tbuckley/cabot-search huggingface dataset:
Clinical outcome of Russian HER2-positive breast cancer patients with brain metastases: Retrospective review.
Authors: L.G. Zhukova, E. Lubennikova, I. Ganshina, A. H. Bekyashev, E. Kobyakova, E. Moskvina, E. Vetlova, K Zeynalova
Journal: Journal of Clinical Oncology (2018)

e13025 Background: HER2 amplification/overexpression is a prognostic and predictive factor for the development of breast cancer (BC) metastases to central nervous system. Anti-HER therapy improve overall survival (OS) in HER2-positive patients with brain metastases (BM). Treatment results in Russian population were analyzed. Methods: 64 patients with BM of HER2+ BC (I stage – 6,3%, II – 40,6%, III – 32,8%, IV – 20,3%), treated in National Medical Cancer Research Center from 2002 to 2014 were included in this retrospective review. Median age at the time of BM diagnosis was 49,9 years (range: 27-78), at the time of primary BC diagnosis – 46 years (range: 26-76). Previously treatment with anti-HER agents (trastusumb/lapatinib) was given to 73,4% of patients (trastuzumab only – 87,2%, trastuzumab and lapatinib sequentially – 12,8% ). Only BM as metastatic site was detected in 10,9% (n = 7) of cases. Results: As the first site of recurrence BM were detected in 26,6% (n = 17) with the median time to BM 16,4 mos. The median time from primary BC diagnosis to BM was 31,3 months. Median time from mBC to BM was 10,5 mos and significantly correlated with anti-HER therapy: 16,3 mos in patients received trastuzumab vs 9,5 mos in group without antiHER treatment (p = 0,007). Median OS HER2+BC patients after BM detection was 5,2 months. Survival was depends on treatment options and was significantly better in patients received anti-HER therapy: 25,3 mos vs 5,24 mos for patients never received or 2,1 mos for patients who stopped anti-HER therapy after BM diagnosis (р < 0,001). Combined treatment, including local methods (surgery or/and radiosurgery) and anti-HER treatment (n = 14) allowed to increase median OS up to 31,5 months. Conclusions: Our data supports the continued use of HER2-targeted therapy after BM diagnosis. Combined aproach of systemic therapy, including anti-HER agents, and local treatment to BM, provided best results.
A quarter of people are not being active enough to stay healthy
Authors: Jacqui Thornton
Journal: BMJ (2018)

More than a quarter of the world’s adult population—1.4 billion people—are at risk of disease from not doing enough physical activity, a study has found.

Researchers from the World Health Organization found that the highest rates of insufficient activity in 2016 were in adults in Kuwait (67%), American Samoa (53%), Saudi Arabia (53%), and Iraq (52%), where more than half of people do not do enough to stay healthy.1 Around 40% of adults in the United States, 36% in the United Kingdom, and 14% in China were insufficiently active, putting them at greater risk of cardiovascular disease, type 2 diabetes, dementia, and some cancers.

Countries with the lowest rates of insufficient physical activity in 2016 were Uganda and Mozambique (6% each).

The study, …
Serial measurements of myeloid derived suppressor cells (MDSC) in metastatic urothelial carcinoma (mUC) patients (pts) treated with immune checkpoint inhibitors (CI).
Authors: Moshe Chaim Ornstein, C. Marcela Diaz-Montero, Patricia A. Rayman, Paul Elson, Samuel Haywood, Jin Sub Kim, Paul G Pavicic, James Finke, Brian I. Rini, Jihad Kaouk, Marcelo Lamenza, Priscilla Dann, Kim Schach, Sarah Devonshire, Jennifer S Ko, Georges-Pascal Haber, Marc S. Ernstoff, Christopher J. Hoimes, Jorge A. Garcia, Petros Grivas
Journal: Journal of Clinical Oncology (2017)

