tbuckley/cabot-search huggingface dataset:
Prognostic impact of residual HPV ctDNA detection after chemoradiotherapy for anal canal carcinoma.
Authors: Luc Cabel, Emmanuelle Jeannot, Ivan Bieche, Sophie Vacher, Celine Callens, Alice Bernard, Adeline Morel, Astrid Lièvre, Joelle Otz, Mathieu Minsat, Louis Bazire, Jean-Yves Pierga, Bruno Buecher, Pascale Mariani, Francois Clement Bidard, Wulfran Cacheux
Journal: Journal of Clinical Oncology (2018)

3565 Background: Chemoradiotherapy (CRT) is the current standard of care for patients diagnosed with locally advanced anal squamous cell carcinoma (ASCC), but some patients will present a local and/or a distant relapse during follow-up. We previously reported the analytical validity of HPV circulating tumor DNA (HPV-ctDNA) detection by droplet digital PCR in HPV-related cancers. The current study aimed at monitoring HPV ctDNA levels during CRT in locally advanced ASCC. Methods: We analyzed prospectively collected samples from patients with HPV16 or HPV18-positive locally advanced ASCC. Plasma samples collected at diagnosis (before CRT initiation) and at the end of CRT. Cell-free DNA from serum or plasma was extracted, quantified and subjected to HPV16 or HPV18 ctDNA detection as previously published with droplet digital PCR. Results: 36 stage II-IV ASCC patients were included. HPV-ctDNA detection had a sensitivity of 89% (n = 32/36). All 4 patients with no ctDNA detected had a stage II ASCC (detection rate 33% versus 100% for higher stage, p = 0.001). In patients with detectable ctDNA before CRT, median ctDNA levels were significantly associated with lymph node(s) status: the median ctDNA level was 102 copies/ml (range 8.7-9333) in N+ ASCC vs 32 copies/ml (range 3-1350) in N- ASCC (p = 0.026). Among 18 patients with available paired samples (before and after RCT), only 3 (17%) displayed residual detectable HPV-ctDNA at the end of CRT. Residual ctDNA detection was correlated with the patients’ outcome, such as these 3 patients were the only patients to experience a metastatic relapse (Fisher exact test, p = 0.001). Residual HPV-ctDNA after CRT was strongly associated with relapse-free survival (p < 0.0001). Conclusions: This is to our knowledge the first proof of concept study assessing the prognostic value of ctDNA after CRT in locally advanced ASCC. In most patients, HPV-ctDNA can be detected before CRT but drops below detection limits during CRT. We show here that residual ctDNA levels at the end of CRT are associated with a very poor outcome, suggesting the use of HPV-ctDNA as tool to select high-risk patients that may be eligible for further systemic treatments
Differential response to adjuvant chemotherapy based on Lauren subtype affects clinical outcome of gastric cancer: A cohort study and meta-analysis.
Authors: Kunning WANG, En Xiao Li, Rita A Busuttil, Joseph C Kong, Sharon Tracy Pattison, Joseph J.Y. Sung, Jun Yu, Emad M El-Omar, Julie A Simpson, Alex Boussioutas
Journal: Journal of Clinical Oncology (2018)

4048 Background: There remains significant questions on the efficacy of adjuvant chemotherapy for Lauren subtype of gastric cancer (GC). We aimed to clarify whether intestinal gastric cancer (IGC) patients have improved response to current chemotherapy regimens resulting in better survival when compared to diffuse gastric cancer (DGC) patients after adjuvant chemotherapy. Methods: A dataset comprising 8599 GC patients from 23 publications, combined with our cohort, was included in the meta-analysis. Results: In our cohort, the overall survival of IGC receiving adjuvant chemotherapy (chemoIGC) (median OS 5·01 years, IQR 2·63-6·71) was significantly higher than that of DGC receiving adjuvant chemotherapy (chemoDGC) (median OS 1·33 years, IQR 0·78-3·33, P = 0·0001). The HR for OS of the chemoIGC compared to chemoDGC was 0·27 (95% CI 0·13-0·52). There was a significant difference of OS between chemoIGC and IGC (HR 0·32, 95% CI 0·16-0·64, P = 0·001) whereas no difference between chemoDGC and DGC (HR 1·26, 95% CI 0·69-2·29, P = 0·46), indicating that IGC patients benefit more from adjuvant chemotherapy than DGC patients. After adjusting for age, gender and stage, adjuvant chemotherapy was an independent risk factor for survival in Lauren subtype of GC (HR for OS of the chemoIGC / chemoDGC 0·33, 95%CI 0·17-0·65, P < 0·001). Importantly, the meta-analysis results of 24 studies consisting of 4050 chemoIGC and 4549 chemoDGC patients indicated that chemoIGC showed significantly improved OS (HR 0·78; 95% CI, 0·72-0·84; P < 0·0001) and PFS (HR 0·80; 95% CI, 0·64-0·99; P = 0·04) comparing to similarly treated patients of chemoDGC. Conclusions: Our results support consideration of a change of clinical practice in the decisions related to administration of adjuvant chemotherapy for DGC patients. We found, DGC patients may not attain the same survival or efficacy as IGC from adjuvant chemotherapy. The Lauren subtype may be useful in treatment decisions in GC patients. We contend that Lauren classification and molecular subgroup should be used to stratify treatment regimens to GC patients, with particular relevance to diffuse subtype which is more difficult to treat with current regimens.
Ranolazine after doxorubicin treatment: Cardioprotective effects in vitro and in vivo.
Authors: Nicola Maurea, Carmela Coppola, Giovanna Piscopo, Gennaro Riccio, Carlo Maurea, Roberta Caputo, Antonio Barbieri, Claudio Arra, Michele De Laurentiis
Journal: Journal of Clinical Oncology (2016)

