tbuckley/cabot-search huggingface dataset:
Cervical cancer harboring a Rb1 mutation may sensitize to cisplatin via PI3K/AKT pathway by regulating apoptosis.
Authors: Peng Luo, Jingwen Zou, Junguo Bu, Hui Meng, Jie Chen, Jian Zhang
Journal: Journal of Clinical Oncology (2019)

5531 Background: Cervical cancer is one of the most common malignant tumors in women and major causes of cancer death in women. Although concurrent chemoradiotherapy has improved the treatment of cervical cancer, due to the heterogeneity of the tumor to chemotherapy or radiation therapy, especially the varied response to chemotherapy, the patients respond differently to the same therapeutic regimen, furthermore some patients get rapid progression. Therefore, we attempted to analyze the potential relationship between genomic mutation and chemotherapy response and survival in cervical cancer patients. Methods: Clinical information and sequencing data of Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (CESC) in Genomic Data Commons (GDC) data portal were obtained through TCGAbiolinks. Only patients with stage IIB-IV CESC who received cisplatin only and were included. Cisplatin sensitivity data and sequencing data of CESC cell lines were obtained from the Genomics of Drug Sensitivity in Cancer (GDSC). Cox regression analysis, Kaplan-Meier survival analysis, differential analysis of gene expression and functional enrichment were used to explore the role of different mutations in survival and cisplatin sensitivity. Results: A total of 48 patients with stage IIB-IV CESC were enrolled. 77 genes with mutation frequency &gt; 10% were included in final analysis . Multivariate analysis showed that the mutation of Rb1 was an independent predictor of overall survival (OS) (HR = 0.07, 95%CI 0.01-0.73, P = 0.026). Patients with mutant Rb1 had better overall survival (134.2 versus 86.8 months) compared with patients with wild-type Rb1. The half maximal inhibitory concentration (IC50) of the mutant Rb1 cell line to cisplatin was significantly lower than that of the wild-type cell line (3.49 versus 10.15μM, P = 0.038). A total of 332 differently expressed genes (DEGs) were identified and the KEGG pathway enrichment analysis showed that most DEGs were enriched in the PI3K/AKT pathway (P = 0.015). Conclusions: We found that Rb1 mutation was an independent survival predictor in stage IIB-IV CESC, and CESC patients with Rb1 mutation may be more sensitive to cisplatin.
Inclusion of patient-reported outcomes (PROs) in randomized controlled trials (RCTs) with elderly cancer patients: A systematic review.
Authors: Francesco Sparano, Neil K Aaronson, Mirjam A.G. Sprangers, Peter Fayers, Andrea Pusic, Jacobien M Kieffer, Jonathan Rees, Chonghua Wan, Mike Pezold, Sarah Fuzesi, Sumit Isharwal, Amelie Anota, Emilie Charton, Marco Vignetti, Francesco Cottone, Jane M. Blazeby, Fabio Efficace
Journal: Journal of Clinical Oncology (2019)

e18217 Background: Inclusion of PROs in RCTs involving elderly cancer patients may be particularly important, as the elderly are often frail and vulnerable, and treatment decisions need to carefully balance potential burden against benefit. We aimed to determine how many RCTs involving elderly patients have included a PRO endpoint, and identified the most relevant PRO information available in this area. Methods: A systematic review in PubMed/Medline and Cochrane Library identified RCTs with PRO endpoint that enrolled a cancer sample (breast, colorectal, lung, prostate, gynaecological and bladder cancer) with a mean/ median age ≥70 years, published from January 2004 to June 2018. The quality of PRO reporting was evaluated using the ISOQOL-PRO recommended criteria. Two reviewers independently performed data extraction. RCTs meeting at least two-thirds of the recommended criteria were considered as “probably-robust” and therefore most likely to be able to inform patient care. Results: Out of the 610 RCTs with PRO endpoint identified, only 67 RCTs (11%) enrolled a sample that met the above criteria. In 19 RCTs (28.4%) PROs were the primary endpoint and 35 RCTs (52.2%) were conducted in a metastatic population. Less than one-third of these trials (n = 21) were considered as probably-robust. In 10 (47.6%) out of the 21 probably-robust RCTs, PROs favored the experimental arm and in 8 (38.1%) the arms did not differ. Overall survival (OS) was an endpoint in 13 of the probably-robust RCTs. In only 3 of these RCTs (23.1%) did OS improve in the experimental arm and in 10 (76.9%) there was no difference in OS between arms. In about half of the probably-robust trials evaluating OS (n = 7, 53.8%), PROs provided information that contrasted with survival findings. In two RCTs, OS improved in the experimental arm, while PROs either did not change between arms (n = 1) or favoured the control arm (n = 1). Conversely, in 5 RCTs (38.5%), OS did not differ between arms whereas PROs favoured the experimental arm. Conclusions: Among cancer RCTs including PROs, the proportion of those conducted in the elderly is low. However, PRO data may provide useful information for these type of patients and their clinicians.
Tobacco cessation practices among primary care physicians in northern Illinois.
Authors: Cheryl Nocon, Mihir Bhayani, Amanda Karcioglu
Journal: Journal of Clinical Oncology (2019)

