bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sequenced circulating tumor (ct) DNA to detect the molecular landscape in advanced GIST.
Authors: Kelly Ciara Marie , D'Angelo Sandra P. , Dickson Mark Andrew , Gounder Mrinal M. , Keohan Mary Louise , Wheeler Samantha , Hasan Maysun , Berger Michael F. , Antonescu Cristina R. , Tap William D. , Chi Ping 
Published: March 2020

11036 Background: Molecular (mol) characteristics-guided precision therapy has well-established utility in GIST management. The GIST mol landscape is poorly represented by selective tumor biopsy (bx) material, especially in metastatic and treatment-refractory GIST. ctDNA can overcome some of the limitations of selective tissue bx specimens and provide comparable or greater mol information. ctDNA represents an emerging mol biomarker in advanced (adv) GIST. Methods: Next generation sequencing analyses (MSK-IMPACT or custom-capture GIST specific panel) were performed on ctDNA prospectively collected from patients (pts) with adv GIST. MSK-IMPACT was performed on tumor material (archival tissue or paired tissue bx specimens taken in parallel with ctDNA collection from clinical trial participants). The primary objective was to determine the concordance between the mol landscape of GIST identified by sequenced tumor tissue versus ctDNA. Secondary objective was to correlate characteristics of sequenced ctDNA with standard measurements of response assessment. Results: 47 ctDNA samples collected from 25 pts with adv GIST were sequenced using MSK-IMPACT ( > 400 genes). MSK-IMPACT was performed on archival tumor material. Sequenced ctDNA detected the mutational spectrum of tumor tissue in 48% of cases. In 50% of these cases, ctDNA identified novel treatment-resistance mutations not previously identified in the archival tissues. To optimize sensitivity of detection, a custom-designed GIST specific ctDNA sequencing panel was developed incorporating 19 of the most commonly altered genes observed from MSK-IMPACT analysis performed on > 75 imatinib-refractory adv GIST tumor samples. 52 ctDNA samples collected from 30 pts with paired tumor bx samples have been sequenced using the custom-capture GIST panel. The tumor bx samples have been sequenced using MSK-IMPACT. Results are pending and will be presented. A separate cohort of ctDNA samples serially collected in the setting of a prospective clinical trial are being sequenced. The mol results with correlated treatment response by RECIST will also be presented. Conclusions: ctDNA could detect a broad spectrum of mol heterogeneity and potentially be used as a biomarker to guide precision therapy in adv GIST. Further research is necessary to determine the optimal ctDNA sequencing assay and the appropriate clinical setting to utilize in GIST.
Impact of overweight, obesity, and post-treatment weight changes on occupational reintegration of breast cancer (BC) survivors.
Authors: Di Meglio Antonio , Menvielle Gwenn , Dumas Agnes , Gbenou Arnauld S. , Bovagnet Thomas , Martin Elise , Ferreira Arlindo R. , Vanlemmens Laurence , Arsene Olivier , Ibrahim Mahmoud , Wassermann Johanna , Martin Anne-Laure , Lemonnier Jerome , Del Mastro Lucia , Jones Lee , Partridge Ann H. , Ligibel Jennifer A. , Andre Fabrice , Michiels Stefan , Luis Ines Maria Vaz Duarte 
Published: March 2020

11562 Background: Overweight and obesity are strongly linked to poorer BC-specific outcomes, quality of life and financial burden in cancer care. Weight loss interventions have the potential to improve such outcomes. Fewer data exist on whether excess weight and post-diagnosis weight changes impact the ability of BC survivors to return to work (RTW). Methods: CANTO (NCT01993498) is a multicenter prospective longitudinal study of 12000 patients (pts) with stage I-III BC that characterizes long-term toxicities of BC treatment. Of 5801 pts enrolled from 2012-2014 (last data lock), we identified 1874 pts who were professionally active at BC diagnosis, ≥5 years (yrs) younger than minimum legal retirement age (62 yrs) and with updated work status 