tbuckley/cabot-search huggingface dataset:
Distinct patterns of somatic mutation clearance and association with clinical outcome in patients with AML.
Authors: Koichi Takahashi, Feng Wang, Keyur Patel, Carlos E. Bueso-Ramos, Ghayas C. Issa, Xingzhi Song, Jianhua Zhang, Samantha Tippen, Latasha Little, Curtis Gumbs, Farhad Ravandi, Tapan M. Kadia, Naval Guastad Daver, Courtney Denton Dinardo, Marina Konopleva, Michael Andreeff, Jorge E. Cortes, Elias Jabbour, Andrew Futreal, Hagop M. Kantarjian
Journal: Journal of Clinical Oncology (2017)

7005 Background: Persistence of somatic mutations at the time of complete remission (CR) was associated with poor outcome in patients (pts) with AML. Methods: We studied 95 pts with AML who were treated with frontline induction and subsequently achieved CR. We sequenced pre-treatment and CR bone marrow samples by targeted capture sequencing of 295 genes (median 280x coverage). We defined 3 levels of mutation clearance (MC) based on variant allele frequency (VAF): MC2.5, persistent mutation with VAF&lt;2.5%; MC1.0, persistent mutation with VAF&lt;1%; and complete mutation clearance (CMC). Results: In the pre-treatment samples, we detected 597 mutations in 78 genes in 87 (92%) patients. In the matching CR samples, 62 (10%) and 82 (14%) mutations persisted at VAF≥2.5% and ≥1%, respectively, which corresponded to 43 (49%), 34 (39%), and 30 (34%) patients achieving MC2.5, MC1.0 and CMC, respectively. Table 1 shows the differential patterns of MC based on the mutations and pathways. Mutations associated with clonal hematopoiesis of indeterminate potential (CHIP), DNA methylation, and splicing pathways had low rate of MC, whereas mutations in transcription factors or receptor tyrosine kinase (RTK) had high rate of MC. Pts who achieved MC1.0 (median 31.2 vs. 12.5 months, P = 0.04) or CMC (median 31.2 vs. 12.5 months, P = 0.049) had significantly better relapse-free survival (RFS). Conclusions: Somatic mutations associated with CHIP, DNA methylation, and splicing pathways persisted frequently in CR samples suggesting preleukemic origin. Pts with deeper MC had significantly better RFS. Somatic mutation clearance may help risk prediction of AML. [Table: see text]
Response to: ‘Revised 2017 international consensus on ANCA testing in small vessel vasculitis: support from an external quality assessment’ by Broeders <i>et al</i>
Authors: Jan Damoiseaux
Journal: Annals of the Rheumatic Diseases (2018)

The correspondence by Broeders et al 1 is very welcome because it is seeking further support for the revised 2017 international consensus on ANCA testing in small vessel vasculitis.2 3 The support is based on the results of an external quality assessment (EQA) in Belgium. Based on a single sample from a patient strongly suspected of having antineutrophil cytoplasmic antibodies (ANCA)-associated vasculitis (AAV), it was concluded that the real-life performance of antigen-specific immunoassays is better than the performance of indirect immunofluorescence (IIF) testing. Besides this, interesting information about the testing algorithm and type of immunoassay in the Belgian clinical laboratories is also provided. The main question is, however, whether solid conclusions can be drawn from the results obtained by the EQA.

Among the 90 participating laboratories, 13 laboratories only use antigen-specific immunoassays and apparently have abandoned IIF, as advocated in the revised 2017 consensus. Seventy laboratories still use the combination of IIF and immunoassays according to the 1999 international consensus statement on ANCA testing,4 while seven laboratories only perform IIF and therefore seem not to have accepted neither the 1999 …
Oncohematological diseases in Armenia.
Authors: Nata Melkikyan, Smbat Daghbashyan, Lusine Sahakyan
Journal: Journal of Clinical Oncology (2016)