e23054 Background: Tobacco cessation is an acknowledged key component of cancer survivorship programs, but significant barriers to program implementation exist. In a 2012 ASCO member survey, 86% of respondents agreed that tobacco cessation should be a routine part of clinical care. However, only 29% reported adequate training. A 2013 survey of physicians at NCI Cancer Centers also showed high levels of support for such programs, but only 1% of oncologists personally engaged themselves. This view is in line with ASCO guidelines that recommend cessation interventions by primary care (PCPs). There is a disconnect between the oncologist’s desire to provide high quality tobacco cessation support for cancer patients and the delegation and delivery of such support. The goal of our study is to evaluate current tobacco cessation practices of PCPs in a large integrated healthcare system. Methods: An electronic survey was sent to all PCPs (n = 165) of the NorthShore Medical Group (Northern Illinois) with questions about their views and practices regarding tobacco cessation. Results: 53 PCPs responded to the survey (response rate of 32%). 94% of respondents believe that PCPs are primarily responsible for addressing tobacco cessation with general patients. 89% believe that PCPs are also responsible for cancer patients, although 34% believe the responsibility should be shared with oncologists. 100% believe that tobacco use affects cancer outcomes in their patients, and 98% report sufficient training in providing cessation support. 90% always ask their patients about tobacco status at the initial visit; this drops to 21% at follow-up visits. For current smokers, 57% of PCPs recommend tobacco cessation all the time and 36% recommend services most of the time. Lack of patient willingness was the most frequently cited barrier to tobacco cessation efforts (74%), followed by lack of time (46%) and lack of resources (42%). Conclusions: PCPs view themselves as primarily responsible for addressing tobacco cessation with their patients but are limited by multiple factors. This primary care-based approach is endorsed by ASCO and other clinical guidelines. More financial and clinical support should be allocated for successful efforts against tobacco dependency.
Characteristics, treatment patterns, and survival from three cohorts of advanced or metastatic cancer patients using healthcare claims data in the United States.
Authors: Francois-Xavier Lamy, Daniel C Beachler, Leo J Russo, Stephan Lanes, Jade Dinh, Devon H Taylor, Ruihua Yin, Aziza Jamal-Allial, Patrice Verpillat
Journal: Journal of Clinical Oncology (2019)

e13082 Background: Our main objective was to identify, in healthcare claims data, patients with advanced or metastatic: urothelial carcinoma (amUC), gastric cancer (amGC) and non-small cell lung cancer (amNSCLC) and to report on their characteristics, treatments, and survival rates using contemporaneous real-world data. Methods: This cohort study was conducted in the HealthCore Integrated Research Database (HIRD), from January 2010 to January 2018, which contains healthcare claims data from commercial health plans across the US (60 million lives). We applied algorithms, previously validated on registry data, to the HIRD to define 3 cohorts of advanced stage cancer. Cohort characteristics and treatment patterns were described. Patient vital status was captured through probabilistic linkage with the National Death Index (NDI) and survival was assessed using the Kaplan-Meier method. Results: Algorithms to predict advanced stage cancer resulted in the following cohorts: 1,501 amUC, 6,253 amGC and 38,451 amNSCLC cases. Most patients in each cohort were de novo advanced or metastatic, but subsets were diagnosed at early stage and progressed to advanced stage (ranging from 15.1% for amNSCLC to 23.1% for amUC). Patient characteristics, treatments and survival outcomes are described in Table. Not all received systemic treatment; Immune Checkpoint inhibitors (ICI) were used in 5.3%, 2.2% and 10.8% of treated amUC, amGC and amNSCLC patients, respectively. Conclusions: In these cohorts of advanced or metastatic cancer patients, median survival time was limited despite most receiving treatment: radiation, systemic therapy or surgery. Treatment with ICI was low despite recent data in amUC and amNSCLC. Characteristics, treatments, and survival from estimated advanced stage date. [Table: see text]
Understanding Limitations of the National Inpatient Sample to Facilitate its Proper Use—Reply
Authors: Krish C. Dewan, Suparna M. Navale, Edward G. Soltesz
Journal: JAMA Surgery (2019)