e23148 Background: Doxorubicin (D) has been shown to be effective in a wide range of tumors; however, it can produce heart failure by multiple mechanisms, which include, Na+ dependent Ca2+ overload due to SERCA2a activity reduction and inappropriate opening of the RyR2, and impaired myocardial energetics. Ranolazine (R) is a potent and selective late inward sodium current (INaL ) inhibitor, which reduces Na+ dependent Ca2+ overload, thus it leads to myofilament activity reduction, in presence of lower diastolic Ca2+ concentrations, and spares ATP. Here, we propose to assessing whether R, diminishing intracellular Ca2+ by inhibition of INaL , prevents D cardiotoxicity. Methods: To assess for toxicity in vitro, rat H9C2 cardiomyoblasts and human fetal cardiomyocytes were pretreated with R (1 or 10 μM) for 72 hours and then treated with D (1 μM) for additional 72 hours. To evaluate cardiac function in vivo, fractional shortening (FS) and ejection fraction (EF) were measured by M/B mode echocardiography and radial strain (RS) was measured using 2D speckle-tracking echocardiography, in C57/BL6 mice, 2-4 mo old, at day 0, and after 2 and 7 days of daily administration of D (2.17 mg/kg/day, ip). These measurements were repeated after 5 days of R treatment (305 mg/Kg/day, gavage, dose comparable with that used in humans of 750 mg twice) initiated at the end of D treatment. Results: In vitro studies shown that R reduces cardiotoxicity in rat H9C2 cardiomyoblasts and human fetal cardiomyocytes as evidenced by higher viability rate of cells treated with R+D than cells treated with D alone. In in vivo studies, after 7 days with D, FS decreased to 50.5±8.4% vs 61.5±1% (sham), p < 0.05, EF to 82.2±8.1% vs 91.3±0.5% (sham), p < 0.05, RS to 14.3±4.7% vs 40.5±4.8% (sham), p < 0.01. In mice treated with R for 5 days after D treatment, cardiac function was recovered: FS was 61.5±1.1%, EF was 91.25±1.1% vs mice treated 5 days in absence of R after D treatment to exclude spontaneous recovery (FS 52.3±7, EF 83.1±8.3) p < 0.01; RS was 29.5±3.4% vs mice treated 5 days in absence of R after D treatment (15.2+4.9), p < 0.05. Conclusions: R post-treatment reduces cardiotoxic effects due to D, as demonstrated by in vitro study and the normalization in vivo of the values of FS, EF and RS.
Cellular immune biomarkers to prognosticate for survival to adoptive T-cell therapy in advanced nasopharyngeal cancer.
Authors: Han Chong Toh, Richard Hopkins, Qian Ting Ching, Veonice Bijin AU, Lynn Xue WU, Whay-Kuang Chia, Bernett Lee, Who-Whong WANG, Michael Podinger, Joseph Wee, Joanna Ng, Timothy Shuen, John E. Connolly
Journal: Journal of Clinical Oncology (2017)

