine-Refractory CLL: Final Results of the CLL2H Trial of the GCLLSG and Comprehensive Analysis of Prognostic Markers." Blood 112, no. 11 (November 16, 2008): 329. http://dx.doi.org/10.1182/blood.v112.11.329.329.

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Abstract The multicenter CLL2H trial of the GCLLSG evaluated subcutaneous alemtuzumab 3 × 30 mg weekly in fludarabine refractory CLL. From September 2002 to February 2006, 103 patients were enrolled and received at least one dose of alemtuzumab. Median age was 63 (35.1–81.8) years, 72% were male, 74% were Binet C, and a median of 3 (1–10) prior lines had been given. Unfavorable genetics were frequent (17p deletion: 29%, 11q deletion: 19%, unmutated IgVH: 68%, TP53 mutation 34%). Subcutaneous treatment was performed on an outpatient basis in 96% and had to be temporarily interrupted in 65 patients due to neutropenia (27%), anemia (3%), thrombocytopenia (8%), infections (36%), and was stopped early in 65 cases due to insufficient response (43%), hematotoxicity (14%) and infections (29%). The median alemtuzumab dose given was 722 (3–2203) mg. Toxicity during treatment period was mostly grade I/II apart from hematotoxicity. Grade 3/4 neutropenia, thrombocytopenia, anemia occurred in 56%, 57%, and 50% of patients, respectively. Grade 3/4 non-cytomegalovirus infection occurred in 29%. CMV reactivation was observed in 15 % total, Grade 3/4 occurred in 8% of patients. All CMV episodes were successfully treated with anti-CMV therapy, and there was no CMV-related death. Injection site reaction occurred in 34% and was grade 1 or 2 except in 1 patient who had grade 3 reaction. Pegfilgrastim prophylaxis was scheduled for the second half of the trial. Grade 3/4 neutropenia occurred in 70% vs 46% and non-CMV infections occurred in 32% vs 24% in the first and second half, respectively. Development of anti-alemtuzumab antibody was assessed in samples from 21 patients. Plasma anti-alemtuzumab antibody was detectable in only 1 patient, who had a concentration marginally above the detection threshold and was found to be negative in a re-test 5 months later. Stable disease was achieved in this patient. After a median follow-up time of 37.9 months, there were 75 (73%) deaths, 56% due to disease progression, 31% due to infection, and 13% not related to CLL. Overall response rate was 34% (CR 4%, PR 30%), median progression free survival time was 7.7 months, and median overall survival time was 19.1 months. Clinical and biologic parameters (age, sex, B-symptoms, stage, ECOG, number of prior lines, node size, hepato-spenomegaly, WBC, LDH, β2-MG, TK, VH status, genomic aberrations and TP53 mutation) were evaluated for their prognostic role. In univariate analyses, OS was significantly inferior for age > 65 y (12.2 vs 29.0 mo, p<.001), ECOG > 1 (10.8 vs 21.5 mo, p=.011), TK > median (26U/L) (14.9 vs 29.0 mo, p=.001), and β2- MG > 5 (13.6 vs 27.2 mo, p=.004). Median PFS and OS were not different for 17p-, 11q-, other cytogenetic and TP53 mutation subgroups. Multivariate analysis by Cox regression revealed only age (HR 1.6, p<.001) as significant prognostic factor, while TK (p=.11), β2- MG (p=.089), and 17p- (p=.528) showed no significant impact. The choice of next therapy significantly affected survival. Seventy-four patients received subsequent salvage treatment or allogeneic stem cell transplantation (SCT). The median OS since next therapy in these patients was 11.5 months. The 2-year OS rate for allogeneic SCT as compared to other subsequent treatments (chemo-, immuno-, or chemoimmunotherapies) was 86% and 27% (p=0.009).

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Lee, Lauren J., Alina S. Gerrie, Helene Bruyere, Tanya L. Gillan, Stephen J. T. Huang, Cynthia L. Toze, and Khaled M. Ramadan. "Comparison of Outcomes in Chronic Lymphocytic Leukemia (CLL) with the Addition of Rituximab to Initial Treatment: A Comparative Effectiveness Analysis in the Province of British Columbia (BC), Canada." Blood 124, no. 21 (December 6, 2014): 3344. http://dx.doi.org/10.1182/blood.v124.21.3344.3344.

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Abstract Background: Clinical trials report that chemoimmunotherapy with rituximab (R) improves overall survival (OS) and progression-free survival in the treatment (tx) of symptomatic CLL patients (pts). R has been available for first-line CLL tx in BC, population 4.5 million, since 2004. We compared clinical outcomes with and without addition of R to chemotherapy in a large unselected provincial cohort of pts treated for CLL, to determine the "real world" effectiveness of addition of R to standard chemotherapy. Methods: Three large provincial databases (db) were used to identify eligible pts: the BC Provincial CLL db, the BC Lymphoid Cancer db, and the Providence Hematology CLL db. All pts who received minimum 1 cycle of first-line tx for confirmed CLL were included. Pts with > 1 hematologic malignancy (n=8) were excluded. Baseline features of pts treated with (+R) or without R (No R) were compared using Chi-squared for categorical and Kruskal-Wallis test for continuous variables. OS was calculated from date of initial tx to date of death from any cause. Treatment-free survival (TFS) was calculated from date of initial tx to date of next tx/death from any cause. Multivariate analysis (MVA) was performed using Cox proportional hazard models to evaluate the effect of R on OS/TFS, after controlling for covariates including age (³60 yrs vs <60 yrs), Rai stage (3-4 vs 0-2), CD38 status (pos vs neg), presence of 17p (17p-) and 11q (11q-) deletions, and first-line tx with purine analogs (PAs). Results: A total of 1784 pts diagnosed with CLL from 1973-2014 were identified, of which 726 pts (41%) received tx in follow-up. Of treated pts, 393 (54%) received R and 333 (46%) received chemotherapy alone. Among the No R group, tx included: chlorambucil 56%; fludarabine (F) 34%; cyclophosphamide (C)-based 8%; cladrabine 2%. Among the +R group, tx included: FR 75%; C-based + R 17%; FCR 7%; chlorambucil + R 1%. 103 pts underwent bone marrow transplant (BMT) during their tx course (19% No R vs 10% +R, P=.002). Median age at diagnosis (dx) and tx between groups were not statistically different (No R vs +R: 60.6 vs 60.8 yrs and 64.7 vs 63.9 yrs, respectively). There were no clinically significant differences in diagnostic parameters including % with elevated LDH, lymphocyte count >20x109/L , Rai stage 3-4. Median follow-up time in survivors was longer in the No R group (13.0 vs 6.8 yrs, P<.001). Among 467 pts with known CD38 status, CD38 pos was more common in +R vs No R groups (47 vs 36%, P=.02). FISH was performed in 586 pts, with no significant differences in abnormalities between tx groups. Poor-risk FISH, 17p- or 11q-, were present in 29% (No R) and 27% (+R). Median time from dx to initial tx was 2.8 yrs (range 0-20.6) in No R vs 2.5 yrs (range 0-22.7) in +R groups (P=.84). OS was longer in the +R cohort (median OS 11.8 vs 7.1 yrs, P<.001), Fig. 1. Significant improvements in OS were also seen in pts <60 yrs of age at tx (median OS 11.3 vs 3.1 yrs, P<.0001), without 17p- (median OS 9.3 vs 5.2 yrs, P<.0001), and treated with PAs (median OS 9.4 vs 6.4 yrs, P=.0001). Median TFS was longer in pts treated with R (3.3 vs 2.3 yrs, P= .004), Fig. 2, and in those without 17p- (median TFS 3.1 vs 1.3 yrs, P<.001). MVA confirmed that the addition of R to chemotherapy remained a strong independent predictor of mortality (HR 0.66, 95% CI: 0.44-0.98, P=.04) and TFS (HR 0.6, 95% CI: 0.46-0.79, P<.001) after controlling for covariates. Other independent predictors of OS included age ³60 yrs (HR 2.77, 95% CI 1.87-4.10, P<.001) and presence of 17p- (HR 1.23, 95% CI 1.62-3.76, P<.001), whereas for TFS, presence of 17p- (HR 2.08, 95% CI: 1.49-2.91, P<.001) and CD38+ (HR 1.32, 95% CI: 1.03-1.68, P=.025) were independent negative predictors. Conclusion: In this large, population based cohort of pts treated for CLL, we confirm that the addition of R to chemoimmunotherapy as initial tx significantly improves OS, resulting in a 44% lower risk of overall mortality (95% CI, 2% to 66%) after controlling for covariates. We have also demonstrated that the addition of R to first-line therapy significantly delays the time to subsequent therapy, a finding not previously reported in a population based setting to our knowledge. This study complements clinical trial [Hallek, Lancet 2010] and US Registry data [Danese, Blood 2011], demonstrating benefit of the addition of R to standard therapy for first-line treatment of CLL and shows the generalizability of such results in a real world setting. Figure 1 Figure 1. Disclosures Gerrie: Roche: Honoraria, Research Funding. Ramadan:Roche: Honoraria, Research Funding.

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Karlsen, Micaela, Kara Livingston, Dasha Agoulnik, Akari Miki, Alice Lichtenstein, Sara Folta, Christina Economos, Cheryl Gilhooly, Paul Jacques, and Nicola McKeown. "Theoretical Intakes of Modern-Day Paleo Diets: Comparison to U.S. Dietary Reference Intakes." Current Developments in Nutrition 5, Supplement_2 (June 2021): 420. http://dx.doi.org/10.1093/cdn/nzab038_032.

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Abstract Objectives To evaluate the nutrient adequacy of theoretical, modern-day Paleo meal plans relative to the U.S. Dietary Reference Intakes (DRIs). Methods This analysis used data from the Adhering to Dietary Approaches for Personal Taste (ADAPT) Feasibility Study, which captured data on 9 726 self-reported, popular diet followers. Paleo respondents (N = 925) reported sources of recipes and diet guidance. Five days from each of the top six sources were used to generate 30 days of meal plans among a random sample of n = 200 Paleo respondents. Nutrition Data System for Research (NDSR) was used to estimate daily nutrient content of meal plans which was compared to DRIs and recommendations, as follows: recommended daily allowances (RDAs) for vitamins D, E, and folate, which do not vary by age (years, y)/sex; sex and age-specific RDAs for vitamins A, C, calcium (Ca), magnesium (Mg), and iron (Fe); adequate intakes (AIs) for potassium (K) and fiber; upper intake level (UL) for sodium (Na); and Dietary Guidelines for Americans (DGA) upper threshold to limit saturated fat and Na. Results Estimated daily nutrient intakes of theoretical Paleo meal plans met or exceeded RDAs for the following (Paleo vs. RDA): vitamin A for men or women (1481 RAE µg vs. 900 μg and 700 µg), vitamin D (56 µg vs. 15 μg), vitamin E (27 mg vs. 15 mg), folate (489 µg vs. 400 μg), vitamin C for men or women (225 mg vs. 90 mg and 75 mg), Mg for men and women 31–70 y (539 mg vs. 420 mg and 320 mg), and Fe for men (16 mg vs. 8 mg). Theoretical estimates did not meet the following: RDAs for carbohydrate (91 g vs. 130 g), Fe for women 19–50 y (16 g vs.18 mg), Ca for men and women 61–70 y (562 mg vs. 1000 mg and 1200 mg), and AI for K (4027 mg vs. 4700 mg) or dietary fiber (25 g vs. 28 g/2000 kcal). Estimated levels of Na exceeded the UL (2763 mg vs. 2300 mg), saturated fat exceeded the DGA (19% vs. 10% kcal), and added sugar levels fell within the recommendation (1% vs. 10%). Conclusions While certain aspects of the Paleo diet offer improvements over typical reported intakes of US adults, saturated fat is high, and carbohydrate, fiber, Ca, and K levels of these theoretical diets do not meet DRIs. High levels of saturated fat present concern for cardiovascular health. Optimal nutrition may be challenging to sustain on a Paleo diet. Funding Sources Supported by USDA Cooperative Agreements 58-8050-9-004 and 58-8050-9-003.

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Zhou, H., Y. Ro, Y. Koizumi, T. Kobayashi, H. Harada, and I. Okada. "Thermomechanical fatigue behavior of the third-generation, single-crystal superalloy TMS-75: Deformation structure." Metallurgical and Materials Transactions A 35, no. 6 (June 2004): 1779–87. http://dx.doi.org/10.1007/s11661-004-0086-8.

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Wang, Yu, Lan-Ping Xu, Kaiyan Liu, Xiao-Hui Zhang, Chen-hua Yan, and Xiao-Jun Huang. "Impact of Cytoreductive Therapy and Depth of Response before Allogeneic Transplantation for Advanced Myelodysplastic Syndrome." Blood 134, Supplement_1 (November 13, 2019): 4607. http://dx.doi.org/10.1182/blood-2019-124046.

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Introduction Cytoreduction either with hypomethylating agents (HMA) or induction chemotherapy (IC) before hematopoietic cell transplantation (HCT) for patients with advanced myelodysplastic syndromes (MDS) has been used in an attempt to decrease post-HCT relapse, but the benefit for post-HCT long-term survival remains a debatable issue. We investigated the impact of previous therapy, and depth of response, as well as donor source on the outcome of allo-HCT for patients with advanced MDS. Method After excluding patients who had chronic myelomonocytic leukemia, we analyzed 303 advanced MDS patients (96 (32%) with RAEB-I, 148 (49%) with RAEB-2, and 59 (19%) with tAML) who underwent transplantation from a matched related/unrelated (MSD/URD, n=75/12) or haploidentical (n= 216) donor (HID) after preparation with myeloablative conditioning regimens (identical with BUCY for MSD and BUCY+ATG for HID) between year 2015 and 2018. Results Baseline characteristics Median age was 42 years old. Of the 303, 142 (47%) received only best supportive care (BSC) before HCT; 18 (6%) received IC, 54 (18%) received HMA, and 89 (29%) received both (IC+HMA). Before therapy, 45 (15%), 141 (46%) and 117 (39%) patients had intermediate 1,2 or high-risk scores per the International Prognostic Scoring System (IPSS). Thirty-six (12%) achieved complete remission (CR), 81 (27%) had marrow CR, 160 (53%) had stable disease, and 26 (9%) had progressive disease before HCT defined by International Working Group (IWG). Patients in CR or marrow CR were grouped together as responders (OR) while patients not in CR were grouped together as non-responders (NR) at HCT. Patients had more high-risk disease by WHO and IPSS in the IC and IC+HMA groups. Other patient and donor characteristics known to affect outcomes such as age, time from diagnosis to HCT, IPSS-R, donor source are comparable between groups. Outcome for the entire cohort CR rate at HCT was 6%, 33%, and 30% for HMA, IC, and IC+HMA groups, respectively (P =.001) while OR rate was 37%, 56%, and 70%, respectively (P =.001). With a median follow-up of 727 days, 2-year disease-free survival (DFS) was 77%, 69%,60%, and 62% for BSC, HMA, IC, and IC+HMA groups, respectively (P = .075); 2-y DFS was 77%, 72%,and 56% for untreated, OR, and NR groups, respectively (P = .026); 2-y DFS was 77%, 78%,and 60% for untreated, CR, and non-CR groups, respectively (P = .008); 2-y DFS was 80% and 57% for MSD/URD and HID groups, respectively (P = .051). Multivariate analyses revealed that older age (hazard ratio [HR], 1.03; P< .0001); higher-risk histologic subtypes (HR, 2.3; P =.003), time from diagnosis to HCT (HR,1.005; P =.027), haploidentical donor (HR, 1.9; P =.012) and NR at HCT (HR, 1.6; P =.05) were poor prognostic factors for DFS. Outcome for patients with EB2 and t-AML Focusing on the 207 patients who had BM blasts of 10% or higher before therapy, CR rate at HCT was 6%, 35%, and 33% for HMA, IC, and IC+HMA groups, respectively (P =.007) while OR rate was 44%, 59%, and 74%, respectively (P =.001); 2-year DFS was 77%, 68%,58%, and 62% for BSC, HMA, IC, and IC+HMA groups, respectively (P = .20); 2-y DFS was 77%, 71%,and 50% for untreated, OR, and NR groups, respectively (P = .025); 2-y DFS was 77%, 77%,and 58% for untreated, CR, and non-CR groups, respectively (P = .015); 2-y DFS was 75% and 64% for MSD/URD and HID groups, respectively (P = .43). Propensity score analysis To allow for potential confounding factors between treatments that could influence outcome, a 1:1 ratio propensity score matching was also performed. Included in the propensity score model were: WHO stage, IPSS score, age, time from diagnosis to HCT, and donor source. We were able to pair-match 104 untreated with 104 cytoreductive and 2-y DFS were 80% vs 68% (p= .14); 2-y DFS was 80%, 76%,and 63% for untreated, OR, and NR groups, respectively (P = .19); 2-y DFS was 80%, 94%,and 64% for untreated, CR, and non-CR groups, respectively (P = .015); 2-y DFS was 85% and 68% for MSD/URD and HID groups (P = .044) and the rate was 82% vs 70% after excluding EB-1 (p= .30). After excluding IC group (n=8), 2-year DFS was 80%, 67%, and 75% for BSC, HMA, and IC+HMA groups, respectively (P = .28). Conclusion In this analysis, various therapy approaches before HCT did not lead to different transplantation outcomes. There was no evidence of a benefit in post-HCT outcome associated with prior cytoreductive therapy for advanced MDS. Further randomized studies need to delineate the role of debulking strategy. Disclosures No relevant conflicts of interest to declare.

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Janikova, Andrea, Robert Pytlik, Pavel Klener, Zbynek Bortlicek, Vit Campr, Natasa Kopalova, Katerina Benesova, et al. "Population-Based Analysis of Elderly Patients (>70 YEARS) with Peripheral T-CELL Lymphoma: A Results from Czech Lymphoma Study Group (CLSG) Registry." Blood 128, no. 22 (December 2, 2016): 3000. http://dx.doi.org/10.1182/blood.v128.22.3000.3000.