2 yrs after diagnosis. Logistic regression models evaluated the impact of body mass index (BMI) at diagnosis and of weight changes over 2 yrs after diagnosis on odds of non-RTW, adjusting for age, education, income, BC treatment and recreational physical activity (PA). Results: 37% pts were overweight or obese at diagnosis (BMI ≥25 kg/m2): 34% of them gained ≥5% and 16% lost ≥5% weight after diagnosis. Rates of non-RTW at 2 yrs were significantly higher in overweight or obese vs under or normal weight pts (27% vs 18%, p≤.001; adjusted odds ratio 1.37, 95% Confidence Interval [CI] 1.04-1.80, p = .017). Overweight and obese pts who did not RTW experienced higher increments in weight (mean [95% CI]: +3.6% [+2.3, +4.9] vs +1.5% [+0.8, +2.2]) and reported more modest changes in PA (mean [95% CI]: +1.0 [-1.4, +3.5] vs +2.1 [+0.8, +3.3] MET-h/week) vs those who did RTW. Weight changes independently impacted odds of non-RTW in overweight and obese pts (p for interaction weight change*BMI ≤.001): a 5% weight gain was associated with 17% increase in adjusted odds of non-RTW (95% CI 2-35%, p = .024), whereas a loss ≥5% with 60% reduced odds of non-RTW vs weight gain (95% CI 18-82%, p = .013). Conclusions: Excess weight and weight changes are significantly associated with occupational reintegration after BC in overweight and obese pts. Randomized studies testing dedicated weight control interventions should also measure outcomes of social rehabilitation in this large subset of survivors. Clinical trial information: NCT01993498.
Second solid (SMN) and hematologic malignant neoplasms (HMN) among 24,900 United States testicular cancer survivors (TCS) after chemotherapy (CHEM), radiotherapy (RT), or surgery only (SURG).
Authors: Abu Zaid Mohammad Issam , Milano Michael T. , Dinh Paul C , Fosså Sophie , Yang Hongmei , Feldman Darren R. , Travis Lois B. , Fung Chunkit 
Published: March 2020

11573 Background: No large, population-based U.S. study has comprehensively examined SMN and HMN risks after TC, taking into account initial therapy and focusing on recent decades. Methods: Standardized incidence ratios (SIR) for SMN and HMN stratified by site and time since TC diagnosis were calculated for 24,900 TCS (median age, TC diagnosis: 33 y) reported to population-based cancer registries in the NCI SEER program (1973-2014). TCS were initially given CHEM (n=6,340), RT (n=9,058), or SURG (n=8,995), with each group accruing 80,700, 156,735, and 128,039 person-years (PY) of follow-up, respectively. Results: During 372,709 PY of follow-up, 1,625 TCS developed SMN and 228 developed HMN, including 107 lymphomas, 92 leukemias, and 29 plasma cell dyscrasias. Among all TCS, overall risk of SMN was increased by 1.06-fold (95% CI 1.01-1.1). Risks of SMN were increased after RT (SIR 1.1, 95% CI 1.06-1.2) and CHEM (SIR 1.3, 95% CI 1.1-1.4); but not after SURG (SIR 0.8). After CHEM, significant excesses of SMN of the pancreas (SIR 2.2), soft tissue (SIR 4.0), kidney (SIR 1.7), thyroid (SIR 3.3) occurred; after RT, significantly elevated risks for SMN of the stomach (SIR 1.7), rectum/sigmoid (SIR 1.4), pancreas (SIR 2.7), soft tissue (SIR 2.2), bladder (SIR 1.5), and thyroid (SIR 2.0) were observed. The 30 year cumulative incidence of SMN after SURG, CHEM, and RT was 8.9% (95% CI 7.8-9.9), 10.1% (95% CI 8.8-11.5) and 17.0% (95% CI 15.8-18.2), respectively. Significantly increased risks of leukemia followed CHEM (SIR 2.7) and SURG (SIR 1.8) and were driven by increased risks for acute myeloid leukemia, with significant excesses restricted to 1-10 y and 1-5 y after TC diagnosis, respectively; nonsignificant 2-fold excesses occurred 1-10 y after RT. Risks for lymphoma and plasma cell dyscrasias were not elevated (1.02 and 1.27, respectively). Conclusions: In the largest population-based study of U.S. TCS to date, we report significant 6% excesses of SMN and 2-fold increased risks of leukemias. Efforts to minimize CHEM exposure and decrease doses/field size of RT in TC should continue. TCS should be educated about cancer prevention and screening.