6047 Background: We have published a Phase II clinical trial in 35 advanced incurable stage 4c NPC patients employing upfront first line chemo-immunotherapy of four cycles of gemcitabine and carboplatin, followed by six cycles of adoptive transfer autologous EBV-specific cytotoxic T lymphocytes (CTL). The 2- and 3-year overall survival rates were 62.9 and 37.1% respectively, which represent the best reported survival outcome for first-line treatment of advanced NPC when compared to historical clinical trials. Methods: From this Phase II trial, we completed serial multiple deep immune phenotyping analyses including flow cytometry, nanostring, and multiplex ELISA assays. We then investigated how these factors influence and determine successful therapy using 2-year survival rates. Results: Longitudinal modular transcriptome analysis of patient PBMCs revealed significant increases in T cell, NK, and B cell modules post chemotherapy within the 2-year survivor group. Administration of CTLs restored expression of lymphocyte transcripts in the non-survivor group at 2-weeks post infusion. However, as immunotherapy proceeded, 2-year survivors displayed significant increases in multiple lymphocyte module associated transcripts. These immune correlates were associated with increased IFN-γ and decreased myeloid chemokine concentrations in peripheral sera during immunotherapy in 2-year survivors. Longitudinal immunophenotyping of patient PBMCs at serial timepoints showed that 2-year survivors displayed significant decreased amounts of monocytic myeloid-derived suppressor cells (mMDSCs), compared to non-survivors after chemotherapy, which subsequently determined successful CTL immunotherapy survival benefit. Conclusions: This is the first report in human cancer patients that successful adoptive T cell immunotherapy correlates with lower mMDSCs following chemotherapeutic preconditioning. We have also identified potential prognostic immune biomarkers that effectively predicts efficacy of CTL immunotherapy, following upfront combination chemotherapy, and thus survival. Lymphodepletion with chemotherapy appears to be vital for adoptive T cell therapy efficacy.
TCT-240 Long-Term (5 to 7 Years) Clinical Outcomes After Cobalt-Chromium Everolimus-Eluting Stent Implantation
Authors: Shoichi Kuramitsu, Yuichi Tanaka, Takashi Hiromasa, Makoto Hyodo, Shinichi Shirai, Kenji Ando
Journal: Journal of the American College of Cardiology (2018)
A phase 2, multicenter, open-label study of the safety and efficacy of luspatercept in subjects with myeloproliferative neoplasm (MPN)-associated myelofibrosis and anemia with or without RBC transfusion dependence.
Authors: Ruben A. Mesa, Giovanni Barosi, Claire N. Harrison, Jean-Jacques Kiladjian, Robert Peter Gale, Abderrahmane Laadem, Torsten Gerike, Peter G. Linde, Matthew L. Sherman, Joseph Pariseau, Srdan Verstovsek
Journal: Journal of Clinical Oncology (2018)

TPS7083 Background: Anemia is an important complication of MPN-associated myelofibrosis. There are few effective therapies other than RBC transfusions, and responses to other therapies are typically brief. Anemia and RBC transfusion dependence are independent adverse prognostic and predictive variables for survival. Luspatercept is a fusion protein consisting of a modified type IIB activin receptor linked to the Fc domain of human IgG1. Luspatercept acts as an erythroid maturation agent by binding specific TGFβ superfamily ligands such as GDF11, blocking their inhibitory effect and leading to increased RBC production. Luspatercept ameliorated anemia in preclinical models and preliminary data have shown it is effective and well tolerated in subjects with lower-risk myelodysplastic syndromes and anemia, with or without RBC transfusion dependence. Methods: Eligible subjects have MPN-associated myelofibrosis, are aged ≥18 y, and have anemia (hemoglobin < 9.5 g/dL) or RBC transfusion dependence (defined as receiving 2–4 U RBC/28 d averaged over 84 d). There are 3 cohorts: (1) cohort 1: 20 subjects with anemia only, no ruxolitinib received in the past 112 d; (2) cohort 2: 20 subjects with RBC transfusion dependence, no ruxolitinib; and (3) cohort 3: 30 subjects with anemia or RBC transfusion dependence receiving a stable ruxolitinib dose. Luspatercept is given subcutaneously at a starting dose level of 1.0 mg/kg every 3 w for 8 cycles. The primary endpoint is anemia response, defined as a hemoglobin increase of ≥1.5 g/dL from baseline or RBC transfusion independence for ≥84 d. Responders can continue therapy in an extension phase. Secondary endpoints include time to response, response duration, health-related quality of life, and safety. Response rates with 95% confidence interval will be calculated. The statistical analyses are descriptive. Enrollment began November 2017. Clinical trial information: NCT03194542.
Ibrutinib plus anti-CD20-interferon alpha fusion protein for treatment of B cell lymphomas.
Authors: Ryan F. Kendle, Davis Kipkemboi Kimaiyo, Reiko E Yamada, Patricia Young, Alex Vasuthasawat, Ryan K Trinh, Sherie L Morrison, John Timmerman
Journal: Journal of Clinical Oncology (2016)

