tbuckley/cabot-search huggingface dataset:
Deleterious alterations of DNA damage response and repair (DDR) genes in association with clinical benefit to programmed cell death protein-1 (PD-1)/PD ligand 1 (PD-L1)-based therapy in esophageal squamous cell carcinoma (ESCC).
Authors: Jhe-Cyuan Guo, Chia-Chi Lin, Ta-Chen Huang, Chun-Jung Chang, Hung-Yang Kuo, Chih-Hung Hsu
Journal: Journal of Clinical Oncology (2020)

28 Background: Previous studies have indicated genetic alterations (GA) of DDR genes and tumor mutational burden (TMB) as potential markers for anti-PD-1/PD-L1 therapy in several cancer types. The study explored whether GA of DDR genes and TMB are associated with clinical benefit (CB) for ESCC patients receiving anti-PD-1/PD-L1 therapy. Methods: Thirty-five ESCC patients treated with PD-1/PD-L1 blockade antibody, alone or in combination, were enrolled. Tumor response was evaluated per RECIST 1.1, and CB was defined as complete response, partial response or stable disease at least 6 months. Formalin-fixed paraffin-embedded ESCC tissues were analyzed by FoundationOne CDx. All loss-of-function alterations were considered as deleterious according to previous reports (Teo MY, et al: Clin Cancer Res 2017; 23:3610-8 and J Clin Oncol 2018; 36:1685-94). Results: All of 35 enrolled patients was male: 16 and 19 received PD-1/PD-L1 blockade alone and PD-1/PD-L1-based combination therapy, respectively. The response rate was 14%, and the CB rate was 29%. All patients had GA of TP53 (100%), followed by CDKN2A/B (71%), and FGF3, FGF4 plus FGF19 (40%). The median TMB was 4 muts/Mb (range 1-16) and all evaluable ESCC tissues (N=31) were microsatellite stable. Twenty-one (60%) patients had GA of DDR genes, but only 4 (11%) patients had deleterious GA of DDR genes. The clinicopathological characteristics were not significantly different between patients with or without GA of DDR genes or those with or without deleterious GA of DDR genes. Patients harboring deleterious GA of DDR genes trended to have improved response rate (25% vs. 12.9%, P = 0.063), CB rate (50% vs. 22.6%, P = 0.268), and median PFS (4.1 vs. 1.8 mon, P = 0.074). Neither TMB nor all GA of DDR genes was associated with response or CB. Conclusions: Deleterious GA of DDR genes may be associated with therapeutic efficacies of anti-PD-1/PD-L1 therapy in patients with ESCC. (Funded by NHRI-107A1-CACO-01181816, NHRI-108A1-CACO-01191916, MOST-106-2314-B-002-225-MY2, NTU-108L901403, and MOST 108-3017-F-002-004-).
Association of Subclinical Hypothyroidism and Cardiovascular Disease With Mortality
Authors: Kosuke Inoue, Beate Ritz, Gregory A. Brent, Ramin Ebrahimi, Connie M. Rhee, Angela M. Leung
Journal: JAMA Network Open (2020)

