tbuckley/cabot-search huggingface dataset:
Construction and validation of a simple-to-use nomogram incorporating clinicopathological parameters into the TNM staging system to predict prognosis for stage II colorectal cancer.
Authors: Shaobo Mo, Yaqi Li, Junjie Peng, SanJun Cai
Journal: Journal of Clinical Oncology (2020)

31 Background: Survival outcomes are significant different in stage II colorectal cancer (CRC) patients with diverse clinicopathological features. Objective of this study is to establish a credible prognostic nomogram incorporating easily obtained parameters for stage II CRC patients. Methods: A total of 1708 stage II CRC patients at Fudan University Shanghai Cancer Center (FUSCC) during 2008 to 2013 were retrospectively analyzed in this study. Cases were randomly separated into training set (n = 1084) and validation set (n = 624). Univariate and multivariate Cox regression analyses were used to identify independent prognostic factors which were subsequently incorporated into a nomogram. The performance of the nomogram was evaluated by C-index and ROC curve to calculate the area under the curve (AUC). The clinical utility of the nomogram was evaluated using decision curve analysis (DCA). Results: In univariate and multivariate analyses, eight parameters were correlated with disease free survival (DFS), which were subsequently selected to draw prognostic nomogram based on DFS. For DFS predictions, the predicted concordance index (C-index) of the nomogram was 0.842 (95% confidence interval (CI), 0.710-0.980), and 0.701 (95% CI, 0.610-0.770) for training and validation set, respectively. The AUC values of ROC predicted 1, 3 and 5-year survival of nomogram in the training and validation groups were 0.869, 0.858, 0.777 and 0.673, 0.714, 0.706, respectively. The recurrence probability calibration curve showed good consistency between actual observations and nomogram-based predictions. DCA showed better clinical application value for the nomogram compared with TNM staging system. Conclusions: A novel nomogram based on a large population study was established and validated, which is a simple-to-use tool for physicians to facilitate the postoperative personalized prognostic evaluation and determine therapeutic strategies for stage II CRC patients.
Reply
Authors: Hye‐Mee Kwon, Gyu‐Sam Hwang
Journal: Hepatology (2020)

Potential conflict of interest: Nothing to report. We would like to thank Dr. Kim et al. for their great interest regarding our recent research. First, our definition of pulmonary hypertension (PH) using tricuspid regurgitation (TR) >2.8 m per second is clear. It is based on guidelines for the echocardiographic assessment of the right heart in adults from the American Society of Echocardiography. Moreover, TR > 2.8 m per second is also used to indicate PH in the criteria of “Redefining cirrhotic cardiomyopathy for the modern era.”1 In these, there are no recommendations for the use of pulmonary vascular resistance (PVR) or right ventricular end‐diastolic volume (RVEDV), possibly because PH itself incorporates PVR, given that pulmonary blood pressure = cardiac output × PVR. For RVEDV, there is still weak evidence for the hard event (e.g., mortality) in liver transplantation (LT), but this only exists for examining “softer” events such as acute kidney injury. Therefore, we used the standard parameter of PH to avoid testing every possible or subsequent variable until one was statistically significant. In our study, PH was significant for 90‐day mortality in crude analysis, but this did not remain in multivariable analysis. We speculated that preoperative PH is either treated before LT or excluded because of severe resistive porto‐PH, as has been done in many modern‐era institutions. Second, we agree this is the case. Despite our 10‐year observation for 90‐day cardiovascular mortality, we acknowledged an insufficient sample size for further analysis of cause‐specific mortality (34 of 2,799, 1.21%). However, there exist numerous published articles suggesting that all‐cause mortality is the primary outcome with ejection fraction (EF) and cardiac strain.2 Cardiac dysfunction and events ultimately lead to increasing mortality and risk of graft failure.3 Third, the approach of receiver operating characteristic (ROC) curve analysis and Youden index consider an event as fixed over time; however, in practice, mortality is time varying in the longitudinal study. Our best EF cutoff to distinguish between survivors and nonsurvivors was based on the minimum P value by log‐rank tests including survival days, an iterative process that explored potential EF thresholds. Therefore, we do not acknowledge that the Youden index is appropriate as a sensitivity analysis. Rather, time‐dependent ROC, ROC as a function of time, would be more appropriate, if needed. Fourth, unlike in prospective clinical trial studies, the expected mortality and graft failure does not exist; therefore, the calculation of power itself is questionable and seems to be irrelevant in the current retrospective study design. Nonetheless, as consistently seen in our results, after multivariate adjustment (further rigorous adjustment with inverse probability of treatment weighting of the propensity score and optimism correction), EF was significantly associated with 90‐day all‐cause mortality, which fully supports our findings.
Tumor microenvironment evaluation to predict pembrolizumab benefit of metastatic gastric cancer: Results from phase II clinical trial.
Authors: Dongqiang Zeng, Wangjun Liao, Min Shi, Rui Zhou, Na Huang, Yunfang Yu, Wenying Peng, Jiani Wu, Zilan Ye
Journal: Journal of Clinical Oncology (2020)