e16005 Background: MDSC are a heterogeneous population of immunosuppressive cells with potentially predictive implications in UC pts receiving CI. We hypothesized that MDSC populations may change after CI exposure. Methods: Serial peripheral blood samples were collected from mUC pts treated with CI. MDSC were measured in fresh unfractionated whole blood (WB) and in peripheral blood mononuclear cells (PBMC). MDSC were identified by flow cytometry in WB and defined as LinloCD33+/HLADR- [(T)otal MDSC]. MDSC subsets were defined as (G)ranulocytic (CD15+CD14-), (M)onocytic (CD15-CD14+), (I)mmature (CD15-CD14-), or CD11b+. MDSC populations were presented as % of live nucleated blood cells and as absolute numbers from WB. The Wilcoxon signed rank and rank sum tests were used to assess changes in MDSC populations while on CI. Results: 17 pts treated with CI (9 atezolizumab [A], 8 pembrolizumab [P]) had ≥ 2 MDSC samples for analysis. Median age at diagnosis was 71 (46-81), 12 men, 29% never smokers; 53% / 29% / 18% ECOG PS 0/1/2 and 59% visceral metastasis at the time of 1 st sample collection. 10 pts received CI as 1st line therapy (Tx) in metastatic setting; 7 pts received chemotherapy as 1st-line Tx for mUC (6 platinum-based, 1 docetaxel) and CI as 2nd-line Tx. In 16 pts with samples before 1 st dose, there was a relative decrease (median 36.3%, range -59.7 to +21.2) in PBMC % I-MDSCs between 1st and 2nd samples (p=0.06). Interestingly, PBMC %M-MDSC and %I-MDSC tended to increase compared to baseline in pts treated with P, while they tended to decrease in pts treated with A (Table). Conclusions: In this cohort of pts with mUC treated with CIs,MDSC changes differed based on CI (anti-PDL1 or anti-PD1). Further study in larger cohort with various prior Tx lines and longer follow up as well as correlations with Tx response, toxicity and outcomes are ongoing. [Table: see text]
Therapeutic outcomes in non-small cell lung cancer with BRAF mutations: A single institution, retrospective cohort study.
Authors: Irena Tan, Tom Stinchcombe, Neal E. Ready, Michael B. Datto, Rebecca J Nagy, Lin Gu, Jeffrey Melson Clarke
Journal: Journal of Clinical Oncology (2018)

e21222 Background: Data describing therapeutic outcomes in patients with non-small-cell lung cancers (NSCLC) harboring BRAF alterations remains limited. Methods: A retrospective cohort study was conducted based upon 37 patients with NSCLC who were treated at Duke University Hospital and had been identified by tissue and/or plasma next-generation sequencing methods to harbor a BRAF mutation or amplification. Results: The mean age was 64 years old, 84% of whom were Caucasian, and 70% of whom were current or former smokers. 92% of cancers were adenocarcinomas by histology, and 81% were stage IV at time of diagnosis. 16 patients had a BRAF V600E mutation, 16 patients had a non-V600E mutation, and 5 patients had a BRAF amplification. Investigator-assessed median progression-free survival (PFS) in the 26 patients who received first-line chemotherapy was 6.2 months (95% CI 2.8 to 10.6) compared to 1.3 months (95% CI 0.1 to 4.3) in the three patients who received first-line immunotherapy (hazard ratio (HR) of 0.20; 95% CI 0.05 to 0.74, p < 0.01). Overall survival (OS) in first-line chemotherapy was 19 months (95% CI 10.0 to 34.9) compared to 9.9 months (95% CI 0.7 to 9.9) in first-line immunotherapy (HR of 0.29; 95% CI 0.06 to 1.42, p = 0.11). Median PFS in second-line chemotherapy (n = 2) compared to second-line immunotherapy (n = 8) was 9.1 months compared to 2.5 months, and median PFS in third-line chemotherapy (n = 5) compared to third-line immunotherapy (n = 3) was 5.3 months compared to 0.4 months. We did not find a statistically significant difference in OS in patients with BRAF V600E, BRAF amplification, or non-V600E mutations (18.4 months vs 19.0 months vs 30.9 months, respectively, p = 0.77). There was also no difference in OS in patients not treated with targeted BRAF inhibitors (n = 28) compared to those who were treated with targeted BRAF inhibitors (n = 7), with median OS of 19.0 months compared to 18.4 months (p = 0.37). Conclusions: Although the sample size was small, the survival curves are suggestive of limited clinical activity with immunotherapy in this patient population.
A novel correlation between KIT promoter DNA methylation and prognostic of gastrointestinal stromal tumors.
Authors: Haibo Qiu, Wei Zhuang, Xueding Wang, Min Huang, Zhiwei Zhou
Journal: Journal of Clinical Oncology (2018)