<h3>Importance</h3> Subclinical hypothyroidism is a common clinical entity among US adults associated in some studies with an increase in the risk of cardiovascular disease (CVD) and mortality. However, the extent to which CVD mediates the association between elevated serum thyrotropin (TSH) and mortality has not yet been well established or sufficiently quantified. <h3>Objective</h3> To elucidate the extent to which subclinical hypothyroidism, elevated serum TSH and normal serum free thyroxine, or high-normal TSH concentrations (ie, upper normative–range TSH concentrations) are associated with mortality through CVD among US adults. <h3>Design, Setting, and Participants</h3> This cohort study relied on representative samples of US adults enrolled in the National Health and Nutrition Examination Survey in 2001 to 2002, 2007 to 2008, 2009 to 2010, and 2011 to 2012 and their mortality data through 2015. Data were analyzed from January to August 2019. <h3>Main Outcomes and Measures</h3> Cox proportional hazards regression models were used to investigate associations between the TSH concentration category (subclinical hypothyroidism or tertiles of serum TSH concentrations within the reference range; low-normal TSH, 0.34-1.19 mIU/L; middle-normal TSH, 1.20-1.95 mIU/L; and high-normal TSH, 1.96-5.60 mIU/L) and all-cause mortality. Mediation analysis was used within the counterfactual framework to estimate natural direct associations (not through CVD) and indirect associations (through CVD). <h3>Results</h3> Of 9020 participants, 4658 (51.6%) were men; the mean (SD) age was 49.4 (17.8) years. Throughout follow-up (median [interquartile range], 7.3 [5.4-8.3] years), serum thyroid function test results consistent with subclinical hypothyroidism and high-normal TSH concentrations were both associated with increased all-cause mortality (subclinical hypothyroidism: hazard ratio, 1.90; 95% CI, 1.14-3.19; high-normal TSH: hazard ratio, 1.36; 95% CI, 1.07-1.73) compared with the middle-normal TSH group. Cardiovascular disease mediated 14.3% and 5.9% of the associations of subclinical hypothyroidism and high-normal TSH with all-cause mortality, respectively, with the CVD mediation being most pronounced in women (7.5%-13.7% of the association) and participants aged 60 years and older (6.0%-14.8% of the association). <h3>Conclusions and Relevance</h3> In this study, CVD mediated the associations of subclinical hypothyroidism and high-normal TSH concentrations with all-cause mortality in the US general population. Further studies are needed to examine the clinical benefit of thyroid hormone replacement therapy targeted to a middle-normal TSH concentration or active CVD screening for people with elevated TSH concentrations.
Should signet-ring cell histology alter the treatment approach for clinical stage I gastric cancer?
Authors: Michael K. Turgeon, Adriana C. Gamboa, Manali Rupji, Rachel M. Lee, Jeffrey M. Switchenko, Maria C. Russell, Kenneth Cardona, David A. Kooby, Charles A. Staley, Shishir K. Maithel, Mihir M. Shah
Journal: Journal of Clinical Oncology (2020)

321 Background: Upfront surgery is standard of care for stage I gastric cancer. Despite this, many clinicians administer preoperative therapy for clinical stage I disease with signet ring cell histology, given its aggressive biology. We aimed to assess the validity of this practice. Methods: The National Cancer Database (2004-2015) was reviewed for pts with non-metastatic signet ring cell gastric cancer who underwent treatment with surgery alone, perioperative chemotherapy, neoadjuvant therapy, or adjuvant therapy. Analysis was stratified by preoperative clinical stage and pathologic stage. Primary outcome was overall survival (OS). Results: Of 3000 pts, median age was 61 (IQR: 51-70). 34% were clinical stage I (n = 1018) of which 53% received surgery alone (n = 542), 5% perioperative chemotherapy (n = 47), 12% neoadjuvant therapy (n = 125), and 30% adjuvant therapy (n = 304). Median follow-up was 26 mos. For clinical stage I disease, surgery alone was associated with improved median OS (108 mos) when compared to perioperative chemotherapy (80 mos), neoadjuvant therapy (41 mos), or adjuvant therapy (73 mos, all p &lt; 0.001). For pathologic stage I, surgery alone had equivalent survival to perioperative and adjuvant therapy (5-yr OS: 81 vs 82 vs 79%, p = 0.22). Concordance between clinical and pathologic stage I was 56%, specifically, 41% of clinical stage I pts were upstaged to pathologic stage II (44%) and stage III (56%). Adjuvant therapy for these pts was associated with improved median OS compared to pretreatment (perioperative chemotherapy / neoadjuvant therapy) for those upstaged to pathologic stage II (122 vs 37mos, p &lt; 0.001) or stage III (40 vs 18mos, p &lt; 0.001) disease. Conclusions: Our stage-stratified study demonstrates improved survival with upfront surgery for clinical stage I signet ring cell gastric cancer. Despite 41% of clinical stage I pts being upstaged to stage II or III on final pathology, adjuvant therapy offers a favorable rescue strategy, with improved outcomes compared to those treated preoperatively. Surgery alone also affords similar survival for pathologic stage I disease compared to multimodal therapy. This study challenges the intrinsic bias to over-treat stage I signet ring cell gastric cancer.
Lentiviral interferon with immune checkpoint blockade: A novel method for gene therapy in bladder cancer.
Authors: Sharada Mokkapati, Andrea Kokorovic, Jonathan J. Duplisea, Devin Plote, Amy Lim, Vikram M. Narayan, Michael J. Metcalfe, Kenneth Dunner, Bogdan Czerniak, Tiina Nieminen, Tommi Heikura, Seppo Yla-Herttuala, Nigel Parker, David James McConkey, Colin P.N. Dinney
Journal: Journal of Clinical Oncology (2020)