425 Background: Clinical studies support the efficacy of immune checkpoint blockades (ICBs) in a subset of patients with metastatic gastric cancer (mGC). With the aim of identifying determinants of response to ICBs, we performed molecular characterization of tissues from 61 patients with mGC who were treated with pembrolizumab as salvage treatment in a prospective phase 2 clinical trial (NCT#02589496). Methods: Of 61 patients, 60 patients underwent pretreatment biopsy and 45 specimens were of sufficiently high quality for RNA sequencing. TMEscore, which was previously established to quantify the tumor microenvironment (TME), was used to estimated TME of pretreatment specimens. The predictive value and correlation of integrative molecular characterization were systematically explored. Results: We established a methodology (TMEscore) to evaluated the TME of GC patients, which was previously found to be a robust prognostic and predictive biomarker for patients treated with ICBs. By applying ROC curve analysis, the TMEscore was found to be a best predictive biomarker (TMEscore: AUC = 0.891; CPS: AUC = 0.830; TMB: AUC = 0.672; MSI status: AUC = 0.708; EBV status: AUC = 0.727; respectively). Moreover, TMEscore was the most significant gene signature that correlated with tumor response (TMEscore: P = 1.7 × 10 −5 ; GEPs: P = 0.00035; ImmunoScore: P = 0.29106; CD8+ T cell fraction: P = 0.00011; Immune checkpoint score: P = 0.00149; respectively). TMB was not correlated with TMEscore (Kruskal-Wallis test, P = 0.14). A higher TMEscore was significantly associated with EBV+ and high-MSI TCGA molecular subtypes (Kruskal-Wallis test, P = 0.002) which were reported to benefit from ICBs of GC. Conclusions: These findings indicate that the assessment of TMEscore via high throughput-sequencing and PCA algorithm provides a robust biomarker for the selection of GC patients who may derive greater benefit from pembrolizumab. Our data also suggest that TMEscore may be a more accurate predictive biomarker than TMB, MSI and EBV status, and this resource may help facilitate the development of precision immunotherapy. Clinical trial information: NCT#02589496.
Drug-drug interaction (DDI) potential of oral napabucasin in healthy adults.
Authors: Xiaoshu Dai, Michael D. Karol, Matthew Hitron, Marjie Hard, Matthew T. Goulet, Colleen F. Mclaughlin, Scott J. Brantley
Journal: Journal of Clinical Oncology (2020)

