tbuckley/cabot-search huggingface dataset:
Outcomes of ICU admission of patients with progressive metastatic gastrointestinal (GI) cancer.
Authors: Andrew S. Epstein, Andrew Yang, Lauren Colbert, Louis Voigt, Jason Meadows, Jessica Goldberg, Leonard Saltz
Journal: Journal of Clinical Oncology (2016)

e18124 Background: It is unclear if ICU admissions result in long term survival or the ability to administer subsequent cancer treatments, and if such treatments benefit patients. We therefore examined the ICU admissions at a comprehensive cancer center of patients with advanced GI cancers. Methods: An institutional database was queried to identify characteristics of cancer patients of the GI medical oncology service of Memorial Sloan Kettering Cancer Center with at least one ICU admission during 2014. Records were manually reviewed to assess benefit of cancer treatment received after the ICU admission. Results: 28 patients who had progressed beyond at least first line chemotherapy for metastatic adenocarcinoma of GI origin were admitted to the ICU for clinical deterioration involving other than post-procedure management, GI bleeds, or acute hypersensitivity reactions. The median age at ICU admission was 62 (range 38-80), the most common cancers were colon (36%) and pancreas (32%), the most common reasons for ICU admission were sepsis (39%) and acute respiratory failure (29%), and the median number of prior lines of chemotherapy was 2. Of these 28, 3 month survival was 21% and 6 month survival was 7%. Ten died in the ICU, 3 died during the same hospitalization after ICU discharge, and 15 were discharged from the hospital. Of these 15, the median overall survival from hospital discharge was 2.2 months and the median number of readmissions was 1 (range 0-9). Of the 15, 6 received further chemotherapy, but none achieved clinical benefit. Of these 6, 3 lived over 5 months but with multiple readmissions, and the treatment of 5 entailed recycling of previously ineffective (3) chemotherapy agents or those originally used in the adjuvant setting (2). Two of these patients received liver-directed therapy, without benefit. Conclusions: Admissions to the ICU in this cancer population were associated with high morbidity and mortality and did not result in benefit from future cancer treatment. While further research is needed, these data do not support the use of ICU care in this clinical setting, and can be used to help establish realistic expectations and care goals in previously treated metastatic GI cancer patients with clinical deterioration.
RNA editing in breast cancer: Role in carcinogenesis and clinical implications.
Authors: Joline Si Jing Lim, Jaymie Siqi Lin, Vanessa Hui En Ng, Henry Yang, Soo Chin Lee, Polly Leilei Chen
Journal: Journal of Clinical Oncology (2016)

11613 Background: In humans, the most prevalent RNA editing event is the deamination of adenosine to inosine (A-to-I), catalyzed by the ADAR family of proteins. This mutational process has been implicated in various cancers such as liver, gastric and esophageal cancers but its role in breast cancer carcinogenesis is still not well understood. Methods: We hypothesized that monitoring the expression of ADARs and the overall RNA editing frequencies may facilitate prognostication and characterization of breast cancer subtypes. Public databases Gene Expression across Normal and Tumor Tissue (GENT) and The Cancer Genome Atlas (TCGA) were utilized for bioinformatics analyses. Tissue microarray (TMA) slides with 100 breast cancer cores (Shanghai Outdo Co.) were used to validate TCGA data, and results were analyzed using the Vectra Imaging System. In vitro, overexpression of estrogen receptor (ER) and ADAR1 in MB231 ER- cell line was performed followed by tumorigenicity assays. Results: GENT revealed higher expression of ADAR1 in breast cancer tissues compared to normal tissues. Analysis of TCGA datasets showed poorer overall survival (OS) in patients with high ADAR1 compared to low ADAR1 expression amongst ER+ breast cancers (median OS 8.12 years vs 11.71 years, p = 0.007). The converse was true for ER- tumours, with better OS for patients with high ADAR1 expression (median OS 9.51 years vs 5.48 years, p = 0.046). We further validated this phenomenon using TMA slides, and survival data from this cohort supported the TCGA data. In vitro, ER- MB231 cell line was first stably over expressed with ER or empty vector (EV), then both cell types were subjected to a second round of over expression with ADAR1 or EV. Tumorigenicity tests including XTT, invasion/migration, soft agar and foci formation assays consistently showed opposite functional phenotypes with or without overexpression of ADAR1, corroborating the TCGA findings. Conclusions: ADAR1 expression predicts for differential overall survival in ER+ and ER- breast cancer patients. In vitro, ADAR1 overexpression also exhibited higher tumorigenic potential. ADAR1 is a potential biomarker for prognostication of survival outcomes in breast cancer patients.
Phase 2, open-label study of venetoclax in combination with carfilzomib and dexamethasone in patients with relapsed/refractory multiple myeloma.
Authors: Orlando Bueno, Tu Xu, Jaclyn Cordero, Lura Morris, Jeremy Ross, Kevin Freise, Wijith Munasinghe, Joel Leverson, Sarah Mudd, Maria Verdugo
Journal: Journal of Clinical Oncology (2017)