33 Background: Gene therapy for bladder cancer (BLCA) is rapidly evolving. We reported that intravesical adenoviral interferon-alpha (Ad-IFNα) produced a complete response in 35% of patients with BCG-unresponsive BLCA enrolled in a Phase II trial. Lentivirus (LV) is another potential vector for intravesical delivery of IFNα. LV can infect non-dividing cells and integrate into the host’s genome, making it more efficient gene delivery vectors. As treatment with IFN upregulates checkpoint inhibitors, we also wanted to investigate the role of checkpoint inhibitors with and without IFN gene therapy. Methods: Murine BLCA cell lines were transduced in-vitro with LV-IFNα (MOI 2:1). IFNα levels were measured by ELISA. Cell viability was assessed using Trypan blue dye exclusion. qPCR was used to identify expression of IFNα target genes. A LV-βGalactosidase reporter construct was delivered intravesically, and urinary IFNα levels were measured in mice treated with LV-IFNα or control virus to assess gene transfer. To assess survival benefit, the MB49 intravesical tumor model and p53+/- C57/B6 mouse model were employed. We also assessed the role of combination therapy with immune checkpoint blockade using PD1 antibody using our MB49 intravesical model. Results: Efficient LV-IFNα transduction of BLCA cells resulted in increased expression of IFNα and its target genes and reduced cell viability vs. controls (p&lt;0.001). Mechanistically, TRAIL dependent cytotoxicity in the LV-IFNα cells was rescued by Caspase8 inhibition. Urinary IFNα levels were elevated in mice receiving LV-IFNα compared with control virus. Overall survival improved in the MB49 model and BBN model in treated mice. LV-IFN induced intratumoral CD8+ T cell infiltration, high expression of PD-L1, and inhibited angiogenesis in BBN model whereas in the MB49 tumor response was mediated by TRAIL. Combination therapy with PD1 resulted in further improved survival. Conclusions: LV-IFNα effectively upregulated IFNα target genes, was cytotoxic to murine BLCA cells, and improved the survival in mouse models. Combining it with PD1 therapy appears to further improve survival.
リチウム‐ピロカルピン誘発慢性側頭葉てんかんによるP糖蛋白質を過剰発現しているラットにおけるフェニトイン耐性を克服するPluronicP85被覆ポリ(シアノアクリル酸ブチル)ナノ粒子【Powered by NICT】
Authors: Fang Ziyan, Chen Shuda, Qin Jiaming, Chen Bao, Ni Guanzhong, Chen Ziyi, Zhou Jueqian, Li Ze, Ning Yuping, Wu Chuanbin, Zhou Liemin
Journal: Biomaterials (2016)
Regorafenib in patients with unresectable hepatocellular carcinoma (uHCC) in routine clinical practice: Interim analysis of the prospective, observational REFINE trial.
Authors: Ho Yeong Lim, Philippe Merle, Richard S. Finn, Catherine Frenette, Gianluca Masi, Masafumi Ikeda, Hong Zebger-Gong, Sabine Fiala-Buskies, Kirhan Ozgurdal, Masatoshi Kudo, Shukui Qin
Journal: Journal of Clinical Oncology (2020)

542 Background: Regorafenib significantly improved overall survival (OS) versus placebo in patients (pts) with uHCC who progressed on prior sorafenib therapy in the phase 3 RESORCE trial. The multicenter, international REFINE trial was designed to evaluate the safety and effectiveness of regorafenib in uHCC in the real-world setting. Methods: This prospective, observational trial aims to recruit 1000 pts with uHCC for whom a decision to treat with regorafenib has been made by the treating physician prior to enrollment according to the local health authority approved label. The primary endpoint is the incidence of treatment-emergent adverse events (TEAEs) and dose modifications due to TEAEs (NCI-CTCAE v4.03). Secondary endpoints are OS, progression-free survival, time to progression, best overall tumor response, and duration of treatment. Tumor response and progression are assessed per investigator according to local standard. An interim analysis includes the first 500 pts observed for ≥4 months. We report baseline characteristics, starting dose, and treatment duration for the interim analysis. Results: Of 498 pts evaluable for analysis, median age was 67 years (range: 22–91) and 84% were male. 59% were from Asia. Proportions of pts with ECOG performance status 0–1/≥2 were 82%/5% (missing 13%); 67% and 11% of pts had Child–Pugh A and B liver function, respectively (missing/not evaluable 21%). 60% of pts had metastases and 33% had vascular invasion. HCC etiology included hepatitis B 37%, alcohol use 26%, hepatitis C 23%, and NASH 7%. Baseline alpha-fetoprotein levels were &lt; 400/≥400 ng/mL in 44%/26% of pts (missing 31%). The initial regorafenib dose was 160 mg/day (d) in 58% of pts, 120 mg/d in 13%, and 80 mg/d in 28% (8 pts initiated at 40 mg/d). The mean (SD) initial daily dose was 131 mg/d (37). Median duration of treatment was 3.7 months (IQR: 1.9–8.5). Conclusions: In this interim analysis of the observational REFINE study, some differences were observed in the characteristics of pts treated with regorafenib from the phase 3 RESORCE trial, reflecting less stringent inclusion criteria in a real-world study. Efficacy and safety analyses are ongoing. Clinical trial information: NCT03289273.
Immune checkpoint inhibitor use in cancer patients with a pre-existing history of autoimmune disorders.
Authors: Karine Tawagi, Victoria Simenson, Helen Yuan, Cruz Velasco-Gonzalez, Daniel Johnson, Marc Ryan Matrana
Journal: Journal of Clinical Oncology (2020)