e19077 Background: It is well-known that there is a growth in oncohematological morbidity rates around the world, which is mainly due to the increased morbidity rates of lymphoproliferative disaorders. This article aims to investigate the oncohematological morbidity rates and reveal the need of implementation of bone marrow transplantation in Armenia. Methods: Epidemiological studies were conducted in the area of oncohematology in Armenia for the periods 1966-1971, 1998-2004 and 2007-2011. The structure outpatient oncohematology in Hematology Center of Armenia was studied in 2012 and average annual assesment of the need of bone marrow transplantation was conducted. Results: Analysis of the overall average annual indices of blood malignances for a period of more than 30 years (1966- 1971 and 1998-2004) shows increase in incidence rates from 9.12 to 12.16 per 100 000 people. Moreover, the incidence rate of Non-Hodgkin and Hodgkin lymphomas and multiple myeloma has increased by 2.6, 1.3, 5.6 times, respectively. Comparison of the overall annual indices of blood malignances for a period of 10 years (2007-2011 and 1998-2004) shows increase in incidence rates by 1.17 times and does not reveal considerable changes with regard to morbidity indices of Non -Hodgkin and Hodgkin lymphomas but shows increased morbidity of multiple myeloma by 1.8 times. In the structure of hematologic pathologies of outpatient department of Armenian Hematology Center, lymphoproliferative disorders represent about 56,2%, myeloproliferative disorders -24.3%, leukemias and myelodisplasias- 20%. Each year more than 100 patients need bone marrow transplantation out of which 41% are patients, who suffer from Lymphoproliferative disorders (Non -Hodgkin and Hodgkin lymphomas, multiple myeloma), 7% from CML, 35% from acute leukemiaa and myelodysplasia, 14% from aplastic anemia and thalassemia. Conclusions: Establishment of bone marrow transplantation department will promote the development of oncohematology in Armenia.
M1-polarized macrophages as predictor of poor response to trabectedin treatment in myxoid liposarcoma.
Authors: Bruno Vincenzi, Marco Fioramonti, Michele Iuliani, Francesco Pantano, Giulia Ribelli, Daniele Santini, Giuseppe Tonini
Journal: Journal of Clinical Oncology (2016)

e22537 Background: Myxoid liposarcoma (MLS) represents a specific subtype of liposarcoma, one of the most common malignant soft tissue tumors affecting adults. Trabectedin is a DNA-binding agent interfering with gene transcription, regulation, and DNA repair machinery and is able to induce cell cycle perturbation. Although an high sensitivity of MLS to trabectedin has been reported, patients become resistant to the drug. A well-established model to study this phenomenon is the trabectedin-resistant (ET) 402-91 cell line and its counterpart wild type (WT). The aim of this study is to understand the key role of M1/M2 polarized macrophages in the acquisition and selection of trabectedin-resistant phenotype in MLS. Methods: WT and ET 402-91 cell lines were cultured according to standard protocol. Green Fluorescent (GFP) WT 402-91 and Red Fluorescent (RFP) ET 402-91 cell lines were obtained by stable transfections with lentiviral particles. Macrophages were differentiated from CD14+ monocytes and polarized in M1/M2 using LPS and interleukin-4 respectively. Co-culture experiments between MLS cell lines and M1/M2 macrophages were performed using transwell system. Results: M1 macrophages inhibits WT 402-91 proliferation after 96 hours of co-culture compared to control (single culture) and to WT 402-91-M2 co-culture. Conversely, M1 and M2 macrophages have no impact on proliferation of ET 402-91 cells. Population doubling time (PDT) of M1 co-cultured WT 402-91 is 5.11 hours higher than PDT of M1 co-cultured ET 402-91 (28.97 hours vs 23.86; P = 0.036). This data is confirmed co-culturing GFP+ WT 402-91 and RFP+ ET 402-91, cell-to-cell contact, under influence of M1/M2 macrophages in transwell; indeed RFP+ ET 402-91 percentage become progressively higher than GFP+ WT 402-91 after 96 hours in presence of M1 macrophages compared to M2 macrophages (75%-35% vs 52%-48%; P = 0.04). Conclusions: These data show that the presence of M1 macrophages could promote the selection of trabectedin-resistant phenotype in MLS. Moreover our findings suggest that M1 infiltrating macrophages may predict a poor response to trabectedin treatment in MLS patients but further analyses are warranted to confirm this hypothesis.
Abstract 15512: Sodium Intake and All-Ccuse Mortality Over 20 Years of Follow-up
Authors: Nancy R Cook, Lawrence J Appel, Paul K Whelton
Journal: Circulation (2015)

