tbuckley/cabot-search huggingface dataset:
Prospective study of a tailored comprehensive cancer gene (TCCG) set built on a next generation sequencing (NGS) platform in incurable head and neck squamous cell carcinoma (The Pro-TCCG Protocol).
Authors: Kevin Yee Kai Chen, Andrew J Bredemeyer, Jessica C. Ley, Loren S. Michel, Tanya Marya Wildes, Ravi Uppaluri, Ling Chen, Douglas Adkins
Journal: Journal of Clinical Oncology (2015)

e17076 Background: The genetic landscape of HNSCC is heterogeneous. However, only one targeted therapy (an EGFR inhibitor) has shown efficacy, albeit modest. We hypothesized that a TCCG set of 40 clinically relevant and currently targetable cancer genes (TCCG-40) would identify personalized therapeutic options in patients (pts) with incurable HNSCC. Methods: Targeted sequencing of 40 genes utilizing a NGS platform was performed on DNA from FFPE tissue. Single nucleotide variants and insertions/deletions were reported. Actionable genetic variants described in the TCCG-40 were PIK3CA, PTEN, PDGFRA, MAPK1, RET, VHL, JAK2, KIT, FGFR4, ERBB2, ASXL-1, ALK and others. Genetic variants were reported as Level 1 (predictive/prognostic in HNSCC), 2 (predictive/prognostic in other cancer), 3 (reported in cancer), 4 (variant, unknown significance), or 5 (polymorphism). The primary objective was to determine the clinical benefit rate of the TCCG-40 in pts with incurable HNSCC, defined as selection of a targeted therapy based on the TCCG-40 gene set that resulted in disease control (CR, PR, SD by RECIST 1.0) [H0: 1%; H1: > 10%). Secondary objectives were to determine obstacles in TCCG-40 implementation and administration of TCCG-40-directed targeted therapy. Results: The TCCG-40 gene set was performed in 24 (62%) of 39 pts enrolled. Specimens were obtained at recurrence (7) or diagnosis (17). 61 mutations among 25 genes were identified. Most commonly mutated genes were TP53 (28%), NOTCH1 (16%), and ATM (7%). Actionable (Level 1/2) mutations were identified in only 3 (7.7%) pts, and included variants of PIK3CA and PTEN. To date, none of these pts have been treated with agents that target these variants. Level 3-5 variants were identified in 19 pts. Common obstacles to testing were: no financial coverage (33%) and insufficient tissue (27%). Conclusions: The maximum potential clinical benefit rate of the TCCG-40 was low (7.7%) and the test could not be performed in 38%. Overcoming these obstacles will be required for successful application of a tailored TCCG gene set based on NGS platform to achieve clinical benefit in pts with incurable HNSCC.
Cation Exchange Resin in the Treatment of Congestive Heart Failure
Authors: J. R. ELKINTON, R. D. SQUIRES, W. C. KLINGENSMITH
Journal: Circulation (1952)

Electrolyte balances were measured in four edematous cardiac patients receiving cation exchange resin. It was found that such therapy would increase the fecal loss of sodium and, in some of the cases, would result in the loss of edema which had been refractory to other forms of therapy. In these cases the main route of sodium excretion was through the kidneys and not through the intestinal tract. The resin appeared to potentiate the renal action of simultaneously administered mercurial diuretics.
Increasing utilization of multi-parametric magnetic resonance imaging in prostate cancer active surveillance.
Authors: Avinash Maganty, Michelle Yu, Liam C Macleod, Jonathan G Yabes, Mina M Fam, Jathin Bandari, Robert Turner, Alessandro Furlan, Christopher Paul Filson, Benjamin John Davies, Bruce Lee Jacobs
Journal: Journal of Clinical Oncology (2019)

