tbuckley/cabot-search huggingface dataset:
γ-H2AX as a novel prognostic marker in patients with non-small lung cancer.
Authors: Dimitrios Matthaios, Panagiotis Hountis, Grigorios Trypsianis, Athanasios Zissimopoulos, Demosthenes Bouros, Petros Karakitsos, Stylianos Kakolyris
Journal: Journal of Clinical Oncology (2012)

e17553 Background: Phosphorylation of the H2AX histone is an early indicator of DNA double-strand breaks and of the resulting DNA damage response. In the present study we assessed the expression of γ-Η2ΑΧ in a cohort of 96 patients with non-small cell lung carcinoma and evaluated its role as a prognostic indicator in resectable NCSLC patients. Methods: 96 parafin-embedded specimens of non-small lung cancer patients were examined. All patients underwent radical thoracic surgery of primary tumor (lobectomy or pneumonectomy) and regional lymph nodes dissection. γ-Η2ΑΧ expression was assessed by standard immunohistochemistry.Multivariate Cox proportional hazards regression analysis, using a backward selection approach, were performed to explore the independent effect of variables on survival. All tests were two tailed and statistical significance was considered for p values &lt;0.05. Results: Follow-up was available for all patients; mean duration of follow-up was 27.50 ± 14.07 months (range 0.2-57 months, median 24 months). Sixty-three patients (65.2%) died during the follow-up period. The mean survival time was 32.2 ± 1.9 months (95% CI = 28.5 to 35.8 months; median 30.0 months); one, two and three-year survival rates were 86.5 ± 3.5%, 57.3 ± 5.1% and 37.1 ± 5.4% respectively. Low γ-H2AX expression was associated with a significant better survival as compared with those having high γ-H2AX expression (23.2 months for high γ-Η2ΑΧ expressin vs 35.3 months for low γ-H2AX expression, p=0.009; HR=1.95, 95% CI=1.15-3.30). Further investigation with multivariate Cox proportional hazards regression analysis revealed that high expression of γ-H2AX remained independent prognostic factors of worse overall survival (HR=2.15, 95% CI=1.22-3.79, p=0.026). Conclusions: Our study is the first study to demonstrate that overexpression of γ-Η2ΑΧ is an independent prognostic indicator of worse overall survival in patients with non-small lung cancer. Further studies are needed to confirm our results.
Impact of AAV2 and Hepatitis B Virus Integration Into Genome on Development of Hepatocellular Carcinoma in Patients with Prior Hepatitis B Virus Infection
Authors: Kenji Tatsuno, Yutaka Midorikawa, Tadatoshi Takayama, Shogo Yamamoto, Genta Nagae, Mitsuhiko Moriyama, Hayato Nakagawa, Kazuhiko Koike, Kyoji Moriya, Hiroyuki Aburatani
Journal: Clinical Cancer Research (2019)

Hepatitis B viral (HBV) DNA is frequently integrated into the genomes of hepatocellular carcinoma (HCC) in patients with chronic HBV infection (chronic HBV, hereafter), whereas the frequency of HBV integration in patients after the disappearance of HBV (prior HBV, hereafter) has yet to be determined. This study aimed to detect integration of HBV and adeno-associated virus type 2 (AAV2) into the human genome as a possible oncogenic event.Virome capture sequencing was performed, using HCC and liver samples obtained from 243 patients, including 73 with prior HBV without hepatitis C viral (HCV) infection and 81 with chronic HBV.Clonal HBV integration events were identified in 11 (15.0%) cases of prior HBV without HCV and 61 (75.3%) cases of chronic HBV (P < 0.001). Several driver genes were commonly targeted by HBV, leading to transcriptional activation of these genes; TERT [four (5.4%) vs. 15 (18.5%)], KMT2B [two (2.7%) vs. five (6.1%)], CCNE1 [zero vs. one (1.2%)], CCNA2 [zero vs. one (1.2%)]. Conversely, CCNE1 and CCNA2 were, respectively, targeted by AAV2 only in prior HBV. In liver samples, HBV genome recurrently integrated into fibrosis-related genes FN1, HS6ST3, KNG1, and ROCK1 in chronic HBV. There was not history of alcohol abuse and 3 patients with a history of nucleoside analogue treatment for HBV in 8 prior HBV with driver gene integration.Despite the seroclearance of hepatitis B surface antigen, HBV or AAV2 integration in prior HBV was not rare; therefore, such patients are at risk of developing HCC.
A novel anti-DR5 antibody-drug conjugate possesses a high-potential therapeutic efficacy for leukemia and solid tumors
Authors: Shuyong Zhang, Chao Zheng, Wan Zhu, Peng Xiong, Dongdong Zhou, Changjiang Huang, Dexian Zheng
Journal: Theranostics (2019)