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An effective and accurate algorithm for measuring the tumor mutation burden of cancer patients plasma.
Authors: Bo Liu, Shuang Zhou, Yu Hang Cai, Ying Yang, Mingzhi Ye, Tai Ping Shi
Journal: Journal of Clinical Oncology (2019)

e14177 Background: Tumor Mutation Burden (TMB) is deemed to be one of the effective genomic biomarkers that are used to predict the response to PD-1/PD-L1 blockade immunotherapy. As an exciting biomarker for diagnose and an alternative assess method for tissue TMB (tTMB), blood TMB (bTMB) is measured to further distinguish the patients who may benefit from immunotherapy. However, there is no recognized rule to calculate bTMB so far. Methods: In this study, we developed an in-house algorithm called PTAB to calculate bTMB of plasma, all credible single nucleotide variants and insertion-deletions whose allele frequency is greater than 1% are selected in PTAB without synonymous mutations and drive mutations. We also constructed a 636 genes panel which region size is 1.95Mb to identify all the associated mutations, due to the high costs and long turnaround time of WES. Results: Meanwhile, we assessed a cohort of 50 lung cancer plasma samples and paired tissues to ensure the consistency of different algorithm used for tissue and plasma. The results show that Pearson correlation coefficient (R 2 ) between bTMB and tTMB in 50 patients is 0.7128. In addition, we found that the consistency of lung squamous carcinomas obviously higher than that of lung adenocarcinoma (0.8932 vs. 0.5947). We also described the distribution of bTMB and tTMB value of Chinese patients, including 594 tissue samples and 561 plasma samples from 8 types of cancers, including lung cancer, colorectal cancer, breast cancer, et al. The overall comparative analysis of 1155 previous data suggested that the distribution modes of bTMB and tTMB were almost same in certain cancer type, though the level of bTMB was generally lower than that of tTMB. Conclusions: Preliminary data highlight that PTAB is an effective and accurate algorithm for measure the TMB of plasma. The applicability of bTMB testing on liquid biopsy needs further investigation and may be clarified within the ongoing clinical trials.
Radiomics analysis for pathological classification prediction in BI-RADS category 4 mammographic calcifications.
Authors: Chu-qian Lei, Wei Wei, Zhen-yu Liu, Qian-Qian Xiong, Ci-Qiu Yang, Teng Zhu, Liu-Lu Zhang, Mei Yang, Jie Tian, Kun Wang
Journal: Journal of Clinical Oncology (2019)

e13055 Background: To establish and validate a radiomics-based imaging diagnostic model to predict Breast Imaging Reporting and Data System (BI-RADS) category 4 calcification of breast with mammographic images before biopsy and assess its value. Methods: A total of 212 BI-RADS category 4 pathology-proven mammographic calcifications without obvious mass on mammography were retrospectively enrolled (159 in primary cohort and 53 in validation cohort). All patients received ultrasound inspection and the results were available. 8286 radiomic features were extracted from each mammography images. We utilized machine learning to build a radiomic signature based on optimal features. Independent clinical factors were selected by multivariable logistic regression analysis, and we incorporated the radiomic signatures and risk clinical factors to build a radiomic nomogram. The performance of the radiomic nomogram were assessed by the area under the receiver-operating characteristic curve (AUC). Results: Six features were selected to develop the radiomic signatures based on the primary cohort. Combining with menopausal states, the individualized radiomic nomogram reached an AUC of 0.803 in the validation cohorts, and its clinical utility was confirmed by the decision curve analysis. The difference was significant between the AUC value of differentiating results of the radiomic nomogram compared with ultrasound, mammography and combined modality respectively(p &lt; 0.05 in all three groups). Especially, for patients with MG+/US- calcifications, radiomics nomogram can be screen out benign calcifications. Conclusions: Based on mammographic radiomics, we developed a method for prediction of pathological classification in BI-RADS IV calcification, which has a certain predictive effect.
Impact of the Affordable Care Act on insurance for adolescents and young adults with cancer.
Authors: Lena Winestone, Lauren Hochman, James Sharpe, Elysia Marie Alvarez, Laura Becker, Eric Jessen Chow, Jonathan D. Fish, Joseph Reiter, Jill P. Ginsberg, Jeffrey H. Silber
Journal: Journal of Clinical Oncology (2019)