125 Background: Multi-parametric resonance imaging (mpMRI) has emerged as a tool that may improve risk-stratification and decrease repeated biopsies in men electing active surveillance. However, the extent to which mpMRI has been implemented in active surveillance has not been established. Therefore, we sought to characterize the use of multiparametric magnetic resonance imaging (mpMRI) in Medicare beneficiaries electing active surveillance for prostate cancer. Methods: SEER-Medicare claims data, we identified men with localized prostate cancer diagnosed between 2008-2013 and managed with active surveillance. We classified men into two treatment groups: active surveillance without mpMRI and active surveillance with mpMRI. We then fit a multivariable logistic regression models to examine changing mpMRI utilization over time, and factors associated with the receipt of mpMRI. Results: We identified 9,467 men on active surveillance. Of these, 8,178 (86%) did not receive mpMRI and 1,289 (14%) received mpMRI. The likelihood of receiving mpMRI over the entire study period increased by 3.7% (p = 0.004). On multivariable logistic regression, patients who were younger, white, had lower comorbidity burden, lived in the northeast and west, had higher incomes and lived in more urban areas had greater odds of receiving mpMRI (all p &lt; 0.05). Conclusions: From 2008-2013, use of mpMRI in active surveillance increased gradually but significantly. Receipt of mpMRI among men on surveillance for prostate cancer varied significantly across demographic, geographic and socioeconomic strata. Going forward, studies should investigate causes for this variation and define ideal strategies for equitable, cost-effective dissemination of mpMRI technology.
Determinants of early mortality in 37,568 colon cancer patients participating in 25 clinical trials of the ACCENT database.
Authors: Winson Y. Cheung, Lindsay A. Renfro, Greg Yothers, Richard G. Gray, Daniel G. Haller, Chris Twelves, Thierry Andre, Eric Van Cutsem, Leonard Saltz, Axel Grothey, Roberto Labianca, Steven R. Alberts, Hans-Joachim Schmoll, Katherine Guthrie, Aimery De Gramont, Carmen Joseph Allegra, Daniel J. Sargent
Journal: Journal of Clinical Oncology (2015)

6580 Background: Clinical trials are the gold standard for evaluating novel therapeutics. Accrual of patients (pts) at substantial risk of significant treatment toxicity or early mortality compromises trial integrity, may pose greater harm than benefit, and can complicate trial interpretation. We aimed to define prognostic factors that may be used to guide risk-benefit assessments among pts being considered for phase III adjuvant colon cancer (CC) studies. Methods: A pooled, retrospective analysis of individual level data from CC pts enrolled in randomized trials of adjuvant systemic therapy was conducted. Separate multivariate logistic regression models with different definitions of early mortality (30, 60, 90 days, and 6 months from trial randomization) as outcome variables were constructed, adjusting for clinically and statistically significant variables from univariate and interaction tests. Results: We included 37,568 pts from 25 trials. Median age 61 years (IQR 53-68), 54% men, 90% White, 29% and 71% stage II and III disease, and 79%, 20%, and 1% ECOG performance status (PS) 0, 1, and 2+, respectively. Rates of early mortality were low: 109 (0.3%) at 30 days, 215 (0.6%) at 60 days, 281 (0.8%) at 90 days, and 540 (1.4%) at 6 months in the pooled cohort. On univariate analyses, increasing age, male gender, poorer PS, and stage III vs. stage II disease predicted for higher likelihood of early mortality. Race, body mass index, lymph node ratio, micro-satellite status as well as study time era were not associated with worse outcomes. In multivariate models, increased age and poorer PS were associated with early mortality at all time-points (age: p < 0.0001 and PS: p = 0.05 at 6 months), with pts aged > / = 80 years having a 6 month death rate of 4.6% as compared to < 1% for the youngest and pts with PS 2+ having a 6 month death rate of 4.4% as compared to 1.7% and 1.1% for PS 1 and 0, respectively. Conclusions: Early mortality in adjuvant trials of CC was infrequent. However, it was more prevalent in the elderly and among individuals with PS 2+, underscoring the need for specific trial designs that can accommodate the vulnerabilities of these underrepresented subsets of the population.
Protective Role of RNA Helicase DEAD-Box Protein 5 in Smooth Muscle Cell Proliferation and Vascular Remodeling
Authors: Ye Fan, Yikuan Chen, Jing Zhang, Feng Yang, Yanhua Hu, Li Zhang, Chunyu Zeng, Qingbo Xu
Journal: Circulation Research (2019)