142 Background: Napabucasin is an NQO1-bioactivatable investigational agent hypothesized to affect multiple oncogenic cellular pathways including pSTAT3 through the generation of reactive oxygen species. This phase 1 open-label study evaluated the DDI potential of napabucasin and its major metabolite (M1) with respect to 7 major human drug cytochrome P450 (CYP) enzymes and the breast cancer resistance protein (BCRP) transporter. Methods: Healthy adult subjects who initially demonstrated they could tolerate administration of 240 or 480 mg twice daily (BID) napabucasin over 2-days (D) received single doses of the CYP and transporter substrates, followed by ≥7-day washout. In the DDI portion, subjects received napabucasin 240 mg BID on D1–11 with the phenotyping cocktail administered on D6 (omeprazole [CYP2C19] 20 mg, caffeine [CYP1A2] 100 mg, flurbiprofen [CYP2C9] 50 mg, bupropion [CYP2B6] 150 mg, dextromethorphan [CYP2D6] 30 mg, and oral midazolam [CYP3A] 2 mg), intravenous (IV) midazolam 2 mg on D7, repaglinide (CYP2C8) 0.25 mg on D8, and rosuvastatin (BRCP transporter) 10 mg on D9. Results: DDI potential was evaluated in 17 subjects. Exposure to omeprazole, flurbiprofen, and oral midazolam with (test) or without (reference) napabucasin 240 mg BID were similar. Napabucasin increased exposure (area under the curve to infinity) to caffeine (124%), IV midazolam (118%), repaglinide (127%), and rosuvastatin (213%); and decreased exposure to bupropion (79%) and dextromethorphan (71%). None of these changes were expected to be clinically meaningful. The exposure of the major metabolites of the probe drugs with or without napabucasin or M1 were similar. Of the 17 subjects, 12 (70.6%) reported adverse events (AEs); 58.8% reported gastrointestinal disorders. One patient had a grade 3 AE (neutrophil count low); no serious AEs were observed. Conclusions: The data suggest minimal in vivo DDI potential for napabucasin with respect to 7 major human drug CYP enzymes and the BCRP transporter. Napabucasin 240 mg BID was generally tolerable in healthy subjects. Co-administration of napabucasin with CYP and transporter substrates was safe and tolerable. Clinical trial information: NCT03411122.
Identification of cancer hallmarks associated with benefit in advanced gastroesophageal adenocarcinoma patients treated with checkpoint blockade.
Authors: Emon Elboudwarej, Carrie Brachmann, Daniel V.T. Catenacci, David Cunningham, Eric Van Cutsem, Richard D. Kennedy, Shauna Lambe, Gemma E. Logan, Jean Philippe Metges, Kei Muro, Taroh Satoh, Atsuo Takashima, Zev A. Wainberg, Steven M. Walker, Kensei Yamaguchi, Marianna Zavodovskaya, Scott D. Patterson, Pankaj Bhargava, Narikazu Boku, Manish A. Shah
Journal: Journal of Clinical Oncology (2020)

439 Background: The benefit of checkpoint blockade in advanced gastric cancer is limited and biomarkers related to response are needed. Novel gene expression analysis software was used to identify Hallmarks of Cancer associated with clinical benefit following nivolumab treatment in &gt;2 nd line advanced gastroesophageal adenocarcinoma (GEA). Methods: RNA-sequencing data from baseline GEA patient diagnostic tumor samples (103 from NCT02862535; 5 from NCT02862535) were analyzed using the clara T platform (V2.0.0, Almac Diagnostic Services). 62 gene signatures were quantified representing 6 key Hallmarks of Cancer (Avoiding Immune Destruction, Activating Invasion and Metastases, Sustaining Proliferative Signaling, Inducing Angiogenesis, Resisting Cell Death and Genome Instability and Mutation). Clinical benefit (CB) was defined as tumor response or overall survival (OS) &gt; 1 year. HER2 status was from medical records. Survival analyses used cox proportional hazards models. Results: Gene expression signatures (GES) identified 5 molecular subgroups (C1-C5). Rate of CB in each molecular subtype are outlined in Table. C3 and C4 had significantly improved OS compared to C2, (HR = 0.45; p= 0.02 and HR = 0.42; p= 0.02). Greater proportions of HER2+ subjects were present in C4 and C3 vs. C2, with C3 statistically significant (60% vs. 14%; p= 0.012). Gene expression characterized by chromosomal instability (CIN) and homologous recombination repair deficiency (HRD) were associated with HER2(+) (wilcox p= &lt; 0.05). Patients selected by only using CIN &amp; HRD had significant improvement in OS (HR = 0.63; p= 0.03). Conclusions: Interferon-based GES did not predict benefit from immune checkpoint blockade. GES representing HRD and activation of HER2, EGFR and MAPK (each enriched in CIN) were associated with improved survival upon checkpoint blockade in advanced GEA patients. Clinical trial information: NCT02862535 . [Table: see text]
Conceptualization, History, and Future of the Paraphilias
Authors: Charles Moser, Peggy J. Kleinplatz
Journal: Annual Review of Clinical Psychology (2020)

There is no accepted definition of the term paraphilia despite its being listed as an essential feature of a class of mental disorders known as the paraphilic disorders. The origin of the term, history of its inclusion as a diagnosis, and logical flaws inherent in the various definitions are discussed in this review. We examine the basis for pathologizing individuals with paraphilias, consider what paraphilias can tell us about how humans develop their sexual interests, and question the usefulness of dividing sexual interests into paraphilias and normophilias. The construct of the paraphilias appears to be poorly conceived and has outlived its usefulness.
Electrical stimulation in obstructive sleep apnoea: the less invasive the better?
Authors: Martino Pengo, Esther Irene Schwarz, Joerg Steier
Journal: European Respiratory Journal (2020)