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Abstract INTRODUCTION: Peripheral T-cell lymphoma (PTCL) is a heterogeneous group of aggressive lymphomas with usually poor prognosis. Age was identified as the independent risk factors in many studies. Elderly patients suffer from comorbidities, impaired organ functions, and poor performance status resulting in worse tolerance of therapy and its efficacy. Data on outcome, prognosis and treatment efficacy for elderly patients with PTCLs are sparse. METHODS: We used data of 941 newly diagnosed PTCLs registered into CLSG database between January 1999 and March 2015 with last follow-up in February 2016. CLSG database covers approximately 85% of all newly diagnosed NonHodgkin´s lymphomas (NHLs) in Czech Republic. For the analysis, 208 patients with age >70 years at diagnosis were selected. RESULTS: Totally, PTCLs accounted for about 8.7% (454/5210) patients of all NHLs in population younger 60 years, but only about 5.8% (208/3561) NHL patients older 70 years. Median age was 76ys (71-91ys), 94 (45%) were women, lactate dehydrogenase (LDH) was elevated in 130/208 (62.5%) pts., ECOG ≥2 had 80 (38%) pts., and advanced clinical stage III-IV presented 132/208 (63.5%) pts. We identified following PTCL subtypes: PTCL-NOS (Peripheral T-cell lymphoma not otherwise specified) 89/208 (43%), Anaplastic large cell lymphoma (ALCL) 34/208 (16.3%), Cutaneous Anaplastic large cell lymphoma (C-ALCL) 10/208 (4.8%), Mycosis fungoides/ Sézary syndrome (MF/SS) together 29/208 (14%), NK/T nasal lymphoma (NK/T) 2/208 (1%), Angioimmunoblastic lymphoma (AITL) 17/208 (8.1%), Cutaneous CD30+ T lymphoproliferative disease 1/208 (0.5%), T-lymphoblastic lymphoma/leukemia (T-LBL) 3/208 (1.4%), T-cell lymphoma without specification (T-NHL) 17/208 (8.1%). Distribution of PTCL subtypes changed significantly with age. There was higher proportion of PTCL-NOS (43% vs. 34%; p.001) and MF/SS (14% vs. 4.8%; p<.001) in elderly patients (>70ys) compared to younger cohort (≤70ys; n=725). Contrary, percentage of ALCL (16.3% vs. 27%; p<.001) with main difference in ALK+ cases (2% vs. 11%; p<.001), and NK/T (1% vs. 5%; p.003) was lower in elderly PTCLs, whereas the incidence of AITL (8.1% vs. 6.6%) or EATL (3.4% vs. 3%) was similar in both age subgroups. For the whole cohort of PTCLs (>70ys), the 5-year overall survival (OS) was 30% and 5-year progression free survival (PFS) was 21% regardless of subtype or stage. Progression is fatal event in elderly patients with median survival about 8 months only. There were significant survival differences between patients (>70ys vs. ≤70ys) according to PTCL subtype; PTCL-NOS 5 yr-OS 23% vs. 43% (p.00001), ALCL ALK+ 5-yr OS not reached vs. 79% (p.01), ALCL ALK- 5 yr-OS 24% vs. 50% (p.001). Patients with AITL or EATL showed no age-related survival differences. First-line chemotherapy was administered in majority of cases (67%); CHOP-like regimen was given in 78 (37%) pts., COP-like in 44 (21%) pts., and other chemotherapy in 18 (9%) cases. Local therapy (surgery, radiotherapy) was administered in first line in 17 (8%) pts., no or palliative therapy (corticoids) was given in 34 (17%) pts., initial therapy was unknown in 17 (8%) cases. We compared two subgroups of patients according to first line chemotherapy CHOP (n=75) vs. COP (n=41). Median age was 74ys (71-84) vs. 79ys (71-89), high IPI was presented in 29% vs. 50% of patients (p.001). Complete response (CR) was achieved in 35/75 (47%) CHOP treated patients, and in 7/41 (17%) patients managed with COP (p.001). Contrary, there were 12/75 (16%) progression in CHOP arm compared to 10/41 (24%) COP treated pts. Five-year OS was 28% vs. 15% better in CHOP group (p.029) and 5-yr PFS 25% vs. 10%, respectively. CONCLUSIONS: In population-based analysis of adult Caucasian PTCL patients, we identified mild decreasing incidence with age. There were significant age-related distribution differences of PTCL subtypes with shift to preponderance of PTCL-NOS, Mycosis fungoides, and NK/T nasal lymphoma in elderly. Worse survival in elderly PTCLs in comparison to younger patients was evident especially for PTCL-NOS and ALCL subtypes. Despite the baseline differences (COP managed pts. had higher IPI), there is tendency that anthracycline-based chemotherapy (CHOP) brings better results with higher proportion of CR and lower progression/relapse rate projected in longer survival. Disclosures Belada: Seattle Genetics: Research Funding. Mayer:AOP Orphan Pharmaceuticals: Research Funding; Novartis: Research Funding.

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Boeld, Tina J., Kristina Doser, Corinna Lang-Schwarz, Elisabeth Huber, Reinhard Andreesen, Petra Hoffmann, and Matthias Edinger. "Efficient Treatment of Murine Acute Graft-Versus-Host Disease with In Vitro Expanded CD4+CD25+ Regulatory T Cells." Blood 118, no. 21 (November 18, 2011): 2987. http://dx.doi.org/10.1182/blood.v118.21.2987.2987.

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Abstract Abstract 2987 Acute graft-versus-host disease (GVHD) is a frequent complication after allogeneic bone marrow transplantation (BMT). We previously showed that the adoptive transfer of donor-type CD4+CD25+ regulatory T cells (Treg) at the time of BMT prevents acute GVHD in murine models. However, the therapeutic potential of donor-derived Treg cells for the treatment of established acute GVHD has not yet been examined in detail. In analogy to potential clinical applications we now tested the capacity of in vitro expanded Treg cells to ameliorate acute GVHD after haploidentical BMT (BALB/c→CB6F1). CD4+CD25highCD62L+ Treg cells were purified by FACS and stimulated polyclonally using anti-CD3/CD28-coated beads. Cells expanded on average 130±19-fold (n=7) within 2 wks and maintained high levels of FoxP3 expression (96, 8±0, 8% FoxP3+ cells; n=7) as well as potent immunosuppressive activity in vitro. For the induction of acute GVHD CB6F1 recipients were lethally irradiated and transplanted with 2.5×106 BM cells in combination with 5×106 splenocytes. All animals developed severe GVHD by d11, as revealed by an increase of the GVHD severity score (2.3±0.4 in GVHD animals vs 0±0 in BM controls, p<0.001, n=1–11) and by histological analyses of the gut (score: 7.8±0.4 for the GVHD group vs 0.2±0.2 for BM controls, p =0.046, n=3). When animals with acute GVHD were treated with 5×106 expanded CD4+CD25highCD62L+ Treg cells on d11 after BMT, they initially developed progressive GVHD comparable to non-treated GVHD animals, as indicated by weight loss and an increase of the GVHD score. However from d44 post BMT onwards, Treg-treated GVHD animals regained body weight (d44: 75±3% vs 67±2% of initial weight; p <0.05; n=9–10) and their clinical GVHD score (d44: 6±0 vs 4.3±0.4; p <0.05; n=9–10) decreased. While all non-treated GVHD animals succumbed to disease by d67 after transplantation, 50% of Treg-treated GVHD animals survived for at least 100d (p =0, 002; n=16–21). As immune reconstitution and in particular reconstitution of the lymphocyte compartment is impaired in animals with GVHD, we analyzed the effect of Treg therapy on the reconstitution of the lymphoid and myeloid compartment. At d21 after BMT spleen and BM of non-treated as well as Treg-treated GVHD animals were completely lymphopenic as compared to control mice and both organs contained exceptionally high numbers of granulocytes. Unlike non-treated GVHD animals, however, Treg-treated recipients by d60 showed a recovery of the lymphocyte compartment in spleen (10±2.6×106 T cells and 23.5±12.5×106 B cells in Treg-treated vs 3.0±0.6×106 T cells and 1.5±0.4×106 B cells in non-treated GVHD animals vs 26.25±2.6×106 T cells and 63.9±9.1×106 B cells in BM controls) and BM (0.7±0.1×106 T cells and 8.6±4×106 B cells in Treg-treated vs 0.3±0.01×106 T cells and 0.7±0.4 ×106 B cells in non-treated GVHD animals vs 0.4±0.03×106 T cells and 11.2±0.6×106 B cells in BM controls), while the number of granulocytes decreased constantly. Successful treatment with Treg cells was finally accompanied by a reconstitution of the lymphatic system comparable to control mice. Furthermore, successfully treated mice showed only mild histological signs of gut GVHD at d100 that was significantly lower then those in non-treated GVHD animals with end-stage disease (score: 4.2±1 vs 9.9±1.5 in treated vs non-treated animals, p =0.006, n=4–6). Taken together, these results indicate that in vitro expanded natural Treg cells may not only be effective for the prevention, but also for the treatment of acute GVHD after allogeneic BMT. Disclosures: No relevant conflicts of interest to declare.

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Vij, Ravi, Michael Wang, Sundar Jagannath, Ruben Niesvizky, Andrzej J. Jakubowiak, Edward Kavalerchik, Mei Huang, and David S. Siegel. "Relationship Of Serum Free Light Chain Reduction To Best Overall Response In Phase 2 Single-Agent and Combination Studies Of Carfilzomib In Patients With Relapsed Or Relapsed and/Or Refractory Multiple Myeloma." Blood 122, no. 21 (November 15, 2013): 1965. http://dx.doi.org/10.1182/blood.v122.21.1965.1965.

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Abstract Introduction In patients (pts) receiving novel anti-multiple myeloma (MM) therapy, an early marker of response would be useful for predicting patient outcomes. Markers in blood with a short half-life, such as serum free light chain (sFLC), may have the potential to be predictive of early response to treatment. Herein, we report results from a retrospective analysis evaluating the relationship of a reduction in sFLC to best overall response (OR) and progression-free survival (PFS) from 2 phase 2 studies of single-agent carfilzomib (CFZ) in pts with relapsed and/or refractory MM (R/RRMM) (PX-171-003-A1 [003; NCT00511238], median 5 [range 1–20] prior therapies; PX-171-004 [004; NCT00530816], median 2 [range 1–3] prior therapies) and a phase 1/2 study of CFZ, lenalidomide (LEN), and dexamethasone (DEX) (CRd) in pts with relapsed or progressive MM (PX-171-006 [006; NCT00603447], median 2 [range 1–5] prior therapies). Methods Pts in the 003 and 004 studies received CFZ on days (d) 1, 2, 8, 9, 15, and 16 in 28-day cycles. Pts in the 003 study received CFZ at a starting dose of 20 mg/m2 in cycle 1; pts had their dose escalated to a target dose of 27 mg/m2 thereafter for up to 12 cycles. The 004 study included bortezomib (BTZ)-naive and BTZ-treated pts; pts received either CFZ 20 mg/m2 during all cycles or a starting dose of 20 mg/m2 during cycle 1 and a target dose of 27 mg/m2 thereafter. Pts in 006 received CRd in 28-day cycles—CFZ (15–27 mg/m2) on d1, 2, 8, 9, 15, 16; LEN (10–25 mg) orally d1–21; and weekly DEX (40 mg). Responses were assessed by IMWG criteria with minimal response per EBMT criteria on d15 of cycle 1, d1 of cycles 2–12, and at the end of the study. Pts with measurable disease by serum or urine protein electrophoresis were included; pts with disease measurable only by sFLC assay were excluded. An analysis of longitudinal changes in the difference between involved and uninvolved sFLC levels before first evidence of a very good partial response (VGPR) was conducted in pts with k/l <0.26 or >1.65 and involved sFLC ≥50 mg/L. sFLC changes were evaluated using 2 mixed linear models (single-agent: 003 and 004; combination: 006): best OR (≥VGPR vs <VGPR) and time points (d15, 29, 57 of therapy) were the covariates in model 1; PFS (≤6 months, >6 months) and time points (d15, 29, 57) were the covariates in model 2. Correlation between sFLC reduction at d15 and best OR was evaluated using a chi-squared test. Reported P values are 2-sided and with no multiplicity adjustment. Results A total of 221 out of 503 enrolled pts were included in the sFLC analysis. Of these 221 pts, 160 had their sFLC measured at d15. When sFLC changes were assessed in model 1, pts achieving ≥VGPR had greater decreases in sFLC at d15 vs baseline (BL) compared with pts whose best response was <VGPR in both the 003 and 004 populations (P<.0001) and the 006 population (P<.0001). In model 2, pts with PFS >6 months had greater decreases in sFLC from BL vs pts with PFS ≤6 months in 003 and 004 (P<.0001). Pts with PFS >6 months had greater decreases in sFLC from BL vs pts with PFS ≤6 months in 006 study; this change was not significant (P=.1859). Results in Table 1 showed that sFLC decreased significantly more in pts with best OR ≥VGPR than in those with best OR <VGPR at d57 (003), d15 (004) and d15, d29 and d57 (006). In 003, 004, and 006, significantly more pts with a ≥75% reduction in sFLC from BL to d15 achieved ≥VGPR (17/30 [57%]) compared with pts with <75% reduction from BL to d15 (8/130 [6%]; P<.0001) (Table 2). Findings were similar whether pts received single-agent CFZ (003 and 004, P<.0001) or CRd (006, P=.0127). When study groups were compared (003 and 004 vs 006), a significantly greater proportion of pts treated with CRd achieved a ≥75% reduction in sFLC from BL to d15 compared with pts who were treated with single-agent CFZ (45% vs 10%; P<.0001) (Table 3). Conclusions Findings from this retrospective analysis indicate that pts with R/RRMM who are treated with either single-agent CFZ (003, 004) or CRd combination therapy (006), and who exhibit rapid reduction of sFLC levels by d15 of therapy, show a greater predilection for achieving a best response of VGPR or better. A decrease of ≥75% in sFLC from BL on d15 may be associated with increased response (as measured by best OR ≥VGPR) and is more common with CRd than single-agent CFZ. The findings from this analysis—specifically the association of a decline in sFLC at d15—merit further exploration in additional CFZ studies. Disclosures: Vij: BMS: Honoraria; Lilly: Honoraria; Celgene: Research Funding, Speakers Bureau; Onyx: Research Funding, Speakers Bureau; Millenium: Speakers Bureau. Off Label Use: Carfilzomib is a selective proteasome inhibitor that is approved in the US for the treatment of relapsed and refractory multiple myeloma. Wang:Novartis: Research Funding; Janssen: Research Funding; Pharmacyclics: Research Funding; Millennium: Research Funding; Celgene: Honoraria, Research Funding; Onyx: Honoraria, Research Funding. Jagannath:Millennium: Honoraria; Celgene: Honoraria; Onyx Pharmaceuticals: Honoraria; Merck: Honoraria; Ortho Biotech: Membership on an entity’s Board of Directors or advisory committees; Imedex: Membership on an entity’s Board of Directors or advisory committees; Medicom WorldWide: Membership on an entity’s Board of Directors or advisory committees; OptumHealth Education: Membership on an entity’s Board of Directors or advisory committees; PER Group: Membership on an entity’s Board of Directors or advisory committees. Niesvizky:Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Research Funding, Speakers Bureau. Jakubowiak:Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: Consultancy, Honoraria, Research Funding; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Janssen-Silag: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Kavalerchik:Onyx: Employment, Equity Ownership. Huang:Onyx: Employment, Equity Ownership. Siegel:Celgene Corporation: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Millennium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau.

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Belitsky, V., I. Lapkin, M. Fredrixon, D. Meledin, E. Sundin, B. Billade, S. E. Ferm, et al. "SEPIA – a new single pixel receiver at the APEX telescope." Astronomy & Astrophysics 612 (April 2018): A23. http://dx.doi.org/10.1051/0004-6361/201731458.

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Context. We describe the new Swedish-ESO PI Instrument for APEX (SEPIA) receiver, which was designed and built by the Group for Advanced Receiver Development (GARD), at Onsala Space Observatory (OSO) in collaboration with ESO. It was installed and commissioned at the APEX telescope during 2015 with an ALMA Band 5 receiver channel and updated with a new frequency channel (ALMA Band 9) in February 2016. Aim. This manuscript aims to provide, for observers who use the SEPIA receiver, a reference in terms of the hardware description, optics and performance as well as the commissioning results. Methods. Out of three available receiver cartridge positions in SEPIA, the two current frequency channels, corresponding to ALMA Band 5, the RF band 158–211 GHz, and Band 9, the RF band 600–722 GHz, provide state-of-the-art dual polarization receivers. The Band 5 frequency channel uses 2SB SIS mixers with an average SSB noise temperature around 45 K with IF (intermediate frequency) band 4–8 GHz for each sideband providing total 4 × 4 GHz IF band. The Band 9 frequency channel uses DSB SIS mixers with a noise temperature of 75–125 K with IF band 4–12 GHz for each polarization. Results. Both current SEPIA receiver channels are available to all APEX observers.

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Wolferts, Guido, Daniel Schicke, and K. Wolfgang Delank. "Langzeitergebnisse und Patientenzufriedenheit nach Tympanoplastik mit Titan-Clip-Prothesen." Laryngo-Rhino-Otologie 96, no. 10 (October 2017): 698–703. http://dx.doi.org/10.1055/s-0042-12450.

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ZusammenfassungZiel der vorliegenden Arbeit ist die Evaluation der Langzeitergebnisse nach Ossikelkettenrekonstruktion mittels Titan-Clip Prothesen. Hierzu wurde eine retrospektive Analyse mit prospektivem Follow-up bei allen Patienten durchgeführt, bei denen in den Jahren 2002–2013 ein Clip-PORP implantiert wurde. Es erfolgten audiologische Messungen, otoskopische Untersuchungen sowie die Evaluation der Lebensqualität mittels Glasgow Benefit Inventory. 48 Patienten (51 Ohren, 29 Männer, 19 Frauen, Durchschnittsalter 44,1 Jahre) konnten für das Follow-up rekrutiert werden, der Nachbeobachtungszeitraum lag im Mittel bei 6,3 Jahren. Die Schallleitungskomponente wurde insgesamt (0,5–4 kHz) von präoperativ 22,8 dB auf 14,6 dB postoperativ reduziert (p≤0,001). Häufigste Operationsindikation waren Cholesteatome und -Rezidive (52%), gefolgt von chronischen Otitiden (12%), Radikalhöhlenrevisionen (8%) und Schallleitungsstörungen nach Voroperation (14%). In 47 Fällen war das Trommelfell verschlossen (92,2%), 4x (7,8%) bestand ein Defekt. Die Prothese war 39 Mal (75%) in situ, 6x (11,8%) lag eine Protrusion bzw. 2x (4%) eine Verkippung vor, 1x (2%) war die Prothese fehlend und 3x (5,9%) konnte es nicht beurteilt werden. Die postinterventionelle Patientenzufriedenheit wurde insgesamt positiv bewertet (8,4 Punkte), ebenso die allgemeine Unterskala während bei den Unterskalen soziale Unterstützung und körperliche Gesundheit keine Veränderung auftraten. Zusammenfassend ist die Ossikuloplastik mittels Titan-Clip Prothesen ein sicheres und etabliertes Verfahren. Auch langfristig werden gute und stabile audiologische Messresultate durch Reduktion der Schallleitungskomponente aufgezeigt. Die subjektive Lebensqualität ist insgesamt nachhaltig verbessert.