e14567 Background: Anti-CD20 antibody-IFNα fusion protein induces apoptosis and promotes in vivo eradication of CD20-expressing murine and human B cell lymphomas. Bruton’s tyrosine kinase (BTK) is critical to the survival of certain non-hodgkin lymphomas (NHL); inhibition of BTK with ibrutinib shows clinical activity in B-cell malignancies. We report the additive anti-lymphoma activity of combination anti-CD20-human IFNα (anti-CD20-hIFNα) or anti-CD20-murine IFNα (anti-CD20-mIFNα ) fusion proteins with ibrutinib. Methods: Combination ibrutinib and anti-CD20-hIFNα was evaluated against human B cell NHL lines including diffuse large B cell (SUDHL-5, OCI-Ly10, OCI-Ly19, HBL-1) and mantle cell (Granta-519) lymphomas, in vitro. The combination of ibrutinib with anti-CD20-mIFNα was tested against murine lymphoma cell lines A20, BCL-1, and 38C13-huCD20, in vitro. Proliferation was measured by [3H]-thymidine incorporation. Synergy was evaluated by the method of Chou-Talalay. Survival of A20 tumor-bearing BALB/c mice treated with combination therapy was evaluated. Results: In vitro additive effects on cell proliferation, with combination treatment in human lymphoma and murine lymphoma cell lines, was observed (Chou-Talalay combination index ≤ 1). Against A20 tumor-bearing mice, combination treatment with ibrutinib and fusion protein achieved improved survival compared to fusion protein alone (p = 0.043). Additionally, combination of fusion protein plus ibrutinib showed improved survival vs. unfused anti-CD20 plus ibrutinib (p = 0.043). Fusion protein plus ibrutinib showed improved survival when compared to a combination of ibrutinib and anti-PD-L1, in vivo (50% survival vs 12% survival at 90 days). Conclusions: Anti-CD20-IFNα fusion protein, in combination with ibrutinib, demonstrated potent growth inhibition of human and mouse B cell lymphoma cell lines, in vitro. This additive effect translated to significantly improved survival of tumor-bearing mice. A first in human anti-CD20-hIFNα fusion protein (IGN002) is being evaluated in a phase I, dose-escalation study in patients with refractory NHL (NCT02519270). Our results provide a pre-clinical rationale to combine Ibrutinib with IGN002.
Medical assistance in dying in British Columbia: Attitudes and experiences of oncology practitioners in the first year of legalization.
Authors: David William Fenton
Journal: Journal of Clinical Oncology (2018)

e22002 Background: MAiD was legalized in Canada June 17, 2016. Most patients who request MAiD have incurable cancer but oncologists had been somewhat resistant to MAiD legalization. The aim of this study was to assess the experiences and attitudes of oncology practitioners in BC one year after legalization and inform the process moving forward. Methods: A survey was sent to 280 practitioners with responses converted to a 3-point Likert scale: Agree, Disagree, Neither. Results: Of the 44% who responded, 46.3% were medical oncologist, 30.1% radiation oncologists, 11% general practitioners of oncology and 12% nurse practitioners of oncology. In the prior year, most (72.6%) had a patient declare an interest in MAiD, 13.1% had done an assessment, less than 1% had provided MAiD, 35.8% indicated they would probably be assessors and 9.7% would be willing to provide MAiD in the future while 20.3% considered themselves conscientious objectors. Challenges included: difficulty with key eligibility criteria and assessing vulnerability (28.2% to 44.1%), insufficient time for assessments (35.5%), concern about prosecution or professional sanctions (31.5%), concerns over worsening work quality of life (48.4%), shifting focus from equitable access to high quality palliative care (31.7%) and damage to the patient-practitioner relationship (15.3%). Improving the process for cancer patients in the future could include ensuring an oncology practitioner is always one of the assessors (50.8%), always having an evaluation by the palliative care team (72.6%) and referral to a multidisciplinary MAiD assessment team (70.2%) and/or specialized MAiD provision service (73.4%). Conclusions: Most respondents were approached about MAiD but few became involved in the process. This may not be optimal. There are legitimate concerns driving this disparity that can likely be improved with further education and practice modification. This survey highlights several possible mechanisms by which the MAiD process in BC can be improved for cancer patients.
Efficacy and safety of crizotinib in patients with anaplastic lymphoma kinase-positive stage IV non-small cell lung cancer.
Authors: Ahmed M. Mohi El.Din, Ayman Ahamd Rasmy
Journal: Journal of Clinical Oncology (2017)