100 Background: Patients with a history of autoimmune disorders (AID) were generally excluded from immune checking inhibitor (CPI) trials because of concerns that these individuals might be at greater risk for developing serious immune-related adverse events (irAEs). This presents a knowledge gap, because a significant proportion of cancer patients also carry a diagnosis of AID. Methods: We retrospectively collected data from patients with AID treated with CPI at a single institution. irAEs were assessed using the CTCAEv5 criteria. Response was assessed using RECIST v1.1. Results: Of 47 cancer patients with a broad spectrum of malignancies and AIDs, 45% had active AID symptoms at the time of CPI initiation, of which 19% were on steroid-sparing agents (SSAs), 11% were on steroids, and 9% were on simultaneous steroids and SSAs. A total of 12 patients (25%) developed an AID flare, of which 100% were grade 1 or 2. Of these patients, 11 required systemic steroids, with 6 patients (55%) requiring greater than 12 weeks of oral steroids, and 3 patients required discontinuation of their CPI. Conventional irAEs developed in 10 patients (21%), of which 4 patients required systemic steroids, and 3 patients (27%) required discontinuation of their CPI. Efficacy outcomes for these patients, including radiographic response, will be available at time of data presentation. Conclusions: AID exacerbations or new irAES occurred in 25% and 21% of patients with a history of AID respectively, and were generally manageable. Only a minority of patients required cessation of their CPI due to toxicity.
Propensity-score-matched analysis of a multi-institutional dataset to compare the postoperative complications after distal gastrectomy between Billroth I and Roux-en-Y.
Authors: Koki Nakanishi, Mitsuro Kanda, Seiji Ito, Yoshinari Mochizuki, Hitoshi Teramoto, Kiyoshi Ishigure, Toshifumi Mmurai, Takahiro Asada, Akiharu Ishiyama, Hidenobu Matsushita, Dai Shimizu, Chie Tanaka, Daisuke Kobayashi, Michitaka Fujiwara, Yasuhiro Kodera
Journal: Journal of Clinical Oncology (2020)

292 Background: Billroth I (B-I) or Roux-en-Y (R-Y) are common reconstruction technique after distal gastrectomy, each with advantages and disadvantages and which is the most successful remains unclear. The aim of the present study was to clarify the difference of postoperative complications between the two techniques. Methods: A multi‐institutional retrospective database comprising clinical information of 3484 patients who received resection of gastric cancer from 2010 to 2014 at nine institutions. Using propensity scores to strictly balance the significant variables, and we compared the overall and severity postoperative complications. We considered Clavien–Dindo grade ≥ II postoperative complications clinically relevant, and grade ≥ III severe postoperative complications. Results: After matching, we enrolled 1086 patients (n=543 in each group). The incidence of postoperative complications in the R-Y group was significantly higher vs the B-I group (28% vs 17%, respectively; P&lt;0.0001). The incidence of intra-abdominal abscess (4.2% vs 1.7%, P=0.0120), pancreatic fluid leakage (3.1% vs 1.1%, P=0.0204), bowel obstruction (2.8% vs 0.7%, P=0.0109), and delayed gastric emptying (5.0%s 0.9%, P&lt;0.0001) in the R-Y group was significantly higher vs the B-Ⅰ group, respectively; but not significant difference in leakage (3.2% vs 3.3%, respectively; P=0.8636). The incidence of severe postoperative complications in the R-Y group was also significantly higher vs the B-I group (15% vs 6.3%, respectively; P&lt;0.0001). Multivariable analysis for severe postoperative complications found that R-Y reconstruction was an independent risk factor (odds ratio, 2.20, P=0.0005). Subgroup analysis found that R-Y reconstruction was associated with a greater risk of severe postoperative complications in most subgroups, but not the subgroup of patients receiving intraoperative transfusions. Conclusions: R-Y reconstruction was associated with increasing overall postoperative complications, as well as grade ≥ III severe postoperative complications.
Herd Protection Against Oral HPV Infection
Authors: Ruo-Yu Zhuang, Hua-Guo Xu
Journal: JAMA (2020)

