tbuckley/cabot-search huggingface dataset:
Tumor-targeted oncolytic adenovirus demonstrates high cytotoxicity for human lung and renal cell carcinomas independently of the level of tumor PD-L1 expression.
Authors: Jia Yao, Svetlana Atasheva, Cedrick Young, Viraj A. Master, Dmitry Shayakhmetov
Journal: Journal of Clinical Oncology (2020)

3596 Background: Immuno-checkpoint (IC) inhibitors targeting PD1-PD-L1 pathway have proven highly effective at extending survival of cancer patients. However, the clinical benefits of IC inhibitors are limited to only about 20% patients who have moderate to high levels of tumor PD1 and/or PD-L1 expression. To develop therapeutics that would provide clinical benefits to a larger proportion of cancer patients, we engineered oncolytic adenovirus for targeted infection of human tumor cells via CD46 and integrins of α3β1 or α6β4 classes, overexpressed on many epithelial human cancers. Methods: Here, we analyzed the infectivity and cytotoxicity of this novel oncolytic virus in a panel of human non-small cell lung cancers (NCSLC) cell lines, primary patient derived NSCLC xenografts, and tumor surgical explants from patients with renal cell carcinoma (RCC). Results: The in vitro analysis of NSCLC cells lines (N = 17) demonstrated that over 60% of them were highly sensitive to virus infection. The genome-wide transcriptional profiling showed that only 3 out of 12 cell lines that were sensitive to oncolytic virus infection, expressed PD-L1 ( &gt; 4.5 Log2 RPMK). Furthermore, although the pre-treatment of these cell lines with IFN-I activated PD-L1 expression, IFN-I treatment did not reduce the efficacy of tumor cell infection by the oncolytic virus. The analysis of virus infectivity on primary human tumor cells from patients with NSCLC (N = 4) and RCC (N-24) demonstrated that primary tumors were highly sensitive to oncolytic virus infection. Specifically, tumor-targeted oncolytic virus demonstrated strong cytotoxicity in 22 out of 24 analyzed primary isolated RCC cell samples. Next, we subcutaneously grafted PD-L1-negative NSCLC A549 cells to NSG mice, treated them with oncolytic virus intravenously, and the kinetics of tumor growth and animal survival was monitored. This analysis showed that after intravenous administration, oncolytic virus was able to infect tumor cells and suppress tumor growth. Whereas the median survival in mock-treated group was 26 days, all mice survived up to 100 days post oncolytic virus therapy (endpoint). Conclusions: Our study showed that tumor-targeted oncolytic adenovirus infects human tumor cell lines independently of their PD-L1 expression status and is not sensitive to IFN-I inhibition. This novel tumor-targeted oncolytic virus has the potential to provide clinical benefits to cancer patients, who do not respond or became resistant to ICI drugs.
Cardiomyopathy risk among childhood cancer survivors of African ancestry and its molecular mechanisms.