Preemptive versus reactive topical clobetasol for regorafenib-induced hand-foot reactions: Results from the ReDOS trial.
Authors: Jatoi Aminah , Ou Fang-Shu , Ahn Daniel H. , Boland Patrick McKay , Ciombor Kristen Keon , Jacobs Nisha Lassi , Pasche Boris , Cleary James M. , McCune Jeannine S. , Pedersen Katrina , Barzi Afsaneh , Chiorean E. Gabriela , Heying Erica N. , Lenz Heinz-Josef , Sloan Jeff A. , Lacouture Mario E. , Grothey Axel , Bekaii-Saab Tanios S. 
Published: March 2020

11586 Background: Hand-foot skin reaction (HFSR) is the most common regorafenib adverse event. However, no intervention has demonstrated efficacy in preventing or palliating this adverse event, short of modulating the regorafenib dose. Methods: The Regorafenib Dose Optimization Study (ReDOS) was a randomized trial ( https://clinicaltrials.gov/ct2/show/NCT02368886 ); here we describe an a priori secondary analysis of ReDOS with the goal of assessing whether clobetasol 0.05% cream (a potent corticosteroid) applied to the palms and soles twice per day is more effective when prescribed pre-emptively (before the development of HFSR) versus reactively (after the development of HFSR). Patients were assessed during the 1st 2 cycles of regorafenib. Results: Among 116 evaluable patients, 61 received pre-emptive clobetasol, and 55 reactive clobetasol. Baseline demographics were comparable between groups. During the 1st regorafenib cycle, 46% and 52% of patients developed HFSR with pre-emptive and reactive clobetasol, respectively (p = 0.52). However, during the 2nd cycle, 56% (of 47 total patients) and 80% (of 41 total patients), developed this toxicity with pre-emptive and reactive clobetasol, respectively (p = 0.02). Of note, during the 2nd cycle, rates of grade 1,2, and 3 HFSR were 40%, 11%, and 4% (pre-emptive) and 45%, 25%, and 10% (reactive) (p = 0.07). A sensitivity analysis to examine rates of no HFSR over all 2 regorafenib cycles showed that no HFSR occurred in 33% (of 61 total patients) with pre-emptive clobetasol versus 15% (of 55 total patients) with reactive clobetasol (p = 0.02). Patient-reported outcomes showed HFSR compromised activities of daily living, including getting dressed, preparing meals, walking, and even driving, with seemingly worse descriptive outcomes in patients who received reactive therapy. No adverse events from clobetasol were reported. Conclusions: Compared to reactive therapy, pre-emptive topical clobetasol might lessen regorafenib-induced HFSR. Clinical trial information: NCT02368886.
Response to A+CHP by CD30 expression in the ECHELON-2 trial.