TPS8056 Background: A significant unmet need for multiple myeloma (MM) therapy remains as many patients eventually relapse after or become refractory to current treatment options. Investigation of novel agents and combinations in relapsed/refractory (R/R) patients are therefore critical to advance therapy and improve patient outcomes. Venetoclax is a potent, selective, orally bioavailable inhibitor of BCL-2. Combination of venetoclax with dexamethasone and bortezomib, a proteasome inhibitor that can inhibit MCL-1 indirectly via stabilizing the MCL-1-neutralizing protein NOXA, showed high rates of clinical response in a Phase 1 study. The mechanism of MCL-1 inhibition is thought to be a class effect of proteasome inhibitors. Given the clinical data supporting the combination of venetoclax with a proteasome inhibitor, this study will evaluate whether venetoclax combined with carfilzomib and dexamethasone can provide a well-tolerated and efficacious treatment option for R/R MM patients. Methods: This Phase 2, open-label study will assess the combination of venetoclax, carfilzomib, and dexamethasone in patients with R/R MM (NCT02899052). Primary objectives are to assess the safety and tolerability of this combination. Secondary objectives include evaluation of the pharmacokinetics of venetoclax and carfilzomib, preliminary efficacy of the combination (including overall response rate, very good partial response or better rate, progression-free survival, time to progression, and duration of response), and minimal residual disease (MRD) in bone marrow by next generation sequencing. Exploratory objectives will assess pharmacodynamic and predictive biomarkers, MRD by PET, pharmacogenetics, and patient-reported outcomes. Safety and pharmacokinetic profiles of the combination will be evaluated in initial dose escalation cohorts to determine appropriate doses of venetoclax and carfilzomib to be used with dexamethasone; a dose expansion phase will evaluate the safety and efficacy profiles of the combination based on selected doses. Study recruitment began in January 2017, with target enrollment of ~40 patients from 10–15 sites in the United States. Clinical trial information: NCT02899052.
Standard or split TPF induction chemotherapy followed by bioradiation: ICRAT randomized phase II study.
Authors: Carmen Stromberger, Rainald Knecht, Jan D Raguse, Ulrich Keilholz, Silke Tribius, Chia-Jung Busch, Oliver Koelbl, Matthias Hautmann, Andreas Schreiber, Arne Gruen, Eva-Tessina Becker, Inge Tinhofer, Volker Budach
Journal: Journal of Clinical Oncology (2016)

6035 Background: TPF induction chemotherapy (IC) is a reasonable treatment for locally advanced (LA) squamous cell carcinoma (SCC) of the head and neck. Substantial toxicity may compromise compliance and thereby efficacy. In this 3-armed trial, we compared two TPF-IC regimens followed by cetuximab and radiation (bioradiation) vs. chemoradiation (CRT) in terms of efficacy, toxicity & survival. Methods: Eligible patients with LASCC of the oro- (ORO), hypopharynx (HYP) and oral cavity (OC) wererandomly assigned 1:1:1 to receive either 3 cycles of standard TPF (arm A) with TP (75 mg/m2, day 1) and F (750 mg/m2/24h days 1-4) or split-course TPF (arm B) with TP (40 mg/m2, days 1 + 8) and F (1500 mg/m2/24h days 1 + 8) followed by cetuximab (250mg/m2) bioradiation vs. PF-CRT (arm C) to 72 Gy. Exploratory end-points: best overall response (BOR; RECIST1.1), hematologic acute toxicity (CTCAE v.4.02) of TPF-IC, on time application of bioradiation week 10 ± 7 days & survival (progression-free: PFS; metastasis-free: MFS; recurrence-free: RFS; overall: OS). Results: 94 patients were randomized across 8 centres (A: 34, B: 30, C: 30). Median age: 56 years. Tumorsite: 49% ORO, 34% HYP, 17% OC. 89% had IMRT. BOR (complete, partial remission) was similar for both TPF-arms, A 88% , B 83%. Hematologic toxicity did not improve with split-course TPF-IC (neutropenia G4/5: B 13/3%, A 29/0%; thrombocytopenia G4: B 0%, A 3%). Two patients died from neutropenic sepsis in split-course arm B. Compliance to TPF-IC was higher in the standard arm (A 77%, B 57%). Bioradiation started on time (range: 2-13 weeks) in 85% and 73% and was completed in 94% and 90% of patients in A and B, respectively. At 1-year PFS was 74%, 73% and 43%, MFS was 94%, 78% and 87%, RFS was 76%, 82% and 69%, and OS was 85%, 80% and 59% for A, B and C, respectively. According to univariate Cox regression analysis, TPF-IC was not associated with improved OS (hazard ratio: 1.16 [95% CI: 0.8-1.6; P = n.s]) Conclusions: Split-course TPF-IC lowered compliance and increased hematologic toxicity over standard TPF-IC with similar efficacy. Standard TPF-IC should not be modified outside of clinical trials. This trial was not statistically powered for survival differences. Some secondary end-points are pending. Clinical trial information: NCT01181401.
Apatinib as a salvage treatment in gynecologic cancer patients failed from two or more lines of prior chemotherapy.
Authors: Congying Xie, Meng Su, Xiance Jin
Journal: Journal of Clinical Oncology (2017)