Authors: Yadav Sapkota, Na Qin, Matthew J. Ehrhardt, Zhaoming Wang, Carmen Louise Wilson, Jeremie Estepp, Parul Rai, Jane E Hankins, Paul Burridge, John L. Jefferies, Jinghui Zhang, Melissa M. Hudson, Leslie L. Robison, Gregory T. Armstrong, Daniel A. Mulrooney, Yutaka Yasui
Journal: Journal of Clinical Oncology (2020)

10514 Background: Cardiomyopathy occurs at significantly higher rates in survivors of childhood cancer than the general population, but few studies have evaluated racial/ethnic disparities. Utilizing whole-genome sequencing data in the St. Jude Lifetime Cohort (SJLIFE), we previously identified two risk loci on chromosomes 1 (rs6689879) and 15 (rs9788776) for ejection fraction (EF) and cardiomyopathy in survivors of African ancestry. The rs6689879*C was associated with 4.2% reduction in EF and 21.6-fold risk of cardiomyopathy and the rs9788776*G was associated with 5.6% reduction in EF and 46.8-fold risk of cardiomyopathy. However, molecular mechanisms behind these genetic associations are unknown. Methods: We assessed the risk of clinically-assessed/graded (per the National Cancer Institute Common Terminology Criteria for Adverse Events) cardiomyopathy in childhood cancer survivors of African ancestry (n = 301) by comparing them with those of European ancestry (n = 1870), adjusting for known cardiovascular risk factors including hypertension, abnormal glucose metabolism, hypercholesteremia, hypertriglyceridemia, sedentary behavior, risky alcohol drinking and smoking. Molecular mechanisms underlying the chromosome 1 locus was investigated using DNA methylation data in 265 SJLIFE survivors of African ancestry and gene expression profiles in human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) of breast cancer patients. Results: Multivariable analysis showed survivors of African ancestry had 1.46-fold ( P= 0.067) and 2.43-fold ( P= 0.0039) higher risks of grade 2-4 and grade 3-4 cardiomyopathy. Results from DNA methylation data showed rs6689879*C was correlated with hypomethylation of a probe (cg16996019) located within the promoter region of PHTF1 (β = -0.10; P= 0.0014). Notably, the cg16996019 was also hypomethylated in survivors with cardiomyopathy (β = -0.15; P= 0.0028). These observations were further supported by upregulation (β = 0.45; P= 0.028) of PHTF1 in hiPSC-CMs samples derived from doxorubicin-exposed breast cancer patients with and without experiencing cardiotoxicity (n = 3 each). Conclusions: Childhood cancer survivors of African ancestry are at higher risk of cardiomyopathy than those of European ancestry. Dysregulation of PHTF1 may represent the molecular mechanism underlying the rs6689879-cardiomyopathy association. These findings have potential implications for long-term cardiac surveillance as well as up front cancer care for patients of African descent.
Potential germline findings identified during somatic tumor testing: Room for improvement.
Authors: Sundas Khan, Heather Wright, Melissa Cuke, Edmund Folefac, Claire F. Verschraegen, Marie Wood
Journal: Journal of Clinical Oncology (2020)

1543 Background: Genomic testing, useful for treatment planning and identification of patients for clinical trials, may indicate the presence of a germline mutation. We sought to evaluate the incidence of potentially actionable germline mutations detected via genomic testing and determined rates of germline testing among patients with potential germline mutations. Methods: This was a retrospective review of patients undergoing genomic testing at The University of Vermont Cancer Center (UVMCC) between 03/02-11/19. Testing was reviewed for mutations in 60 genes associated with hereditary cancer and recognized as clinically actionable by the American College of Medical Genetics. Records were reviewed for clinical follow-up. Positive (pathogenic or likely pathogenic) genomic test results were evaluated with descriptive analyses. Proportions with 95% confidence intervals are presented and comparisons made using a χ 2 test. Results: 342 patients underwent genomic testing at UVMCC over the study period, with a median age of 61. Common tumor types include: CNS (19%), NSCLCA (17%), ovarian (8%), and sarcoma (7%). 59% (203/342) had a mutation in ≥ 1 gene associated with hereditary cancer. Most common tumor types with potential germline mutations include: NSCLCA (25%), CNS (18%), ovarian (8%), sarcoma (8%), and endometrial (7%). Potential germline mutations were most commonly identified in TP53, CDKN2A, PTEN, and RB1 (each with mutations in &gt;6% of patients). 58 patients in the cohort have undergone germline testing, of which 19% were positive for germline mutations. Of patients with mutations in the highly penetrant BRCA, PALB2, and Lynch genes, 71% were positive for germline mutations. Young age ( &lt; 50) did not enrich for germline mutations (p &gt; 0.05). Only 18% (36/203) of patients with potential germline results were referred for genetic counseling. Conclusions: Genomic testing can reveal hereditary cancer syndromes. While the majority of patients with tumor mutations in genes associated with hereditary cancer will not have germline mutations, genetic testing is the only way to confirm this. 19% of patients who underwent genetic testing in this cohort had a pathogenic germline mutation. This was enriched to 71% when considering genes rarely mutated in tumors (BRCA, PALB2, and Lynch genes). Only 17% of this cohort underwent genetic testing, representing a significant missed opportunity given the implications of these findings for both patients and families. Patients and their providers should be aware of the potential for germline findings when genomic testing is performed.