Authors: Advani Ranjana H. , Horwitz Steven M. , Iyer Swaminathan Padmanabhan , Bartlett Nancy L. , Kim Won Seog , Tilly Herve , Belada David , Feldman Tatyana , Illés Árpád , Jacobsen Eric D. , Huettmann Andreas , Zinzani Pier Luigi , O'Connor Owen A. , Trepicchio William L. , Miao Harry H. , Rao Shangbang , Onsum Matthew , Manley Thomas John , Illidge Tim 
Published: March 2020

7538 Background: Brentuximab vedotin (BV) is an antibody-drug conjugate that targets CD30. The ECHELON-2 (E-2) study demonstrated significantly longer progression-free and overall survival with BV plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus CHOP in frontline treatment of patients (pts) with CD30+ peripheral T-cell lymphoma (PTCL). Complete remission (CR) rate (A+CHP 68%; CHOP 56%) and objective response rate (ORR) (A+CHP 83%; CHOP 72%) were also significantly increased. Expression of CD30 is universal in systemic anaplastic large-cell lymphoma (sALCL) but variable among non-sALCL subtypes. As ORR is a direct measure of antitumor activity, we examined response to A+CHP by CD30 expression. Methods: Pts with CD30+ (≥10% by local review) PTCL were included in E-2. Eligible histologies included ALK+ sALCL (IPI ≥2), ALK− sALCL, PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), adult T-cell leukemia/lymphoma, enteropathy-associated T-cell lymphoma, and hepatosplenic T-cell lymphoma. We analyzed the relationship between CD30 expression (IHC Ber H2 antibody) above and below the median (median CD30=18% PTCL-NOS; 25% AITL) and CR rate, ORR, and duration of CR (DOCR) in pts with AITL and PTCL-NOS treated with A+CHP. Results: Most (26/29, 90%) AITL pts had CD30 expression between 10% and 30%. PTCL-NOS pts were more evenly distributed across levels of CD30 expression ranging from 10% to 100%. CD30 levels were neither predictive of response (Table) nor significantly associated with DOCR in pts with AITL (P=0.30) or PTCL-NOS (P=0.90) (log-rank test). Response by CD30 expression. Clinical trial information: NCT01777152. Conclusions: CD30 expression above vs below median (or at 10%) did not predict response to A+CHP in E-2 non-ALCL subtypes, as responses were seen across CD30 levels. This may be due to intra- and inter-tumoral heterogeneity of CD30 expression, limitations of IHC, the nature of CD30 on the cell surface, and multiple mechanisms of action of BV. Further evaluation of the expression-response relationship in PTCL pts with CD30 <10% is warranted.[Table: see text]
Neoadjuvant atezolizumab in resectable non-small cell lung cancer (NSCLC): Interim analysis and biomarker data from a multicenter study (LCMC3).
Authors: Kwiatkowski David J. , Rusch Valerie W. , Chaft Jamie E. , Johnson Bruce E. , Nicholas Alan , Wistuba Ignacio Ivan , Merritt Robert , Lee Jay M. , Bunn Paul A. , Tang Yan , Phan See-Chun , Waqar Saiama Naheed , Patterson Alexander , Haura Eric B. , Toloza Eric M. , Reckamp Karen L. , Raz Dan , Schulze Katja , Johnson Ann , Carbone David Paul 
Published: March 2020

8503 Background: Small pilot studies (e.g., N Engl J Med. 2018;378:1976) have shown that preoperative immune checkpoint inhibitor therapy may be of benefit in early-stage NSCLC. This large multicenter trial assesses the benefit of neoadjuvant treatment with atezolizumab (atezo; NCT02927301). Methods: Patients (pts) with stages IB to selected IIIB resectable NSCLC receive 2 cycles of atezo 1200 mg (days 1, 22) then undergo resection (day 40 ± 10). Primary tumor +/- node biopsies and blood samples are obtained before atezo and at surgery for biomarker studies. The primary endpoint is major pathological response (MPR), defined as ≤ 10% viable tumor cells in the resection specimen. Secondary endpoints include safety and correlation of response with PD-L1 expression, tumor mutation burden (TMB) and gene expression signatures. Results: For this interim efficacy analysis (5 Sep 2018 data cut), we report on the first 101 of 180 planned pts: 47 males, median age, 64 y; all ECOG PS 0-1; 23 current and 68 former smokers; 66 non-squamous NSCLC; clinical stages IB/IIA/IIB/IIIA/IIIB n = 11/16/28/39/7. There were 2 treatment-unrelated Gr 5 AEs (cardiac death post surgical resection; death due to disease progression), 29 Gr 3-4 AEs (6 [6%] treatment related). 90 pts had surgery. Excluding 8 pts who had driver mutations (7 EGFR, 1 ALK, no MPR), MPR rate was 15/82 (18%, 95% CI 11%-28%), 4 pts had pathological complete response (pCR). By RECIST, 6/82 pts had PR, 72 had SD and 4 had PD. Two of 26 (8%) PD-L1− (TC0 and IC0, clone SP142) and 10 of 35 (29%) PD-L1+ had MPR ( P= 0.055). Five of 44 (11%) TPS < 50 (PD-L1 clone 22C3) and 7 of 20 (35%) TPS > 50 had MPR ( P= 0.040). Exome sequencing data was available for 47/101 pts. Median TMB was 10.4 (range, 1.5-46.5) mutations per Mb and was not different in those with MPR compared with those without MPR. Further analysis of TMB, mutation signatures, and gene expression profiling is ongoing. Conclusions: Atezo in the neoadjuvant setting was well tolerated, and pCR and MPR rates are encouraging in this large multicenter trial. Efficacy interim analysis passed its futility boundary, and study enrollment continues. Safety, efficacy results and ongoing correlative analyses will be presented. Clinical trial information: NCT02927301.
