tbuckley/cabot-search huggingface dataset:
Selumetinib (Sel) and cisplatin/gemcitabine (CisGem) for advanced biliary tract cancer (BTC): A randomized trial.
Authors: Mark Doherty, Vincent C. Tam, Mairead Geraldine McNamara, David W. Hedley, Neesha C. Dhani, Eric Xueyu Chen, Raymond Woo-Jun Jang, Patricia A. Tang, Hao-Wen Sim, Grainne M. O'Kane, Stephanie DeLuca, Lisa Wang, Kelly Brooks, Jennifer J. Knox
Journal: Journal of Clinical Oncology (2018)

4084 Background: Sel (AZD6244, ARR142886) is an oral MEK inhibitor, with preclinical evidence of synergy with Gem in BTC. CisGem is standard first-line treatment for advanced BTC. This trial assessed the efficacy of Sel in continuous or sequential combination with CisGem in first-line advanced BTC. Methods: This randomized multicentre phase II trial (NCT02151084) enrolled patients (pts) with advanced cholangiocarcinoma (CC) or gallbladder cancer (GBC). CisGem was given at standard doses. Sel started at 75mg BID, daily (continuous – Arm A) or day 1-5, 8-19 every 21 days (sequential – Arm B). Arm C was CisGem alone. Sel starting dose was reduced to 50mg BID for toxicity concerns after 32 enrolled pts (protocol amendment). Primary endpoint was % change in RECIST tumor size of 48 evaluable pts: Arm A or B vs Arm C at 10 wks. Secondary endpoints: PFS, OS, ORR, disease control rate (DCR) and toxicity. Results: 57 pts were enrolled: 29 female; 22 intrahepatic CC, 16 extrahepatic CC and 19 GBC. Baseline characteristics were similar across arms. Mean change in tumor size was not significantly different between either Sel arm and the control arm (Arm A p = 0.37, Arm B p = 0.53 [Table]). There were no significant differences in other efficacy endpoints. Toxicities appeared more frequent in Arm A; dose intensity of Gem and Sel were lower. More pts in Arms A and B stopped treatment due to toxicity than Arm C. Conclusions: Adding Sel to CisGem failed to improve tumor response at 10 wks, or prolong survival, but added toxicity and led to lower dose intensity. Exploration of biomarkers may identify a group deriving benefit, but it should not be studied further in unselected BTC. Clinical trial information: NCT02151084. Arm A (N = 19) Arm B (N = 19) Arm C (N = 19) overall p-value Mean % change in tumor size at 10 wks (95% CI) -7.3 (-24.3,+9.7) -16.3 (-26.2,-6.4) -13.2 (-25.2,-1.3) 0.80 ORR (%) 36 29 29 0.91 DCR (%) 86 88 88 0.95 Median PFS (months) 6.0 6.6 6.4 0.58 Median OS (months) 10.9 14.8 12.7 0.76 Treatment discontinuation reason Disease progression 7 7 13 Toxicity 4 6 0 Death 0 0 2 Withdrawn consent 1 3 1 Non-protocol surgery 0 1 0 Toxicity Events (Grade [G]) G 3 63 52 40 G 4 8 13 10 G 5 2 1 0 Non-hematologic G3-5 55 34 34 Relative Dose Intensity C1-3, % Cis 92.2 94.5 93.2 0.21 Gem 85.7 93.8 94.1 0.10 Sel 74.1 85.6 - 0.28
P05.85 Mismatch repair system and immune-checkpoints profile in brain metastasis: study of 65 patients
Authors: M Patanè, C Calatozzolo, M Farinotti, F C Cacciatore, A Silvani, E Anghileri, F DiMeco, B Pollo
Journal: Neuro-Oncology (2018)

Brain metastases (bMTS) represent the most common intracranial tumors occurring in 10–20% of patients with cancer. Despite several therapeutic approaches, patients continue to face a dismal prognosis. Immunotherapies could represent a promising challenge to improve the prognosis. Immune checkpoints (PD-L1/PD-1, CTLA-4/CD80 and CD28) are negative regulators of T-cells and the inhibition of this pathway could activate the intrinsic immune response against tumor. FDA has recently approved Pembrolizumab, a PD-1 inhibitor, for metastatic solid tumors displaying mismatch-repair system (MMR) deficiency. The MMR system allows the repair of DNA mismatches during replication and consists of two heterodimers: MSH6/MSH2 and PMS2/MLH1. Mutations in MMR genes are associated to higher risk of developing cancers, but the high rate of acquired somatic mutations generates the exposure of neoantigens activating immune response. To investigate the occurrence and the role of MMR deficiency in bMTS, we have performed an immunohistochemical analysis (IHC) on 65 bMTS from lung, breast, colon, kidney