Rationale: RNA helicases, highly conserved enzymes, are currently believed to be not only involved in RNA modulation, but also in other biological processes. We recently reported that RNA helicase DDX (DEAD-box protein)-5 is required for maintaining the homeostasis of vascular smooth muscle cells (SMCs). However, the expression and function of RNA helicase in vascular physiology and disease is unknown. Objective: To investigate the role of RNA helicase in vascular diseases. Methods and Results: We showed here that DDX-5 was the most abundant DEAD-box protein expressed in human and rodent artery, which mainly located in SMCs. It was demonstrated that DDX-5 levels were reduced in cytokine-stimulated SMCs and vascular lesions. DDX-5 knocking down or deficiency increased SMC proliferation and migration, whereas overexpression of DDX-5 prevented aberrant proliferation and migration of SMCs. Mechanistic studies revealed transcription factor GATA (GATA-binding protein)-6 as a novel downstream target of DDX-5, which directly interacted with GATA-6 and protected it from MDM (mouse double minute)-2–mediated degradation. Our ChIP assay identified a previously unreported binding of p27 Kip1 promoter to GATA-6. DDX-5 increased the recruitment of GATA-6 to p27 Kip1 promoter, which enhanced p27 Kip1 expression and maintained SMC quiescence. Finally, we showed exacerbated neointima formation in DDX-5 SMC-deficient mice after femoral artery injury, whereas overexpression of DDX-5 potently inhibited vascular remodeling in balloon-injured rat carotid artery. Conclusions: These findings provide the first evidence for a role of RNA helicase DDX-5 in the protection against SMC proliferation, migration, and neointimal hyperplasia. Our data extend the fundamental role of RNA helicase beyond RNA modulation, which provides the basic information for new therapeutic strategies for vascular diseases.
Overall survival outcomes with the use of adjuvant chemotherapy, radiation therapy and hormone therapy in high-risk, very-high-risk and node-positive prostate cancer post radical prostatectomy: A NCDB analysis.
Authors: Alina Basnet, Margaret K Formica, Poornima Ramadas, Sam Benjamin
Journal: Journal of Clinical Oncology (2019)

118 Background: Phase III trials have not consistently demonstrated overall survival (OS) advantage of adjuvant radiation therapy (ART) in prostate cancer (PC) with high risk/very high risk features after radical prostatectomy (RP). Adjuvant hormone therapy (AHT) in PC after RP improved OS in patients with positive lymph nodes (pLNs). We report an observational study on the impact of AHT to ART in NCCN defined high-risk/very high risk (Group 1), and adjuvant chemotherapy (ACT) to AHT in pLNs (group 2) post RP on OS. Methods: We conducted a retrospective study of PC patients (group 1 and group 2) who underwent RP and/or pelvic lymph node dissection. OS was calculated using Kaplan Meier analysis. Group 1 compared ART+AHT vs ART and Group 2 AHT+ ACT vs AHT within 16 weeks of RP. Multivariate analysis was performed with Cox proportional hazard regression model to adjust for different variables. Results: Out of 1,390,357 PC patients reported in NCDB (2004-2015) 182,653 and 11,972 met our inclusion criteria for Group 1 and Group 2 respectively. 3.37% of Group 1 received ART and/or AHT. 19.81% of Group 2 received AHT and/or ACT. Patients who received ART + AHT were more likely to be older, Non-Hispanic white, more likely to have pT4, and have higher prostate specific antigen (PSA) and Gleason scores (GS). Patients who received AHT+ACT were more likely to be younger, with private insurance, and lower Charlson-Deyo Score (CDCC) score. Five and seven year OS with adjusted hazard ratio (aHR) among Group 1 and Group 2 are depicted in table. Conclusions: No statistically significant difference in OS was seen among respective treatment groups. Limitations that exist with this registry based study include lack of randomization, differences in surgical and radiation techniques, duration and choices of ACT and AHT.[Table: see text]
Wellbeing—for patients and doctors
Authors: Fiona Godlee
Journal: BMJ (2019)