e23514 Background: Aberrant DNA methylation level were found that associated with aggressiveness of GIST and may potentially serve as biomarkers for predicting aggressive GISTs with poor survivability. To investigate epigenotype events in GIST, we performed KIT promoter DNA methylation detection and evaluated correlations between DNA methylation and prognosis in GIST patients. Methods: A set of 47 GIST patients obtained from Sun Yat-Sen University Cancer Center in Guangzhou, China, were included in this study. A total 935 bp length of KIT promoter and first exon 1 were analyzed (chr4:54657211-54658145) by MassCLEAVE (Agena) technology to quantify the methylation status in tumor tissue and paired normal tissue. E2F1 knock down by siRNA, KIT mRNA level was detected by Q-PCR and cell proliferation was detected by CCK-8. Results: The mean KIT DNA methylation and most of CpG sites of tumor tissue were significant lower than paired normal tissue in GISTs carried KIT mutation, but not in wild type GISTs. And -212 CpG site was associated with PFS (P= 0.006). 39, 100, 164 CpG sites and mean of promoter were significantly associated with recurrent risk and metastasis (P< 0.05). And online transcription factor prediction (Alggen.lsi.upc.es) predict that E2F1 could bind the several CpG sites in KIT promoter. E2F1 knock down could decreased the proliferation and KIT mRNA level in GIST-T1 and GIST882 cell lines. KIT might be regulated by E2F1, and in tumor conditions this pathway is aggravated through de-methylation in specific CpG site. But more evidence should be investigated. Conclusions: KIT DNA methylation specific CpG site could be supplementary biomarker for GIST prognosis. E2F1 might be a crucial transcription factor in GIST progression.
Association between efficacy of immunotherapy and rate of cancer progression at the time of initiation of immunotherapy: An analysis in metastatic non-small cell lung cancer (NSCLC).
Authors: Thiru Prasanna, Malmaruha Arasaratnam, Adnan Nagrial, Catriona M. McNeil, Rebecca Asher, Megan Barnet, Michael J. Boyer, Steven Chuan-Hao Kao
Journal: Journal of Clinical Oncology (2018)

e21225 Background: Despite improvements in survival with treatment using single agent Programmed Cell Death Protein-1 inhibitors (PD1i) in second and subsequent line setting for metastatic NSCLC, a significant proportion of patients(pts), even when selected based on PD-L1 expression, do not respond. We investigated the impact of rate of disease progression(ROP) prior to the commencement of PD1i on the efficacy of PD1i. Methods: Retrospective data of pts with metastatic NSCLC, who have failed prior systemic therapy, and treated with either nivolumab or pembrolizumab during the period 1/2014 and 5/2017 were collected. The ROP was calculated based on the two most recent scans prior to PD1i therapy (ROP = 100 * (V2-V1)/V1 / t2-t1). Pts were divided into 3 groups according to the ROP (%increase per day) before the initiation of PD1i: slow ( < 0.5), moderate (0.5-1.0) and rapid ( > 1.0 % increase or new lesions). Results: 74 patients were included; median age was 66 years, adeno ca 72%, EGFR/ALK/ROS1 15%, and KRAS 9%. Most had an ECOG performance status of 0-1 (89%). Majority have received 2 or more lines of prior systemic therapy, while 39% had 1 line of prior therapy. Median follow-up was 11.5 months. There were 33 deaths and 55 progressions. On a multivariate analysis, compared to those with slow progression, rapid progression at the time of initiation of PD1i was significantly associated with worse progression-free survival (1.7 v 5.4 months, HR 2.36; 95% CI 1.32-4.19, p = 0.01), overall survival (5.6 v 18.7 months, HR 2.73; 95% CI 1.27-5.90, p = 0.04) and numerically lower response rates (17% v 40%). Presence of a targetable mutation was an additional independent predictor of outcome. Conclusions: Outcomes from PD1i may be associated with ROP immediately prior to the commencement of PD1i, with worse outcomes in patients with rapid progression. ROP at the time of initiation of PD1i is a readily available parameter, which may provide useful information regarding potential clinical outcomes and should be included for analysis in future randomised trials.
A multidisciplinary toxicity team for cancer immunotherapy-related adverse events.
Authors: Jarushka Naidoo, Laura Cappelli, Evan J. Lipson, Patrick M. Forde, William Howard Sharfman, Jiajia Zhang, Jenna Mammen, Kendall Moseley, Karthik Suresh, Seema Mehta, Inbal Sander, John Probasco, Alyssa Parian, Rosanne Rouf, Meghan Berkenstock, Patricia Brothers, Joanne Riemer, Leisha A. Emens, Clifton O. Bingham, Julie R. Brahmer
Journal: Journal of Clinical Oncology (2018)