cancers and melanomas to evaluate the expression of MMR proteins (MSH6, MSH2, PMS2, MLH1) and immune checkpoints (PD-L1, CTLA-4 and CD28). We have also characterized infiltrating lymphocytes and myeloid cells by IHC for CD3, CD4, CD8, CD20, CD68, CD163 and Iba1 expression. All results obtained have been related to clinical data. We have found a loss of expression of MMR proteins (mostly PMS2 and MLH1) in 40% of patients, significantly related to a worst prognosis. The 20% of cases showed overexpression of PD-L1 on tumor cells, while CTLA-4 and CD28 were mainly expressed in infiltrating lymphocytes. The expression of these markers was mainly related to MMR protein loss, especially in bMTS derived from lung cancer. Many bMTS showed high presence of infiltrating lymphocytes and microglia, both in the tumor mass and surrounding parenchyma, not strictly related to MMR loss expression, but linked to a good prognosis. In our study we proposed that it is possible to define the MMR status and the immunological profile of bMTS with an IHC analysis, and this study confirmed that MMR evaluation by IHC could be also used to assess quickly microsatellites instability in bMTS avoiding further expensive analysis. This method could provide an early prognostic panel useful for the clinicians, and these data may suggest which patients could be good candidates for immunotherapy.
Differences between Japan and rest of world (ROW) in disease presentation and outcome of previously treated adult t-cell leukemia-lymphoma (ATL) using therapy with a monoclonal antibody to CCR4, mogamulizumab (moga).
Authors: Adrienne Alise Phillips, Steven M. Horwitz, Graham P. Taylor, Jeffrey S. Humphrey, Kensei Tobinai, Takashi Ishida, Ryuzo Ueda
Journal: Journal of Clinical Oncology (2016)

e19056 Background: ATL, a rare but aggressive peripheral T-cell malignancy caused by HTLV-1, occurs more frequently in regions where HTLV-1 infection is endemic and may differ by geographical location. Two recent trials of moga for previously treated ATL in Japan and ROW enable comparison of disease presentation and outcomes in endemic and nonendemic regions. Methods: Study 0761-002 (NCT00920790) enrolled 28 relapsed CCR4+ ATL subjects in Japan. Study 0761-009 (NCT01626664) enrolled 71 relapsed or refractory ATL subjects in the USA, EU, and Latin America of whom 47 received moga. All subjects received moga 1 mg/kg weekly x 4 weeks. After 4 weeks, subjects in Japan received weekly moga for 4 more weeks; in ROW, subjects received additional moga every other week thereafter until progression. Objective Response Rate (ORR) was assessed by independent review (by modified Tsukasaki criteria). Results are from Clinical Study Reports. Results: Demographically, the main difference was ethnicity: 100% Japanese in 0761-002; 2/47 (4.3%) Asian in 0761-009. ROW subjects presented with more prior treatment (tx), worse performance status (PS), and higher prevalence of lymphoma subtype. CCR4 was expressed in > 90% of subjects in both regions. ORR to moga was lower in ROW than Japan (23% vs 50%). In terms of AEs (tx-emergent, drug related), for ROW vs Japan the infection rates were similar (15% vs 19%, respectively) but there were fewer infusion reactions (47% vs 89%) and less rash/drug eruptions (26% vs 52%). Conclusions: Different ATL outcomes in Japan vs ROW were associated with differences in initial disease presentation (ROW subjects had more lymphoma subtype, prior therapy, refractory disease and worse baseline PS) and trial methodology. Further characterization of ATL in ROW will help interpret results between regions. Clinical trial information: NCT01626664. Baseline Characteristics 0761-002 N = 27 (safety cohort) 0761-009 N = 47 Lines of prior tx: median (range) 1 (1-3) 2 (1-6) CR/PR rate to immediate prior tx 100% 26% ECOG PS 0/1/2 (%) 56/26/19 26/34/40 ATL Subtypes: Acute/Lymphoma/Chronic (%) 52/22/26 32/55/13 Expression of CCR4 100% 91.5%
Risk of infectious, hematological, and gastrointestinal side effects in patients treatedwith ibrutinib: A systematic review and meta-analysis of randomized controlled trials.