It is well known that tumor necrosis factor-related apoptosis inducing ligand receptor 1 or 2 (DR4/DR5) is specifically expressed in various tumor cells, but less or no expression in most normal cells.Many first generations of TRAIL agonists including recombinant preparations of TRAIL, agonistic antibodies against DR4/DR5 have been developed in phase I/II clinical trials for cancer therapy.However, the outcomes of clinical trials by using DR4/DR5 agonist mono-therapy were disappointed even though the safety profile was well tolerance.In the present study, we report an anti-DR5 antibody-drug conjugate (ADC, named as Zapadcine-1) possesses a higher potential for the therapy of lymphocyte leukemia and solid cancers.Methods: Zapadcine-1 was made by a fully humanized DR5-specific monoclonal antibody (Zaptuzumab) coupled via a cleavable linker to a highly toxic inhibitor of tubulin, monomethyl auristatin D (MMAD), by using ThioBridge technology.Cytotoxicity of the ADC in various tumor cells was identified by luminescent cell viability assay and the efficacy in vivo was determined in cells derived xenografts (CDX) of Jurkat E6-1, BALL-1, Reh, and patient derived xenografts (PDX) of human acute leukemia.Preliminary safety evaluation was carried out in rat and monkey.Results: Zapadcine-1 possesses a similar binding ability to the death receptor DR5 as the naked monoclonal antibody Zaptuzumab, and can be rapidly endocytosed into the lysosome of cancer cells.Zapadcine-1 specifically kills human lymphocyte leukemia cells and solid tumor cells, but not normal cells tested.More importantly, Zapadcine-1 drastically eliminates the xenografts in both CDX and PDX models of human acute leukemia.The excellent and comparable therapeutic efficacy is also observed in lung cancer NCI-H1975 CDX mouse model.The maximum-tolerated dose (MTD) of single injected Zapadcine-1 in rat and cynomolgus monkey shows an acceptable safety profile.Conclusion: These data demonstrate a promising anti-cancer activity, meriting further exploration of its potential as a novel cancer therapeutic agent, especially for the acute lymphocyte leukemia.
The prognostic role of hepatic venous pressure gradient in cirrhotic patients undergoing elective extrahepatic surgery
Authors: Enric Reverter, Isabel Cirera, Agustín Albillos, Wilma Debernardi-Venon, Juan G. Abraldes, Elba Llop, Alexandra Flores, Graciela Martínez-Palli, Annabel Blasi, Javier Martínez, Fanny Turon, Juan Carlos García-Valdecasas, Annalisa Berzigotti, Antoni M. de Lacy, Josep Fuster, Virginia Hernández-Gea, Jaume Bosch, Joan Carles García-Pagán
Journal: Journal of Hepatology (2019)
Phase II trial of combination therapy using S-1, cisplatin, and radiation for distant metastatic esophageal cancer (stage IVb).
Authors: Hiroaki Iwase, Masaaki Shimada, Tomoyuki Tsuzuki, Hidemi Goto
Journal: Journal of Clinical Oncology (2012)