6538 Background: Immune checkpoint inhibitors (ICI) cause immune-related adverse events (irAEs). The spectrum of irAEs requiring referral to non-oncology specialists has not been well described. We established an immune-related toxicity (IR-Tox) team of oncology (n = 8) and medical subspecialists (n = 20), to support multidisciplinary irAE diagnosis and management. Methods: Patients (pts) treated with ICIs were electronically referred to the IR-Tox team between 01/2017-03/2018. IR-Tox team met monthly to discuss complex irAEs, and identify areas of clinical need. Pt demographics, treatment, and irAE details were collected. Pt features and irAE associations were analyzed using Chi-square tests. Results: The IR-Tox Team received 92 referrals for 80 pts (outpt: 61%, inpt: 39%). Median age was 65 years (range: 21-91), 55% were male, and 14% had prior autoimmune disease. Pts most commonly had non-small cell lung cancer (35%), melanoma (19%), or gynecologic malignancies (10%). Pts received ICI monotherapy (56%) or combination immunotherapy (44%), as standard-of-care (46%) or on clinical trials (54%). Referrals related to diagnosis (32%), management (11%), or both (51%) were received from faculty (68%), fellows (12%), and nurses (20%). Referrals were for suspected irAE (90%), pre-ICI assessment in known autoimmune disease (9%), or ICI re-challenge (1%). Sixty-three irAEs were confirmed (CTCAE grade 1 = 19%; 2 = 43%; 3+ = 38%), and 26 patients developed > 1 irAE (2 irAEs = 19, 3 irAEs = 7). IrAEs included pneumonitis (22%), arthritis (17%), dermatitis (13%), colitis/diarrhea (13%), idiopathic thrombocytopenia purpura (5%) hepatitis (5%) and thyroid dysfunction (5%). A new irAE of bony inflammation was identified (n = 2). Grade 3+ irAEs (p = 0.04) and colitis/diarrhea (p = 0.01) were more likely with combination immunotherapy. Medical specialty input was obtained in 85% of pts, and 35% required an invasive procedure for irAE diagnosis or management. Conclusions: Creation of an IR-Tox Team facilitated identification and management of complex irAEs. This new model provides a valuable forum to identify educational/service needs, manage multi-system irAEs, identify new irAEs, stratify irAE risk, and establish research collaborations.
Alterations in serum bilirubin during enasidenib treatment in patients with or without <i>UGT1A1</i> mutations.
Authors: Amir Tahmasb Fathi, Courtney Denton Dinardo, Irina Kline, Nora Tu, Eyal C. Attar, Eytan M. Stein, Stéphane de Botton
Journal: Journal of Clinical Oncology (2018)