Defining the prognostic role of MGMT methylation value by pyrosequencing assay in glioblastoma patients: A large Italian multicenter study.
Authors: Giuseppe Lombardi, Matteo Simonelli, Luisa Bellu, Veronica Villani, Simona Rizzato, Tamara Ius, Francesco Pasqualetti, Marco Russo, Federica Franchino, Amoroso Rosina, Roberta Bertorelle, Francesco Cavallin, Angelo Dipasquale, Mariantonia Carosi, Stefano Pizzolitto, Daniela Cesselli, Marina Paola Gardiman, Mario Caccese, Marta Padovan, Vittorina Zagonel
Journal: Journal of Clinical Oncology (2020)

2539 Background: MGMT methylation (MGMTmet) status represents an important prognostic factor for glioblastoma (GBM) patients (PTS). Quantitative pyrosequencing approach has proven to be feasible for MGMTmet testing but its value is still unclear. We performed a large, multicentre, retrospective study to identify the association between MGMTmet values and clinical outcome. Methods: from 9 Italian neuro-oncology centres, we collected consecutive GBM PTS with assessment of MGMTmet by pyrosequencing approach evaluating CpG islands from 75 to 84. Other inclusion criteria were: histological diagnosis of GBM, ECOG PS ≤2, therapy with RT+TMZ. Kaplan-Meier method was used to estimate the survival curves, time-dependent ROC curve for defining the optimal cut-off value of mean percentage of MGMTmet in terms of 2y-OS, Cox regression for multivariable analysis, and restricted cubic spline to investigate the non-linear association between methylation values and OS. Results: 681 PTS were enrolled; median age was 60 ys; ECOG PS was 0 in 292 PTS, 1 in 306 PTS, 2 in 83 PTS; 391 PTS (58%) had a complete resection. 8% of PTS received a second surgery. IDH was mutated in 6%. 2y-OS was 31.6%, median OS was 17.4 ms. Median MGMTmet was 3.5% (IQR 0-22%). ROC curve identified a cutoff of 15% of MGMTmet in terms of 2y-OS (sens 78%, spec 57%, AUC = 0.67). 2y-OS was 19.7% and 53.7% for PTS with MGMTmet &lt; and ≥15%, respectively (p &lt; 0.0001). At multivariable analysis, MGMTmet &lt; 15% was associated with impaired survival (HR 2.7, 95% CI 2.1-3.4; p &lt; 0.00001), adjusting for age, KPS, type of surgery and second surgery. A non-linear association between MGMT methylation and survival was identified (non-linear term: p &lt; 0.0001), with lower values of MGMT methylation associated with lower survival; indeed, estimated median OS was lowest (14 months, 2ys-OS: 17.4%) with MGMTmet of 4%, 21ms (2yr-OS: 40.9%) with MGMTmet of 20%, 27ms (2yr-OS: 40.9%) when MGMTmet was 40%, then leveled around 30ms (2yr-OS: 54.5-59.8%) when MGMTmet was &gt; 40%. Conclusions: this study represents one of the largest trials analyzing MGMTmet by pyrosequencing approach. Lower values of MGMTmet were associated with impaired survival and the relationship was non-linear. Noteworthy, we identified a strong prognostic value of MGMTmet which could be used as stratification factor in prospective clinical trials
Differences in self-reported health-related quality of life in heterosexual and sexual minority women surviving cancer: 2013 to 2018 national health interview survey.