Authors: Myo Zaw, Kyaw Zin Thein, Aung Tun, Lukman Tijani, Elizabeth Guevara
Journal: Journal of Clinical Oncology (2017)

e18265 Background: Bruton’s tyrosine kinase (BTK) is essential for signaling of B-cell and chemokine receptors. Ibrutinib targets BTK and has become frontier in many hematologic malignancies. We undertook systematic review and pooled analysis of randomized controlled trials (RCTs) to determine infectious, hematological and gastrointestinal risks associated with ibrutinib. Methods: We performed a comprehensive literature search using MEDLINE, EMBASE databases and meeting abstracts through December 31, 2016. The RCTs that mention infectious, hematological and gastrointestinal side effects as adverse effects were incorporated in the analysis. Mantel-Haenszel method was used to calculate the estimated pooled risk ratio with 95% confidence interval (CI). Results: Four RCTs with a total of 1505 patients were eligible for the analysis. Studies compared Ibrutinib (I) vs ofatumumab, I vs chlorambucil, I+ bendamustine (B)+ rituximab (R) vs placebo + B+ R and I vs temsirolimus were included in the analysis. The relative risks (RR) of all-grade side effects were as follows: infection, 1.34 (95% CI: 1.04 – 1.74; p = 0.02); pneumonia, 1.16 (95% CI: 0.82–1.66; p = 0.38); anemia, 0.77 (95% CI: 0.64 – 0.93; p = 0.007); neutropenia, 0.99 (95% CI: 0.87 – 1.14; p = 0.98); thrombocytopenia, 0.86 (95% CI: 0.71 – 1.04; p = 0.12); diarrhea, 1.74 (95% CI: 1.48 – 2.05; p &lt; 0.0001); nausea, 0.94 (95% CI: 0.80 – 1.10; p = 0.45); and vomiting, 0.98 (95% CI 0.74 – 1.30; p = 0.93). The RR of high-grade adverse effects were as follows: febrile neutropenia, 1.32 (95% CI: 0.84 – 2.08; p = 0.21); infection, 1.20 (95% CI: 0.73 – 1.98; p = 0.45); pneumonia, 1.22 (95% CI: 0.76–1.95; p = 0.39); anemia, 0.48 (95% CI: 0.33 – 0.71; p &lt; 0.0001); neutropenia, 0.99 (95% CI: 0.86 – 1.15; p = 0.94); thrombocytopenia, 0.61 (95% CI: 0.47 – 0.81; p = 0.001); diarrhea, 1.72 (95% CI: 0.88 – 3.34;p = 0.10); nausea, 2.56 (95% CI: 0.59 – 10.99; p = 0.20); and vomiting, 0.42 (95% CI 0.11 – 1.63; p = 0.21). Conclusions: Ibrutinib increased the risk of all-grade diarrhea and infection whereas the risks of all-grade anemia, high-grade anemia and thrombocytopenia were significantly lower in the study arm, favoring ibrutinib.
Prognostic relevance of tumor sequencing in metastatic lung adenocarcinomas.