Real-world experience and molecular features of response to immune checkpoint blockade in patients with recurrent small cell lung cancer.
Authors: Lai Wei-Chu Victoria , Rizvi Hira , Egger Jacklynn V. , Plodkowski Andrew J. , Ginsberg Michelle S. , Kris Mark G. , Beras Amanda , Rekhtman Natasha , Poirier John T. , Hellmann Matthew David , Rudin Charles M. 
Published: March 2020

8556 Background: Immune checkpoint blockade (ICB) is now a routine component of treatment in recurrent small cell lung cancer (SCLC). We evaluated the response to ICB in patients (pts) with recurrent SCLC and genomic features of response using next-generation sequencing (NGS). Methods: Pts with recurrent SCLC treated with ICB were identified. The majority of pts were treated outside of a clinical trial to focus emphasis on the real-world experience. Tumor mutation burden (TMB) and the landscape of somatic variants were determined by targeted NGS using MSK-IMPACT. Objective response rate (ORR) to ICB was determined using RECIST v1.1. PFS and OS were measured from the start of ICB and analyzed using Kaplan-Meier. Results: Between December 2013 and October 2018, 108 pts with SCLC were treated with ICB (57 subjected to NGS). Pts received PD-1 monotherapy alone (n = 28) or in combination with CTLA-4 blockade (n = 80). Median line of therapy was 2 (range 1-6). ORR was 14% (15/108, 95% CI 8-22%). From the start of ICB, median PFS was 1.4 months in non-responders and 10.8 months in responders (HR 0.2; 95% CI 0.13-0.32). Median OS was 6.3 months in non-responders and undefined in responders (range 8-44 months) (HR 0.26, 95% CI 0.16-0.44). Four responders remain on ICB treatment. TMB in the ICB-treated cohort was similar to that of an unselected cohort (n = 233) of SCLC (median 8.8 Mt/MB vs 8.2 Mt/MB, p = 0.71). Clinical benefit was enriched among those with a higher TMB (upper vs middle/lower tertile PFS HR 0.48, 95% CI 0.28-0.84, p = 0.01 and ORR 26% [5/19] vs ORR 8% [3/38]). Rates of whole genome duplication and commonly altered genes in SCLC ( TP53, RB1, KMT2C/D, NOTCH1/2/4, PTPRD, APC) were similarly distributed across responders and non-responders. Completion of whole-exome sequencing and PD-L1 testing is in progress. Conclusions: In pts with recurrent SCLC receiving routine clinical care, the ORR to ICB is comparable to reports from clinical trials. A high TMB was associated with a longer median PFS and better response. Further investigation into the genomic landscape of recurrent SCLC is needed to identify biomarkers predictive of response to ICB.
Using MALDI-TOF mass spectrometry for tracking of minimal residual disease in peripheral blood from patients with multiple myeloma.