e20516 Background: Crizotinib is an oral small-molecule tyrosine kinase inhibitor targeting ALK, MET, and ROS1 tyrosine kinases. It was first approved by the Food and Drug Administration (FDA) in 2011 for treatment of patients in late-stage (locally advanced or metastatic) non-small cell lung cancer (NSCLC) with abnormal anaplastic lymphoma kinase (ALK) gene as detected by an FDA-approved test, as it confers improved progression-free survival comparison with chemotherapy. Methods: This is a retrospective chart review study of patients with stage IV ALK-positive NSCLC who attended the medical oncology department of Kuwait Cancer Control Centre (Kuwait) and King Fahad Specialist Hospital (Saudi Arabia) between January 2013 and May 2016. The efficacy and safety of crizotinib (250 mg orally, twice daily, with or without food.) were evaluated based on overall survival (OS), progression-free survival (PFS), Objective response rate (ORR), time to objective response, duration of response, and dose reduction or cessation because of crizotinib toxicity. Results: Twenty-three patients were involved in this study with a median age of 55.5 years and male-to-female ratio of 2.4:1 The median OS from initiation of crizotinib has not been reached; 1-year overall survival was 71.2%. Crizotinib treatment demonstrated median PFS of 9.6 months (95% CI, 3.0-24.1 months). The ORR was 70.9%. Complete response was achieved in 4.2% of patients, and partial response was achieved in 66.7% of patients. The most frequently reported adverse effects of crizotinib (Grade 1 / 2) were muscle ache, fatigue, nausea, vomiting, diarrhea, constipation, edema, elevated transaminases, bradycardia, and vision disorders. Grade 3 / 4 diarrhea was reported in 12.5% of patients. The proportion of patients who required dose reduction because of Crizotinib-induced bradycardia was 8.3% of patients. Conclusions: Crizotinib appears to be a very favorable option for treating patients with stage IV ALK-positive NSCLC. Crizotinib showed a very tolerable toxicity profile.
Exploring the role of RB and AR in a phase II randomized multicenter trial of abiraterone acetate with or without cabazitaxel in metastatic castration-resistant prostate cancer (mCRPC).
Authors: Susan F. Slovin, Karen E. Knudsen, Emily Carbone, Abosede Showunmi, Melanie Hullings, Michael J. Morris, Karen A. Autio, Lewis J. Kampel, Ana M. Molina, Yu Chen, Gabrielle Arauz, Tracy Curley, Kin Tse, Susan Halabi, Howard I. Scher, William Kevin Kelly
Journal: Journal of Clinical Oncology (2016)

TPS5093 Background: Retinoblastoma (RB) loss of function has been identified as a process by which castration-resistant tumors develop. Up to 60% of CRPC tumors show loss of RB function. This can drive the transition to castration resistance in human xenograft models. The androgen receptor (AR) appears to be under stringent RB control; RB loss results in AR deregulation and bypass of androgen deprivation therapy. Tumors lacking RB are compromised for DNA damage checkpoints that allow for repair after genomic insult. Thus,tumors devoid of RB function are hypersensitive to chemotherapy. These findings support the hypothesis that RB status can guide treatment with specific chemotherapies and improve disease outcome. RB status may be a potential biomarker for pts who fail AR-directed drugs such as abiraterone (AA). While docetaxel is the standard first line chemotherapy for mCRPC, cabazitaxel (CBZ) is a more potent microtubule inhibitor. This trial will determine the effect of AA followed by CBZ upon disease progression versus an upfront combination of AA and CBZ in pts with chemotherapy naïve mCRPC. RB status at baseline and the feasibility of obtaining RB status from circulating tumor cells (CTCs) were examined. Methods: Chemotherapy naïve mCRPC pts received AA 1000 mg po daily + prednisone 5 mg po BID either in combination with CBZ 25 mg/m2 IV q 3 weeks (up to 9 cycles) or followed by CBZ upon progression. The primary endpoint was radiographic progression free survival with a planned accrual of 80 pts. Correlatives included baseline tumor biopsies, RB status based on immunohistochemistry and gene signature, CTCs using the EPIC Sciences platform, and serial androgen levels. EPIC Sciences established the N-terminal expression cut-off using spiked healthy donor blood with PC3 and LnCaP cells. FISH analyses to assess RB loss were defined as: Non-Deleted: RB = copy control, RB deletion: RB < copy control; 13q deletion: RB and copy control both < 2. CTCs were non-evaluable and not included in FISH analysis if: < 4 CTCs/slide, Apoptotic CTCs, low signal and/or loss of CTC during processing. Twenty-four pts are enrolled to date. Supported by Sanofi-Aventis, PCF Clinical trial information: NCT02218606.