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Wolferts, Guido, Daniel Schicke, and K. Wolfgang Delank. "Langzeitergebnisse und Patientenzufriedenheit nach Tympanoplastik mit Titan-Clip-Prothesen." Laryngo-Rhino-Otologie 96, no. 10 (May 12, 2017): 698–703. http://dx.doi.org/10.1055/s-0042-124509.

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ZusammenfassungZiel der vorliegenden Arbeit ist die Evaluation der Langzeitergebnisse nach Ossikelkettenrekonstruktion mittels Titan-Clip Prothesen. Hierzu wurde eine retrospektive Analyse mit prospektivem Follow-up bei allen Patienten durchgeführt, bei denen in den Jahren 2002–2013 ein Clip-PORP implantiert wurde. Es erfolgten audiologische Messungen, otoskopische Untersuchungen sowie die Evaluation der Lebensqualität mittels Glasgow Benefit Inventory. 48 Patienten (51 Ohren, 29 Männer, 19 Frauen, Durchschnittsalter 44,1 Jahre) konnten für das Follow-up rekrutiert werden, der Nachbeobachtungszeitraum lag im Mittel bei 6,3 Jahren. Die Schallleitungskomponente wurde insgesamt (0,5–4 kHz) von präoperativ 22,8 dB auf 14,6 dB postoperativ reduziert (p≤0,001). Häufigste Operationsindikation waren Cholesteatome und -Rezidive (52%), gefolgt von chronischen Otitiden (12%), Radikalhöhlenrevisionen (8%) und Schallleitungsstörungen nach Voroperation (14%). In 47 Fällen war das Trommelfell verschlossen (92,2%), 4x (7,8%) bestand ein Defekt. Die Prothese war 39 Mal (75%) in situ, 6x (11,8%) lag eine Protrusion bzw. 2x (4%) eine Verkippung vor, 1x (2%) war die Prothese fehlend und 3x (5,9%) konnte es nicht beurteilt werden. Die postinterventionelle Patientenzufriedenheit wurde insgesamt positiv bewertet (8,4 Punkte), ebenso die allgemeine Unterskala während bei den Unterskalen soziale Unterstützung und körperliche Gesundheit keine Veränderung auftraten. Zusammenfassend ist die Ossikuloplastik mittels Titan-Clip Prothesen ein sicheres und etabliertes Verfahren. Auch langfristig werden gute und stabile audiologische Messresultate durch Reduktion der Schallleitungskomponente aufgezeigt. Die subjektive Lebensqualität ist insgesamt nachhaltig verbessert.

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Carvalho, Pedro, Bruno Oliveira, Renata Barros, Patrícia Padrão, Pedro Moreira, and Vítor Hugo Teixeira. "Impact of Fluid Restriction and ad Libitum Water Intake or an 8% Carbohydrate-Electrolyte Beverage on Skill Performance of Elite Adolescent Basketball Players." International Journal of Sport Nutrition and Exercise Metabolism 21, no. 3 (June 2011): 214–21. http://dx.doi.org/10.1123/ijsnem.21.3.214.

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Twelve adolescent athletes underwent, in a crossover-design study, 3 separate 90-min training sessions in the following conditions: no fluid ingestion allowed (NF), ad libitum ingestion of water (W), and ad libitum ingestion of a commercial 8% carbohydrate-electrolyte sports beverage (CSB). After each session athletes performed a set of basketball drills (2-point, 3-point, and free-throw shootout, suicide sprints, and defensive zigzags). Body weight (before and after sessions), rating of perceived exertion (RPE), urine color, and beverage acceptability were determined in each session. Athletes also completed a survey about their knowledge and behaviors regarding hydration and fluid replacement. The percentage of weight loss was significantly higher in NF (2.46% ± 0.87%) than in the other 2 conditions (W, 1.08% ± 0.67%, p = .006; CSB, 0.65% ± 0.62%, p = .001) but also higher in W than CSB (p = .012). RPE was higher in NF (16.8 ± 1.96) than in the W (14.2 ± 1.99, p = .004) and CSB (13.3 ± 2.06, p = .002) trials. Athletes’ fluid intake was positively correlated with proper self-reported behaviors (r = .75, p = .005) and knowledge (r = .76, p = .004) about fluid and hydration. In conclusion, fluid restriction during exercise was associated with a greater level of dehydration and increased perceived exertion but had no impact on basketball performance compared with ad libitum drinking of water or a CSB. Athletes with more knowledge about hydration and better self-reported hydration behaviors ingested more fluids during training sessions.

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Trudel, Suzanne, Susan Lee, Christopher J. Kirk, Nashat Gabrail, Sagar Lonial, Luhua Wang, Robert Z. Orlowski, et al. "Inhibition of the Proteasome in Bone Marrow-Derived CD138+ Tumor Cells Following Carfilzomib Administration in Relapsed or Refractory Myeloma Patients." Blood 114, no. 22 (November 20, 2009): 1845. http://dx.doi.org/10.1182/blood.v114.22.1845.1845.

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Abstract Abstract 1845 Poster Board I-871 Background: Proteasome inhibition is an effective strategy for the treatment of multiple myeloma. In patients, proteasome inhibition has primarily been measured in peripheral blood samples (whole blood or mononuclear cells). However, it is unknown whether myeloma cells in the bone marrow (BM) are equally sensitive to proteasome inhibitors such as bortezomib (BTZ) and carfilzomib (CFZ). Aim: To measure proteasome inhibition in purified tumor cells from BM samples taken from patients enrolled in two ongoing Phase 2 trials of single agent CFZ in relapsed or refractory myeloma: PX-171-003 (003) and PX-171-004 (004). Methods: CFZ was administered as an IV bolus of 20 mg/m2 on Days 1, 2, 8, 9, 15 and 16 of a 28-day cycle on both trials. Bone marrow samples, from an optional sub-study of both trials, were taken during screening and Day 2 (post-treatment) and sorted into CD138+ and CD138− cells. Proteasome activity was measured by an enzymatic assay using a fluorogenic substrate (LLVY-AMC) for the chymotrypsin-like (CT-L) activity and an active site ELISA (ProCISE) to quantitate levels of the CT-L subunits of the constitutive proteasome (Beta5) and immunoproteasome (LMP7) and the immunoproteasome subunit MECL1. Results: Whole blood samples from patients treated with CFZ showed inhibition of CT-L activity of ∼80+, similar to values obtained in Phase 1 studies. A total of 10 CD138+ screening samples, 6 from 004 and 4 from 003, and 9 post-dose samples, 5 from 004 and 4 from 003, were analyzed for proteasome levels and activity. In addition, 15 CD138−screening samples, 7 from 004 and 8 from 003, and 9 post-dose samples, 5 from 004 and 4 from 003, were analyzed. When compared to the average base-line activity, CFZ treatment resulted in 88% CT-L inhibition in CD-138+tumor cells from 004 patients (P = 0.0212 by unpaired t-test) and 59% CT-L inhibition in CD-138+ tumor cells from 003 patients (P = 0.25). Baseline CT-L activity in CD138+ tumor cells was 3-fold higher in 004 than 003, which includes a more heavily pre-treated patient population with greater prior exposure to BTZ. Higher specific enzymatic activity was due to increased levels of both constitutive and immunoproteasomes in tumor cells, where immunoproteasomes account for >75% of total cellular proteasomes. No differences between trials were seen in baseline CT-L activity from non-tumor (CD138−) cells. Inhibition in CD138− cells was 84% (P = 0.0380 and 42% (P = 0.38) in 004 and 003, respectively. Using ProCISE, we measured inhibition of LMP7 (66%), beta5 (48%) and MECL1 (64%) in CD138+ tumor cells from 004 patients. Three patients from 004 and one from 003 had both a screening and post-dose tumor cell samples available for analysis. Inhibition of CT-L activity was >80% in two of the 3 patients on 004; the third patient showed no proteasome inhibition by ProCISE and was unavailable for analysis by CT-L. CT-L activity in the CD138+ tumor cells in the 003 patient was not inhibited, however, inhibition was seen in non-tumor cells. Conclusions: CFZ inhibits the proteasome activity of myeloma cells in the bone marrow of relapsed and refractory myeloma patients. The levels of inhibition were similar to those measured in whole blood samples, supporting the use of the blood-based assay as a surrogate marker for proteasome inhibition in tumor cells. CFZ treatment resulted in inhibition of both CT-L subunits as well as additional subunits of the immunoproteasome in tumor cells. Reduced baseline activity in the more heavily pretreated 003 patients may reflect reduced tumor-dependency on the proteasome and may be related to prior treatment with BTZ in these patients. More samples are needed in order to make correlations between levels of proteasome inhibition in bone marrow tumor cells and prior therapies or response. These observations support further evaluation of proteasome activity and the effects of this promising new agent in primary tumors cells from myeloma patients. Disclosures: Trudel: Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria. Lee:Proteolix, Inc.: Employment. Kirk:Proteolix, Inc.: Employment. Lonial:Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. Wang:Proteolix, Inc.: Research Funding. Kukreti:Celgene: Honoraria. Stewart:Genzyme, Celgene, Millenium, Proteolix: Honoraria; Takeda, Millenium: Research Funding; Takeda-Millenium, Celgene, Novartis, Amgen: Consultancy. Jagannath:Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees. McDonagh:Proteolix: Research Funding. Zonder:Celgene: Speakers Bureau; Pfizer: Consultancy; Seattle Genetics, Inc.: Research Funding; Amgen: Consultancy; Millennium: Research Funding. Bennett:Proteolix: Employment.

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Kantarjian, Hagop, Susan O'Brien, Elias Jabbour, Guillermo Garcia-Manero, Alfonso Quintas-Cardama, Jenny Shan, Mary Beth Rios, et al. "Improved survival in chronic myeloid leukemia since the introduction of imatinib therapy: a single-institution historical experience." Blood 119, no. 9 (March 1, 2012): 1981–87. http://dx.doi.org/10.1182/blood-2011-08-358135.

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Abstract A total of 1569 patients with chronic myeloid leukemia (CML) referred to our institution within 1 month of diagnosis since 1965 were reviewed: 1148 chronic phase (CP), 175 accelerated phase (AP), and 246 blastic phase (BP). The median survival was 8.9 years in CP, 4.8 years in AP, and 6 months in BP. In CP, the 8-year survival was ≤ 15% before 1983, 42%-65% from 1983-2000, and 87% since 2001. Survival was worse in older patients (P = .004), but this was less significant since 2001 (P = .07). Survival by Sokal risk was significantly different before 2001 (P < .001), but not since 2001 (P = .4). In AP, survival improved over time (P < .001); the 8-year survival in patients treated since 2001 was 75%. Survival by age was not different in years < 2001 (P = .09), but was better since 2001 in patients ≤ 70 years of age (P = .004). In BP, the median survival improved over time (P < .001), although it has been only 7 months since 2001. In summary, survival in CML has significantly improved since 2001, particularly so in CP-AML and AP-CML. Imatinib therapy minimized the impact of known prognostic factors and Sokal risk in CP-CML and accentuated the impact of age in AP- and BP-CML.

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ERICKSON, MARILYN C., LI M. MA, and MICHAEL P. DOYLE. "Clostridium botulinum Toxin Production in Relation to Spoilage of Atlantic Salmon (Salmo salar) Packaged in Films of Varying Oxygen Permeabilities and with Different Atmospheres." Journal of Food Protection 78, no. 11 (November 1, 2015): 2006–18. http://dx.doi.org/10.4315/0362-028x.jfp-15-004.

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Shelf life of fish packaged under modified atmosphere (MA) is extended, but within the United States, commercial application of MA with impermeable packaging films is restricted due to concerns that botulinum toxin production would precede spoilage when contaminated fish are held at abusive storage temperatures. Use of semipermeable packaging films has been advocated; however, previous studies are inconclusive in determining the oxygen transmission rate (OTR) of a film that is needed to achieve an acceptable margin of safety (i.e., toxin production occurs only after spoilage). This study was conducted to determine the influence of OTR (target OTRs of 3 to 15,000) on the development of spoilage volatiles and toxin in salmon inoculated with type E Clostridium botulinum and subjected to air, vacuum, or 75:25 CO2:N2 MA and storage temperatures of 4, 8, 12, or 16°C. The most dominant headspace volatile peak that was produced during spoilage of samples at 4, 8 or 12°C was a peak, having a Kovats retention index (KI) of 753, and at which external standards of 2- or 3-methyl 1-butanol also eluted. Under anaerobic conditions, both the aerobic microbial populations and the size of the KI 753 spoilage peak were less in inoculated samples compared with uninoculated samples. C. botulinum–inoculated samples that were stored at 12 or 16°C under conditions favorable for anaerobic growth were also characterized by a KI 688 peak. Using a previously developed model that related the percentage of elderly consumers who would prepare a sample having the KI 753 spoilage peak of a specific size, it was determined that for salmon packaged with 3 or 3,000 OTR films under any atmosphere and stored at 12 or 16°C, 2 to 61% of the consumers could potentially prepare toxin-contaminated samples. Hence, when abusive storage conditions are suspected, the fish should not be consumed.

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Harding, Kassandra L., Susana L. Matias, Malay K. Mridha, Stephen A. Vosti, Sohrab Hussain, Kathryn G. Dewey, and Christine P. Stewart. "Eating down or simply eating less? The diet and health implications of these practices during pregnancy and postpartum in rural Bangladesh." Public Health Nutrition 20, no. 11 (June 20, 2017): 1928–40. http://dx.doi.org/10.1017/s1368980017000672.

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AbstractObjectiveTo: (i) determine the prevalence of self-reported eating less and eating down during early and late pregnancy and postpartum, and explore risk factors associated with eating less; (ii) examine the association between eating less and diet quality; and (iii) determine the association between eating less and weight gain during pregnancy.DesignData were collected longitudinally from a cohort of women participating in a community health programme. Diet was assessed at three time points (≤20 weeks’ gestation, 36 weeks’ gestation, 6 months’ postpartum), body weight was measured during study enrolment (≤20 weeks’ gestation) and at 36 weeks’ gestation, and information about the woman and her household was collected at enrolment.SettingThe Rang-Din Nutrition Study in the Rangpur and Dinajpur districts of Bangladesh.SubjectsWomen (n 4011).ResultsThe prevalence of self-reported eating less differed by time point (75·9 % in early pregnancy, 38·8 % in late pregnancy, 7·4 % postpartum; P<0·001). The most common reason for eating less across all time periods was food aversion or loss of appetite. Women who reported eating less in late pregnancy had consumed animal-source foods less frequently in the preceding week than women who reported eating more (mean (sd): 11·7 (7·4) v. 14·8 (9·2) times/week; P<0·001) and had lower weekly weight gain than women who reported eating more (mean (se): 0·27 (0·004) v. 0·33 (0·004) kg/week; P<0·001).ConclusionsEating less has negative implications with respect to diet quality and pregnancy weight gain in this context.

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Gafarov, V. V., E. A. Gromova, D. O. Panov, I. V. Gagulin, A. N. Tripelgorn, and A. V. Gafarova. "Sleep disorder trends in 1988–2018 among the 25–64 years old population in Russia/Siberia (WHO MONICA Psychosocial study)." Neurology, Neuropsychiatry, Psychosomatics 13, no. 3 (June 24, 2021): 42–47. http://dx.doi.org/10.14412/2074-2711-2021-3-42-47.

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Objective: to study sleep disorders prevalence and trends among the population of Novosibirsk (age group 25–64 years) in 1988–2018.Patients and methods. We screened a representative sample of a 25–64-year-old population: in 1988–1989 (II screening: 725 men, mean age – 43.4±0.4 years, response – 71.3%; 710 women, mean age – 44.8±0.4 years, response – 72%); in 1994–1995 (III screening: 647 men, mean age – 44.3±0.4 years, response – 82.1%; 391 women, mean age – 45.4±0.4 years, response – 72.5%); in 2003–2005 (IV screening: 576 men, mean age – 54.23±0.2 years, response – 61%; 1074 women, mean age – 54.27±0.2 years, response – 72%); in 2013–2016 (V screening: 427 men, mean age – 34±0.4 years, response – 71%; 548 women, mean age – 35±0.4 years, response – 72%); in 2016–2018 (VI screening: 275 men, mean age – 49±0.4 years, response – 72%; 390 women, mean age – 45±0.4 years, response – 75%) according to the standard MONICA Psychosocial study (MOPSY) protocol. Sleep disorders in the studied population were assessed with Jenkins Sleep Questionnaire.Results and discussion. We found a high prevalence of sleep disorders among the 25–64 years old population with the following trends: decrease from 1988–1989 to 1994–1995 (men – 11 and 8.6%, women – 21.8 and 16.6% respectively); increase in 2003–2018 (men – 13.1%, women – 20.5%). An increase in sleep disorders prevalence in 2003–2018 occurred mainly due to older age groups – 45–64 years (χ2 =122.061; υ=16; p<0.001 – men; χ2 =230.626; υ=16; p<0.001 – women). In 1988–2018 there was a 2-fold increase in sleep disorders prevalence among women than men in all age groups. This increase in sleep disorders prevalence was associated with increasing age, reaching its maximum in the 55–64 age group (men: 1988–1989 – 20.8%, 1994–1995 – 12.1%, 2016–2018 – 19.7%; χ2 =41.093; υ=12; p<0.001; women: 35.8; 21.8; 24.9% respectively; χ2 =22.01; υ=12; p<0.001). Different trends were observed in 25–44 years old women in 1988–2018 and in 35–44 years old men in 2013–2016: sleep disorders prevalence decreased (25–44 years old women: in 1988–1989 – 13.7%, in 1994–1995 – 7.9%, in 2013–2016 – 5.7%; χ2 =24.715; υ=8; p<0.001; 35–44 years old women 35–44: in 1988–1989 – 17.9%, in 1994–1995 – 20%, in 2013–2016 – 14.2%, in 2016–2018 – 10.3%; χ2 =21.177; υ=12; p<0.001 respectively; men: in 1988–1989 – 9.5%, in 1994–1995 – 9.3%, in 2013–2016 – 4.2% and in 2016–2018 – 11%; χ2 =12.67; υ=12; p<0.05 respectively).Conclusion. We found a high prevalence of sleep disorders among the 25–64 years old population with the following trends: a decrease from 1988–1989 to 1994–1995; an increase in 2003–2018 mainly due to older age groups. Sleep disorders prevalence decreased in younger women in 1988–2018. There also was a 2-fold increase in sleep disorders prevalence in women than men in all age groups and with increasing age in 1988–2018.

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White, J. W., R. M. Ochoa, F. P. Ibarra, and S. P. Singh. "Inheritance of seed yield, maturity and seed weight of common bean (Phaseolus vulgaris) under semi-arid rainfed conditions." Journal of Agricultural Science 122, no. 2 (April 1994): 265–73. http://dx.doi.org/10.1017/s0021859600087451.