e17009 Background: The aim of this study was to evaluate the efficacy and safety of apatinib, an oral VEGFR2 inhibitor, in the treatment of advanced cervical and ovarian cancer patients who failed from two or more lines of chemotherapy. Methods: The advanced cervical and ovarian cancer patients, who experienced two or more lines of chemotherapy and treated with apatinib from April 2015 to January 2017, were retrospectively reviewed. All eligible patients received continuous apatinib treatment until disease progression, death, or intolerable toxicity. Survival and toxicities outcome were evaluated by Kaplan-Meier method and according to NCI-CTC4.0. Results: Twenty-six patients were eligible (cervical cancer:12 and ovarian cancer:14). After dose adjustment, 14 patients (53.8%) received 500 mg daily of apatinib, 8 patients received 250mg, 3 received 425mg and 1 received 675mg daily. The median progression-free survival (PFS) of cervical cancer and ovarian cancer were 8 months (95%CI:3.83-12.17) and 4 months (95%CI:1.57-6.44), respectively. Objective response rates in cervical cancer and ovarian cancer were 50% and 50%, respectively. Disease control rates were 100% for cervical cancer and 71.4% for ovarian cancer. Complete response was not observed in either cervical cancer or ovarian cancer. A 52-year old patient with recurrent ovarian cancer, experienced two lines of chemotherapy failure, was orally administered with apatinib at a dose of 250mg daily from November 2015, got partial response (PR) after one month, PFS have not yet reach. A 43-year old female patient with advanced cervical cancer, experienced three lines of chemotherapy failure, was orally administered with apatinib at a dose of 250mg daily from September 2015, got PR with a PFS of 14 months. The toxicities associated with apatinib treatment was generally acceptable with 8 patients developed grade 3/4 toxicity. The most common adverse events in this study were hypertension(n = 17), hand-foot syndrome(n = 24), and mouth mucositis(n = 20). Conclusions: Apatinib monotherapy showed promising efficiency with tolerable toxicity for advanced/recurrent cervical and ovarian cancer patients who failed from two or more lines of chemotherapy.
TCT-445 Feasibility of analysis of a novel quantitative method to assess aortic regurgitation after TAVI: Preliminary results of the ASSESS-REGURGE Protocoled Quantitative ASSESSment of aortic regurgitation using Videodensitometry in a multicenter study in Rotterdam, montrEal, yamaGUchi, segebeRG, amstErdam
Authors: Mohamed Abdel-Wahab, Rodrigo Modolo, Osama Soliman, Mohammad Abdelghani, Yosuke Miyazaki, Chun Chin Chang, Norihiro Kogame, Michele Pighi, Zouhair Rahhab, Yoshinobu Onuma, Nicolo Piazza, Nicolas Van Mieghem, Patrick Serruys
Journal: Journal of the American College of Cardiology (2018)
The Phosphodiesterase Inhibitor Pentoxifylline as a Novel Adjunct to Antidepressants in Major Depressive Disorder Patients: A Proof-of-Concept, Randomized, Double-Blind, Placebo-Controlled Trial
Authors: Sahar Mohamed El-Haggar, Mai AbdelRaouf Eissa, Tarek Mohammed Mostafa, Khaled Sabry El-Attar, Mahmoud Samy Abdallah
Journal: Psychotherapy and Psychosomatics (2018)