e19003 Background: Enasidenib is a targeted inhibitor of mutant IDH2 (mIDH2) proteins. In a phase 1/2 study (NCT01915498) in patients (pts) with mIDH2 myeloid malignancies, 38% of pts had bilirubin elevations, likely due to off-target inhibition of UGT1A1 enzyme, which metabolizes bilirubin. A protocol amendment added UGT1A1 gene testing at screening. Homozygous UGT1A1 mutations (mUGT1A1) are associated with Gilbert Syndrome. Methods: Enasidenib doses ranged from 50 to 650 mg/day. Total blood bilirubin (TB) was assessed in all pts at baseline (BL) and at each site visit. Normal TB ranges varied among reference labs (~3-25 µmol/L). Results: As of Sept 2017, UGT1A1 data were available for 65 pts: 16 had homozygous mUGT1A1 (UGT1A1m/m), 27 had heterozygous mUGT1A1 (UGT1A1m/wt), and 22 had wild type UGT1A1 (UGT1A1wt). 60 pts received enasidenib 100 mg/d and 5 pts (UGT1A1m/m n = 2; UGT1A1m/wt n = 3) received > 100 mg/d. Mean TB at BL was similar among the 3 genotypes (Table). Pts with UGT1A1m/m had more rapid TB increases during early treatment (Tx) vs the 2 other genotypes, followed by stabilization of levels; mean increases from BL indicated mild hyperbilirubinemia (~1.5 x ULN). Mean TB levels during Tx in pts with UGT1A1m/wt or UGT1A1wt were within normal range (Table). Indirect bilirubin increases followed similar patterns. AST or ALT increases to ≥3 x ULN during Tx were not more common in UGT1A1m/m pts (6%) than in UGT1A1m/wt (15%) or UGT1A1wt (14%) pts. Adverse events (AEs) were similar among genotypes though more pts with UGT1A1m/m or UGT1A1m/wt had grade 3 bilirubin events vs UGT1A1wt (13% and 11% vs 0%, respectively). Dose interruption or reduction due to increased TB was infrequent in pts with mUGT1A1 and none were reported for UGT1A1wt pts. Conclusions: These data suggest initial enasidenib dose restriction is not necessary for pts with UGT1A1 mutations; however, dose reductions for hyperbilirubinemia should follow the drug label. Clinical trial information: NCT01915498.Mean ±SD Total Bilirubin UGT1A1m/m N = 16 UGT1A1m/wt N = 27 UGT1A1wt N = 22 µmol/L BL 10.9 ±7.1 9.5 ±4.2 9.7 ±4.0 C1D15 27.9 ±21.0 18.4 ±9.0 16.1 ±6.7 C2D1 31.8 ±26.7 18.2 ±6.7 18.7 ±8.4 C2D15 28.4 ±14.0 22.9 ±10.4 20.0 ±8.8 C3D1 28.8 ±14.1 21.6 ±13.3 20.8 ±8.0 C4D1 29.3 ±14.3 21.9 ±16.2 22.3 ±9.1 C, cycle; D, day
Suggested reclassification strategy applied to intermediate and poor risk nonseminomatous germ cell tumors (NSGCT): A two-institution combined analysis.
Authors: Andrea Necchi, Gregory Russell Pond, Nicola Nicolai, Nabil Adra, Patrizia Giannatempo, Daniele Raggi, Nasser H. Hanna, Roberto Salvioni, Lawrence H. Einhorn, Costantine Albany
Journal: Journal of Clinical Oncology (2016)