e18125 Background: The 2010 Dependent Coverage Provision (DCP) of the Affordable Care Act (ACA) allowed young adults to remain on their parents' health insurance until age 26 years (y), whereas pre-DCP the cut-off varied, but was most often 18 y. Our objective was to compare rates of insurance disenrollment among patients with cancer who were DCP-eligible compared to those who were not. Methods: A retrospective cohort from the OptumLabs Data Warehouse, which includes claims data for privately insured enrollees in a large US health plan, was used. Patients born between 1982-93 diagnosed with cancer between 2000-15 were included. In the Recent Cohort, patients who turned 19 in 2010-12 (who were always eligible to stay on parents’ insurance) were matched to patients who turned 19 in 2007-09 (who were not protected by the DCP when they turned 19). Sensitivity analyses paired patients in an Earlier Cohort, who turned 19 (in 2001-03 and 2004-06), none of whom were eligible for the DCP when they turned 19. Patients were matched on cancer type, diagnosis date, and additional clinical characteristics. Using a time to loss of coverage analysis (defined as &gt; 90 d interruption in insurance enrollment), hazard ratios (HR) were calculated using Cox proportional hazards models. Difference-in-difference between pairs from the Recent and Earlier cohorts was evaluated. Results: Of the 3,013 patients who turned 19 in 2010-12, 2,829 were matched. Median time to disenrollment was 26 months (m) compared to 22 m among patients who turned 19 in 2007-09 (HR 0.88, 95% CI 0.81-0.95, p = 0.0009). In the 4,489 pairs of patients who turned 19 between 2001-06, median time to disenrollment was 20 m among both the younger and older patients in the pair (p = 0.047). In grouped analyses, the difference-in-difference between the Recent and Earlier sets of pairs displayed a 14% reduction in the hazard for losing coverage (p &lt; 0.0001), favoring those who turned 19 after DCP became available. Conclusions: In pediatric cancer patients and survivors, a vulnerable population that needs continuous insurance coverage, these data suggest that the DCP of the ACA lowers the insurance drop-out rate.
Clinically approved CFTR modulators rescue Nrf2 dysfunction in cystic fibrosis airway epithelia
Authors: Dana C. Borcherding, Matthew E. Siefert, Songbai Lin, John Brewington, Hesham Sadek, John P. Clancy, Scott M. Plafker, Assem G. Ziady
Journal: Journal of Clinical Investigation (2019)

Cystic Fibrosis (CF) is a multi-organ progressive genetic disease caused by loss of functional cystic fibrosis transmembrane conductance regulator (CFTR) channel. Previously, we identified a significant dysfunction in CF cells and model mice of the transcription factor nuclear-factor-E2-related factor-2 (Nrf2), a major regulator of redox balance and inflammatory signaling. Here we report that approved F508del CFTR correctors VX809/VX661 recover diminished Nrf2 function and colocalization with CFTR in CF human primary bronchial epithelia by proximity ligation assay, immunoprecipitation, and immunofluorescence, concordant with CFTR correction. F508del CFTR correctors induced Nrf2 nuclear translocation, Nrf2-dependent luciferase activity, and transcriptional activation of target genes. Rescue of Nrf2 function by VX809/VX661 was dependent on significant correction of F508del and was blocked by inhibition of corrected channel function, or high-level shRNA knockdown of CFTR or F508del-CFTR. Mechanistically, F508del-CFTR modulation restored Nrf2 phosphorylation and its interaction with the coactivator CBP. Our findings demonstrate that sufficient modulation of F508del CFTR function corrects Nrf2 dysfunction in CF.
Lethality and mitotic activity of T98G glioblastoma cells under the influence of pulsed magnetic fields and ionizing radiation.
Authors: Ivan A. Popov, Alla I. Shikhlyarova, Oleg I. Kit, Eduard Evgenevich Rostorguev, Marina A. Gusareva, Natalya N. Timoshkina, Dmitrii S. Potemkin, Dmitriy P. Atmachidi, Ludmila Ya. Rozenko, Mikhail S. Zinkovich, Galina V. Zhukova
Journal: Journal of Clinical Oncology (2019)