Background: There is evidence for an association between major depressive disorder (MDD) and both inflammatory and phosphodiesterase (PDE) pathways. This study aimed to evaluate the adjunct role of the PDE inhibitor pentoxifylline (PTX), a compound with anti-inflammatory properties, in the treatment of adult patients with MDD. Methods: This was a prospective, 12-week, double-blind study of parallel groups. Eighty adult outpatients who met the DSM-IV criteria for MDD participated in the trial. Patients were required to have a baseline Hamilton Rating Scale for Depression (HAM-D) score of at least 18. Patients were allocated randomly: 40 received escitalopram 20 mg/day plus placebo while the other 40 received escitalopram 20 mg/day plus PTX (400 mg b.i.d.). Patients were assessed by a psychiatrist at baseline, and 4, 8, and 12 weeks after the medication had been started. The serum levels of TNF-α, IL-6, IL-10, BDNF, 8-OHdG, and serotonin were measured at baseline and after therapy. Results: After 8 and 12 weeks, the PTX group showed a statistically significantly greater improvement in HAM-D score compared to the control group (least squares mean difference [LSMD] –3.29, p = 0.000 and LSMD –3.49, p = 0.000, respectively). Moreover, the PTX group showed a statistically significantly greater reduction in the serum levels of TNF-α, IL-6, IL-10, and 8-OHdG along with a statistically significant increase in the levels of BDNF and serotonin in comparison with the control group after the treatment. Conclusion: The findings of this study suggest that PTX could be a promising adjunct to antidepressants in the treatment of MDD patients.
Correlation of early tumor shrinkage (ETS) and depth of response (DoR) with resectability in patients (pts) with unresectable locally advanced pancreatic cancer (LAPC) undergoing primary treatment with FOLFOXIRI.
Authors: Caterina Vivaldi, Silvia Catanese, Lorenzo Fornaro, Carla Cappelli, Chiara Caparello, Gianna Musettini, Giulia Pasquini, Irene Pecora, Monica Lencioni, Enrico Vasile, Alfredo Falcone
Journal: Journal of Clinical Oncology (2017)

e15777 Background: FOLFIRINOX is a reasonable option in LAPC. GONO FOLFOXIRI has been shown to provide similar efficacy in advanced disease. ETS and DoR, emerging as relevant endpoints in colorectal cancer, have been rarely investigated in LAPC. Methods: Unresectable LAPC pts treated with FOLFOXIRI were identified. Computed tomography (CT) scan was performed every 8 weeks; after that, multidisciplinary team assessed resectability. ETS was defined as the reduction of ≥20% of target lesions’ diameters at first evaluation. DoR was the % of maximal tumor shrinkage at the nadir compared to baseline. Primary endpoint was the correlation of ETS and DoR with radical (R0) resection. Secondary endpoints were correlation of ETS and DoR with overall survival (OS) and progression-free survival (PFS). Radiologist was blinded to survival data. Survival curves were estimated using the Kaplan-Meier method. Log-rank and chi-square tests were applied. Results: Sixty pts were included. Median age was 62 years (range: 34-74), tumor location was head in 68% and body-tail in 32%. At a median follow-up of 26.9 months, response rate was 37%, median OS and PFS were 15.7 and 10.3 months, respectively. Thirty patients (50%) underwent R0 surgery after chemotherapy. Two pts died due to early surgical complication and were censored at the date of surgery for survival analyses. Among 55 evaluable pts, ETS was reached in 19 pts and median DoR was -17% (range: -65 to +100). A strong association between ETS (p = 0.0002) and DoR (p &lt; 0.0001) with R0 resection was observed. In the overall population, ETS was significantly associated with better PFS (14.5 vs 9.4 months, p = 0.037), while no difference in OS was shown (p = 0.63). DoR was significantly associated both with PFS (13.6 vs 7.8 months, p = 0.014) and OS (19.8 vs 14.5 months, p = 0.047). Conclusions: FOLFOXIRI may allow achieving resectability in selected pts. ETS and DoR are significantly associated with R0 resection. Maximizing response with active regimens could be an effective strategy in LAPC. Further validation of ETS and DoR as surrogate endpoints in larger prospective series is required.
Computer extracted shape features of prostate capsule from MRI to predict biochemical recurrence of prostate cancer post-treatment.
Authors: Soumya Ghose, Rakesh Shiradkar, Mirabela Rusu, Jhimli Mitra, Rajat Thawani, Amar Gupta, Andrei Purysko, Anant Madabhushi
Journal: Journal of Clinical Oncology (2017)