Authors: Megan Leigh Gleason Hutchcraft, Joanne G Patterson, Andreas A Teferra, Lauren Montemorano, Floor Jenniskens Backes
Journal: Journal of Clinical Oncology (2020)

e19038 Background: Health related quality of life (HRQoL) is associated with excess morbidity and mortality after cancer diagnosis. While a growing body of research indicates that sexual minority women (lesbian and bisexual women; SMW) experience greater risk for cancer diagnoses and cancer-related mortality, there is a paucity of evidence describing HRQoL in this population. This is a critical omission as assessment of sexual orientation differences in HRQoL may inform clinical interventions to improve health and survival of SMW after cancer diagnosis. This study examined associations between sexual orientation and HRQoL domains among female cancer survivors. Methods: Data from the 2013-2018 National Health Interview Survey (NHIS) was pooled. HRQoL was defined using individual indices across physical health, mental health, social, and financial domains. The association between sexual orientation and individual indices of HRQoL was assessed using weighted multivariable logistic regression analyses. Results: The sample included 97909 heterosexual, 1424 lesbian, and 1235 bisexual women who reported a cancer diagnosis. Sexual minority women were more likely to be college graduates (p &lt; 0.001) and employed (p &lt; 0.001); however, they had higher rates of being uninsured (p = 0.01) than their heterosexual counterparts. Reproductive cancers—including breast, ovarian, cervical, and uterine—accounted for 51% of cancer diagnoses in heterosexual women and 57.2% in SMW (p = 0.06). Sexual minority and heterosexual women had more similarities than differences in individual indices of HRQoL; however, several pertinent differences were noted. Specifically, SMW had higher odds of moderate (OR 1.46 [1.01-2.13]) and severe psychological distress (OR 2.10 [1.17-3.77]); chronic health conditions, including COPD (OR 1.72 [1.06-2.80]) and heart disease (OR 1.93 [1.32-2.83]); financial concerns about retirement (OR 1.36 [1.01-1.83]); food insecurity (OR 2.13 [1.23-3.68]), and severe food insecurity (OR 2.44 [1.28-4.67]). Conclusions: Sexual minority women with cancer diagnoses report worse indices of HRQoL. Poorer HRQoL may influence excess morbidity and mortality evidenced in these populations; however, future longitudinal studies are needed to assess prospective risk. Given our results, implementing interventions in the cancer setting to identify sexual minority patients in need of physical and mental health and financial services may reduce disparities.
A randomized phase I/IIa study to evaluate the safety and efficacy of SNK01 (non-genetically modified autologous natural killer cells with enhanced cytotoxicity) plus pembrolizumab in patients with stage IV non-small cell lung cancer.
Authors: Eo Jin Kim, Dae-Hyun Ko, Wonjun Ji, Jin Kyung Rho, Jae Cheol Lee, Paul Y. Song, Chang-Min Choi
Journal: Journal of Clinical Oncology (2020)

3037 Background: Despite the increased promise of checkpoint inhibitors in the treatment of lung cancer, the overall response rate is approximately 30% with up to 30% moderate to severe side effects. Natural killer (NK) cells have recently been implicated in antitumor response to immune checkpoint inhibitors. SNK01 is a novel non-genetically modified autologous natural killer cell therapy with enhanced cytotoxicity which has been found to have tumoricidal effects against several lung cancer cell lines. Methods: 18 patients with Stage IV NSCLC (PD-L1+, EGFR-, ALK-) who all failed prior frontline platinum-based therapy were randomized 2:1 to Pembrolizumab every three weeks +/- 6 weekly infusions of SNK01 at either 2 x 10 9 or 4 x 10 9 cells per infusion. Primary endpoint is safety and secondary endpoints are objective response rate (ORR), progression-free survival (PFS), overall survival (OS), time to progression (TPP), and quality of life (QoL). Results: 14 patients have been enrolled up to date and 9 have completed treatment. Median age is 69 (52-73). Two patients discontinued treatment prior to receiving their first dose of SNK01 due to Grade 3 toxicity to Pembrolizumab. Three patients have completed therapy with Pembrolizumab alone and all had progressive disease. Three patients have completed Pembrolizumab with 2 x 10 9 SNK01 and three patients have completed Pembrolizumab with 4 x 10 9 SNK01. Of patients receiving full combination therapy, there have been no adverse events or any reported toxicity while overall QoL has been improved. The week 9 overall response rate in the combination group is 66% using iRECIST (3/6 cPR, 1/6 PR). All remaining planned patients are currently being enrolled and a full update will be presented. Conclusions: These preliminary results demonstrate that combination therapy with Pembrolizumab and SNK01 is very safe and even appears to reduce checkpoint associated toxicity while increasing overall tumor response compared to Pembrolizumab monotherapy alone in Stage IV NSCLC patients who have failed prior platinum-based treatment.