Introduction: While several studies suggest beneficial effects of lower sodium on cardiovascular disease, the relationship with total mortality remains controversial. Some have reported a J-shaped curve, but this may be due to poor quality exposures or confounding bias. Methods: Two trials [Phase 1 (1987-90) and Phase 2 (1990-5) of the Trials of Hypertension Prevention] implemented sodium reduction interventions, over 18 months in Phase I and 36 months in Phase II. Multiple 24-hour urine specimens were collected from pre-hypertensive adults aged 30-54. In extended post-trial follow-up, deaths were ascertained through December 31, 2013 using the National Death Index. We assessed the relation of the randomized sodium interventions, as well as average sodium excretion among those not assigned to an active sodium intervention, with all-cause mortality through 23-26 years. Results and Conclusions: Among 744 Phase I and 2382 Phase II participants randomized to sodium reduction or control, 251 deaths occurred, with a nonsignificant 15% lower risk among those in the active intervention (RR=0.85, 95% CI=0.66-1.09, p=0.19). Among 3021 usual care participants, 273 deaths occurred. There was a direct but nonsignificant association of average sodium excretion with mortality, with hazard ratios (HRs) of 0.73, 0.97, 1.00 (reference), and 1.03 (p-trend = 0.38) over &lt;2300, 2300-&lt;3600, 3600-&lt;4800, and &gt;=4800 mg/d after adjustment for trial variables, with an HR=1.10 per 1000 mg/day (95% CI = 0.98-1.24, p=0.09). There was no evidence of a J-shape or other nonlinear relation. The sodium/potassium ratio had an HR=1.11 per unit (95% CI = 0.99-1.25, p=0.07). While the results did not reach statistical significance, they are consistent with a benefit of sodium reduction on total mortality over a period of over 20 years. This study, with carefully characterized measures of sodium intake, found no inverse relation with total mortality, even at the lowest levels of sodium intake.
A comparative safety analysis for durvalumab in patients with locally advanced, unresectable NSCLC: PACIFIC versus pooled durvalumab monotherapy studies.
Authors: Scott Joseph Antonia, Matthew David Hellmann, Phillip A. Dennis, Giovanni Melillo, Shaad Essa Abdullah, Andrew Lloyd, Naiyer A. Rizvi
Journal: Journal of Clinical Oncology (2018)

8556 Background: In PACIFIC, durvalumab significantly extended PFS compared with placebo (HR 0.52; P<0.0001) for pts with locally advanced, unresectable NSCLC who had previously received concurrent chemoradiotherapy (cCRT). The safety profile of durvalumab in this study was similar to placebo. Here we report a safety analysis of a descriptive comparison of PACIFIC with a pooled dataset of durvalumab monotherapy studies. Methods: Data were pooled for pts treated with durvalumab monotherapy (10 mg/kg IV Q2W) from three trials (N=1,889), the Phase III PACIFIC (n=475), Phase II ATLANTIC (n=444 advanced NSCLC pts), and Phase I/II 1108 (n=970 solid tumor pts, including 304 NSCLC pts) studies. The incidences of all-causality AEs (as of Feb 13, 2017, data cutoff for the PACIFIC analysis) were graded using CTCAE v4.03 and summarized descriptively for comparison between PACIFIC and the pooled dataset. Results: Compared with the pooled dataset (Table), PACIFIC had lower incidences of grade 3/4 AEs and SAEs, but a higher rate of AEs leading to discontinuation (15.4% [durvalumab] vs. 9.8% [placebo] compared with 9.4% [pooled dataset]). In a separate comparison excluding PACIFIC from the pooled dataset (N=1,414), any-grade (grade 3/4) pneumonitis/radiation pneumonitis occurred in 33.9% (3.4%) of pts on durvalumab and 24.8% (3.0%) on placebo in PACIFIC (with similar grade 3/4 incidences for both) and 2.3% (0.5%) of pts in the reduced pooled dataset. Conclusions: Durvalumab monotherapy has a well-defined and acceptable safety profile. Differences observed in the rates of AEs with durvalumab on the PACIFIC regimen may be attributable to the pt population or prior cCRT. PACIFIC Demographics Pooled monotherapy dataset (N=1,889) Durvalumab (n=475) Placebo (n=234) Median age (range), years 63.0 (19–96) 64.0 (31–84) 63.5 (23–90) Age ≥75 years, % 10.0 7.6 7.7 Male, % 59.8 70.1 69.7 Overview of AEs Exposure-adjusted grade 3/4 AEs,* n 94.0 47.5 46.8 Exposure-adjusted SAEs,* n 79.5 42.5 38.2 Any AE leading to discontinuation, % 9.4 15.4 9.8 Any AE with outcome of death, % 5.4 4.4 6.0 Any AESI, % 55.5 65.5 48.7 Any imAE, % 15.6 24.2 8.1 *Reported as events per 100 pt-years
Prognostic value of post treatment PET scan in small cell lung cancer.
Authors: Mohamed Farouq Alsharedi, Aneel A. Chowdhary, Mina Shenouda, Todd W. Gress
Journal: Journal of Clinical Oncology (2017)