e14596 Background: S-1 is an orally active fluoropyrimidine that enhances the efficacy of radiotherapy (RT) and has low gastrointestinal toxicity. Our previous phase II study demonstrated that definitive chemoradiotherapy (CRT) with S-1 and cisplatin was well-tolerated and had favorable activity for locally advanced esophageal cancer (Iwase H et al, Proc. ASCO 2011, Abst 4034). The present study was a phase II trial of combination therapy using S-1, cisplatin, and RT for distant metastatic esophageal cancer (DMEC). Methods: S-1 (80 mg/m 2 /day) was given orally for 14 consecutive days from Day 1 and cisplatin (70 mg/m 2 ) was administered on Day 14, both with 3 weeks of RT (2.0 Gy per traction) 5 times per week for the primary lesion and metastases in the neck, which initiated on Day 1. One Cycle equals 5 weeks, 2 weeks of chemotherapy concurrent with 3 weeks of RT followed by 2 weeks of complete rest. After 2 cycles, only chemotherapy with S-1 and cisplatin were administered. Results: Forty-one patients with DMEC (Stage IVb) were enrolled between March 2002 and February 2011. 37/male7/female, median age 67.5 years (48-82). The median survival follow-up time was 16.6 months and 37 patients (90.2%) completed the combination treatment. The most common adverse event was neutropenia. Grades 3 and 4 neutropenia were observed in 29.2% and 12.2%, respectively. In general, non-hematological adverse events were mild and the most common were Grade 2 nausea (34.1%), esophageal pain and oral mucositis (17.1% each), and renal dysfunction (9.8%). The overall response rate was 65.9% comprising 93.2% in the primary lesion, 60% in the liver metastasis, 64.3.% in the lung, 54.5% in the distant lymph node, 83.3% in the regional lymph node metastasis, and 50% in the other distant metastases. Thirty-nine patients (88.6%) showed improvement in their dysphagia score. The median progression-free and overall survival durations were 5.3 [95% confidence interval (CI), 4.1 to 6.0] and 13.1 months (95% CI, 9.8 to 15.6), respectively. Conclusions: Combination therapy using S-1, cisplatin, and RT has a promising safety and efficacy profile. Potentially, this regimen could become the baseline treatment for patients with DMEC.
Artificial intelligence and machine learning in clinical development: a translational perspective
Authors: Pratik Shah, Francis Kendall, Sean Khozin, Ryan Goosen, Jianying Hu, Jason Laramie, Michael Ringel, Nicholas Schork
Journal: npj Digital Medicine (2019)

Abstract Future of clinical development is on the verge of a major transformation due to convergence of large new digital data sources, computing power to identify clinically meaningful patterns in the data using efficient artificial intelligence and machine-learning algorithms, and regulators embracing this change through new collaborations. This perspective summarizes insights, recent developments, and recommendations for infusing actionable computational evidence into clinical development and health care from academy, biotechnology industry, nonprofit foundations, regulators, and technology corporations. Analysis and learning from publically available biomedical and clinical trial data sets, real-world evidence from sensors, and health records by machine-learning architectures are discussed. Strategies for modernizing the clinical development process by integration of AI- and ML-based digital methods and secure computing technologies through recently announced regulatory pathways at the United States Food and Drug Administration are outlined. We conclude by discussing applications and impact of digital algorithmic evidence to improve medical care for patients.
Phase I-II trial of irinotecan (CPT) and cisplatin (P) as concurrent chemo-radiotherapy (CCRT) for patients (pts) with primary local advanced cervical cancer (LACC): A KCOG 0328 trial
Authors: K. Ito, M. Kita, K. Hosokawa, S. Toyoda, M. Kozuki, M. Hayashi, T. Takata, Y. Miyoshi, H. Koshiba, T. Tabata
Journal: Journal of Clinical Oncology (2006)