肝肠吻合在肝门胆管横断伤中应用的临床分析
Authors: 鲁葆春, 任培土
Journal: BMJ (2012)

对2006年1月至2011年8月诊治的6例肝门胆管横断损伤行肝肠吻合术治疗的患者临床资料,进行回顾分析.6例手术均获成功,仅1例术后出现少量胆漏,经保守治疗2周后治愈,随访5个月～5年,无胆管狭窄发生.提示肝肠吻合操作简单、灵活,应用于复杂、高位胆管损伤患者的胆道重建,效果好、并发症少。
The effects of hidden female smokers on the association between smoking and chronic obstructive pulmonary disease in Korean adults
Authors: H.S. Ock, S.W. Hwang, H.J. Lee, C.H. Kim, S.H. Kim, T.H. Kim, J.H. Lee, J.S. Lee
Journal: Pulmonology (2020)

Smoking is an important causative factor of chronic obstructive pulmonary disease (COPD), and females are considered more susceptible to the effects of smoking than males. However, in previous Korean studies, the effects of sex differences on the association between smoking and COPD have been controversial. In this study, the effects of sex differences on the association between smoking and COPD and the effects of female hidden smokers on that association in Korean adults were investigated.Data were acquired from the Korea National Health and Nutrition Examination Surveys (KNHANES).The multivariate logistic regression analysis showed that self-reported smoking status for ex-smoker and current smoker correlated with COPD (odds ratio, OR: 1.67 and OR: 2.41, respectively). Self-reported smoking status for ex-smoker and current smoker correlated with COPD in men (OR: 1.61, OR: 2.43, respectively). Female self-reported current smoking status correlated with COPD (OR: 2.52), but female ex-smoker status was not significantly correlated with COPD. The ratios of cotinine-verified to self-reported smoking rates were 1.95 for women and 1.07 for men.The results of this study were that sex differences might affect the association between COPD and smoking and that female hidden smoking might affect the association between smoking and COPD in Korean adults.
Veliparib (V) monotherapy (monoTx) following combination therapy with V + carboplatin/paclitaxel (CP) in patients with g<i>BRCA</i>-associated advanced breast cancer: Exploratory results from BROCADE3.
Authors: Hyo S. Han, Banu Arun, Bella Kaufman, Hans Wildiers, Michael Friedlander, Jean-Pierre M. Ayoub, Shannon L Puhalla, Bruce Allen Bach, Matthew Dudley, Madan Gopal Kundu, David Maag, Christine Ratajczak, Veronique Dieras
Journal: Journal of Clinical Oncology (2020)

1091 Background: In BROCADE3 (NCT02163694), addition of PARP inhibitor V to CP resulted in improved progression-free survival (PFS) (HR 0.71 [95% CI 0.57−0.88], p=0.002) in patients (pts) with advanced HER2-negative breast cancer and g BRCA1/2 mutation. A subset of pts transitioned to V/placebo (PL) monoTx at an intensified dose/schedule after CP discontinuation prior to progression (investigator discretion). Here, we evaluate the impact of this transition on efficacy and safety. Methods: Pts were randomized 2:1 to CP with V (n=337) or PL (n=172). V (120 mg po BID) or PL was given on Days (D) −2 to 5, C (AUC 6) on D1, and P (80 mg/m 2 ) on D1, 8, and 15 (21-day cycles). Pts who transitioned to monoTx received V/PL 300-400mg BID daily until progression. A Cox model with a time varying covariate indicating transition from V/PL with CP to V/PL monoTx was fit to estimate treatment effect during combination and monoTx phases. PFS by cycles of CP prior to monoTx and AEs during monoTx are summarized. Results: A subgroup of 136 (40%) and 58 (34%) pts on the V and PL arms, respectively, received monoTx. When a Cox model with a time-varying covariate was fit