e13511 Background: Development of alternative methods of non-invasive therapy in neurooncology is determined by the need to prevent the continued growth of glioblastoma and radiation-induced complications. Usage of electromagnetic influence for these reasons is determined by the oscillatory nature of intracellular processes and results of previous studies on the effect of weak electromagnetic radiation in tumor growth. The purpose of the study was to reveal the effect of a pulsed magnetic field (PMF) and ionizing radiation (IR) on human T98G glioblastoma cells. Methods: Human T98G glioblastoma cells were cultured in the RPMI-1640 medium (Biolot, Russia) supplemented with 10% fetal bovine serum (Thermo Scientific HyClone, USA). The culture was seeded in the Biofil plates (at least 8x10 5 cells per 3 mL of the medium), incubated (CB 150 Binder, Germany) and exposed to IR 10 Gy (TheratronEquinox-BestTheratronics) for 11.7 min. and/or PMF 15 mT or 300 mT with a sequence of frequencies 0.3-3.0-9.0 Hz for 7 min. (Neiro-MS/D by Neirosoft, Russia). The efficiency criteria were lethality and the mitotic activity of human T98G glioblastoma cells. Results: The highest cellular lethality was registered 3 hours (18.7 vs. 5.2% in controls, p≤0.05) and a day after IR exposure. PMF 15 or 300 mT alone increased lethality by 2.5-2.8 times compared to controls (p &lt; 0.05). IR plus PMF (15 mT) did not caused increased lethality. At the same time, the most pronounced decrease in the mitotic activity a day after exposure (by 4.7 times, p &lt; 0.05) was registered in PMF alone (15 mT). Conclusions: The inhibitory effect of PMF on the viability of human glioblastoma cells indicates the prospects for its use as an accompanying treatment in neurooncology.
Neoadjuvant cytoreductive treatment with BRAF/MEK inhibition of prior unresectable regionally advanced melanoma to allow complete surgical resection: REDUCTOR trial.
Authors: Stephanie A. Blankenstein, Maartje W. Rohaan, W. Martin. C. Klop, Bernies Van Der Hiel, Bart A. Van De Wiel, Daniel S. Peeper, John B. A. G. Haanen, Alexander Christopher Jonathan Van Akkooi
Journal: Journal of Clinical Oncology (2019)

9587 Background: The aim of this study is to evaluate the potency of short-term neoadjuvant cytoreductive therapy with dabrafenib and trametinib (BRAF and MEK inhibitor respectively) to allow radical surgical resection in patients with unresectable BRAF-mutated, locally advanced stage III or oligometastatic stage IV melanoma. Methods: A total of 25 patients with BRAF-mutated, unresectable locally advanced stage III or oligometastatic stage IV (≤3 metastases) melanoma will be treated with dabrafenib and trametinib for 8 weeks. Response evaluation by positron emission tomography/computed tomography (PET/CT) will occur at 2 and 8 weeks. If sufficient downsizing occurs, surgical resection will be performed. Biopsies for translational research will be taken at baseline and 2 weeks. The dissection specimen will be stored at 8 weeks. Results: Currently 20 patients have been included. Of these, 2 patients showed PD upon treatment and did not proceed to surgery. In 17/18 (94%) patients resection was possible after neoadjuvant treatment, of which 16 (94%) were R0 resections. Median follow-up time is 28 months with a median recurrence free survival of 9 months in patients undergoing surgery. The 1-year overall survival (OS) was 94% and 2-year OS 82%. Median OS was not reached. Metabolic response rates (RR) on PET/CT at 8 weeks were: 4 (20%) CR, 14 (70%) PR, 0 (0%) SD, 2 (10%) PD. Pathologic RR differed: 7 (35%) CR, 7 (35%) PR, 3 (15%) SD, 0 (0%) PD and in 3 patients (15%) no pathologic response was measured, since no resection was performed. Most patients (85%) experienced any toxicity, of which 50% was grade 1, 20% grade 2 and 3 patients (15%) experienced grade 3 toxicity. The most common reported toxicity was fever. Conclusions: Neoadjuvant dabrafenib and trametinib shows to be a potent cytoreductive treatment, allowing radical resection of metastases in 16/20 (80%) patients with prior unresectable locally advanced melanoma. Patients with no recurrence remained disease-free for a prolonged period of time. If there was recurrent disease, this usually occurred within months after surgery and this may present an opportunity for further tailored adjuvant therapy. Clinical trial information: NTR4654.