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SUMMARYTo develop an effective breeding programme for rainfed production of the common bean (Phaseolus vulgaris L.), the inheritance of seed yield under such conditions should be understood, preferably considering the effects of environment to account for site or season specificity. Thus, heritability, expected and realized gain from selection, and combining ability were evaluated for a nine-parent diallel of common bean without reciprocals but including parents, at two locations each in Mexico and Colombia, using the F2 and F3 population bulks. Heritability estimated from regressions of F3 on F2 ranged from 0·09 ± 0·18 (S.E.) to 0·75±0·25 for seed yield, from 0·26±009 to 0·34±009 for days to maturity and from0·57±004 to 0·80±004 for 100-seed weight. Expected gain from selection in the F2 was estimated as a percentage of the population mean, selecting the upper 20% of the populations. Expected gain in seed yield ranged from 1·8 to 8·4% in Mexico and from 6·5 to 28·1% in Colombia. Realized gains in seed yield in the F3 were 0·4–7·4% in Mexico and 2·9–15·7% in Colombia. Realized gain values for days to maturity were < 2·2%, and for 100-seed weight > 13·4%. General combining ability (GCA) mean squares (estimated using Griffing's Method 2, Model 1) were significant (P <0·01) and larger than those for specific combining ability (SCA) for all traits at all locations. The parents from the Mexican highlands tended to have a positive GCA effect for yield in Mexico but negative values in Colombia, whereas parents adapted to mid-elevation tropical environments showed the opposite tendency. However, all significant GCA values of breeding line V8025 were positive in both countries.

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Ma, Hui, Huandong Lin, Yu Hu, Xiaoming Li, Wanyuan He, Xuejuan Jin, Jian Gao, et al. "Serum ferritin levels are associated with carotid atherosclerosis in Chinese postmenopausal women: the Shanghai Changfeng Study." British Journal of Nutrition 114, no. 7 (August 12, 2015): 1064–71. http://dx.doi.org/10.1017/s0007114515001944.

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Postmenopausal women are at increased risk of CVD: the increased serum ferritin level may be involved in the pathogenesis. The aim of the present study is to investigate the relationship of ferritin and carotid atherosclerosis in postmenopausal women. A total of 1178 postmenopausal women (mean age, 60·8 years) were enrolled from the Changfeng Study. A standard interview, anthropometric measurements and laboratory analyses were performed for each participant. Bilateral CIMT (carotid intima–media thickness) were measured using ultrasonography, and the presence of carotid plaques was assessed. Serum ferritin was measured using electrochemiluminescence immunoassay. The results showed that serum ferritin was 181·9 (sd 65·8) ng/ml in the postmenopausal women. Multivariate, linear, stepwise regression analysis demonstrated that age (standardised β = 0·233, P< 0·001), alanine transaminase (standardised β = 0·194, P< 0·001), log homeostasis model assessment index for insulin resistance (standardised β = 0·181, P< 0·001), TAG (standardised β = 0·083, P= 0·003), Hb (standardised β = 0·080, P= 0·004) and PPG (2-h glucose levels following a 75-g oral glucose challenge) (standardised β = 0·079, P= 0·004) were independently associated with serum ferritin. Compared with the ferritin level of subjects in the first quartile, that in the fourth quartile had greater CIMT, and higher prevalence of carotid plaque. After adjusting for conventional CVD risk factors, Hb, leucocytes, log urine albumin:creatinine ratio and liver function, the ferritin level of postmenopausal women in the fourth quartile had a 1·587-fold increased risk of carotid plaques relative to those in the lowest quartile. In conclusion, these results suggest that serum ferritin is independently and positively associated with carotid atherosclerosis in postmenopausal women and that ferritin may be implicated in atherosclerosis.

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Nizovtseva, I. G., and P. K. Galenko. "Travelling-wave amplitudes as solutions of the phase-field crystal equation." Philosophical Transactions of the Royal Society A: Mathematical, Physical and Engineering Sciences 376, no. 2113 (January 8, 2018): 20170202. http://dx.doi.org/10.1098/rsta.2017.0202.

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The dynamics of the diffuse interface between liquid and solid states is analysed. The diffuse interface is considered as an envelope of atomic density amplitudes as predicted by the phase-field crystal model (Elder et al. 2004 Phys. Rev. E 70 , 051605 ( doi:10.1103/PhysRevE.70.051605 ); Elder et al. 2007 Phys. Rev. B 75 , 064107 ( doi:10.1103/PhysRevB.75.064107 )). The propagation of crystalline amplitudes into metastable liquid is described by the hyperbolic equation of an extended Allen–Cahn type (Galenko & Jou 2005 Phys. Rev. E 71 , 046125 ( doi:10.1103/PhysRevE.71.046125 )) for which the complete set of analytical travelling-wave solutions is obtained by the method (Malfliet & Hereman 1996 Phys. Scr. 15 , 563–568 ( doi:10.1088/0031-8949/54/6/003 ); Wazwaz 2004 Appl. Math. Comput. 154 , 713–723 ( doi:10.1016/S0096-3003(03)00745-8 )). The general solution of travelling waves is based on the function of hyperbolic tangent. Together with its set of particular solutions, the general solution is analysed within an example of specific task about the crystal front invading metastable liquid (Galenko et al. 2015 Phys. D 308 , 1–10 ( doi:10.1016/j.physd.2015.06.002 )). The influence of the driving force on the phase-field profile, amplitude velocity and correlation length is investigated for various relaxation times of the gradient flow. This article is part of the theme issue ‘From atomistic interfaces to dendritic patterns’.

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Pini, Rodolfo, Gianluca Faggioli, Giuseppe Indelicato, Enrico Gallitto, Chiara Mascoli, Mohammad Abualhin, Andrea Stella, and Mauro Gargiulo. "Anatomical Predictors of Flared Limb Complications in Endovascular Aneurysm Repair." Journal of Endovascular Therapy 26, no. 4 (May 29, 2019): 550–55. http://dx.doi.org/10.1177/1526602819851251.

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Purpose: To evaluate possible predictors of complications with flared iliac stent-graft limbs for ectatic common iliac arteries (CIAs) associated with abdominal aortic aneurysms treated with endovascular aneurysm repair (EVAR). Materials and Methods: A retrospective comparative analysis was conducted of 533 EVAR patients (mean age 75 years; 442 men) treated between 2012 and 2017 who had complications associated with the stent-graft limbs (n=1066). Complications, including type Ib endoleak, type IIIa endoleak, and limb occlusion, were compared between patients with nondilated (<16 mm) CIAs treated with standard iliac limbs (SLs, n=808) vs patients with ectatic CIAs treated with flared limbs (FLs, n=258). Follow-up included a duplex scan at 3, 6, and 12 months and yearly thereafter; computed tomography angiography was performed in case of iliac complications. Risk factors for iliac complications in FLs were investigated using Cox regression and Kaplan-Meier analyses; results of the regression analysis are presented as the hazard ratio (HR) and 95% confidence interval (CI). Results: Overall, no iliac complications occurred at 30 days, but over a mean follow-up of 38±8 months, there were 10 (1%) events (4 limb occlusions, 6 type Ib endoleaks): 7 (3%) in FLs and 3 (0.4%) in SLs (p=0.20). Kaplan-Meier analysis found no differences at 5 years in SLs vs FLs for freedom from limb occlusion (99%±1% vs 98%±1%, respectively; p=0.30) or type Ib endoleak (96%±3% vs 97%±1%, respectively; p=0.44). Similarly, the overall 5-year iliac complication rates were similar in SLs vs FLs (96%±3% vs 95%±2%, p=0.21). Regression analysis found CIA length ≤30 mm (HR 4.7, 95% CI 1.02 to 21.6, p=0.04) and a diameter ≥20 mm (HR 7.8, 95% CI 1.05 to 64.8, p=0.03) to be independent predictors of iliac complications in FLs. Kaplan-Meier estimates of iliac complication–free survival in FLs were significantly worse when the CIA length was ≤30 mm (79%±9% vs 98%±1%, p=0.003) or the diameter was ≥20 mm (85%±7% vs 99%±1%, p=0.02). The combination of both risk factors produced significantly poorer iliac complication–free survival compared with cases in which there was one or no risk factor (67%±19% vs 96%±2% vs 99%±1%, respectively; p<0.001). Conclusion: Iliac limb complications are infrequent in EVAR, regardless of the type of iliac limb chosen; however, CIAs ≤30 mm in length or ≥20 mm in diameter significantly increased the risk of late iliac complications in FLs. If both characteristics were present, this risk was further elevated.

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Xing, Dezhi, Anne Louise Kjølbye, Jørgen S. Petersen, and James B. Martins. "Pharmacological stimulation of cardiac gap junction coupling does not affect ischemia-induced focal ventricular tachycardia or triggered activity in dogs." American Journal of Physiology-Heart and Circulatory Physiology 288, no. 2 (February 2005): H511—H516. http://dx.doi.org/10.1152/ajpheart.00720.2004.

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The role of gap junction intercellular communication (GJIC) in ischemia-induced focal ventricular tachycardia (VT) is unknown. We have developed a new, stable antiarrhythmic peptide analog named ZP123 that selectively increases GJIC and prevents reentrant VT. Our aim in this study was to use ZP123 as a tool to assess the role of GJIC on occurrence of ischemia-induced focal VT and triggered activity (TA) due to delayed afterdepolarizations (DADs). Focal VT was induced by programmed stimulation in α-chloralose-anesthetized, open-chest dogs 1–4 h after coronary artery occlusion. Three-dimensional activation mapping was done using 6 bipolar electrograms on each of 23 multipolar needles in the risk zone. Dogs were randomly assigned to receive either saline or ZP123 cumulatively at three dose levels (an intravenous bolus followed by a 30-min infusion per dose). Attempts to induce VT were repeated in each dose. Mass spectrometry was used to measure plasma ZP123 concentrations. Standard microelectrode techniques were used for in vitro study of DADs and TA. Twenty-six dogs with focal VT were included. ZP123 did not affect the inducibility of focal VT at any plasma concentrations vs. saline (0.8 ± 0.1 nM, 77 vs. 75%; 7.8 ± 0.4 nM, 86 vs. 77%; and 78.8 ± 5.0 nM, 77 vs. 91%). In vitro, ZP123 did not affect the induction of DADs (12/12) and TAs (10/10) in ischemic tissues or tissue removed from the origin of focal VT (DADs, 8/8; TAs, 4/4). Therefore, although indirect, the data with the doses and concentrations used suggest that GJIC may not play a major role in the genesis of focal activity in the ischemic models studied.

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Chin, Lay Fong, Kathryn S. Hayward, Audrey Lik Ming Chai, and Sandra G. Brauer. "A Self-Empowered Upper Limb Repetitive Engagement Program to Improve Upper Limb Recovery Early Post-Stroke: Phase II Pilot Randomized Controlled Trial." Neurorehabilitation and Neural Repair 35, no. 9 (July 19, 2021): 836–48. http://dx.doi.org/10.1177/15459683211032967.

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Background. Time outside therapy provides an opportunity to increase upper limb (UL) use during post-stroke hospitalization. Objective. To determine if a self-directed UL program outside therapy (Self-Empowered UL Repetitive Engagement, SURE) was feasible and to explore the potential effect of the SURE program on UL use and recovery. Methods. Twenty-three patients from an inpatient rehabilitation center who were ≤21 days post-stroke and had a Fugl Meyer UL (FMUL) score ≤50 and a positive motor evoked potential (MEP+) response were randomized (stratified by impairment) to either experimental group (SURE: individualized, UL self-exercise and use outside therapy for 6 hours/week for 4 weeks) or control group (education booklet). Feasibility was evaluated by program adherence, dropout rate, adverse events, and satisfaction. Potential effect was measured by paretic UL use via accelerometry weekly during the intervention, FMUL and Action Research Arm Test (ARAT) at baseline (Week 0), post-intervention (Week 4), and follow-up (Week 8 and Week 16). Results. Adherence to SURE was high: 87% program completion (mean 313±75 repetitions/day). There were no dropouts, no adverse events related to SURE, and patient satisfaction averaged 7.8/10. Experimental participants achieved an additional hour of UL use daily (range: .3–1.2 hours/day) compared to control. Significant improvements in FMUL and ARAT were observed in both groups from Week 0 to Week 4 and to Week 8 ( P ≤ .002), which were maintained to Week 16. There were no differences between groups ( P ≥ .119). Conclusions. SURE was a feasible self-directed program that increased UL use in MEP+ individuals with moderate-severe impairment early post-stroke. Further studies with larger sample sizes and potentially higher dose are required to determine efficacy.

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Hagen, M., K. Tascilar, M. Reiser, L. Valor, J. Haschka, A. Kleyer, A. Hueber, et al. "OP0318 TREATMENT TAPERING AND WITHDRAWAL IN RHEUMATOID ARTHRITIS WITH STABLE REMISSION - FINAL ANALYSIS OF THE RETRO STUDY." Annals of the Rheumatic Diseases 80, Suppl 1 (May 19, 2021): 194–95. http://dx.doi.org/10.1136/annrheumdis-2021-eular.2174.

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Background:Due to better treatment strategies and higher remission rates the management of rheumatoid arthritis (RA) patients in sustained remission is of increasing interest (1). The Rheumatoid Arthritis in Ongoing Remission (RETRO) study investigated the possibility to taper and stop disease modifying anti-rheumatic drugs (DMARDs).Objectives:To compare one-year remission and relapse rates in rheumatoid arthritis patients randomized to continued treatment, reduced treatment or gradual treatment withdrawal after stable remission under routine care.Methods:Primary data of the phase III, randomized, controlled RETRO trial in RA patients with stable conventional synthetic and/or biologic DMARD treatment in sustained (>6 months) DAS28-ESR remission (<2.6 units). Patients were randomized 1:1:1 into three strategy arms (continuation of 100% DMARD dose, CONT; tapering to 50% DMARD dose, TAP; 50% tapering followed by withdrawal of DMARDs, STOP). The primary endpoint was the proportion of patients in sustained DAS28-ESR remission after 1 year.Results:316 RA patients in sustained remission were included, 303 were randomized (CONT: N=100; TAP: N=102; STOP: N=101) and 282 (93%) had complete data sets after 1 year (CONT:N=93; TAP: N=93; STOP: N=96; Table 1). After 1 year, 81.2%, 58.6%, 43.3% of patients, maintained their remission state over 1 year in the CONT, TAP and STOP arms, respectively (p=0.0004 with log rank test for trend; Figure 1). Hazard ratios for flare were 3.02 (95%CI 1.69 to 5.40) and 4.34 (95%CI 2.48 to 7.60) for the TAP and STOP arms. RA patients who flared were more likely to be female, have longer disease duration, RF/ACPA positivity and higher baseline DAS-28 scores with standardized mean differences >0.2. Serious adverse events were reported in 10.8%, 7.5%, and 13.5% in the CONT, TAP and STOP arms, respectively.Table 1.Baseline CharacteristicsGroupControlReduceReduce/StopOverallN939396282Age, mean(SD)55.9 (12.7)56.9 (13.0)56.5 (13.3)56.5 (13.0)Female, n (%)53 (57.0)57 (62.0)57 (59.4)167 (59.4)RF, n (%)52 (55.9)58 (62.4)52 (54.2)162 (57.4)ACPA, n (%)53 (57.0)50 (54.9)55 (57.3)158 (56.4)Disease duration, years, mean(SD)7.6 (6.9)7.8 (6.9)6.8 (8.1)7.4 (7.3)Remission duration, months, mean(SD)20.6 (18.0)16.5 (15.9)22.7 (30.4)20.0 (22.6)Biologics, n (%)39 (41.9)44 (47.3)39 (40.6)122 (43.3)Methotrexate, n (%)71 (76.3)67 (72.0)75 (78.1)213 (75.5)Other DMARDs, n (%)24 (25.8)20 (21.5)16 (16.7)60 (21.3)Glucocorticoids, n (%)27 (29.0)23 (24.7)17 (17.7)67 (23.8)CRP, mg/L, mean(SD)0.3 (0.3)0.5 (0.5)0.5 (0.6)0.4 (0.5)ESR, mm/h, mean(SD)11.3 (8.4)12.2 (8.8)13.0 (10.0)12.2 (9.1)Tender joint count, mean(SD)0.2 (0.6)0.0 (0.2)0.1 (0.3)0.1 (0.4)Swollen joint count, mean(SD)0.1 (0.3)0.1 (0.3)0.1 (0.4)0.1 (0.3)Physician VAS,mm, mean(SD)1.8 (4.2)2.6 (4.4)2.0 (3.9)2.1 (4.2)Patient VAS,mm, mean(SD)6.4 (9.0)5.5 (8.3)4.5 (8.4)5.5 (8.6)HAQ, standard, mean(SD)0.2 (0.4)0.2 (0.3)0.2 (0.4)0.2 (0.4)HAQ, alternative, mean(SD)0.2 (0.4)0.1 (0.3)0.2 (0.3)0.2 (0.3)DAS-28, mean(SD)1.7 (0.7)1.7 (0.6)1.7 (0.6)1.7 (0.6)SDAI, mean(SD)1.4 (1.5)1.4 (1.5)1.3 (1.3)1.3 (1.4)DAS-28 remission, n (%)91 (97.8)93 (100.0)95 (99.0)279 (98.9)SDAI remission, n (%)79 (87.8)79 (84.9)88 (92.6)246 (88.5)Boolean remission, n (%)69 (75.8)71 (76.3)76 (79.2)216 (77.1)Conclusion:This randomized controlled study shows that half of RA patients in sustained remission relapse when tapering/stopping their DMARDs. Presence of autoantibodies, higher baseline DAS28-ESR and female sex are predictors for flares.References:[1]Schett G et al. Tapering biologic and conventional DMARD therapy in rheumatoid arthritis: current evidence and future directions. Ann Rheum Dis. 2016 Aug;75(8):1428-37.Disclosure of Interests:Melanie Hagen Speakers bureau: advisory boards, Koray Tascilar Speakers bureau: advisory board, Michaela Reiser: None declared, Larissa Valor: None declared, Judith Haschka Speakers bureau: advisory board, Arnd Kleyer Speakers bureau: advisory board, Axel Hueber Speakers bureau: advisory boards, Bernhard Manger Speakers bureau: advisory boards, Jayme Cobra Speakers bureau: advisory boards, Camille Figuereido Speakers bureau: advisory boards, Stephanie Finzel Speakers bureau: advisory boards, Hans-Peter Tony Speakers bureau: advisory boards, Joerg Wendler Speakers bureau: advisory boards, Stefan Kleinert Speakers bureau: advisory boards, Florian Schuch Speakers bureau: advisory boards, Monika Ronneberger: None declared, Martin Feuchtenberger Speakers bureau: advisory boards, Martin Fleck Speakers bureau: advisory boards, Karin Manger: None declared, Wolfgang Ochs: None declared, Matthias Schmitt-Haendle: None declared, Hanns-Martin Lorenz Speakers bureau: advisory boards, Rieke Alten Speakers bureau: advisory boards, Jörg Henes Speakers bureau: advisory boards, Klaus Krueger Speakers bureau: advisory boards, Jürgen Rech Speakers bureau: advisory boards, Georg Schett Speakers bureau: advisory boards.