Authors: Eveillard Marion , Rustad Even , Roshal Mikhail , Zhang Yanming , Ciardiello Amanda , Korde Neha , Hultcrantz Malin , Hassoun Hani , Smith Eric L. , Lesokhin Alexander M. , Mailankody Sham , Landgren Carl Ola , Thoren Katie 
Published: March 2020

e19525 Background: Minimal residual disease (MRD) negativity after completed therapy is associated with longer progression-free survival (PFS) in patients with multiple myeloma (MM). Current standard of care for MRD testing use flow cytometry and/or next generation sequencing (NGS)-based assays applied on bone marrow (BM) aspirate samples. To develop a strategy for MRD tracking in peripheral blood (PB), we were motivated to evaluate MALDI-TOF head-to-head with established bone marrow-based MRD assays. Methods: We used MALDI-TOF mass spectrometry to detect M-proteins in PB. Our cohort included patients who had serum samples available at 2 timepoints including during active disease and within 60 days of MRD results as determined by flow cytometry of BM aspirates. The cohort enrolled 71 patients (26 females, 45 males) with a median age of 61 years (37-78 years). Twenty-seven patients had high-risk cytogenetics at baseline. Patients were classified at diagnosis as ISS1 (n = 38), ISS2 (n = 18) or ISS3 (n = 6). The flow cytometry based MRD assay was performed using MSKCCs 10-color, single-tube method. MALDI-TOF analysis was performed as described by Mills et al. Samples taken during active disease were used to identify the mass/charge ratio of the M-protein at baseline and in follow-up samples. MALDI-TOF results were compared to flow cytometry bone marrow-based MRD results. Results: The median time between diagnosis and the MRD timepoint was 13.4 months (3.4-91 months). MALDI-TOF in PB and flow cytometry BM-based MRD results were concordant for 44/71 (62%) patients (8+/+, 36 -/- respectively) while 27 were discordant (10 +/-, 17-/+). Fifty-four of 71 patients were in complete response (CR) (45/54 in sCR) at the time of MRD. MALDI-TOF was still positive in 13 of these 54 CR patients. In this cohort, the median PFS since MRD assessment was not reached in the 2 subgroups of double negative patients (n = 31) or in patients with a positive result in at least one technique (n = 23) with a median follow-up of 11.2 months (0-34.6 months). Conclusions: In 44/71 (62%) samples, MALDI-TOF of PB results and flow cytometry BM-based MRD results were concordant. MALDI-TOF of PB may be useful for detecting measurable residual disease and for the monitoring of MM patients during maintenance therapy with the future goal to rule out early recurrent disease.
Inflammation Triggered by Saturated Fat Ingestion Is Linked to Insulin Resistance and Hyperandrogenism in Polycystic Ovary Syndrome
Authors: González Frank , Considine Robert V , Abdelhadi Ola A , Acton Anthony J 
Published: March 2020

AbstractContextInflammation and insulin resistance are often present in polycystic ovary syndrome (PCOS).ObjectiveWe determined the effect of saturated fat ingestion on mononuclear cell (MNC) nuclear factor-κB (NFκB) activation; NFκB, inhibitory-κBα (IκBα), and tumor necrosis factor-α (TNFα) gene expression; and circulating C-reactive protein (CRP) in women with PCOS.DesignCross-sectional study.SettingAcademic medical center.PatientsTwenty reproductive-age women with PCOS (10 lean, 10 with obesity) and 20 ovulatory controls (10 lean, 10 with obesity).Main Outcome MeasuresActivated NFκB, NFκB heterodimer subunits, IκBα and TNFα messenger ribonucleic acid content and NFκB p65 and IκBα protein content were quantified in mononuclear cells (MNC), and CRP was measured in plasma from blood drawn fasting and 2, 3, and 5 h after saturated fat ingestion. Insulin sensitivity was derived from oral glucose tolerance testing (ISOGTT). Androgen secretion was assessed from blood drawn fasting and 24, 48, and 72 h after human chorionic gonadotropin (HCG) administration.ResultsIn response to saturated fat ingestion, women with PCOS regardless of weight class exhibited lipid-induced increases in activated NFκB, NFκB, and TNFα gene expression and plasma CRP and decreases in IκBα protein compared with lean control subjects. Both PCOS groups exhibited lower ISOGTT and greater HCG-stimulated androgen secretion compared with control subjects. Lipid-stimulated NFκB activation was negatively correlated with ISOGTT, and positively correlated with HCG-stimulated androgen secretion.ConclusionIn PCOS, increases in NFκB activation and circulating CRP and decreases in IκBα protein following saturated fat ingestion are independent of obesity. Circulating MNC and excess adipose tissue are separate and distinct contributors to inflammation in this disorder.