15002 Background: Though CCRT based on P is now recommended in LACC, there is no standard regimen. We conducted a phase I-II trial of CPT and P as CCRT in pts with primary LACC. Methods: Eligibility criteria: histologically confirmed primary LACC as FIGO stage III to IVb by para-aortic lymphnode (PAN) metastasis, age 16–75 years, ECOG performance status &lt;2, adequate bone marrow, hepatic and renal function, and written informed consent. Radiotherapy (RT) consisted of external beam 5040cGy in 28 fractions followed by single application brachytherapy, delivering 1800–2400 cGy to point A in 3–4 fractions. The doses of chemotherapy (CT) were set up as follows: dose level (DL) 0; CPT 20 mg/m 2 , P 30 mg/m 2 , DL1; CPT 25mg/m 2 , P 30 mg/m 2 , DL2; CPT 30 mg/m 2 , P 30 mg/m 2 , and the starting level was chosen DL1. CT was curried out weekly 5 cycles concurrently with RT. Toxicities were assessed according to NCI-CTC ver2.0J and responses were assessed according to RECIST. Results: So far 9 pts have been entered. The median age was 52 years (range 29 -73). All pts were FIGO stage IIIb and histrogically squamous cell carcinoma. Among the first 2 pts in DL1, 2 dose-limiting toxicities (DLT) were observed (delay of treatment due to grade 3 diarrhea and nausea) resulting in dose reduction to DL0. In the next 3 pts in DL0, no DLTs were observed and the study is ongoing as phase II. All pts were evaluable for response and toxicity. Eight complete (CR) and 1 partial response (PR) were seen at target region of cervix. But 2 pts showed progressive disease (PD) at non-target region of PAN, lung and liver, then overall response rate assessed by RECIST was 77.8% (CR 7, PD 2). Now the median follow up period is 16 months (range 6 -30). So far 2 pts of PD died and 3 pts relapsed. The median survival time is 10+ months (range 6+ -30+). Toxicity in DL0 was observed febrile neutropenia in 1 pt only. Conclusions: The CCRT with CPT and P in DL0 is feasible and shows promising activity in pts with primary LACC. No significant financial relationships to disclose.
Clonal Hematopoiesis
Authors: Peter Libby, Robert Sidlow, Amy E. Lin, Dipti Gupta, Lee W. Jones, Javid Moslehi, Andreas Zeiher, Siddhartha Jaiswal, Christian Schulz, Ron Blankstein, Kelly L. Bolton, David Steensma, Ross L. Levine, Benjamin L. Ebert
Journal: Journal of the American College of Cardiology (2019)
Neoadjuvant and combined chemoradiotherapy followed by surgery in locally advanced esophageal cancer: A single-centre experience
Authors: R. Diaz, G. Reynes, A. Tormo, A. Segura, A. Santaballa, J. Ponce, A. Giménez, M. De Juan, F. Artes, T. Fleitas
Journal: Journal of Clinical Oncology (2007)