4546 Background: IGCCCG risk classification is used since 1997 to allocate metastatic GCT patients (pts). Recently, its applicability and survival estimates have been called into question. Guidelines recommend 4 cycles of BEP or VIP for both intermediate (int) and poor risk disease. We sought to revisit the outcomes and treatments in a population of int and poor risk NSGCT from Indiana and INT Milano. Methods: Data on consecutive pts receiving first-line chemotherapy (CT) from 1990 to 2014 were collected. Kaplan-Meier method was used to estimate relapse-free survival (RFS) and overall survival (OS). Cox regression analyses were used to evaluate potential prognostic factors of RFS and OS in an univariable model. Forward stepwise selection was used to construct a multivariable (MV) model. A risk factor (RF) model was then constructed and compared with IGCCCG classification using the concordance statistics (CS). Results: 647 pts were identified; median age was 27 years (range 13-60), 115 had a mediastinal primary (PMNSGCT), 60 (9.3%) brain, 131 (20.3%) liver, and 37 (5.7%) bone metastases (mets). 437 (67.5%) had received BEP CT. RF in the MV model were PMNSGCT (HR = 3.23, 95% CI = 2.28-4.59), brain mets (HR = 2.29, 95% CI = 1.48-3.55), lung mets (HR = 1.75, 95% CI = 1.22-2.50) and age at diagnosis ( ≥ 30 vs < 30, HR = 1.67, 95% CI = 1.22-2.29). CS were improved based on the RF model compared to IGCCCG classification (RFS: 0.63 vs 0.58; OS: 0.65 vs 0.59). For int risk, there were no differences between 3 (n = 26) and 4 cycles BEP (n = 160) or BEPx3+EPx1 (n = 31) for both RFS (p = 0.31) and OS (p = 0.055). Conclusions: In this contemporary cohort, the outcomes of int risk NSGCT have improved compared to historical estimates. Many int risk pts would not require BEPx4 to attain a cure. Using new RF, improved risk stratification was observed, which gives further evidence that a reclassification of GCT is needed. N 2-yr RFS (95% CI) 2-yr OS (95% CI) IGCCCG Int 232 80.6 (74.8-85.3) 91.3 (86.5-94.4) IGCCCG Poor 415 56.0 (51.0-60.7) 74.5 (69.9-78.5) 0 RF 126 79.8 (71.5-85.8) 89.9 (82.8-94.1) 1 RF 294 72.5 (66.8-77.3) 86.2 (81.5-89.8) 2 RF 169 52.8 (44.8-60.1) 75.7 (68.2-81.6) ≥ 3 RF 58 27.2 (16.4-39.2) 42.4 (29.0-55.3)
TCT-665 Unselected use of ultrathin strut biodegradable polymer sirolimus-eluting stent versus durable polymer everolimus-eluting stent for coronary revascularization
Authors: Kyohei Yamaji, Thomas Zanchin, Christian Zanchin, Stefan Stortecky, Thomas Pilgrim, Dik Heg, Stephan Windecker, Lorenz Raber
Journal: Journal of the American College of Cardiology (2018)
Changes in clinical trial participation among adolescent and young adult (AYA) cancer patients from 2006 to 2013 in the United States.
Authors: Theresa Keegan, Dolly Penn, Qian Li, Brad Pollock, Marcio H. Malogolowkin, Theodore Wun, Helen M. Parsons
Journal: Journal of Clinical Oncology (2017)

e18037 Background: Stagnant outcomes for AYAs (15 to 39 years) with cancer are partly attributed to poor enrollment onto clinical trials. Initiatives have focused on increasing accrual, but changes at the population-level are unknown. We examined patterns of clinical trial participation over time in AYA cancer patients. Methods: We utilized medical record data from AYAs in two National Cancer Institute Patterns of Care Studies identified through the Surveillance, Epidemiology and End Results (SEER) Program. Among 1,358 AYAs diagnosed with non-Hodgkin lymphoma (NHL), Hodgkin lymphoma (HL), acute lymphoblastic leukemia (ALL), germ cell cancer, and sarcoma in 2006 and 3,560 AYAs diagnosed with NHL, HL, ALL, sarcoma, and breast cancer in 2012/2013, we used unconditional logistic regression to evaluate patient and provider characteristics associated with enrollment by year of diagnosis. Analyses were weighted to reflect the SEER populations and associations are summarized as adjusted odds ratios (OR) with 95% confidence intervals (CI). Results: From 2006 to 2012/2013, clinical trial participation increased from 14.8% to 17.9% among AYAs diagnosed with NHL, HL, ALL and sarcoma (p &lt; 0.0001), primarily due to increased participation among ALL patients (2006: 37.4%; 2012/2013: 42.3%). In 2012/2013, participation varied by type of cancer, with the highest among those with ALL and sarcoma (31.2%), followed by HL (9.4%), NHL (6.9%) and breast cancer (4.3%). In both study years, multivariate analyses demonstrated that younger patients and those treated by pediatric oncologists (OR = 3.5; CI: 2.6-4.7) were more likely to enroll onto clinical trials. Uninsured AYAs were less likely to enroll in 2006 but no association was observed in 2012/2013. Hispanic (OR = 0.5; CI: 0.4-0.6), Black (OR = 0.6; CI: 0.5-0.9) and Asian (OR = 0.4; CI: 0.3-0.6) AYAs were less likely to enroll in 2012/2013 but not 2006. Conclusions: Our study identified increasing overall clinical trial participation over time. Disparities in likelihood of participating for racial/ethnic minority groups increased suggesting the need to improve access to clinical trials for all racial/ethnic groups to improve care and outcomes.