e20013 Background: In most lymphomas, improving patient outcome rely on an assessment of response to therapy. Functional imaging with 18-fluoro-deoxyglucose (FDG) positron emission tomography (PET) increases sensitivity and specificity of disease assessment, predicts outcome and directs future therapies. Lately, PET-scan is more utilized in small cell lung cancer (SCLC) both for initial staging and to assess response to therapy. However, limited data in the literature have evaluated the prognostic value of post-therapy response on PET-scan in SCLC. Methods: This is a retrospective chart-review of SCLC patients who received their first-line chemotherapy between January-2007 and December-2013. Inclusion criteria included complete data on age, sex, race, cancer stage, histologic grade, chemotherapy, radiotherapy, and PET images pre- and post-therapy. CR was defined as either 100% drop in FDG uptake on post-therapy PET-scan. Results: Fifty patients met the inclusion criteria, and served as the basis for this study. 46% had Limited Stage Small Cell Lung Cancer (LS-SCLC), and 54% had Extensive stage small cell lung cancer (ES-SCLC). All were treated with platinum-based chemotherapy in addition to concurrently radiation therapy for the LS-SCLC group. Eleven patients out of the whole cohort achieved CR. Using COX regression model, we evaluated the correlation between achieving CR on post-therapy PET-scan and survival outcome. We found that achieving CR was significantly correlated with worse outcome in ES-SCLC group (HR = 2.70; 95%CI: 1.26-5.81; p = 0.01). While, in the whole cohort and LS-SCLC group, P-value was not statistically significant, nevertheless achieving CR indicated unfavorable outcome (HR = 1.18; 95%CI: 0.51-2.69; p = 0.49) and (HR = 1.99; 95%CI: 0.77-5.13; p = 0.15) respectively. Conclusions: Unlike lymphomas, achieving CR on post-therapy PET-scan in SCLC was associated with worse survival outcome. This might indicate that in aggressive small cell lung cancer, despite excellent response to first-line therapy, the prognosis is still dismal. These results suggest that further prospective studies are warranted to identify the prognostic rule of post-therapy PET-scan in SCLC patients particularly those with ES-SCLC.
Retrospective analysis of safety and efficacy of ipilimumab in elderly patients with advanced melanoma.
Authors: Andrew Cota Shaw, VanAnh Trinh, Roland L. Bassett, Isabella Claudia Glitza, Adi Diab, Rodabe Navroze Amaria, Hussein Abdul-Hassan Tawbi, Michael A. Davies, Wen-Jen Hwu, Patrick Hwu, Sapna Pradyuman Patel
Journal: Journal of Clinical Oncology (2016)

9540 Background: Elderly patients (pts) with advanced melanoma have been under-represented in clinical trials evaluating ipilimumab (IPI) safety and efficacy. Two European Expanded Access Programs have shown that 3 mg/kg is feasible in this population, but with IPI recently approved in the adjuvant setting at 10 mg/kg, safety and efficacy analysis of alternative IPI-based therapy is warranted in this population. Methods: We analyzed the medical records of all pts at MDACC diagnosed with advanced, unresectable melanoma age > 70 who received IPI between 4/1/2011-1/15/2014 for toxicity, PFS, and OS. Results: Of the 429 melanoma pts treated with IPI, 94 were > 70 at treatment initiation, 36 were > 75. Of these pts, 32 received concomitant temozolomide (TEM), 1 received 1 mg/kg, 12 received 10 mg/kg as part of a clinical protocol, and 5 of those pts received maintenance doses (range 5-28 doses). 28 patients received < 4 doses, most commonly due to toxicity. Median progression free survival (PFS) by clinical assessment was 3.7 months, median overall survival (OS) was 17.5 months (95% CI 14.0 – 25.1 months). There was no difference in OS or PFS between those aged 70-74 vs. > 75, dose 1 or 3 mg/kg vs. 10 mg/kg, or with vs. without TEM. Overall, 31% of pts experienced Grade (G)3 or higher adverse events (AEs). The most common AEs were diarrhea/colitis (11%), skin rash/pruritus (6%), fatigue (4%), and transaminitis (3%). 6 pts experienced G4 AEs (4 with diarrhea/colitis, 1 with AKI, 1 with neutropenia/thrombocytopenia), G4 diarrhea/colitis occurred in 3 pts (25%) receiving 10 mg/kg. 1 pt died from myocarditis related to IPI 3 mg/kg. There was no difference in rates of G3/4/5 AEs by age or TEM use, but there was a significant difference for 10 mg/kg vs. 1 or 3 mg/kg, (75% vs. 25%, p = 0.0012). Conclusions: Our data suggests thatIPI-based therapy at 3 mg/kg is safe and efficacious in elderly pts, including those over age 75, with a median OS of 17.5 months. G3/4/5 AEs were 25% in these pts, comparable to the general population at this dose. Consistent with previous experience, toxicity appears to increase with increased dose of IPI in this population.
Retrospective analysis of nadir bone marrow biopsies in predicting need for re-induction therapy in adult acute myeloid leukemia.
Authors: Paz J Vellanki, Kavya Kannamma Kannan, Margaret Murray, Bernard Tawfik, Allison Winter, Heidi D. Klepin, Leslie R. Ellis, Dmitriy Berenzon, Dianna Howard, Susan Lyerly, Bayard L. Powell, Timothy S. Pardee
Journal: Journal of Clinical Oncology (2016)