We read with interest the article by Eastwood et al. [1] on bilateral hypoglossal nerve stimulation for treatment of adult obstructive sleep apnoea (OSA), the BLAST OSA trial. The authors present data on a novel approach, the Genio system, to stimulate the hypoglossal nerve and provide neuromuscular tone to the genioglossus, the main dilator muscle of the upper airway, to improve upper airway patency in OSA. The primary outcomes of the BLAST OSA trial focus on indices describing severity of OSA, the apnoea–hypopnoea index (AHI), and the safety of this approach. The AHI improved by 10.8 events per hour at 6 months, leading to a symptomatic improvement, as measured by the Epworth Sleepiness Scale and the Functional Outcome of Sleep Questionnaire (FOSQ-10), and any serious adverse events observed were related to the surgical procedure; most minor adverse events wore off during the 6-month follow-up period. Electrical stimulation for the treatment of OSA can be delivered invasively, using hybrid methods as well as non-invasively <http://bit.ly/2ogLBFP>
<i>AllergyGenDB</i>: A literature and functional annotation‐based omics database for allergic diseases
Authors: Siqi Chen, Sudhir Ghandikota, Yadu Gautam, Tesfaye B. Mersha
Journal: Allergy (2020)

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
Immune-related adverse events and neutrophil-to-lymphocyte ratio are possible predictive factors for gastric cancer treated with nivolumab.
Authors: Hirotugu Eda, Katsuyuki Tozawa, Kumiko Nakamura, Takashi Kondo, Toshihiko Tomita, Tadayuki Oshima, Hirokazu Fukui, Hiroto Miwa
Journal: Journal of Clinical Oncology (2020)

385 Background: The Immune-related adverse events (irAEs) and neutrophil-to-lymphocyte ratio (NLR) are effective as a predictive factor for lung cancer treated with nivolumab The objective of this study was to determine the effectiveness of irAEs and NLR for patients with advanced gastric cancer (AGC) treated with nivolumab. Methods: This was a retrospective study of patients with AGC treated with nivolumab from October 2017 to August 2019. The NLRs were calculated before the first cycle. Results: Forty patients were enrolled (males 29, females 11) with a median age of 65 years. The overall response rate was 12.5%. The median PFS was 4.2 months (range, 0.5 - 21). Stratified with high NLR (≥5) and low NLR ( &lt; 5), the median PFS was shorter in the high NLR arm (1.1 vs. 5.1 months; p = 0.0003). irAEs were observed in 5 of the 40 study patients (12.5%), including 1 patients (20%) with such events of grade 3 or 4, and 1 patient requiring systemic corticosteroid therapy. Median PFS was 6.5 months (95% CI, 4.4 to not reached [NR]) and 3.9 months (95% CI, 3.0 to 7.5) (P = .09) for patients with or without irAEs, respectively. Conclusions: NLR may be an effective prognostic factor in patients with AGC treated with nivolumab. Development of irAEs was associated with survival outcome of nivolumab treatment in patients with AGC. Further studies are needed to confirm our findings.
Pancreatic ductal adenocarcinoma (PDAC), BRCA: Detailed analysis and outcomes of cohort from Memorial Sloan Kettering Cancer Center (MSK).
Authors: Parisa Momtaz, Catherine Anne O'Connor, Joanne F. Chou, Marinela Capanu, Kenneth H. Yu, Anna M. Varghese, Wungki Park, Alice Zervoudakis, Jia Li, Geoffrey Yuyat Ku, Diane Lauren Reidy, Marina Shcherba, James J. Harding, Zoe Goldberg, Ghassan K. Abou-Alfa, Zsofia Kinga Stadler, Erin E. Salo-Mullen, Eileen Mary O'Reilly
Journal: Journal of Clinical Oncology (2020)