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Terazawa, Tetsuji, Satoru Iwasa, Yusuke Sasaki, Shunsuke Okazaki, Masahiro Goto, Yasushi Kojima, Atsushi Naganuma, et al. "A multicenter phase II study of combination therapy with oral S-1 plus cisplatin in elderly patients with advanced gastric cancer." Journal of Clinical Oncology 35, no. 4_suppl (February 1, 2017): 157. http://dx.doi.org/10.1200/jco.2017.35.4_suppl.157.

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157 Background: The incidence of gastric cancer increases gradually in individuals aged ≥ 75 years who account for about 40% of all patients. From the SPIRITS study, comparing S-1 monotherapy with S-1 and cisplatin (CDDP) combination therapy (median overall survival [OS]: 11.0 versus 13.0 months, p=0.04), S-1 and CDDP chemotherapy (SP regimen) is recognized as one of the standard first-line regimens for patients with advanced gastric cancer in Japan. However, patients in this trial were aged < 75 years. Methods: The aim of this phase II study was to evaluate the efficacy and safety of SP regimen in elderly patients with chemotherapy-naive advanced gastric cancer. Patients aged ≥ 76 years were given oral S-1 twice daily for 21 days, followed by 14 days rest; CDDP was intravenously infused at day 8, repeated every 35 days, for up to eight cycles. The dose of S-1 (50–120 mg/body) and CDDP (30–60 mg/m2) was adjusted depending on the patient’s body surface area and creatinine clearance (Ccr-adjusted SP regimen). The primary endpoint was OS. The threshold and expected OS were estimated at 8 and 14 months, respectively. Secondary endpoints included response rate (RR), progression-free survival (PFS), time to treatment failure (TTF) and adverse events. Results: From December 2012 to October 2014, 40 patients were enrolled at 15 institutions. Patient characteristics were: gender (M/F) 29/11; median age 78 (range, 76–89); ECOG PS0/1, 13/27; and unresectable/recurrence 30/10. The median cycle for each patient was four (range, 1–8). The median OS was 12.3 months (80% confidence interval, 10.2–14.4 months). The median PFS and TTF were 7.8 and 4.3 months, respectively. The RR was 54%. A dose reduction of S-1 and CDDP was made for 30% and 35% of patients, respectively. The protocol was discontinued in 17 patients (43%) for disease progression, 10 patients (25%) for adverse events and 7 patients (17%) for patient refusal. The main adverse events at a grade 3 or higher were anorexia (25%), neutropenia (23%), hyponatremia (20%) and anemia (18%). Treatment-related deaths did not occur. Conclusions: Ccr-adjusted SP regimen showed promising activity and was tolerated well by elderly patients with advanced gastric cancer. Clinical trial information: UMIN000009349.

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Adamkiewicz, Thomas V., Miguel R. Abboud, Carole Paley, Nancy Olivieri, Melanie Kirby-Allen, Elliott Vichinsky, James F. Casella, et al. "Serum ferritin level changes in children with sickle cell disease on chronic blood transfusion are nonlinear and are associated with iron load and liver injury." Blood 114, no. 21 (November 19, 2009): 4632–38. http://dx.doi.org/10.1182/blood-2009-02-203323.

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AbstractChronic blood transfusion is increasingly indicated in patients with sickle cell disease. Measuring resulting iron overload remains a challenge. Children without viral hepatitis enrolled in 2 trials for stroke prevention were examined for iron overload (STOP and STOP2; n = 271). Most received desferrioxamine chelation. Serum ferritin (SF) changes appeared nonlinear compared with prechelation estimated transfusion iron load (TIL) or with liver iron concentrations (LICs). Averaged correlation coefficient between SF and TIL (patients/observations, 26 of 164) was r = 0.70; between SF and LIC (patients/observations, 33 of 47) was r = 0.55. In mixed models, SF was associated with LIC (P = .006), alanine transaminase (P = .025), and weight (P = .026). Most patients with SF between 750 and 1500 ng/mL had a TIL between 25 and 100 mg/kg (72.8% ± 5.9%; patients/observations, 24 of 50) or an LIC between 2.5 and 10 mg/g dry liver weight (75% ± 0%; patients/observations, 8 of 9). Most patients with SF of 3000 ng/mL or greater had a TIL of 100 mg/kg or greater (95.3% ± 6.7%; patients/observations, 7 of 16) or an LIC of 10 mg/g dry liver weight or greater (87.7% ± 4.3%; patients/observations, 11 of 18). Although SF changes are nonlinear, levels less than 1500 ng/mL indicated mostly acceptable iron overload; levels of 3000 ng/mL or greater were specific for significant iron overload and were associated with liver injury. However, to determine accurately iron overload in patients with intermediately elevated SF levels, other methods are required. These trials are registered at www.clinicaltrials.gov as #NCT00000592 and #NCT00006182.

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Latagliata, Roberto, Daniela Bartoletti, Alessandro Andriani, Massimo Breccia, Elena Rossi, Giuseppe Auteri, Florian H. Heidel, et al. "Efficacy and Safety of Ruxolitinib in the Treatment of Elderly Patients with Policythemia Vera Resistant/Intolerant to Hydroxyurea." Blood 138, Supplement 1 (November 5, 2021): 2581. http://dx.doi.org/10.1182/blood-2021-149612.

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Abstract Introduction: Ruxolitinib (Rux) has been recently approved as second-line therapy in patients (pts) with Polycythemia Vera (PV) resistant/intolerant to hydroxyurea (HU). Median age of PV pts enrolled in the pivotal Response trials was around 60 yrs; at present, no data is reported on the use of Rux in elderly pts. Aims: In a real-world cohort of PV pts treated with Rux, we investigated whether the efficacy and safety of Rux were comparable in pts who initiated therapy when aged ≥75 years compared with younger pts. Methods: After IRB approval, clinical/laboratory data of 934 WHO2016-defined PV pts followed in 29 Hematology Centers were retrospectively collected. Of them, 168 (17.9%) were considered resistant/intolerant to HU at any time during follow-up by responsible physician and shifted to Rux as second-line therapy. Results: Among the 168 pts treated with Rux, 42 (25%, median age 78.2 years) were aged ≥75 yrs at Rux start, 74 (44%, median age 67.7) were aged 60-74 and 52 (31%, median age 53) were <60 at Rux start. No significant differences were observed between the 3 groups, apart from a lower need for phlebotomies in pts aged ≥75 yrs and lower presence of palpable spleen in older pts (age ≥60), that more frequently switched to Rux due to HU intolerance (Table 1). Median duration of HU treatment was 41.0 months (IQR 14.6 - 85.8), with a trend for a longer median treatment duration in pts aged ≥75 [61.0 months (IQR 21.5 - 89.6) vs 35.9 months (IQR 13.4 - 79.6), p=0.04]. Rux starting dose was similar across age groups; however, more elderly pts underwent Rux dose reductions during follow-up (45.2% in pts aged ≥75 vs 28.6% in younger pts, p=0.04). Responses during Rux therapy are reported in Table 2, with no significant differences between the 3 groups at any time. In the overall cohort, response on PV-related symptoms at 6 and 12 months was significantly higher in pts who switched to Rux because of HU intolerance; however, this difference was not observed in pts aged ≥75 yrs. As to the most common hematologic Rux-related toxicities, grade 3-4 anemia and thrombocytopenia were observed in only 2 (1.2%) and 5 (3%) pts, with no difference across age groups (p=0.45 and p=0.18). However, any grade anemia and thrombocytopenia during Rux were more frequently observed in pts aged ≥75 (68.3% vs 51.7% of anemia, p=0.06 and 12.2% vs 3.5% of thrombocytopenia in younger pts, p=0.04). Nineteen and 4 pts experienced infectious and thrombotic complications during Rux with incidence rates of 0.59 and 0.12 per 100 patient-months, respectively, comparably in younger and older (≥75) pts (p=0.75 and p=0.29, respectively). Notably, 6 infections were herpes simplex/zoster virus, comparably distributed between the 3 groups (p=0.60). Permanent Rux discontinuation was needed in 14 pts (8.3%) after a median Rux exposure of 7.8 months (IQR 4.6 - 17.6) (incidence: 0.41 per 100 pts/months). Discontinuation was comparable between age groups, with Rux stop in 4 pts aged ≥75 yrs and 10 younger pts (2.4% vs 5.2% at 8 months, log-rank p=0.75). At last follow-up, 2 pts had died (1 from 2 nd neoplasia after 19.1 months from Rux start and 1 from acute leukemia after 3.3 years), both pts aged 60-74 yrs. Conclusions. In this real-world analysis, use of Rux in HU resistant/intolerant elderly PV pts was effective and safe despite the more frequent need for dose reductions. Older age should not discourage Rux therapy, but stricter hematological monitoring may be suggested. Figure 1 Figure 1. Disclosures Latagliata: BMS Cellgene: Honoraria; Pfizer: Honoraria; Novartis: Honoraria. Breccia: Pfizer: Honoraria; Incyte: Honoraria; Bristol Myers Squibb/Celgene: Honoraria; Abbvie: Honoraria; Novartis: Honoraria. Bonifacio: Amgen: Honoraria; Bristol Myers Squibb: Honoraria; Novartis: Honoraria; Pfizer: Honoraria. Cavo: Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Honoraria; 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; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; GlaxoSmithKline: 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. Palandri: AOP: Membership on an entity's Board of Directors or advisory committees; Sierra Oncology: Membership on an entity's Board of Directors or advisory committees; CTI: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Atkins, Michael B., John M. Kirkwood, Jedd D. Wolchok, Margaret K. Callahan, Harriet M. Kluger, Michael A. Postow, Neil Howard Segal, et al. "Long-term follow-up of CA209-004: A phase I dose-escalation study of combined nivolumab (NIVO) and ipilimumab (IPI) in patients with advanced melanoma." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 9533. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.9533.

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9533 Background: We previously reported a 3-year overall survival (OS) rate of 63% with NIVO+IPI concurrent therapy in the initial phase I dose-escalation study for the combination, conducted in patients (pts) with advanced melanoma. Here, we report OS after 5 years of overall study follow-up and assess survival rates after stopping treatment. Methods: Adults with previously treated or untreated unresectable stage III or IV melanoma, and ECOG performance status of 0 or 1, received NIVO + IPI Q3W × 4 as mg/kg in one of the following cohorts: (1) NIVO 0.3 + IPI 3; (2) NIVO 1 + IPI 3; (2a) NIVO 3 + IPI 1; (3) NIVO 3 + IPI 3; (8) NIVO 1 + IPI 3. Cohorts 1-3 received maintenance with NIVO Q3W × 4, then NIVO + IPI Q12W × 8 at assigned doses; cohort 8 received NIVO Q2W for up to 96 weeks. Patients were followed for the primary endpoint of safety and the secondary endpoints of response and progression-free survival for up to 2.5 years, then for the survival exploratory endpoint for up to an additional 3 years, for a maximum study participation of 5.5 years. Results: At a median follow-up of 43.1 months (range 0.9-76.7) in all cohorts (N = 94), the 4- and 4.5-year OS rates were both 57% (95% CI: 47, 67). The 4-year OS rates for pts with normal (n = 58) versus elevated LDH (n = 36) were 62% (48, 74) versus 49% (32, 65); for pts with wild-type (n = 66) and mutant (n = 24) BRAF tumors, 4-year OS rates were 54% (41, 65) and 61% (38, 77), respectively. Following the last dose of study drug (for any reason), overall post-treatment 1-, 2-, and 3-year OS rates were 74% (64, 82), 65% (55, 74), and 56% (46, 66), respectively; in pts who discontinued due to study drug toxicity (n = 32), post-treatment 1-, 2-, and 3-year OS rates were 84% (66, 93), 75% (55, 86), and 65% (45, 79), respectively, and in pts who discontinued for disease progression (n = 30), these were 52% (33, 68), 34% (18, 51), and 24% (11, 41), respectively. Conclusions: This updated analysis from study CA209-004 showed favorable survival outcomes with NIVO+IPI, regardless of BRAF or LDH status, and provided evidence of long-term survival following discontinuation of treatment in pts with advanced melanoma. Clinical trial information: NCT01024231.

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Markovič, Oskar, and Ralph L. Obendorf. "Soybean seed pectinesterase." Seed Science Research 8, no. 4 (December 1998): 455–61. http://dx.doi.org/10.1017/s0960258500004426.

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AbstractMethanol accumulates in axis tissues of maturing soybean seeds, correlating with preharvest seed deterioration. Accumulation of methanol appears to be associated with the enzymic demethylation of pectin methyl esters by pectinesterase (PE; EC 3.1.1.11). To characterize PE in developing and maturing soybean (Glycine max (L.) Merrill) seeds, enzyme activity was assayed in axis and cotyledon tissues. Activity per g fresh weight was 20–25 times higher in axes than in cotyledons with highest activities between 45 and 60 days after flowering (DAF). Twenty to 33% of the total PE activity was in the ‘soluble’ form (extracted with water, 0.5 M sucrose, 1 M sucrose and water). Soluble and cell-wall-bound PE (subsequently extracted with 1 M NaCI) were purified and characterized from axes of seeds at 45–60 DAF. Purification of PE was achieved through concentration of extracts by ultra-filtration, precipitation with ammonium sulfate (30–80% saturation), dialysis, gel filtration on Sephadex G-75 columns, and ion exchange chromatography on CM Sepharose CL-6B. Further purification of both soluble and bound PE was by isoelectric focusing (IEF) on ultrathin layers of polyacrylamide gel with simultaneous detection of protein and PE activity. It was possible to follow seven bands exhibiting PE activity with pl values between 6.0 and 9.5 in 1 M NaCI-extracts of total homogenates. Differences in the IEF patterns of bound and soluble PE were observed. Whereas the bound enzyme exhibited more basic PE bands (pl 8–9.5), the soluble enzyme had more active bands at pl 6.5, 7.0 and 7.5. The Mr was close to 33 000 and the pH optimum was 7.8 for both soluble and bound PE.

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Lyman, Gary H., David C. Dale, Nicole M. Kuderer, Debra A. Wolff, Eva Culakova, Marek S. Poniewierski, and Jeffrey Crawford. "Prospective Validation of a Predictive Model for Early Anemia in Patients Receiving Cancer Chemotherapy." Blood 108, no. 11 (November 16, 2006): 460. http://dx.doi.org/10.1182/blood.v108.11.460.460.

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Abstract Anemia represents the most common hematological toxicity in cancer patients receiving chemotherapy and is associated with considerable morbidity and cost. ASH/ASCO guidelines call for intervention at a hemoglobin (hgb)<10 g/dL. A meta-analysis has demonstrated the clinical value of early (hgb≥10 g/dL) versus late (hgb<10 g/dL) intervention with an erythroid stimulating protein (ESP). An anemia predictive model may help guide intervention sufficiently early in the course of chemotherapy when it can be most effective. A prospective, nationwide study was undertaken to develop and validate risk models for hematologic toxicities of chemotherapy. The analysis presented here is based on 3,640 patients with cancer of the breast, lung, colon and ovary or malignant lymphoma receiving a new regimen prospectively registered at 117 randomly selected U.S. practices. A logistic regression model for hgb<10 g/dL was developed and validated using a 2:1 random selection split sample methodology. Predictive performance characteristics were estimated [±95% CL]. Nadir hgb over 4 cycles of chemotherapy was <8 g/dL in 113 (3%), 8–10 in 959 (26%), 10–12 in 1,847 (51%), and ≥12 in 721 (20%). No significant differences were observed between the two populations. Independent risk factors for nadir hgb<10 g/dL (ORs) were: female gender (1.66); ECOG >1 (1.70); CHF (1.54); history of vascular disease (2.66); ulcer disease (2.58); COPD (1.29); connective tissue disease (1.84); advanced cancer stage (1.19); cancer type and chemotherapy based on anthracyclines (2.15), carboplatin (2.40), gemcitabine (2.48), cyclophosphamide (1.60), etoposide (2.84), topotecan (4.21), or trastuzumab (1.43), planned cycle length >1 week (2.0), while normal baseline hemoglobin, platelet count and GFR were associated with a reduced risk. Model fit was good (P<.001), R2 = 0.35 and c-statistic = 0.81 [.79–.83, P<.0001]. Mean and median predicted risk for hgb<10 g/dL were 0.29 and 0.22, respectively. An increasing risk cutpoint was associated with lower sensitivity and higher specificity. In the highest risk half, quarter and quintile of patients, hgb<10 g/dL was experienced by 47% [45–50], 64% [60–68], and 70% [65–74], respectively. Model performance characteristics at the median risk included: sensitivity: 82% [78–84]; specificity: 64% [62–66]; and diagnostic odds ratio: 7.80 [6.28–9.68]. Most covariates significant in the derivation model remained significant in the validation population. Model fit was good [P<.001] with an R2=.40 and a c-statistic of 0.83 [.81–.86; P<.001]. In the highest risk half, quarter and quintile of patients, hgb<10 g/dL was experienced by 50% [46–54], 67% [62–71], and 70% [65–75], respectively. Test performance of the validation model at the median risk included: sensitivity of 83% [79–86], specificity of 62% [59–66], and a diagnostic odds ratio of 7.90 [5.84–10.69]. Based on good performance characteristics, this validated prediction model identified chemotherapy patients at increased risk for developing clinically significant anemia who may be candidates for early targeted intervention with an ESP. A conditional risk model for subsequent risk of hgb<10 g/dL which includes changes during cycle 1 of chemotherapy has also been developed and will be presented.

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Hunt, N., R. K. Strachan, A. N. Nicolaides, and K. T. Delis. "Incidence, Natural History and Risk Factors of Deep Vein Thrombosis in Elective Knee Arthroscopy." Thrombosis and Haemostasis 86, no. 09 (2001): 817–21. http://dx.doi.org/10.1055/s-0037-1616137.