15086 Background: Concomitant chemoradiotherapy (CT-RT) with CDDP-5FU CT is a standard treatment in locally advanced esophageal cancer (EC). Long-term results are poor. The role of neoadjuvant CT (nCT) and of radical surgery after CT-RT is unclear. Methods: Single-institution, prospective trial in pts with stage II-IVA EC (TNM). PS 0–1. Staging: CT scan, barium x-ray, esophagoscopy and endoscopic ultrasound. Treatment schema: 1 cycle of neoadjuvant CT (CDDP 100 mg/m 2 d1 and 5-FU 1,000 mg/m 2 /24 h d1–5); after 21 days, 50 Gy of RT (1.8 cGy/day, M to F) and 2 cycles of reduced-dose CT (CDDP 15 mg/m 2 d1–5 and 5-FU 800 mg/m 2 /24 h d1–5, q21 days). In pts deemed resectable, surgery was done after 4–6 weeks. In the remainder, a 10 Gy boost was given with 1 cycle of modified CT. Primary endpoint: clinical and pathological response rate (RR) after 1st phase. Secondary endpoints: OS and toxicity rates. Results: 71 pts accrued between 1998 and 2006. Median age 61 yrs (r 44–80). 96% males. 85% squamous cell carcinomas. Middle third: 51%; upper third: 27%; lower third 22%. Gastric involvement: 11%. cT3: 46%, cT4: 28%. cN positive: 48%. Grade 3–4 toxicity with nCT and CT-RT: mucositis (9 and 19.5%), emesis (9 and 9%) and infection (6 and 9%). Full dose CT-RT: 87%. Clinical RR after 1st phase: CR 50%, PR 25%, SD 9%, PD 7%. Confirmation (CT- biopsy): 69%. Surgery: 30%. Reasons for no surgery: comorbidity (11%) and age (10%). Pathologic RR: CR 39%, microscopic rest 39% and macroscopic rest 22%. Downstaging 50%. No pN positive. 3 pts had unresectable disease. 62% received 2nd phase RT boost, 31% with CT. Clinical RR: CR 69%, PR 6%, PD 25%. Median follow-up 50 m (r 6–129 m). Median OS 10.5 m (r 7.4–12.8 m). 4-year OS of 18%. 47% deaths due to progression, 5% treatment-related deaths and 10% in the postoperative period. Only a clinical CR after 1st phase was found to improve OS (13.5 vs 7 m, p 0.0141). Conclusions: This regimen is well tolerated and offers a high response rate. Clinical response evaluation overestimates the pathologic response rate. In our series, the possible survival benefit of surgery is offset by the postoperative death rate. No significant financial relationships to disclose.
Impact of socioeconomic status and degree of ethnic isolation on cervical cancer incidence among Hispanics and Asians in California.
Authors: Marie-Anne Froment, Audrey Roux, Mindy C. DeRouen, Scarlett Lin Gomez, Elizabeth A. Kidd
Journal: Journal of Clinical Oncology (2013)

5605 Background: The incidence of cervical cancer in the United States has declined since the introduction of the pap smear. However, differences exist based on ethnicity and socioeconomic status (SES).This study aimed to evaluate the impact of nativity, neighborhood SES and enclave (degree of ethnic isolation) on the incidence of cervical cancer in California. Methods: Using data from the California Cancer Registry, comprising three of the National Cancer Institute’s Surveillance Epidemiology and End Results (SEER) program registries, information on all primary invasive cervical cancer diagnosed in California from January 1, 1990, through December 31, 2004 was obtained. We analyzed the influence of enclave, SES, and nativity on cervical cancer incidence. Results: Among the 22,189 invasive cervical cancer cases diagnosed between 1990 and 2004, 50% were non-Hispanic white (NHW), 39% Hispanic and 11% Asian women. Seventy percent (70%) of the invasive cervical cancer cases were squamous cell carcinoma (SCC), 19% were adenocarcinoma and 11% other histologies. Approximately half (51%) of patients presented with localized disease, 33% regional disease, 10% distant disease and 6% unknown. By ethnic group, US born women showed lower rates of SCC compared to foreign-born women. Seventy-six percent (76%) of invasive cervical cases were observed in high enclave neighborhoods, and seventy percent (70%) were noted in low SES neighborhoods. Hispanics living in low SES and high enclave had 12.7 times (95% CI; 11.2-14.3) higher rate of cervical cancer than those living in high SES, low enclave neighborhoods. For Asian women incidence rates were 6 times (95% CI; 4.9-7.5) higher in the low SES, high enclave neighborhoods compared to those living in high SES, low enclave neighborhoods. Conclusions: More efforts should be done to reach out to and increase pap smear screening for women living in high enclave neighborhoods to help decrease the incidence of invasive cervical cancer cases in these groups of women.
The BougieCap – a new method for endoscopic treatment of complex benign esophageal stenosis: results from a multicenter study
Authors: Benjamin Walter, Simone Schmidbaur, Imdadur Rahman, David Albers, Brigitte Schumacher, Alexander Meining
Journal: Endoscopy (2019)