e16579 Background: Pre-treatment identification of biochemical recurrence (BCR) from MRI may enable the use of aggressive neo-adjuvant therapies for prostate cancer patients to improve prognosis. BCR is often associated with aggressive cancer growth and/or extra prostatic extension resulting in an irregular bulge and focal capsular retraction. This may induce differences in the shape of the prostate capsule between BCR positive (BCR+) and BCR negative (BCR-) patients as observed on MRI. In this work, we show that computer extracted shape features of the prostate capsule on MRI can identify patients that are at a risk of BCR post-treatment Methods: In a single centre IRB approved study, from a registry of 874 patients, availability of complete image datasets (T1w, T2w and ADC map); no treatment for PCa before MRI; presence of clinically localised PCa; availability of Gleason score; and data available for post-treatment PSA and follow-up for at least 3 years in patients without BCR were used as inclusion criteria to select 80 patients. The prostate capsule was manually segmented on T2w MRI by an experienced radiologist. Two atlases A+ and A- were created for BCR+ and BCR- patients respectively with similar Gleason score (6 to 9), similar numbers in each cohort (25 each) and similar tumor stage (T2 to T3). A t-test based analysis corrected for multiple comparison revealed statistically significant prostate shape differences between A+ and A- in surface of interest (SOI). Curvature features (magnitude and surface normal orientations) were extracted from SOI of the two cohorts. A random forest classifier was trained using the 50 training images (from A+ and A-) and validated using a hold-out validation set of 30 patients. Results: The inter-quartile range, variance, skewness and kurtosis of curvature magnitude and normal orientations were found to be predictive of BCR. The RF classifier trained using these features could predict BCR with an accuracy of 78% and an AUC of 0.71 in the validation set. Conclusions: Curvature magnitude and orientation features of the prostate capsule from the SOI may be predictive of BCR. In future a multi centre independent datasets will be used to validate the findings.
Differential clinical outcome of metastatic colorectal cancer (MCRC) patients (pts) treated with first line FIr-B/FOx adding bevacizumab (BEV) to triplet chemotherapy according to <i>KRAS</i>, <i>NRAS</i> and <i>BRAF</i> genotype detected by massive parallel sequencing.
Authors: Gemma Bruera, Francesco Pepe, Umberto Malapelle, Pasquale Pisapia, Antonella Dal Mas, Paolo Marchetti, Giuseppe Calvisi, Giancarlo Troncone, Enrico Ricevuto
Journal: Journal of Clinical Oncology (2017)

e15041 Background: KRAS/NRAS/BRAF genotypes guide tailoring of first and subsequent lines of MCRC treatment strategy. First line triplet chemotherapy/BEV associations significantly improved progression-free survival (PFS) and overall survival (OS) in overall MCRC patients. OS may be significantly worse in the prevalent KRAS c.35 G &gt; A and BRAFmutant (mt). Evaluation of differential clinical outcome in overall MCRC patients will help identify clinically relevant biomarkers to personalize treatment strategy. Methods: Tumoral samples of 67 MCRC pts treated with FIr-B/FOx (77% overall) were analyzed through a 50 genes panel (PGM/Colon Lung Cancer) by ION Torrent: 58 (86.5%) primary, 9 (13.4%) metastatic samples; 60 (89.5%) pre-, 7 (10.4%) post-treatment. KRAS, NRAS and BRAFcoding frames were analysed. Molecular diagnostic criteria for mutation detection: &gt; 50% coverage; &gt; 1% mutant allelic fraction. Clinical outcomes (PFS and OS) were evaluated and compared by log-rank. Results: Mutant KRAS 2-4 / NRAS 2-4 / BRAF MCRC patients were 49 (73.1%): KRAS 42 (62.6%), NRAS 15 (22.3%), BRAF 5 (7.4%). BRAF mutations were all atypical and concomitant with KRAS and/or NRAS mutations. At median follow-up 21 months (m), overall PFS and OS were 13 and 27m, and KRAS exon 2 wild-type (wt)/mt PFS 14/12m, and OS 28/21m, respectively, consistent with previously reported, and not significantly different. KRAS 2-4 / NRAS 2-4 / BRAF wt/mt, PFS 18/12m, OS 28/22m, not significantly different: KRAS 2-4 wt/mt, PFS 13/12m, OS 27/27m, not significantly different; NRAS 2-4 wt/mt, PFS 16/12m, OS 28/22m, not significantly different; c.35 G &gt; A KRAS mt showed trendy worse PFS/OS 8/14m, respectively; BRAFmt/wt trendy worse PFS 8 vs 14m and OS 11 vs 28m. Conclusions: Retrospective analysis of clinical outcome of MCRC patients treated with intensive first line BEV added to triplet chemotherapy FIr-B/FOx seems to be not significantly affected by KRAS/ NRAS/ BRAF genotype.