How should we better prevent falls among older people?This may not seem the most pressing issue for doctors, but, as reported this week (doi:10.1136/bmj.l880),falls are a leading cause of morbidity and death in people aged over 75, and the costs to health and social care are growing as the population ages.
S-1 as adjuvant chemotherapy for stage III colon cancer: Updated outcomes of ACTS-CC trial.
Authors: Yusuke Kinugasa, Megumi Ishiguro, Eiji Nakatani, Takeshi Endo, Hiroharu Shinozaki, Yasumasa Takii, Yu Takahashi, Hidetaka Mochizuki, Kenjiro Kotake, Shingo Kameoka, Keiichi Takahashi, Toshiaki Watanabe, Masahiko Watanabe, Narikazu Boku, Naohiro Tomita, Kenichi Sugihara
Journal: Journal of Clinical Oncology (2015)

3570 Background: The ACTS-CC trial, a randomized phase III trial, demonstrated that adjuvant therapy with S-1 for stage III colon cancer was non-inferior in 3-year disease-free survival (DFS) to that of tegafur-uracil plus leucovorin (UFT/LV). We updated DFS and overall survival (OS), and performed some clinically relevant subgroup analyses. Methods: A total of 1,535 patients with stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days, 4 courses) or UFT/LV (UFT: 300- 600 mg/day and LV: 75 mg/day on days 1-28 every 35 days, 5 courses). Primary endpoint was DFS. Secondary endpoints were OS and safety. Results: A total of 1518 patients (758 in the S-1 group and 760 in the UFT/LV group) were included in the efficacy analysis. Median follow-up was 63.5 months, the mean age at enrollment was 64.5 years, wide lymph node dissection (D3) was done in 79.8%, the median number of dissected lymph nodes was 17, and stage IIIA/IIIB/IIIC were 15%/71%/14%. The hazard ratio (HR) for DFS was 0.88 (95%CI, 0.74-1.06; p = 0.177). The 5-year DFS rate was 70.2% in the S-1 group and 66.9% in the UFT/LV group. In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the DFS in S-1 and UFT/LV, except for histological type; favors S-1 in patients with poorly-differentiated adenocarcinoma. Approximately 5% of patients in the both groups experienced second cancers. Among the patients with recurrences in each group, 46.3% and 44.7% underwent surgical resection as an initial treatment for recurrence. The HR for OS was 0.92 (95%CI, 0.72-1.17; p = 0.488). The 5-year OS rates were 86.0% and 84.4% in the S-1 and UFT/LV group, respectively. Conclusions: Adjuvant therapy of S-1 for stage III colon cancer was confirmed to be non-inferior both in DFS and OS to those of UFT/LV after long follow-up. Favorable OS might be brought by the high resection rate of recurrent lesions. Clinical trial information: NCT00660894.
Using a European Value-Based Medicine Approach to Evaluate Hepatocellular Carcinoma Care at a US Tertiary Care Center.
Authors: Nicole Ming-Ming Loo, Tamar Hamosh Taddei
Journal: Journal of Clinical Oncology (2015)