Authors: Ronglai Shen, Axel Martin, Ai Ni, Matthew David Hellmann, Emmet Jordan, Arshi Arora, Ryan Ptashkin, Ahmet Zehir, Mark G. Kris, Kathryn Cecilia Arbour, Charles M. Rudin, Michael F. Berger, David B. Solit, Venkatraman E. Seshan, Maria E. Arcila, Marc Ladanyi, Gregory J. Riely
Journal: Journal of Clinical Oncology (2018)

9049 Background: Routine next generation sequencing (NGS) testing for patients with lung cancer allows the rapid identification of a broad array of targetable molecular drivers. We hypothesized that the results of routine NGS testing, exploring both driver and non-driver oncogenes, could be used to develop a prognostic risk score for patients with metastatic lung adenocarcinoma. Methods: We employed an ensemble penalized proportional hazards model to derive a genetic risk score using sequencing results of 341 cancer associated genes in 1,054 patients with metastatic lung adenocarcinoma. A 3-fold cross-validation was used to obtain unbiased estimates of prediction accuracy. Results: A total of 341 genes mutated at least once across the cohort were included in the analysis. The most frequently mutated genes were TP53 (55%), KRAS (30%), EGFR (29%), STK11 (18%), KEAP1 (18%). Mutations in TP53, KRAS, STK11, KEAP1, and SMARCA4 were associated with poor prognosis. Based on the risk score, patients were categorized into risk groups. Patients in the low risk group had a median overall survival of 32.8 months (95% CI: 26.3-38.5) as compared to 7.3 months (95% CI 5.5-10.9) in the high risk group. The three-year survival probability is 47% in the low risk group versus 12% for the high risk group. Concurrent mutations in both STK11 and KEAP1 had the largest adverse prognostic implications. While overall mutation burden and clonal heterogeneity were moderately associated with survival, they did not provide additional prognostic value over the genetic risk score system. The risk score remains a significant independent predictor after adjusting for clinical variables (age, sex, smoking history). Conclusions: Using the results of routine NGS testing, we developed a molecular prognostic risk score for patients with metastatic lung adenocarcinoma. These results demonstrate that NGS testing for patients with lung cancer can be used not only to identify targetable molecular drivers, but also be leveraged to develop a powerful molecular scoring system that can be used for stratification in clinical trials as well as comparisons of patient populations derived from real world data.
Circulating tumor DNA as a non-invasive tool to identify patients at risk for recurrence after chemoradiotherapy in stage III non-small cell lung cancer.
Authors: Steven H. Lin, Xiayu Rao, Kimberly C. Banks, Ting Xu, Jianzhong He, Richard Burnham Lanman, Amirali Talasaz, Jing Wang, Zhongxing X. Liao
Journal: Journal of Clinical Oncology (2016)

8553 Background: Outcomes for curative-intent chemoradiotherapy of unresectable stage III non-small cell lung cancer (NSCLC) remains poor. Heterogeneity in tumors is correlated with therapeutic resistance and poor prognosis. We hypothesize that tumor-specific alterations (alts) in circulating tumor DNA (ctDNA) quantifies tumor heterogeneity and can serve as a non-invasive means to determine prognosis and recurrence. Methods: Between 2009-2013, 156 patients (pts) with unresectable NSCLC receiving definitive radiotherapy (XRT) or chemo-XRT were consented to have blood drawn pre-XRT, 1-2 times during XRT, and 1-2 times in follow up ( > 670 samples). We used a ctDNA NGS assay to detect SNVs in 70 genes, amplifications in 16, and select fusions and indels. Statistical analyses were performed for association between OS/PFS and ctDNA serial samples results. Here we report the initial interim analysis. Results: Of 44 pts, 32 (73%) recurred (PFS range 0-26.6 months) and 12(27%) had no evidence of recurrence as of last contact (1.9-43.5 months post-XRT). We found 4 main patterns of ctDNA changes: specific alts persistent throughout XRT (n = 9); no alts detected in the post-XRT sample (n = 14), increased levels from baseline (n = 10), or fluctuates throughout therapy (n = 11). Alleles which persisted throughout XRT were found in TP53, ARID1A, BRCA2, NF1, KRAS, APC, AR, ERRB2, PIK3CA, ATM, MET, BRAF, PDGFRA, CRCA1, NOTCH1, RAF1, GATA3, KIT. While the 4 patterns of cfDNA fluctuations were not found to be prognostic in this interim analysis, the presence of specific mutations appears to correlate with outcomes, with reappearance of the driver mutations post-tx associated with shorter PFS. Using FDR cutoff of 0.1, NF1 mutations were associated with shorter OS (p = 0.07), and APC/ARID1Amutations associated with shorter PFS (p = 0.09) after adjustment for tumor histology or stage. Conclusions: In this interim analysis, we found that specific mutant alleles in cfDNA are correlated with potentially treatment resistance and early metastatic recurrence. Final analysis of the larger cohort may be required to achieve significance for additional prognostic patterns.