Abstract Background A major limitation of current treatment strategies for nonmalignant upper gastrointestinal stenoses is the lack of either optical or haptic feedback during dilation. Wire guidance and fluoroscopy is often necessary to control the position. Methods A novel device for endoscopic dilation, the BougieCap (Ovesco Endoscopy AG, Tübingen, Germany) was evaluated in a prospective multicenter trial. Primary outcome was successful dilation of stenosis and secondary outcome was alteration in dysphagia symptoms in short-term follow-up. Results 50 patients with benign esophageal strictures were included. Endoscopic bougienage was successful in 96 %. Bougienage failed in two cases because of high resistance. Symptoms of dysphagia decreased significantly after bougienage (59.0 points at Day 0 vs. 28.6 points at Day 14; P &lt; 0.001). Adverse events were loss of BougieCap into the stomach in two cases; no severe adverse events were reported. Conclusions Endoscopic treatment of benign stenoses using the BougieCap enabled direct visual control of the bougienage procedure. This might help to adapt treatment more precisely to the stricture. Symptoms of dysphagia were improved in short-term follow-up. Additional wire guidance may be used for selected cases (e. g. narrow lumen, pediatric scope).
Anti-PD-1/PD-L1 plus chemotherapy versus chemotherapy alone in first-line treatment for patients with metastatic NSCLC that were PD-L1 negative or less than 1%.
Authors: Thierry Landre, Gaetan Des Guetz, Kader Chouahnia, Cherifa Taleb, Alain Vergnenegre, Christos Chouaid
Journal: Journal of Clinical Oncology (2019)

9061 Background: Clinical efficacy of single agent anti-PD-1/PD-L1 in patients with Non-Small-Cell-Lung-Cancer (NSCLC) that were PD-L1 negative or &lt; 1% is controversial. Recent studies have evaluated the combination of anti-PD-1/PD-L1 to chemotherapy (CT) for this population in the first line setting. Methods: We performed a meta-analysis (MA) of randomized trials that compared PD-1/PD-L1 inhibitor plus CT with CT alone in first line of treatment for advanced NSCLC. The outcomes included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) in patients with undetectable PD-L1 expression or &lt; 1%. A fixed-effect or random-effects model was adopted depending on between-study heterogeneity. Results: Four studies evaluated atezolizumab + CT (IMpower 130,131,132 and 150), three studies pembrolizumab + CT (Keynote 021, 189 and 407) and one study evaluated nivolumab + CT (CheckMate 227). The eight eligible studies included 2037 patients (1246 with PD-L1 negative and 791 with PD-L1 expression &lt; 1%). Most of the patients were men and smokers, with a median age of 64 years. There were 1423 Non-squamous (69.8 %) and 614 Squamous tumors (30%). The combination (PD-1/PD-L1 inhibitor + CT) was significantly associated with improvement of OS (hazards ratio [HR], 0.75; 95% CI 0.63–0.89; p &lt; 0.0001), PFS (HR, 0.72; 95% CI 0.65–0.80; p &lt; 0.0001) and ORR (relative ratio [RR], 2.59; 95% CI 1.46–4.60; p &lt; 0.0001). Moreover, median duration of response (DOR) was statistically longer with combination (8.1 months versus 4.9; p &lt; 0.0008). Conclusions: For patients with untreated NSCLC with low ( &lt; 1%) or undetectable PD-L1 expression, the anti-PD-1/PD-L1 combination with chemotherapy, compared with chemotherapy alone, is associated with significantly improved OS, PFS, and ORR.
Forty-billion medical expenditure for dialysis patients in China
Authors: Jing Tan
Journal: Kidney International (2019)

The study by Wang et al.1 revealed a comprehensive description of the burden of chronic kidney disease and end-stage kidney disease in China. The study estimated that there were approximately 553,000 hemodialysis patients and 55,000 peritoneal dialysis patients in China in 2015. The median annual overall cost for each peritoneal dialysis and hemodialysis patient was 73,266 and 87,125 renminbi, respectively.1 According to these data, the total medical expenditure for dialysis patients would have been 40–50 billion renminbi in 2015, but it was reported as 429 million renminbi.