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Summary Aims: to determine the incidence, anatomical distribution and extent of deep vein thrombosis (DVT) in limbs undergoing elective unilateral knee arthroscopy without active prophylaxis, to evaluate its effect on venous function following early diagnosis, and to quantify the impact of risk factors on its incidence. Methods: 102 consecutive patients undergoing unilateral knee arthroscopy without prophylaxis were studied. A history was obtained with emphasis on the risk factors for thromboembolism, and physical examination and colour duplex were performed prior to and within a week after surgery. Patients who developed calf DVT were given aspirin (150 mg) and compression stockings; those with proximal DVT were admitted for anticoagulation (heparin followed by warfarin). Follow-up (mean 118 [range 84-168] days) entailed weekly physical and duplex examinations during the first month and monthly thereafter. Results: 8 patients developed calf DVT in the operated leg (incidence 7.84% [95% Cl: 2.7%-13.2%]); thrombosis was asymptomatic in 4 of those (50%), caused calf tenderness in 4 (50%) and a positive Homan’s sign in one (12.5%). DVT occurred in the following veins: peroneal 4 subjects (50%), soleal 4 (50%), gastrocnemial 2 (25%) and tibial 2 (25%). Propagation of a calf DVT to the popliteal vein was identified in 1 patient (12.5%). After a median period of 118 days, total clot lysis was found in 50% of DVTs, with partial thrombus resorption in the rest; reflux in the thrombosed veins was present in 75% of limbs with DVT. 43% of patients had 1 risk factor for DVT and 20% had ≥2. The incidence of DVT was higher amongst those with two or more risk factors for thromboembolism (p <.05) or those with previous thrombosis alone (p <.005). Symptoms or signs of pulmonary embolism were not documented. Conclusions: Elective unilateral knee arthroscopy performed without prophylaxis is complicated by ipsilateral calf DVT in 7.8% (95% CI: 2.7%-13.2%) of cases. The risk is higher in the presence of previous thrombosis (relative risk: 8.2) and two or more risk factors for DVT (relative risk: 2.94). Thrombosis may propagate to the proximal veins, despite early diagnosis. 50% of calf clots totally lyse in 4 months, yet reflux develops in at least 75% of limbs with DVT. Further studies to determine optimal prophylaxis are warranted.

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Kuleshova, Nadezhda E., Alexander V. Vvedenskii, Elena V. Bobrinskaya, and Elena В. Rychkova. "Роль структурно-морфологического состояния поверхности платины в кинетических и термодинамических характеристиках процесса адсорбции аниона серина." Kondensirovannye sredy i mezhfaznye granitsy = Condensed Matter and Interphases 21, no. 1 (March 6, 2019): 72–83. http://dx.doi.org/10.17308/kcmf.2019.21/718.

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Исследована адсорбция аниона серина на гладком Pt и Pt(Pt)-электроде. Методом кривых заряжения получены стационарные и кинетические изотермы адсорбции. Установлено, что как на гладком, так и Pt(Pt)-электроде, кинетика исследуемых процессов подчиняется уравнению Рогинского-Зельдовича, а стационарное заполнение описывается изотермой Темкина. При этом адсорбция аниона серина на Pt(Pt) сопровождается диссоциацией адсорбата. Найдены основные термодинамические характеристики (константа адсорбционного и изменение свободной энергии Гиббса) процесса адсорбции аниона серина на обоих электродах. ЛИТЕРАТУРА Damaskin B., Petrii A. O., and Batrakar V.Adsorption of Organic Compounds on Electrodes. Plenum Press, New York, 1973. Sobkowski J., Juzkiewics-Herbish M. Metall/Solution Interface: an Experimental Approach, Modern Aspects of Electrochemistry, no. 31. Eds. by J. O¢ Bockris, R. E. White and B. E. Conway. Plenum Press, New York, London, 1997, p. 1. Frumkin A. N. Isbrannie trudi: Electrodnie processi, [Selected Works: Electrode Processes]. Moscow, Nauka Publ., 1987. 336 p. (in Russ.) Delahey P. Dvoinoi sloi i kinetika elektrodnih processov, [Double Layer and Kinetics of Electrode Processes]. Moscow, Mir Publ., 1967, 351 p. (in Russ.) Gileadi E. and Conway B. in:Modern Aspects of Electrochemistry, no. 3 Eds. by J. O’M. Bockris and B. Conway. Butterworths, London, 1964. Electrocatalysis. Ed. by J. Lipkowski, P. N. Ross. Wiley, VCH, New York, Chichester, Weinheim, Brisbake, Singarope, Toronto, 1998, 376 p. Bockris J. O. M., Shahed U. Khan M. Surface Electrochemistry: a Molecular Level Approach. Plenum Press, New York, London, 1993, 1014 p. Applied Infrared Spectroscopy. By A. Lee Smith. Wiley, Chichester, 1979. Gale J. Spectroelectrochemistry: Theory and Practice. Plenum Press, New York, 1988, p. 189. Tehnika eksperimentalnih rabot po electrohimii, korrosii I poverhnostnoi obrabotke metallov [Technique of Experimental Work on Electrochemistry, Corrosion and Surface Treatment of Metals]. Ed. by A. T. Kuna. Saint Petersburg, Khimiya Publ., vol. , 1994, 560 p. (in Russ.) Lasia A. Electrochemical Impedance Spectroscopy and its Application. Modern Aspects of Electrochemistry. Eds. by B. E. Conway, J. O.` Bockris and R. E. White. Kluwer Acad, Plenum Publ., New York, Boston, Dordrecht, London, Moscow, 1999, p. 143. Metodi ismerenii v elektrohimii [Measurement Methods in Electrochemistry]. Ed. by Eger, A. Zalkind. Moscow, Mir Publ., 1997, 585 p. (in Russ.) Theory of Chemisorption. by J. Smith. Berlin, Springer, 1980, 240 p. Horányi G. Electroanalyt. Chem., 1975, vol. 64, iss. 1, pp. 15-19. https://doi.org/10.1016/0368-1874(75)80108-0 Huerta F., Morallon E., Cases F., Rodes A., Vazquez J. L., Aldaz A. Electroanal. Chem., 1997, vol. 421, iss. 1-2, pp. 179-185. https://doi.org/10.1016/s0022-0728(96)04820-6 Huerta F., Morallon E., Cases F., Rodes A., Vazquez J. L., Aldaz A. Electroanal. Chem., 1997, vol. 421, iss. 1-2, pp. 155-164. https://doi.org/10.1016/s0022-0728(97)00542-1 Huerta F., Morallon A., Vazquez J. L, Quijada C., Berlouis L. Electroanal. Chem., 2000, vol. 489, iss. 1-2, pp. 92-95. https://doi.org/10.1016/s0022-0728(00)00202-3 Shi-Gang Sun,Jian-Lin Yao, Qi-Hui Wu, Zhong-Qun Tian. Langmuir, 2002, vol. 18, iss. 16, pp. 6274-6279. https://doi.org/10.1021/la025817f Tumanova E. A., Safonov A. Yu. Elektrokhimiya [Russian Journal of Electrochemistry], 1998, vol. 34, iss. 2, p. 153. (in Russ.) Marangoni D. G., Smith R. S., Roscoe S. G., Marangoni D. G. J. Chem., 1989, vol. 67, iss. 5, pp. 921-926. https://doi.org/10.1139/v89-141 Ogura K., Kobayashi M., Nakayama M., Miho M. Electroanal. Chem., 1998, vol. 449, iss. 1-2, pp. 101-109. https://doi.org/10.1016/s0022-0728(98)00015-1 Gu Y. J., Chen S. P., Sun S. G., Zhou Z. Y. Langmuir, 2003, vol. 19, iss. 23, pp. 9823-9830. https://doi.org/10.1021/la034758i Huerta F., Morallon E., Cases F., Rodes A., Vazquez J. L., Aldaz A. Electroanal. Chem., 1997, vol. 431, iss. 2, pp. 269-275. https://doi.org/10.1016/s0022-0728(97)00212-x Huerta F., Morallon E., Vazquez J. L., Aldaz A. Electroanal. Chem., 1999, vol. 475, iss. 1, pp. 38-45. https://doi.org/10.1016/0022-0728(91)85503-h Horanyi G. Electroanal. Chem., 1991, vol. 304, iss. 1-2, pp. 211-217. https://doi.org/10.1016/s0022-0728(97)00212-x Kong De-Wen, Zhu Tian-Wei, Zeng Dong-Mei, Zhen Chun-Hua, Chen Sheng-Pei, Sun Shi-Gan. J. Chinese Universitie, 2009, vol. 30, no. 10, p. 2040. Safonova T. Y., Hidirov Sh. Sh., Petrii O. A. Elektrokhimiya [Russian Journal of Electrochemistry], 1984, vol. 20, iss. 12, p. 1666. (in Russ.) Kuleshova N. E., Vvedenskyi A. V., Bobrinskaya E. V. Electrokchimiya [Russian Journal of Electrochemistry], 2018, vol. 54, iss. 7, pp. 592-597. https://doi.org/10.1134/s1023193518070042 Frumkin A. N., Podlovchenko B. I. AN SSSR, 1963, vol. 150, iss. 2, p. 349. (in Russ.) Podlovchenko B. I., Iofa Z. A. Journal fisicheskoi himii [Russian Journal of Physical Chemistry A], 1964, vol. 38, no. 1, p. 211. (in Russ.) Damaskin B. B., Petrii O. A., Tsyrlina G. A. Electrokhimiya [Electrochemistry]. Moscow, Khimiya Publ., 2001, 623 p. (in Russ.) Damaskin B. , Petrii O. A., Vvedenie v electrokhimiceskyu kinetiku [Introduction to Electrochemical Kinetics]. Moscow, Vyshaya Shkola Publ., 1983, 399 p. (in Russ.) Frumkin A. N., Bagotskii V. S., Iofa Z. A. Kabanov B. N. Kinetika elektrodnyh processov [Kinetics of Electrode Processes]. Moscow, Izdat. Moskovs.Universiteta Publ., 1952, 319 p. (in Russ.) Bobrinskaya E. V., Vvedenskyi A. V., Kartashova T. V., Krashenko T. G. Korrosia: materialy i zashita [Corrosion: Materials, Protection], 2013, no. 8, pp. 1-8. (in Russ.) Bragin O. V., Liberman A. L. Russian Chemical Reviews, 1970, vol. 39, no. 12, p. 1017. https://doi.org/10.1070/rc1970v039n12abeh002315 Аnderson I. R., Macdonald R. I., Shimoyama Y. Catalysis, 1971, vol. 20, № 2, p. 147. https://doi.org/10.1016/0021-9517(71)90076-5 Levitskii L, Minachev Kh. M. In: Mechanisms of Hydrocarbon Reactions. 1973, Budapest, Academiai Kiado, 1975, Preprint, no. 15, p. 81. Anderson R., Baker B. G. Chemisorption and Reactions on Metallic Films. London, New-York. Acad. Press, 1971, p. 63. Bragin O. V., Preobrazenskii A. V., Liberman A. L., Kazanskii B. A. Kinetica i katalys [Kinetics and Catalysis], 1975, vol. 16, no. 2, p. 472. (in Russ.) Maire G., Corolleur C., Juttard D., Gault F. G. Catalysis, 1971, vol. 21, iss. 2, рp. 250-253. https://doi.org/10.1016/0021-9517(71)90143-6 Corolleur C., Corolleur S., Gault F. G. Catalysis, 1972, vol. 24, iss. 3, pp. 385-400. https://doi.org/10.1016/0021-9517(72)90123-6 Paal Z., Tetenyi P. Chim. Acad. Sci. Hung., 1972, vol. 72, no. 3, p. 277. Barron Y., Maire G., Muller J. M., Gault F. G. Catalysis, 1966, vol. 5, iss. 3, pp. 428-445. https://doi.org/10.1016/s0021-9517(66)80062-3 Muller J. M., Gault F. G. Catalysis, 1972, vol. 24, iss. 2, pp. 361-364. https://doi.org/10.1016/0021-9517(72)90083-8 Contreras A. M., Grunes J., Yan X.-M., Liddle A., Somorjai G. A. Topics in Catalysis. 2006, 39, iss. 3–4, pp. 123-129. https://doi.org/10.1007/s11244-006-0047-0 Khazova A. M., Vasil’ev U. B., Bagotskii V. S. Soviet Electrochemistry, 1967, vol. 3, no. 7, p. 1020. (in Russ.) Podlovchenko B. I., Petuhova R. P.Soviet Electrochemistry, 1972, vol. 8, no. 6, p. 899. (in Russ.)

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Scagliotti, Giorgio Vittorio, Purvish Parikh, Joachim von Pawel, Bonne Biesma, Johan Vansteenkiste, Christian Manegold, Piotr Serwatowski, et al. "Phase III Study Comparing Cisplatin Plus Gemcitabine With Cisplatin Plus Pemetrexed in Chemotherapy-Naive Patients With Advanced-Stage Non–Small-Cell Lung Cancer." Journal of Clinical Oncology 26, no. 21 (July 20, 2008): 3543–51. http://dx.doi.org/10.1200/jco.2007.15.0375.

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PurposeCisplatin plus gemcitabine is a standard regimen for first-line treatment of advanced non–small-cell lung cancer (NSCLC). Phase II studies of pemetrexed plus platinum compounds have also shown activity in this setting.Patients and MethodsThis noninferiority, phase III, randomized study compared the overall survival between treatment arms using a fixed margin method (hazard ratio [HR] < 1.176) in 1,725 chemotherapy-naive patients with stage IIIB or IV NSCLC and an Eastern Cooperative Oncology Group performance status of 0 to 1. Patients received cisplatin 75 mg/m2on day 1 and gemcitabine 1,250 mg/m2on days 1 and 8 (n = 863) or cisplatin 75 mg/m2and pemetrexed 500 mg/m2on day 1 (n = 862) every 3 weeks for up to six cycles.ResultsOverall survival for cisplatin/pemetrexed was noninferior to cisplatin/gemcitabine (median survival, 10.3 v 10.3 months, respectively; HR = 0.94; 95% CI, 0.84 to 1.05). Overall survival was statistically superior for cisplatin/pemetrexed versus cisplatin/gemcitabine in patients with adenocarcinoma (n = 847; 12.6 v 10.9 months, respectively) and large-cell carcinoma histology (n = 153; 10.4 v 6.7 months, respectively). In contrast, in patients with squamous cell histology, there was a significant improvement in survival with cisplatin/gemcitabine versus cisplatin/pemetrexed (n = 473; 10.8 v 9.4 months, respectively). For cisplatin/pemetrexed, rates of grade 3 or 4 neutropenia, anemia, and thrombocytopenia (P ≤ .001); febrile neutropenia (P = .002); and alopecia (P < .001) were significantly lower, whereas grade 3 or 4 nausea (P = .004) was more common.ConclusionIn advanced NSCLC, cisplatin/pemetrexed provides similar efficacy with better tolerability and more convenient administration than cisplatin/gemcitabine. This is the first prospective phase III study in NSCLC to show survival differences based on histologic type.

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West, H. J., S. Lee, L. Reyno, L. Fehrenbacher, A. L. Cohn, J. O. Hopkins, D. H. Irwin, D. A. Smith, T. E. Boyd, and M. R. Olsen. "DN101–004: A multicenter, open label, dose ranging study of DN-101 and docetaxel in patients with stage IIIB or IV non-small cell lung cancer (NSCLC) after platinum-based chemotherapy." Journal of Clinical Oncology 25, no. 18_suppl (June 20, 2007): 7685. http://dx.doi.org/10.1200/jco.2007.25.18_suppl.7685.

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7685 Background: DN-101 is a high-dose oral formulation of calcitriol, the most potent natural ligand of vitamin D receptor. Calcitriol has various anti-neoplastic effects on malignant cells and increases activity of cytotoxic agents, including taxanes. DN-101 in combination with docetaxel was associated with improved survival in a phase II study in androgen-independent prostate cancer and ASCENT 2, a phase III confirmatory study is underway. The objective of the study was to determine the maximum tolerated dose, response rate (ORR), progression-free survival (PFS), and overall survival (OS) of DN-101 in combination with docetaxel in advanced NSCLC patients (pts). Methods: Eligible pts had Stage IIIB or IV NSCLC that progressed on or after platinum-based chemotherapy, ECOG = 1, and measurable disease by RECIST criteria. DN-101 was administered on day 1 in doses of 45 (n=5), 75 (n=4), 135 (n=3), or 180 μg (n=53) in the q21d group, or 180 μg on day 1, followed by 45 (n=5), 90 (n=4), or 180 μg (n=12) on days 8 and 15 in the q7d group. Docetaxel (75 mg/m2 BSA) was given on day 2 q21d for all pts. Results: A total of 86 pts were treated. No unexpected toxicities were reported with DN-101. Grade 3/4 (G3/4) toxicities and fatal adverse events (AEs) were consistent with the reported toxicity of docetaxel alone. Stomatitis (0% in q7d, 9% in q21d) and G3/4 asthenia and fatigue (5% in q7d, 14% in q21d) were less frequent on DN-101 compared to published reports on docetaxel. No pt on DN-101 q21d developed hypercalcemia while 2 pt on DN-101 q7d (180 μg cohort) developed G3/4 hypercalcemia. Three fatal AEs included 2 on DN-101 q21d (1 lung infiltration, 1 pneumonitis) and 1 on DN-101 q7d (intestinal perforation). The ORR was 5.9% (CI 0.1%, 28.7%) and 6.6% (1.8%, 15.9%), median PFS 14.1 (6.0, 20.0) and 11.6 (8.4, 17.4) weeks, median OS 8.8 (7.1, NA) and 6.9 (5.5, 9.7) months, and 1 year survival rate 40% (15.2%, 64.8%) and 31% (18.9%, 42.2%) for the q7d and q21d group, respectively. Conclusions: DN-101 in combination with docetaxel is well-tolerated in advanced NSCLC. The observation of improved PFS, OS, and 1 year survival with weekly DN-101 administration supports further investigation. [Table: see text]

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Zuo, Kevin J., Nisha Umraw, and Robert Cartotto. "Scar Quality of Skin Graft Borders: A Prospective, Randomized, Double-Blinded Evaluation." Journal of Burn Care & Research 40, no. 5 (June 10, 2019): 529–34. http://dx.doi.org/10.1093/jbcr/irz087.

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Abstract Prominent scars may remain around the border of a mature skin graft (SG) at the interface of the SG with normal skin. The border of a SG may be constructed by either exactly approximating (A) or slightly overlapping (O) the edge of the SG on the wound margin. The purpose of this study was to evaluate whether A or O affects the quality of the border scar of SGs applied to burn patients. This prospective study was a within-border design in which adult burn patients requiring SGs served as their own control. Half of each study border was fashioned using O and the immediately adjacent other half was made using A. We randomly assigned O or A to the proximal or distal halves of vertical borders and the medial and lateral halves of horizontal borders. Both halves of the study border were identically fixated with staples or sutures and were managed in the same fashion postoperatively. Blinded evaluations at 3, 6, and 12 months of O and A borders were performed using the Vancouver Scar Scale (VSS), the observer component of the Patient and Observer Scar Assessment Scale (POSAS), and a global binary assessment of which half of the study border “looked better.” Blinded patients also rated each half of the study border with a 10-point Likert scale. Values are reported as the mean ± SD or median (interquartile range), as appropriate. There were 34 borders studied in 15 subjects (46.7% female, age 29 [22,57], % TBSA burn 9.7 ± 5.3, and no inhalation injuries). Study borders were constructed at 7 (5,11) days postburn, had a total length of 12 (9.3,14.5) cm, and all involved split thickness SGs of thickness 13 (12,14)/1000th of an inch. Sheet grafts were applied in 27% and meshed grafts in 73%. SGs were applied immediately after excision in 75% or after allografting in 25%. Border scars matured between 3 and 12 months with reductions in total VSS from 8 (7,8) to 4 (3,6) for O borders (P < .001) and from 8 (7,9) to 4 (1,6) for A borders (P < .001). However, there were no significant differences between O and A borders in total VSS at 3 months (P = .165), 6 months (P = .602), and 12 months (P = .358) or in total OSAS at 3 months (P = .681), 6 months (P = .890), or 12 months (P = .601). At 12 months, 60% of O borders and 40% of A borders were globally rated as “better” (P = .258). There were no significant differences in the patients’ subjective ratings of the O and A borders at 3 months (P = .920), 6 months (P = .960), and 12 months (P = .66). The scar quality at the border of a skin graft does not appear to be affected by the surgical technique used to construct the border at the time of grafting.