e15118 Using a European Value-Based Medicine Approach to Evaluate Hepatocellular Carcinoma Care at a US Tertiary Care Center Background: The Italian Value Based Medicine in Hepatology (VBMH) study proposed 3 outcome indicators (OIs) for the management of hepatocellular carcinoma (HCC)* including 1) survival stratified for BCLC stage/treatment, 2) worsening BCLC score after curative locoregional therapy/resection at 3 months, and 3) very early HCC recurrence within 6 months of curative therapy. We aimed to evaluate our HCC metrics based on the HCC OIs and assess the suitability of the HCC OIs for our center. Methods: Retrospective analysis of data collected by chart review of patients presented to multidisciplinary Liver Tumor Board (LTB) from 2/1/2013-2/28/2014. Start date was when EPIC EHR was introduced at our center. Inclusion criteria included all new patients presented at LTB. Patients without cirrhosis, without confirmed HCC, with prior liver transplantation, who refused treatment, were lost to follow up, or had incomplete EHR data within 6 months of initial LTB presentation were excluded. Results: In the study period, 61/167 of new patients presented to LTB met the inclusion/exclusion criteria. Median age of HCC diagnosis was 61 ± 10 and 87% were male. Etiology was primarily HCV (54.1%). BCLC stage at presentation A (45.9%), B (21.3%), C (11.5%), and D (21.3%). One year survival rates [from first therapy if applicable] based on BCLC stage was A (73.1%), B (33.3%), C (28.6%), and D (15.3%). Only 3/61 (4.9%) patients were excluded from survival data analysis as one year survival was unavailable. Liver decompensation or death within 3 months of initial curative therapy occurred in 5/31 (16.1%) patients. Very early recurrence of HCC after curative therapy occurred in 6/29 (20.7%) patients. Conclusions: Our data suggest we may have a sicker population with more advanced HCC at the time of presentation than in the Italian VBMH cohort. We surmise these differences may be related to comparing outcomes in a US tertiary care referral center to outcomes from a European national health care system that offers more centralized care with a uniform referral process. *Okolicsanyi, S et al (2014). J Hepatol 60(1): S399 [P973]
Radiomics of Multiparametric MRI for Pretreatment Prediction of Pathologic Complete Response to Neoadjuvant Chemotherapy in Breast Cancer: A Multicenter Study
Authors: Zhenyu Liu, Zhuolin Li, Jinrong Qu, Renzhi Zhang, Xuezhi Zhou, Longfei Li, Kai Sun, Zhenchao Tang, Hui Jiang, Hailiang Li, Qianqian Xiong, Yingying Ding, Xinming Zhao, Kun Wang, Zaiyi Liu, Jie Tian
Journal: Clinical Cancer Research (2019)

We evaluated the performance of the newly proposed radiomics of multiparametric MRI (RMM), developed and validated based on a multicenter dataset adopting a radiomic strategy, for pretreatment prediction of pathologic complete response (pCR) to neoadjuvant chemotherapy (NAC) in breast cancer.A total of 586 potentially eligible patients were retrospectively enrolled from four hospitals (primary cohort and external validation cohort 1-3). Quantitative imaging features were extracted from T2-weighted imaging, diffusion-weighted imaging, and contrast-enhanced T1-weighted imaging before NAC for each patient. With features selected using a coarse to fine feature selection strategy, four radiomic signatures were constructed based on each of the three MRI sequences and their combination. RMM was developed based on the best radiomic signature incorporating with independent clinicopathologic risk factors. The performance of RMM was assessed with respect to its discrimination and clinical usefulness, and compared with that of clinical information-based prediction model.Radiomic signature combining multiparametric MRI achieved an AUC of 0.79 (the highest among the four radiomic signatures). The signature further achieved good performances in hormone receptor-positive and HER2-negative group and triple-negative group. RMM yielded an AUC of 0.86, which was significantly higher than that of clinical model in two of the three external validation cohorts.The study suggested a possibility that RMM provided a potential tool to develop a model for predicting pCR to NAC in breast cancer.
Oncogenic Properties of the Antisense lncRNA <i>COMET</i> in <i>BRAF</i>- and <i>RET</i>-Driven Papillary Thyroid Carcinomas
Authors: Roberta Esposito, Daniela Esposito, Pierlorenzo Pallante, Alfredo Fusco, Alfredo Ciccodicola, Valerio Costa
Journal: Cancer Research (2019)