Abstract P286: Macronutrient Intake and Dietary Patterns’ Association with Telomere Length in American Indians: The Strong Heart Study
Authors: Mihriye Mete, Sigal Eilat-Adar, Alexander Zeymo, Jinying Zhao, Amanda M. Fretts, Nawar Shara, Barbara V. Howard
Journal: Circulation (2016)

Introduction: Telomeres are repeated DNA sequences and their associated proteins at the ends chromosomes. A slow and gradual loss of telomere length with increasing age in humans has been reported. Substantial variability observed in the rate of telomere shortening independent of age has been attributed to environmental and lifestyle factors . Hypothesis: This study examines the association between leukocyte telomere length (LTL) and dietary intake among American Indians (AIs). We hypothesized that diets deemed “unhealthy”, with high content of sugar, saturated and trans fats, and alcohol would be associated with shorter LTL. Methods: The current analysis included 2,842 American Indians (AIs) participating in the Strong Heart Family Study (SHFS). LTL was measured by quantitative PCR. Nutrition data were collected via food frequency questionnaire. Four diet patterns were extracted using principal component analysis (Western, Traditional, Healthy and Unhealthy diet patterns). The relationship between LTL and diet was analyzed, separately, by using diet patterns measured in quintiles or by using macronutrient intake in diet including alcohol consumption. The analyses were conducted using multivariate linear mixed models, adjusting for family relatedness, age, diabetes, gender, BMI, physical activity and smoking. Results: The mean age was 40 (SD=17), 60% were female. In models examining diet patterns, the traditional diet pattern, which includes traditional foods, dry beans, Mexican foods, stew, (processed) meats, and hydrogenated vegetable fats, was significantly and negatively associated with LTL. Participants who scored higher on the traditional diet had shorter LTL (shorter by 0.005 per one quintile of traditional diet, p&lt;0.01). We observed no significant association between LTL and other three diet patterns. There was no association of macronutrients (i.e., protein, fat components, carbohydrates, simple and added sugars, dietary cholesterol or fiber) with LTL. However, alcohol intake was significantly and negatively related to LTL in the macronutrients model (shorter by 0.03 per 10-percentage point increase, p&lt;0.05). Conclusions: Our results suggest that, in addition to known factors such as older age, higher BMI and diabetes, traditional diet pattern may reflect a lifestyle associated with accelerated aging of AIs. Alcohol intake seems to be related to the shortening of LTL with an effect size comparable to that of diabetes.
Immunological microenvironment in skin melanoma.
Authors: Elena Yurievna Zlatnik, Oleg Ivanovich Kit, Inna Arnoldovna Novikova, Yury Valentinovich Przhedetskiy, Sergey Kochuev, Victoria V. Pozdnyakova, Olesya N. Selyutina, Galina I. Zakora, Elena Bondarenko
Journal: Journal of Clinical Oncology (2016)

e21060 Background: The purpose of the study was to assess parameters of local cellular immunity in patients with melanomas. Methods: Samples of the blood, tissues of tumor and peritumoral zone of 30 patients (18 women and 12 men aged 31-82 years) were studied. Tumors were localized on upper extremities (3 patients), lower extremities (11), scalp (2), trunk (12) and face (2). Nodular melanoma prevailed; invasion depth (Breslow) amounted to 1-15 mm. Populations and subpopulations of lymphocytes in blood and tissue homogenates obtained during surgery were determined using flow cytometer FACSCantoII (BD). Percentages of lymphocytes expressing CD3, CD4, CD8, CD19 and CD16/56 markers were calculated from the total number of CD45+ lymphocytes, T-regs (CD4+CD25+CD127dim) – from the number of CD3+CD4+ cells. Results: Higher content of T-lymphocytes was found in tumor tissue in comparison with the