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Di Raimondo, Francesco, Charalampia Kyriakou, Martin Schmidt-Hieber, Marie-Christiane Vekemans, Ángel Ramírez Payer, Pal Tore Bentsen, Birgitta Lauri, et al. "European Post-Approval Safety Study (Registry) of Relapsed/Refractory Multiple Myeloma (RRMM): Safety of Patients Treated with Pomalidomide." Blood 128, no. 22 (December 2, 2016): 5680. http://dx.doi.org/10.1182/blood.v128.22.5680.5680.

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Abstract Background: This EU PASS is an observational, non-interventional registry designed to characterize the safety profile of pomalidomide (POM) in the treatment of RRMM in a real-world setting. Objectives:To assess the incidence of adverse events (AEs) of special interest, including neutropenia, thrombocytopenia, venous thromboembolism, peripheral neuropathy, and second primary malignancies in patients (pts) with RRMM treated with POM according to current clinical practice. Methods: Pts with symptomatic RRMM were enrolled at the investigator's discretion and after the decision was made to treat with POM. Thromboprophylaxis was administered per local standard practice. AEs were graded according to National Cancer Institute-Common Terminology Criteria for Adverse Events (version 4). The study is ongoing and open for recruitment in centers across Europe. Results: As of June 2016, 218 pts across 100 institutions in 8 European countries were included in the safety population. At the time of this abstract, 153 pts (70.2%) were ongoing. Median age was 68 yrs (range, 37-88 yrs), with 39.9% of pts < 65 yrs, 32.6% between 65 and 75 yrs, and 27.5% ≥ 75 yrs; 56.9% were male. Median time from diagnosis was 4.7 yrs (range, 0.4-25.4 yrs). Median number of prior therapies was 3 (range, 0-10); 80.8% of pts had at least 3 prior lines. Most pts (95%) received prior lenalidomide (given in second line in 66.1% and in third line in 20.2%). Prior bortezomib was administered in 96.8% of pts (given in second line in 54.6% and in third line in 28.4%). Almost half of the pts (49.5%) had a good performance status (Eastern Cooperative Oncology Group performance status 0-1). In this analysis, median treatment duration was 12.9 wks (range, 0.7-87.9 wks). Overall, 50.9% of pts (n = 111) had grade 3-4 AEs. AEs of all grades occurred in 79.8% (n = 174). Neutropenia of all grades was only reported in 22% of pts (n = 48), and febrile neutropenia in 2.3% of pts (n = 5). Infections of all grades occurred in 44.5% of pts (n = 97); of those, 11.5% were pneumonia. Thrombocytopenia occurred in 7.8% (n = 17). Fatigue occurred frequently in 13.8% of pts (n = 30). There were some gastrointestinal disorders, such as diarrhea in 7.8% (n = 17), constipation in 6.4% (n = 14), and nausea in 6.0% (n = 13) of pts. Peripheral polyneuropathy was uncommon (3.2%; n = 8). Acute myocardial infarction and deep vein thrombosis were observed in 1 pt each, and 1 pt developed basal cell carcinoma. Conclusions: Results of this ongoing non-interventional study in RRMM on the use of POM in the real-world setting show a similar AE profile to that in the pivotal trial published by San Miguel in Lancet Oncology (2013). POM was generally well tolerated, and the overall safety profile is similar to that seen in pivotal trials. Updated data will be presented at the meeting. Disclosures Di Raimondo: ARIAD; Bristol-Myers Squibb; Novartis; Roche: Consultancy; Bristol-Myers Squibb; Celgene; Novartis: Speakers Bureau; Gilead Sciences: Other: Travel Expenses. Bentsen:Celgene, Teva: Other: Travel expenses. Kueenburg:Celgene International Sarl: Consultancy, Honoraria. Lersch:Celgene: Employment. Bacon:Celgene: Employment, Equity Ownership. Plesner:Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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Wickens, Kristin L., Christine A. Barthow, Rinki Murphy, Peter R. Abels, Robyn M. Maude, Peter R. Stone, Edwin A. Mitchell, et al. "Early pregnancy probiotic supplementation with Lactobacillus rhamnosus HN001 may reduce the prevalence of gestational diabetes mellitus: a randomised controlled trial." British Journal of Nutrition 117, no. 6 (March 28, 2017): 804–13. http://dx.doi.org/10.1017/s0007114517000289.

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AbstractThe study aims to assess whether supplementation with the probiotic Lactobacillus rhamnosus HN001 (HN001) can reduce the prevalence of gestational diabetes mellitus (GDM). A double-blind, randomised, placebo-controlled parallel trial was conducted in New Zealand (NZ) (Wellington and Auckland). Pregnant women with a personal or partner history of atopic disease were randomised at 14–16 weeks’ gestation to receive HN001 (6×109 colony-forming units) (n 212) or placebo (n 211) daily. GDM at 24–30 weeks was assessed using the definition of the International Association of Diabetes and Pregnancy Study Groups (IADPSG) (fasting plasma glucose ≥5·1 mmol/l, or 1 h post 75 g glucose level at ≥10 mmol/l or at 2 h ≥8·5 mmol/l) and NZ definition (fasting plasma glucose ≥5·5 mmol/l or 2 h post 75 g glucose at ≥9 mmol/l). All analyses were intention-to-treat. A total of 184 (87 %) women took HN001 and 189 (90 %) women took placebo. There was a trend towards lower relative rates (RR) of GDM (IADPSG definition) in the HN001 group, 0·59 (95 % CI 0·32, 1·08) (P=0·08). HN001 was associated with lower rates of GDM in women aged ≥35 years (RR 0·31; 95 % CI 0·12, 0·81, P=0·009) and women with a history of GDM (RR 0·00; 95 % CI 0·00, 0·66, P=0·004). These rates did not differ significantly from those of women without these characteristics. Using the NZ definition, GDM prevalence was significantly lower in the HN001 group, 2·1 % (95 % CI 0·6, 5·2), v. 6·5 % (95 % CI 3·5, 10·9) in the placebo group (P=0·03). HN001 supplementation from 14 to 16 weeks’ gestation may reduce GDM prevalence, particularly among older women and those with previous GDM.

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Grant, Irene R., Hywel J. Ball, and Michael T. Rowe. "Incidence of Mycobacterium paratuberculosis in Bulk Raw and Commercially Pasteurized Cows' Milk from Approved Dairy Processing Establishments in the United Kingdom." Applied and Environmental Microbiology 68, no. 5 (May 2002): 2428–35. http://dx.doi.org/10.1128/aem.68.5.2428-2435.2002.

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ABSTRACT Over a 17-month period (March 1999 to July 2000), a total of 814 cows' milk samples, 244 bulk raw and 567 commercially pasteurized (228 whole, 179 semiskim, and 160 skim), from 241 approved dairy processing establishments throughout the United Kingdom were tested for the presence of Mycobacterium paratuberculosis by immunomagnetic PCR (to detect all cells living and dead) and culture (to detect viable cells). Overall, M. paratuberculosis DNA was detected by immunomagnetic PCR in 19 (7.8%; 95% confidence interval, 4.3 to 10.8%) and 67 (11.8%; 95% confidence interval, 9.0 to 14.2%) of the raw and pasteurized milk samples, respectively. Confirmed M. paratuberculosis isolates were cultured from 4 (1.6%; 95% confidence interval, 0.04 to 3.1%) and 10 (1.8%; 95% confidence interval, 0.7 to 2.8%) of the raw and pasteurized milk samples, respectively, following chemical decontamination with 0.75% (wt/vol) cetylpyridinium chloride for 5 h. The 10 culture-positive pasteurized milk samples were from just 8 (3.3%) of the 241 dairy processing establishments that participated in the survey. Seven of the culture-positive pasteurized milk samples had been heat treated at 72 to 74°C for 15 s; the remainder had been treated at 72 to 75°C for the extended holding time of 25 s. When typed by restriction fragment length polymorphism and pulsed-field gel electrophoresis methods, some of the milk isolates were shown to be types distinct from those of laboratory strains in regular use within the testing laboratory. From information gathered at the time of milk sample collection, all indications were that pasteurization had been carried out effectively at all of the culture-positive dairies. That is, pasteurization time and temperature conditions complied with the legal minimum high-temperature, short-time process; all pasteurized milk samples tested phosphatase negative; and postprocess contamination was considered unlikely to have occurred. It was concluded that viable M. paratuberculosis is occasionally present at low levels in commercially pasteurized cows' milk in the United Kingdom.

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Chan, Shuk Ying, Rachel M. Hughes, Kimberly Woo, Miguel-Angel Perales, Dionysios Neofytos, and Genovefa Papanicolaou. "Reasons for voriconazole prophylaxis discontinuation in allogeneic hematopoietic cell transplant recipients: A real-life paradigm." Medical Mycology 58, no. 8 (March 14, 2020): 1029–36. http://dx.doi.org/10.1093/mmy/myaa008.

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Abstract We sought to describe the clinical experience of voriconazole as primary antifungal prophylaxis (AFP) in allogeneic hematopoietic cell transplant recipients (allo-HCTr). This was a single-center retrospective study of adult allo-HCTr (1 January 2014 to 31 December 2016) who received ≥two doses of voriconazole-AFP. Voriconazole-AFP was started on day +7 post-HCT and continued at least through day +60 post-HCT, or longer as clinically indicated. We reviewed the rate, reasons, and risk factors of voriconazole-AFP discontinuation until day-100 post-HCT. A total of 327 patients were included. Voriconazole-AFP was continued for a median of 69 days (mean: 57.9; range 1, 100): for a median of 90 days (mean :84; range 2, 100) in 180/327 (55%) in the standard-of-care (SOC) group and 20 days (mean :25.6 ; range 1, 89; P-value < .001) in 147/327 (45%) patients in the early-discontinuation-group. Early-voriconazole-AFP discontinuation was due to adverse events, drug interactions, insurance coverage, and other reasons in 101/147 (68.7%), 27 (18.4%), 13 (8.8%), and 6 (4.1%) patients, respectively. Early-voriconazole-AFP discontinuation occurred in 73/327 (22.3%) patients due to hepatotoxicity. Important predictors for early-voriconazole-AFP discontinuation included: graft-versus-host disease grade ≥2 (odds ratio [OR]: 1.9, P-value: .02), alanine-aminotransferase ≥75 IU/ml on voriconazole-administration day-14 (OR: 5.6, P-value: .02) and total bilirubin ≥1.3 mg/dl on voriconazole-administration day-7 (OR: 3.0, P-value: .03). There were 13 proven/probable invasive fungal infections by day-180 post-HCT (8/147, 5.4%, and 5/180, 2.8% in the early-discontinuation and SOC-groups, respectively; log-rank:0.13). By day-180 post HCT, 23/147 (15.6%) and 14/180 (7.8%) patients in the early-discontinuation and SOC-groups had died, respectively (log-rank:0.03). Voriconazole-AFP was discontinued in up to 45% of allo-HCTr. Hepatotoxicity during the first 2 weeks post-HCT is a significant predictor of early-voriconazole-AFP discontinuation.

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Kucukoner, Mehmet, Erkan Arpaci, Abdurrahman Isikdogan, Mehmet Bilici, Dogan Uncu, Bulent Cetin, Faysal Dane, et al. "Prognostic analysis of the patients with operable gastric cancer and the importance of tolerability of therapy: Study of Anatolian Society of Medical Oncology." Journal of Clinical Oncology 30, no. 15_suppl (May 20, 2012): e14526-e14526. http://dx.doi.org/10.1200/jco.2012.30.15_suppl.e14526.

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e14526 Background: The aims of this study were to evaluate the tolerability and toxicity with adjuvant chemoradiotherapy (CRT) and prognostic analysis of patients with operable gastric cancer. Methods: The retrospective analysis included 723 patients with operable gastric cancer, stage IB-IV (M0), received adjuvant CRT from 8 Medical Centers in Turkey between 2003 and 2010. Patients’ age, sex, tumor localization, Lauren classification, grade, stage, type of dissection, toxicity and tolerability status were analyzed. Results: 73.9% of the patients were with stage III- IVM0. 61.0% of the patients were in the intestinal type, 51.1% of the patients were with the distal type of gastric cancer and 61.4% of the patients had undergone D2 dissection. 545 (75.4%) of patients completed the entire of adjuvant CRT. The median follow-up period was 20.8 months. Overall Survival (OS) rates were 80% and 52% while relapse free survival (RFS) rates were 75% and 48%, at 1, 3 years, respectively. In univariate analysis of groups, according to the group under the age of 65 and above (p=0.16 / p=0.003), Lauren classification (p=0.004 / p<0.001), localization of tumor (p=0.02 / p=0.04), tumor grade (p=0.06 / p=0.003), stage (p<0.001 / p<0.001), type of dissection (p=0.445 / p=0.043), toxicity (p=0.062 / p=0.077), tolerability of therapy (p=0.002 / p=0.001) were significantly different in both RFS and OS. In multivariate analysis, three independent prognostic factors were identified on RFS / OS; stage (ods ratio (OR)=3.0, 95% confidence interval (CI):1.8-5.0, / OR=3.2, CI=1.8-5.4), for Lauren classification (OR=1.5, CI=0.9-2.2 / OR=1.5, CI= 1.1-2.2), for tolerability of therapy (OR=2.0, CI=1.0-3.8 / OR=1.9, CI=1.0-3.6). Conclusions: We found a new independent prognostic factor whether or not tolerate adjuvant CRT because of toxicity, except for the known prognostic factors like tumor stage and Lauren classification. We suggest that the treatment of the patients with intolerable to adjuvant CRT, is to change with less toxic adjuvant therapies.

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Osei-Boateng, Kwabena, Vyshak Alva Venur, Saurabh Dahiya, Lingling Du, Rohan Garje, Paul Elson, Samuel T. Chao, and Manmeet Singh Ahluwalia. "Graded prognostic assessment index for melanoma with brain metastases (MBM)." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 9086. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.9086.

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9086 Background: The Graded Prognostic Assessment (GPA) is a commonly used prognostic index in patients with brain metastases (BM). GPA for melanoma consists of Karnofsky Performance Scale (KPS) and the number of BM present. The purpose of this study was to evaluate the utility of GPA index in a contemporary cohort of patients (pts) with MBM at a single institution to predict Overall Survival (OS). Methods: With IRB approval, the Cleveland Clinic Brain Tumor and Neuro-Oncology Center’s database was used to identify pts with MBM treated between 2000-2012. The primary endpoint was OS from diagnosis of MBM. Cox proportional hazards models were used for data analysis. Stepwise variable selection was used to identify independent prognostic factors. Results: 90 MBM (51 females) median age 57 years (range 24-87) were included for analysis. The median number of BM was 2 (range, 1-11). KPS was 90-100(52%), 70-80 (43%) and <70 (6%). Extracranial metastases was present in 75 patients (83%). Initial treatment included Stereotactic Radiosurgery (SRS) (49%), Whole Brain Radiotherapy (WBRT) (8%), WBRT + SRS (22%), WBRT + Surgery (S)(14%) and SRS + (S) (7%). Median OS was 7.8 months (95% C.I. 6.8-10.1). GPA was prognostic for OS ( p=0.01), however this was because pts with scores of 4 had worse outcomes (median 5.1months) than the other 3 groups, which had similar OS (median 9.0-12.8 months). In addition, number of BM was not associated with OS (p=0.19). In contrast, KPS (p=0.02), Liver (p=0.04) and hemorrhagic metastasis (p=0.02) were independently prognostic for OS. These factors can be used to derive a new prognostic index with 3 groups: Unfavorable, Intermediate and Favorable (see Table). Conclusions: GPA was prognostic for OS in pts with MBM, however separation of the groups was not clear. A new prognostic index consisting of KPS, liver and hemorrhagic metastases is proposed for MBM. [Table: see text]

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Cheson, Bruce D., Neil Chua, Jiri Mayer, Greg Dueck, Marek Trněný, Kamal Bouabdallah, Nathan Fowler, et al. "Overall Survival Benefit in Patients With Rituximab-Refractory Indolent Non-Hodgkin Lymphoma Who Received Obinutuzumab Plus Bendamustine Induction and Obinutuzumab Maintenance in the GADOLIN Study." Journal of Clinical Oncology 36, no. 22 (August 1, 2018): 2259–66. http://dx.doi.org/10.1200/jco.2017.76.3656.

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Purpose To perform an updated analysis of the randomized phase III GADOLIN trial in patients with rituximab-refractory indolent non-Hodgkin lymphoma treated with obinutuzumab (GA101; G) and bendamustine (B). Patients and Methods Patients with histologically documented, rituximab-refractory CD20+ indolent non-Hodgkin lymphoma received G 1,000 mg (days 1, 8, and 15, cycle 1; day 1, cycles 2 to 6) plus B 90 mg/m2/d (days 1 and 2, all cycles) or B 120 mg/m2/d monotherapy. Patients who did not experience disease progression with G-B received G maintenance (1,000 mg every 2 months) for up to 2 years. The primary end point was progression-free survival (PFS). Results Of 413 randomly assigned patients (intention-to-treat [ITT]: G-B, n = 204; B monotherapy, n = 209), 335 had follicular lymphoma (FL; G-B, n = 164; B monotherapy, n = 171). After a median follow-up of 31.8 months, median PFS in ITT patients was 25.8 months (G-B) and 14.1 months (B monotherapy; hazard ratio [HR], 0.57; 95% CI, 0.44 to 0.73; P < .001). Overall survival (OS) also was prolonged (HR, 0.67; 95% CI, 0.47 to 0.96; P = .027). PFS and OS benefits were similar in patients with FL. Grade 3 to 5 adverse events (AEs) were reported by 148 (72.5%) and 133 (65.5%) patients in the G-B and B monotherapy arms, respectively, most commonly neutropenia (G-B, 34.8%; B monotherapy, 27.1%), thrombocytopenia (10.8% and 15.8%), anemia (7.4% and 10.8%), and infusion-related reactions (9.3% and 3.4%). Serious AEs occurred in 89 G-B patients (43.6%) and 75 B monotherapy patients (36.9%); fatal AEs occurred in 16 (7.8%) and 13 (6.4%), respectively. Conclusion This updated analysis confirms the PFS benefit for G-B shown in the primary analysis. A substantial OS benefit also was demonstrated in the ITT population and in patients with FL. Toxicity was similar for both treatments.