Abstract RET rearrangements as well as BRAF and RAS mutations drive differential pathway activation in papillary thyroid carcinomas, leading to different tumor phenotypes and prognoses. Although The Cancer Genome Atlas Consortium has identified tumor subgroups based on protein-coding gene signatures, neither expression of long noncoding RNAs (lncRNA) nor their correlation with specific tumor-driving mutations and rearrangements have been systematically assessed. Here, we reanalyzed our RNA-sequencing data using a de novo discovery approach to identify lncRNAs and define tumor subtype-specific signatures of annotated lncRNAs. Among them, we identified COMET (Correlated-to-MET), a natural antisense transcript that was highly expressed in carcinomas harboring BRAFV600E mutation or RET gene rearrangements (i.e., BRAF-like tumors) and induced the downstream MAPK pathway. In papillary thyroid carcinomas, COMET was part of a coexpression network including different oncogenes belonging to the MAPK pathway, and its expression highly correlated with MET expression. Depletion of COMET resulted in reduced expression of genes within this network, including the MET oncogene. COMET repression inhibited viability and proliferation of tumor cells harboring BRAFV600E somatic mutation or RET oncogene rearrangement and dramatically reduced motility and invasiveness of tumor cells. Moreover, silencing COMET markedly increased sensitivity to vemurafenib, a common inhibitor of mutated B-raf. Collectively, our results suggest COMET as a new target to improve drug-based cancer therapies, especially in BRAF-mutated and MET-addicted papillary thyroid carcinomas. Significance: These results highlight the oncogenic role of lncRNA COMET in thyroid and indicate it as a potential new target to overcome vemurafenib resistance in BRAF-mutated and MET-addicted carcinomas.
Perioperative morbidity and mortality with bleomycin in primary mediastinal non seminomatous germ cell tumor (PMNSGCT).
Authors: Praveen Ranganath, Kenneth Kesler, John Dentel, Lawrence H. Einhorn
Journal: Journal of Clinical Oncology (2015)

4538 Background: PMNSGCT represents one of the most challenging subsets of malignant germ cell tumors. PMNSGCT has a distinctly worse prognosis and is appropriately categorized as poor risk disease. A phase III intergroup study in patients with poor risk germ cell tumors, including PMNSGCT demonstrated equivalent survival in patients with Etoposide, Ifosfamide and Cisplatin (VIP) compared to standard Bleomycin, Etoposide and Cisplatin (BEP) regimen. We have demonstrated that the magnitude of post chemotherapy surgery required for PMNSGCT is higher with potential for serious pulmonary complications including post operative pulmonary failure and death. This retrospective study from 1978-2013 compares perioperative morbidity and mortality associated with Bleomycin (BEP) vs. non Bleomycin (VIP) containing regimens. Methods: From 1978-2013, 221 PMNSGCT patients (mean age, 29 years; ranging from 12- 50 years) who underwent post chemotherapy surgery were reviewed. Results: Of the 221 patients who underwent post chemotherapy surgery, 55 were treated with VIP and 166 with BEP chemotherapy. Among patients who received BEP, 83% had ≥ 3 cycles of Bleomycin. Both groups were well balanced in respect to the number of patients requiring pulmonary resection, extent of pulmonary resection and surgical approach. Post operative complications including acute respiratory failure and/or pneumonia (22 vs. 0, p value 0.004) and prolonged ventilator requirement > 48 hrs (30 vs. 2, p value 0.004) were significantly higher in patients who received BEP compared to VIP chemotherapy respectively . There were 11 post operative deaths reported- 10 patients with post operative respiratory failure and 1 death from pulmonary embolism. All deaths were in BEP chemotherapy group and 0 post operative deaths were reported in patients who received VIP chemotherapy (p value 0.05). Conclusions: Bleomycin containing chemotherapy regimens have traditionally been the standard of care for patients with poor-risk NSGCTs, including PMNSGCTs. Given the high rate of post-operative pulmonary failure after BEP, these results support our present policy of preferring VIP in PMNSGCT patients prior to major thoracic surgical procedures.