e18509 Background: The standard of care for acute myeloid leukemia (AML) is to pursue re-induction chemotherapy if ≥ 5% blasts are present on the nadir bone marrow (BM) biopsy after induction chemotherapy. However, some patients with indeterminate responses (IR) or with residual disease (RD) are unable to undergo re-induction, and some of these patients may still obtain a complete remission (CR). The objective of this analysis is to evaluate long-term outcomes at a large academic medical center for AML patients with IR or RD who did not receive early re-induction chemotherapy. Methods: Between 2002 and 2009, 233 adult patients with newly diagnosed AML received intensive induction chemotherapy at Wake Forest Baptist Medical Center. Decisions to forego or proceed with re-induction based on the 14-day (± 3 days) nadir BM biopsies were reviewed. Response to therapy was based on the nadir and recovery BM aspirates and biopsies. At the nadir, IR and RD were defined as 5 – 20% and > 20% blasts, respectively. CR was achieved if platelets ≥ 100,000/µL, absolute neutrophil count ≥ 1000/µL, and the recovery BM had < 5% blasts. Results: Of 233 patients, 90 (38.6%) had no evidence of leukemia on their nadir BM, 56 (24.0%) had < 5% blasts but features of the BM remained concerning for residual leukemia, 50 (21.5%) had an IR, and 37 (15.9%) had RD. Thirty patients with < 5% blasts, 36 patients with an IR, and 34 patients with RD underwent re-induction. Fourteen patients with an IR did not undergo re-induction, and 9 (64.3%) of these patients were still able to achieve a CR. Twenty-six patients with < 5% blasts on their nadir BM but with features concerning for residual leukemia did not undergo re-induction, and 23 (88.5%) of these patients achieved a CR. Only 3 patients with RD did not undergo re-induction, and none of these patients achieved a CR. Conclusions: Obtaining < 5% blasts on the nadir BM had 92.0% sensitivity in predicting a CR. However, ≥ 5% blasts on the nadir BM had only 38.1% specificity in predicting the failure of achieving a CR. Due to the toxicity associated with AML treatment, better criteria for identifying pathologically occult residual leukemia are urgently needed to help determine which patients need re-induction.
Abstract P323: Urinary Sodium and Potassium Excretion in Relation to Risk of Stroke in Japanese Men and Women: The Circulatory Risk in Communities Study (CIRCS)
Authors: Renzhe Cui, Kazumasa Yamagishi, Hironori Imano, Tetsuya Ohira, Takeshi Tanigawa, Masahiko Kiyama, Takeo Okada, Akihiko Kitamura, Hiroyasu Iso
Journal: Circulation (2016)

Background: Limited evidence is available on the association of urinary sodium and potassium excretion and risk of stroke in population samples of Japanese. Method: A total of 1,403 Japanese men and women aged 40 to 79 years with no history of cardiovascular disease at baseline survey, whose was measured 24-hour urinary excretion of sodium and potassium in the Circulatory Risk in Communities Study (CIRCS). Results: During the median 11.1-years of follow-up, we documented 62 incident strokes and 87 incident cardiovascular disease (stroke and coronary heart disease). The age-adjusted risks of stroke and total cardiovascular disease were higher among persons in the highest tertile of urinary sodium excretion compared with those in the lowest tertile (9.0g/day). These associations did not change substantially after adjusting for cardiovascular risk factors. There were no associations of the urinary potassium excretion with risk of stroke and cardiovascular disease. The respective multivariable hazard ratios (HRs, 95%CI) of stroke and total cardiovascular disease for highest tertile of urinary sodium excretion were 2.06(1.08-3.96) and 1.90(1.09-3.24). For urinary potassium excretion, the corresponding HRs was 1.09(0.51-2.34) and 1.45(0.85-2.49), respectively. Conclusions: Higher excretion of urinary sodium was associated with higher risk of stroke and total cardiovascular disease in general Japanese men and women.