708 Background: Given encouraging responses of platinum agents and poly-ADP ribose polymerase inhibitors (PARPi) in BRCA mutated (mut) PDAC, we sought to identify patients (pts) with BRCA mut PDAC treated at MSKCC and to evaluate outcome. Methods: Institutional database at MSK with IRB approval was queried for PDAC germline (g) or somatic (s) BRCA1/2 mut. Genomic profiling, clinicopathologic characteristics and outcomes were collected. Overall survival (OS) from diagnosis was estimated using Kaplan-Meier method. Results: n = 126 with BRCA1/2 mut PDAC were identified between 1/2011-12/2018. n = 77 (61%) male and median age of 62 (range 24-85) at diagnosis. n = 78 (62%) had g BRCA mut (n = 21 BRCA1; n = 57 BRCA2). n = 54 (43%) had a family history of BRCA-related malignancies; 35pts (28%) with a personal history of other BRCA-associated malignancy. n = 66 (52%) AJCC stage IV; of these 43pts (65%) received platinum-based therapy with a partial response (PR) in 35pts (81%); median duration 7 months (m) (range 0.5-39m). n = 40 (32%) received ≥ 4 lines of therapy (range 1-6 lines). n = 44 (35%) received PARPi and 11% (n = 14) received immunotherapy. Median OS for the entire cohort 32.1 m (95% CI 23.9, 42.6). Median OS for stage I-II 49.9m (95% CI 38.5,-); stage III 43m (95% CI 33.9,-) and stage IV 19.1m (95% CI 19.1 16.1,25.8). We did not observe a statistically significant difference in OS between BRCA1 vs BRCA2 pts. Conclusions: BRCA mut PDAC constitutes a small but likely distinct biologic subgroup. Improved OS was notable relative to historical data, possibly due to the integration of platinum and PARPi therapy and possibly due to contribution from disease biology. [Table: see text]
Feasibility of pharmacist co-management for patients prescribed oral anticancer therapy for gastrointestinal cancers.
Authors: Cathy Cao, James M. Cleary, Anuj K. Patel, Matthew B. Yurgelun, Kimmie Ng, Kimberly Perez, Douglas Adam Rubinson, Brian M. Wolpin, Jeffrey A. Meyerhardt, Nadine Jackson McCleary
Journal: Journal of Clinical Oncology (2020)

77 Background: There is an increased use of oral anti-cancer therapies (OACTs) for treatment of gastrointestinal (GI) cancers. While OACTs provide convenience compared to IV agents, they carry similar risks for drug-drug interactions (DDI), toxicities, and unique challenges like adherence and drug access. Patients on OACTs have fewer touch-points with clinicians, requiring more patient ownership of treatment. Pharmacist co-management of pts has been shown to be successful in teaching and monitoring of IV therapy. We sought to assess feasibility of pharmacist co-management for pts prescribed OACTs for treatment of GI cancers. Methods: In 2019, the Dana-Farber GI Cancer Center (GCC) had an embedded pharmacist 8 hrs/week to help with co-management of pts on OACTs. The pharmacist provided (1) in-person and telephone teaching; (2) comprehensive medication reconciliation; (3) DDI review; and (4) supportive care recommendations. Patients were identified by reviewing provider schedules and through provider referrals. The initial teach visit was one-on-one with each patient before initiation, with joint visits with providers thereafter for monitoring and adherence checks. Data were collected to quantify the types of support/recommendation provided by pharmacist and the impact on clinical workflow. Results: After 4 months in the GCC clinic, the pharmacist has co-managed 26 new pts, 61% seen in-person. In initial visits, the pharmacist identified 3 DDI, updated 15 medication lists, and assisted 11 pts/or providers with drug access and drug information. The pharmacist saw 10 of 26 pts for follow up, totaling 21 encounters. The pharmacist assisted in 17 of the 21 encounters with drug access and drug information. Pharmacist spent 20 min/pt on teaching. For follow-up visits, the pharmacist did not additional incur clinic resources as patients were seen with providers. Conclusions: Pharmacist co-management of patients on OACTs is feasible and offers an added safety resource to pts and providers from initial teaching to monitoring. Future research will focus on the impacts of co-management on clinical outcomes, such as the use of emergency/hospital visits, the duration of therapy, and adherence.
Single-cell transcriptome analysis of human skin identifies novel fibroblast subpopulation and enrichment of immune subsets in atopic dermatitis
Authors: Helen He, Hemant Suryawanshi, Pavel Morozov, Jesús Gay-Mimbrera, Ester Del Duca, Hyun Je Kim, Naoya Kameyama, Yeriel Estrada, Evan Der, James G. Krueger, Juan Ruano, Thomas Tuschl, Emma Guttman-Yassky
Journal: Journal of Allergy and Clinical Immunology (2020)