To the Editor Dr Chaturvedi and colleagues1 provided evidence for herd protection against oral human papillomavirus (HPV) infections in unvaccinated individuals aged 18 to 59 years in the United States. We are concerned about several potential problems in their study design.
Activation of group 2 innate lymphoid cells alleviates aging-associated cognitive decline
Authors: Ivan Ting Hin Fung, Poornima Sankar, Yuanyue Zhang, Lisa S. Robison, Xiuli Zhao, Shanti S. D’Souza, Abigail E. Salinero, Yue Wang, Jiang Qian, Marcy L. Kuentzel, Sridar V. Chittur, Sally Temple, Kristen L. Zuloaga, Qi Yang
Journal: The Journal of Experimental Medicine (2020)

Increasing evidence has challenged the traditional view about the immune privilege of the brain, but the precise roles of immune cells in regulating brain physiology and function remain poorly understood. Here, we report that tissue-resident group 2 innate lymphoid cells (ILC2) accumulate in the choroid plexus of aged brains. ILC2 in the aged brain are long-lived, are relatively resistant to cellular senescence and exhaustion, and are capable of switching between cell cycle dormancy and proliferation. They are functionally quiescent at homeostasis but can be activated by IL-33 to produce large amounts of type 2 cytokines and other effector molecules in vitro and in vivo. Intracerebroventricular transfer of activated ILC2 revitalized the aged brain and enhanced the cognitive function of aged mice. Administration of IL-5, a major ILC2 product, was sufficient to repress aging-associated neuroinflammation and alleviate aging-associated cognitive decline. Targeting ILC2 in the aged brain may provide new avenues to combat aging-associated neurodegenerative disorders.
Fear of the mentally ill: empirical support for the common man's response
Authors: John M. Lagos, Kenneth Perlmutter, Heribert Saexinger
Journal: American Journal of Psychiatry (1977)

The authors studied the hospital records of 400 hospitalized mentally ill patients for evidence of violent behavior leading to admission. They found that 36% of 321 admissions (excluding patients diagnosed as having a personality disorder or as drug-and/or alcohol-dependent) were preceded by some form of violent, fear-inspiring behavior. They suggest that mental health professionals deal with the general public's fear of the mentally ill on the basis of such findings rather than dismiss it as illogical.
Complete neoadjuvant treatment for rectal cancer: A single institution experience.
Authors: John Baekey, Robert Brunault, Howard Safran, Rimini Breakstone, Matthew Vrees, Thomas A. DiPetrillo, Kara Lynne Leonard, Esther Yu, Khaldoun Almhanna
Journal: Journal of Clinical Oncology (2020)

148 Background: Full dose adjuvant chemotherapy following preoperative chemoradiation and surgery is poorly tolerated in stage II and III rectal cancer. We reviewed our institution’s experience with complete neoadjuvant treatment for rectal cancer since publication of the BrUOG R-224 trial results. Methods: After obtaining IRB approval, Data on patients with stage II and III rectal cancer who underwent complete neoadjuvant therapy were collected.. Patients who were planned to receive 8 cycles of modified FOLFOX6, chemoradiation with capecitabine 825 mg/m 2 twice daily and 50.4 Gy intensity-modulated radiation therapy, then surgery were included. Results: Thirty-five patients were treated with complete neoadjuvant therapy between January 2014 and December 2017. Median age was 58 years (27 to 75 y); 1 patient (3%) was clinical stage II and 34 (97%) stage III. Twenty-seven patients (77%) received all 8 cycles of mFOLFOX6, of whom 24 completed subsequent chemoradiation. Therefore 69% of patients completed therapy according to the BrUOG R-224 protocol. Pathologic complete response (ypT0N0) was observed in 9 patients (26%). Treatment related toxicities resulted in dose reductions or treatment interruption in 57% and 29% of patients receiving chemotherapy and chemoradiation respectively. Conclusions: Complete neoadjuvant therapy for clinical stage II to III rectal cancer is well-tolerated in routine practice and offers an alternative to preoperative chemoradiation, surgery, then adjuvant full dose chemotherapy.