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Richardson, Paul G., Craig C. Hofmeister, David Siegel, Sagar Lonial, Mohamad Zaki, Ye Hua, Sheetal Shah, Jianming Wang, and Kenneth C. Anderson. "MM-005: A Phase 1, Multicenter, Open-Label, Dose-Escalation Study to Determine the Maximum Tolerated Dose for the Combination of Pomalidomide, Bortezomib, and Low-Dose Dexamethasone in Subjects with Relapsed or Refractory Multiple Myeloma." Blood 120, no. 21 (November 16, 2012): 727. http://dx.doi.org/10.1182/blood.v120.21.727.727.

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Abstract Abstract 727 Background: Pomalidomide (POM) is a distinct IMiD® immunomodulatory agent whose mechanism of action consists of 3 primary effects: potent direct anti-myeloma activity, inhibition of stromal cell-support, and immune modulation (Quach, Leukemia, 2010). Combining an immune modulator (lenalidomide), a proteasome inhibitor (bortezomib [BTZ]), and dexamethasone (DEX) has shown preclinical synergy as well as promising efficacy both as frontline and salvage treatment in myeloma patients (pts) (Mitsiades, Blood, 2002; Richardson, J Clin Oncol, 2009; Richardson, Blood, 2010). This phase 1 study was conducted in pts with relapsed or refractory multiple myeloma (RRMM) to identify the maximum tolerated dose (MTD) of POM in combination with BTZ and low dose DEX (LoDEX). Based on the MTD finding of this trial, POM + BTZ + LoDEX will be compared with BTZ + LoDEX in a large Phase III confirmatory trial with an estimated sample size of 782 RRMM pts. Methods: Eligible pts had 1–4 prior lines of therapy, were refractory to LEN, and must have been exposed to a proteasome inhibitor (PI) (but could not be BTZ-refractory). Refractory disease was defined as documented progressive disease (PD) during treatment or within 60 days of last dose. MTD determination will follow a traditional 3 + 3 design. Pts were treated with escalating doses of oral POM (cohort [CHT] 1: 1 mg; CHT 2: 2 mg; CHT 3: 3 mg; CHT 4 and 5: 4 mg) on days 1–14 and intravenous BTZ (CHTs 1–4: 1 mg/m2; CHTs 5: 1.3 mg/m2) on days 1, 4, 8, and 11 for cycles 1–8 then on days 1 and 8 for C9 and onward. All CHTs received oral DEX (20 mg or 10 mg for patients ≤ 75 or > 75 years of age, respectively) on days 1, 2, 4, 5, 8, 9, 11, and 12 in 21-day cycles. All pts received thromboprophylaxis with low-dose aspirin, low molecular weight heparin, or an equivalent agent. Herpes zoster prophylaxis was with acyclovir or equivalent per institutional guidelines. Dose-limiting toxicities (DLTs) were assessed during C1. Treatment was continued until PD or unacceptable toxicity. The primary objective was MTD determination. Secondary objectives included safety, response, overall survival, time to response, and duration of response. Results: Based on data available as of 31Jul2012, a total of 9 pts (3 men and 6 women) were enrolled in the first 3 dose CHTs. The median age was 61 years old (range: 36–75) with a median time from diagnosis of 48.9 months (range: 30.1–146.3). The median number of prior anti-MM regimens was 3 (range: 2–4). All 9 pts were refractory to LEN at study entry and had prior exposure to a PI, but were not BTZ refractory. As of 31Jul2012, 8 pts were on study treatment in the first 3 dose CHTs, with a median of 3 cycles (range 1 –6) of treatment. One pt (CHT 1) discontinued treatment at Cycle 5 (C5) due to PD. All pts enrolled in the first 3 CHTs, CHT 1 (n=3), CHT 2 (n=3), CHT 3 (n=3) completed at least 1 treatment cycle. No DLTs were observed in any pts in the first 3 CHTs. Pts in CHT 1, CHT 2 and CHT 3 have been treated for 4 to 6 cycles, 2 to 3 cycles, and 1 cycle respectively. Overall, 9 (100%) pts had at least 1 adverse event (AEs) of any grade reported, with Grade 3 or 4 AEs reported in 7 (78%) pts. No Grade 4 AEs were reported during C1. The following Grade 3 AEs were reported during C1: neutropenia (CHT 3), thrombocytopenia (CHT 3), and UTI (CHT 1). No ≥ Grade 3 peripheral neuropathy was reported. No thromboembolic AEs were reported. No pts required a reduction in POM dosing due to AE. Three pts required interruption of POM due to AE (after C1). Two pts required an interruption/reduction in BTZ dosing due to AEs (after C1). Disease response was assessed using the IMWG criteria by the investigators. In CHT 1, one pt achieved stable disease (SD) prior to discontinuing due to PD at C5; 2 pts achieved confirmed response (1 PR, 1 VGPR) and continue on therapy. In CHT 2, two pts have achieved SD, and 1 pt has reached an unconfirmed PR (uPR) with treatment ongoing in all 3. In CHT 3, one pt achieved SD and 2 pts attained uPR. Enrollment into CHT 4 (POM = 4mg) is underway at this time. Conclusions: POM in combination with 1mg/m2 of IV BTZ and oral LoDEX administered according to the classical schedule appears to be well tolerated from 1 mg up to 3 mg dose levels given daily for 14 days every 3 weeks. This combination shows rapid onset of response and promising clinical activity in LEN-refractory pts with prior exposure to PI therapy. The study is ongoing with rapid accrual; results for all dosing cohorts with longer follow-up will be presented at the meeting. Disclosures: Richardson: Johnson & Johnson: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Hofmeister:Celgene: Advisory board Other, Honoraria. Siegel:BMS: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Onyx: Consultancy; Celgene: Consultancy; Merck: Consultancy. Lonial:BMS: Consultancy; Onyx: Consultancy; Millennium: Consultancy; Novartis: Consultancy; Merck: Consultancy; Celgene Corp: Consultancy. Zaki:Celgene Corp: Employment, Equity Ownership. Hua:Celgene Corp: Employment, Equity Ownership. Shah:Celgene Corp: Employment, Equity Ownership. Wang:Celgene Corp: Employment, Equity Ownership. Anderson:Celgene Corp: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Millennium: Membership on an entity's Board of Directors or advisory committees.

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Saeki, K., T. Tamari, A. Kasamatsu, D. Iwamoto, S. Kameyama, A. Tatemizo, T. Mitani, et al. "69 RELATION OF SPATIAL GENE EXPRESSION PATTERNS IN BOVINE EMBRYOS RECONSTRUCTED WITH SOMATIC CELLS TO BLASTOCYST DEVELOPMENT." Reproduction, Fertility and Development 18, no. 2 (2006): 142. http://dx.doi.org/10.1071/rdv18n2ab69.

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Recently, enhanced development to full term was obtained with embryos reconstructed with bovine early G1 cells rather than with G0 cells (Kasinathan et al. 2001 Nat. Biotechnol. 19, 1176-1178; Urakawa et al. 2004 Theriogenology 62, 714-728). However, the reason why donor somatic cells at the early G1 phase are better for embryo reconstruction is unclear. In this study, we investigated the relation of spatial gene expression patterns at the 4- to 8-cell stage to blastocyst development of embryos reconstructed with early G1 cells. Bovine fibroblasts stably transfected with �-act/luc+/IRES/EGFP were used for embryo reconstruction. M phase cells were prepared as described by Urakawa et al. (2004). Early G1 cells were obtained from cultured M phase cells soon after the M phase cells divided. Quiescent cells (cultured in 0.4% serum for 7 days) were used as G0 cells for a control. The cells were electrofused with enucleated bovine oocytes matured in vitro, and activated with a calcium ionophore and cycloheximide. The reconstructed embryos were cultured until 60 hours post fusion (hpf), and zonae pellucidae of 4- to 8-cell embryos were removed by pronase. To determine gene expression, the LUC+ activity (luminescence) in the embryo blastomeres was detected with an imaging photon counter (Hamamatsu Photonics, Hamamatsu City, Shikuoka Prefecture, Japan) for 10 min. The embryos were categorized as being positive, mosaic, or negative depending on whether all, some or no blastomeres were luminescent, respectively. The embryos were cultured in mSOF medium individually until 168 hpf to assess development to the blastocyst stage. Blastocyst development of reconstructed embryos without detection of luminescence was also examined. Experiments were repeated three times, and the data were analyzed with Fisher's PLSD test following ANOVA. At 60 hpf, 75% (74/99) of embryos reconstructed with early G1 cells and 55% (46/83) of embryos with G0 cells developed to 4- to 8-cell stage embryos. The difference is significant (P < 0.05). The percentages of positive, mosaic, and negative embryos with G1 cells were 49, 35 and 16%, and blastocyst rates were 30, 11, and 0%, respectively. With G0 cells, the percentages were 32, 56, and 12%, and the blastocyst rates were 15, 4, and 0%, respectively. More positive embryos were obtained with early G1 cells than with G0 cells (P < 0.05). Blastocyst rates of the positive embryos with early G1 cells were the same as with G0 cells (P > 0.05). Blastocyst development of positive embryos was higher than that of mosaic and negative embryos in early G1 and G0 groups (P < 0.05). Without detection of luminescence, the blastocyst rates from the reconstructed embryos were 43% (35/81) and 16% (20/125) with early G1 and G0 cells, respectively (P < 0.05). These results suggest that the higher developmental capacity of embryos reconstructed with early G1 cells might be related to the appropriate spatial gene expression at the 4- to 8-cell stage. A part of this study was supported by a grant from the Wakayama Prefecture Collaboration of Regional Entities for the Advancement of Technological Excellence of the JST.

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VYSE, A. J., N. J. ANDREWS, L. M. HESKETH, and R. PEBODY. "The burden of parvovirus B19 infection in women of childbearing age in England and Wales." Epidemiology and Infection 135, no. 8 (February 12, 2007): 1354–62. http://dx.doi.org/10.1017/s0950268807007856.

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SUMMARYA serological survey has been used to investigate the epidemiology of parvovirus B19 infection in England and Wales. A total of 2835 sera representing the complete age range were selected from a convenience collection obtained in 1996 that reflects the general population and screened for parvovirus B19-specific IgG. Antibody prevalence rose nonlinearly with age from 21% in those aged 1–4 years to >75% in adults aged ⩾45 years. Force-of-infection estimates were similar to those previously made in 1991, being highest in those aged <15 years. There was no association between evidence of previous infection and sex or region. Quantitatively strongest antibody responses were found in those aged 15–34 years and IgG levels in females were 28·5% higher than those found in males (P=0·004, 95% CI 8·2–52·6). Applying the upper 95% confidence interval for the force of infection to maternity estimates for England and Wales in 1996, parvovirus infection in pregnancy was estimated to occur on average in up to 1 in every 512 pregnancies each year. This represents 1257 maternal infections, causing up to an estimated 59 fetal deaths and 11 cases of hydrops fetalis annually. An analysis of all available laboratory-confirmed parvovirus infections found a mean of 944 infections per year in women aged 15–44 years highlighting a need for enhanced surveillance of maternal parvovirus B19 infection in England and Wales, including information on both pregnancy and outcome of pregnancy.

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Lund, Ivar, Najlae El Kertaoui, Marisol S. Izquierdo, David Dominguez, Benni W. Hansen, and Patrick Kestemont. "The importance of phospholipids combined with long-chain PUFA in formulated diets for pikeperch (Sander lucioperca) larvae." British Journal of Nutrition 120, no. 6 (July 30, 2018): 628–44. http://dx.doi.org/10.1017/s0007114518001794.

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AbstractDietary phosphoglycerides and n-3 long-chain PUFA (LC-PUFA) play important functions in the development of pikeperch (Sander lucioperca) larvae. This study aimed to determine optimal dietary levels of soyabean lecithin (SBL)-derived phospholipids (PL) in starter feeds for pikeperch larvae 10–30 d post-hatch (DPH) and examine performance and ontogeny by additional supplementation of n-3 LC-PUFA in the form of Algatrium DHA 70 (glyceride product; 660–700 mg/g DHA; EPA 60–75 mg/g). In total, six isoproteic and isoenergetic extruded diets were formulated with increasing levels of PL (3·7, 8·3 or 14·5 % wet weight (w.w.), respectively); however, three of the diets were supplemented with three levels of Algatrium DHA 70 (0·6, 2·0 or 3·4 %, respectively). Liver proteomic analyses of larvae at 30 DPH were included for effects of PL and primarily DHA on performance, physiological expression and interactions in larval proteins. In addition, bone anomalies, digestive enzymatic activity, candidate gene expression and skeleton morphogenesis were examined. Results confirmed the importance of dietary PL levels of at least 8·2 % w.w., and an additional beneficiary effect of supplementation with DHA plus EPA. Thus, combined supplementation of SBL (up to 14·51 % w.w. PL) and n-3 LC-PUFA (1·004 % DM DHA and 0·169 % DM EPA) in the form of TAG resulted in highest growth and lowest incidence of anomalies, improved digestive enzyme activity and had differential effect on liver proteomics. The results denote that essential fatty acids can be supplemented as TAG to have beneficial effects in pikeperch larvae development.

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Kim, Tae Min, Dong-Wan Kim, Yoon-Koo Kang, Goon Jae Cho, Hong-Suk Song, Hyo Jung Kim, Byung Soo Kim, et al. "A phase II trial of ifosfamide, methotrexate, etoposide, and prednisolone (IMEP) for previously untreated stage I, II extranodal natural killer/T-cell lymphoma, nasal type (NTCL): A multicenter study of the Korean Cancer Study Group." Journal of Clinical Oncology 31, no. 15_suppl (May 20, 2013): 8521. http://dx.doi.org/10.1200/jco.2013.31.15_suppl.8521.

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8521 Background: Combination chemotherapy of IMEP was active as a first-line as well as a second-line treatment for NTCL in a retrospective analysis. Thus, we conducted a prospective, multicenter, phase II study of IMEP chemotherapy in previously, untreated stage I/II NTCL. Methods: Patients with chemo-naïve stage I/II NTCL were enrolled between December 2004 and February 2009 and they received 6 cycles of IMEP (ifosfamide 1.5 g/m2 on days 1 to 3; methotrextate 30mg/m2 on days 3 and 10; etoposide 100mg/m2 on days 1 to 3; and prednisolone 60mg/m2/day on days 1 to 5) followed by involved field radiotherapy (IFRT). Response was evaluated every 2 cycles of chemotherapy and 4 to 8 weeks after completion of IFRT using modified Response Evaluation Criteria in Solid Tumors. Results: Overall, 44 patients including 29 males were analyzed by the intent-to-treat principle. Overall response rates were 73% (complete remission [CR], 11 [27%] of 41 evaluable patients) after IMEP chemotherapy and 78% (CR, 18 [67%] of 27) after IMEP followed by IFRT. Grade 3 to 4 neutropenia and thrombocytopenia were documented in 33 (75%) and 7 (16%) patients, respectively. Only 8 (18%) patients experienced grade 3 febrile neutropenia. 2-year progression-free survival (PFS) and overall survival (OS) were 56% and 66%, respectively. High Ki-67 (≥ 70%) and Ann Arbor stage II independently reduced PFS (hazard ration [HR]=5.6, 95% confidence interval [CI] 1.8-17.6; P=.004) and OS (HR=4.8, 95% CI 1.9-12.2; P=.001), respectively. Conclusions: IMEP followed by IFRT is active and safe against patients with previously untreated stage I/II NTCL.

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Siddiqi, Tanya, Kathleen Anne Dorritie, Jacob Drobnyk Soumerai, Deborah Marie Stephens, Jason A. Dubovsky, Heidi H. Gillenwater, Lucy Gong, Jerill Thorpe, Lin Yang, and William G. Wierda. "TRANSCEND CLL 004: Minimal residual disease (MRD) negative responses after lisocabtagene maraleucel (Liso-Cel; JCAR017), a CD19-directed CAR T cell product, in patients (pts) with relapsed/refractory chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL)." Journal of Clinical Oncology 37, no. 15_suppl (May 20, 2019): 7501. http://dx.doi.org/10.1200/jco.2019.37.15_suppl.7501.

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7501 Background: Eradication of MRD in CLL patients may be necessary for deep and durable responses. We assessed safety, pharmacokinetics, and efficacy of liso-cel, an investigational, anti-CD19 CAR T cell product administered as a defined composition of CD4+/CD8+ CAR T cells, in the ongoing phase 1/2 TRANSCEND CLL 004 study. Methods: Eligible pts had CLL/SLL, received ≥2 prior lines of therapy (including Bruton’s tyrosine kinase inhibitors [BTKi] unless medically contraindicated), and had ECOG PS ≤1. Post lymphodepleting chemotherapy, pts received liso-cel infusion at either dose level (DL)1 = 50 × 106 or DL2 = 100 × 106 total CAR+ T cells. Patients were monitored for dose-limiting toxicities (DLTs). Response was assessed by iwCLL 2008 criteria. MRD was assessed by flow cytometry in blood (10−4) and by NGS in bone marrow (BM; 10−6). Results: At data cutoff, 16 pts received liso-cel: DL1, n = 6; DL2, n = 10. 75% of pts had high-risk features ( TP53 mutation, complex karyotype, or del17p); 100% had prior ibrutinib and 50% had prior venetoclax. Median (range) number of prior lines of therapy was 4.5 (2‒11). There was 1 DLT of grade (G) 4 hypertension (DL2). The most common G3/4 treatment-emergent adverse events were cytopenias (thrombocytopenia, 75%; anemia, 69%; neutropenia, 63%; leukopenia, 56%). 1 pt had G3 cytokine release syndrome (CRS); 3 pts had G3 neurological events (NE). Best overall response rate (ORR) in 15 evaluable pts was 87% (13/15). 7 pts (47%) achieved complete remission with/without complete blood count recovery (CR/CRi). ORR at 6 mo was 83% (5/6). 10/15 pts (67%) achieved undetectable MRD (uMRD) in blood by day 30 and in 7/8 pts (88%) in BM. MRD-negative CRs were seen in patients who had failed both BTKi and venetoclax. Median time to peak blood CAR+ T cell level was 16 days (4‒30). Conclusions: In this study of heavily pretreated pts with standard- and high-risk CLL/SLL and previous ibrutinib treatment, liso-cel-related toxicities (ie, CRS and NEs), were manageable. Pts rapidly achieved CR/CRi and uMRD. Additional follow-up will be presented. Clinical trial information: NCT03331198.

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