blood (89.1±1.8 and 69.3±2.4%, respectively), largely due to CD3+CD8+ cells (37.8±2.6 and 22.8±1.4%, respectively). Content of В- and NК-cells in tumor was lower than in the blood (2.9±0.5 vs. 10.7±0.9% for CD19+ and 5.7±1.6 vs. 17.7±1.7% for CD16/56+, respectively). Though CD3+CD4+ levels in tumor tissue and blood were similar, their minor T-regs subpopulation sharply prevailed in tumor (18.6±2.4 and 6.7±0.3%, respectively) (p < 0.05). They were registered in peritumoral zone as well: lymphocytes were similar to the blood, but accumulation of CD3+CD4+ was not accompanied by as high T-regs level as in melanoma tissue supposing their selective migration to tumor tissue. Nodular melanoma showed lower content of T-lymphocytes compared to the superficial form (88.1±2.1 vs. 93.6±0.9%) and higher content of NK-cells (6.4±1.8 vs. 0.9±0.1%) and T-regs (19.8±2.5 vs. 10.6±3.3%); differences were statistically significant (p < 0.05). Thicker melanomas showed decrease in tissue levels of CD3+ and CD3+CD4+ cells and increased content of CD16/56+ lymphocytes; T-regs level in tumor was high irrespective of its invasion depth. Conclusions: Tumor tissue showed a marked predominance of T-lymphocytes, CD3+СD8+ and T-regs especially. A number of differences in local immunity factors were revealed for patients of different ages and various melanoma types and depths of invasion.
TCT-177 Comparison of Percutaneous and Surgical Right Ventricular Assist Device Support Following Durable Left Ventricular Assist Device Insertion
Authors: Ellie Coromilas, Koji Takeda, Masahiko Ando, Marisa Cevasco, Philip Green, Dimitri Karmpaliotis, Ajay Jayant Kirtane, Waqas Malick, Veli Topkara, Melana Yuzefpolskaya, Hiroo Takayama, Yoshifumi Naka, Daniel Burkhoff, Paolo Colombo, Arthur Reshad Garan
Journal: Journal of the American College of Cardiology (2018)
Most common genomic alterations in soft tissue sarcoma: Five centers experience.
Authors: Ioana Bonta, Rabih Bechara, Christopher Parks, Alexandra Thompson, Dacian Bonta, Patricia L. Thompson
Journal: Journal of Clinical Oncology (2016)

11049 Background: In the early 2000, the results of Imatinib targeted treatment in gastrointestinal stromal tumors (GISTs) raised the hope that targeted therapy can be effective in other types of sarcomas. Several such therapies have been tested in sarcomas with modest results. The main limitations are the genomic heterogeneity and complexity of sarcomas as well as lack of actionable targets for bone and soft tissue sarcomas. Methods: We performed a retrospective analysis of a dataset of 164 cases with soft tissue and bone sarcoma (excluding GIST sarcomas), who underwent genomic sequencing. Patients were treated at 5 tertiary referral centers, from October 2012 to August 2015. The recorded data included: age at diagnosis, date of the genomic sequencing, genomic alteration (affected genes and the type of alteration identified). For genomic profiling we used a platform commercially available. Results: We obtained 164 samples from 164 patients, aged between 19 and 80 years, with a median of 56. There were 7 bone sarcomas and 157 soft tissue sarcomas. The three most common soft tissue sarcomas were leiomyosarcoma (51 cases, 32.48%), undifferentiated (30 cases, 19.1%), and liposarcoma (19 cases, 12%). The genomic analysis found 155 affected genes with 532 alterations. In 20 samples were no identified genomic alterations. The most common affected genes in the soft tissue sarcomas are: Tp53 alteration (63 cases), Rb1 24.8% (39 cases), ATRX 10.1% (16 cases), PIK3CA 9.5% (15 cases), CDKN2A/B 8.9% (14 cases), PTEN 8.2% (13 cases), MDM2 7% (11 cases), also 5.7% BRCA2 were mutated (9 cases). Conclusions: Sustained investigations and sequencing of larger numbers of these rare tumors are aiming to identify potential actionable mutations in these tumors. The ultimate goal is to determine new therapies and optimal treatment strategy based on the genomic profile.