for PFS (per investigator), the nominal P-value for treatment by covariate interaction was 0.038. The HRs (95% CI) for V vs PL during combination therapy and monoTx were 0.81 (0.62–1.06) and 0.49 (0.33–0.73). The Table summarizes PFS by cycles of C and/or P prior to monoTx. Common AEs (&gt;20% of pts) during V or PL monoTx were nausea (52%/10%), fatigue (23%/12%), headache (21%/17%), and diarrhea (21%/9%). Seizures (2.2%/0%) were reported during monoTx. Rates of cytopenias for V or PL monoTx were: anemia 12%/14%; neutropenia 13%/12%; and thrombocytopenia 10%/5%. Conclusions: These analyses suggest that pts treated with V + CP derive benefit from both combination therapy as well as V monoTx after CP discontinuation. Pts receiving V monoTx after ≤ 6 cycles of VCP experienced a similar benefit to those who transitioned to monoTx after 7–12 cycles of VCP, suggesting that V maintenance therapy may be suitable following a limited duration of combination therapy. Clinical trial information: NCT02163694 . [Table: see text]
Product characteristics and pharmacological profile of KTE-X19 in patients (pts) with relapsed/refractory (R/R) mantle cell lymphoma (MCL) in the phase II registrational ZUMA-2 trial.
Authors: Michael Wang, John M. Rossi, Javier Munoz, Andre Goy, Frederick Lundry Locke, Patrick Michael Reagan, Caron A. Jacobson, Brian T Hill, Houston Holmes, Samantha Mary Jaglowski, Weimin Peng, Lianqing Zheng, Xiang Fang, Allen Xue, Arati V. Rao, Adrian Bot
Journal: Journal of Clinical Oncology (2020)

3023 Background: ZUMA-2 is a Phase 2 study evaluating KTE-X19, an autologous anti-CD19 CAR T cell therapy, in pts with R/R MCL (1 – 5 prior therapies, including a BTK inhibitor). In the primary efficacy analysis of ZUMA-2 (N = 60), the objective response rate was 93% (67% complete responses) and was generally comparable among high risk pts (Wang et al. ASH 2019 #754). CAR T cell levels in blood were associated with objective response (including minimal residual disease [MRD] negativity) and toxicity. Here, we describe a comparative analysis of KTE-X19 pharmacology profile in higher vs lower risk pts in ZUMA-2. Methods: Product attributes, CAR T cell and serum cytokine levels in blood, and their associations with clinical outcomes, were analyzed using previously described methods (Locke et al. Mol Ther 2017). MRD (10 −5 sensitivity) was assessed by next-generation sequencing. Pharmacology data are reported for all 68 pts treated with KTE-X19 (2 × 10 6 cells/kg). Results: Manufactured KTE-X19 products showed a slight bias to CD8 and effector memory/effector phenotype. Median CD4/CD8 ratio was 0.7 (range, 0.04 – 3.7); T cell phenotypes included naive (median, 24.5%; range, 0.3 – 80.7), central memory (median, 12.8%; range, 2.3 – 51.6), effector memory (median, 24.5% (range, 0.8 – 70.3) and effector (median, 28.7%; range, 2.8 – 65.2). MRD negative (n = 24/29) vs positive pts (n = 5/29) at 1 mo post KTE-X19 had increased median cytokine levels, including IL-15, IL-2, IFN-γ, IL-10, and IL-6, peaking in serum within 7 days post treatment. Pts who were MRD negative by 1 mo post treatment also had increased median peak levels of Granzyme B and soluble PD-L1. Six pts developed Grade 4 neurologic events (NE), including 1 cerebral edema case; 3 had concurrent Grade 4 cytokine release syndrome. These pts had higher peak cytokine levels vs pts without Grade 4 NE, with lack of reversion to baseline by Day 28 of serum IL-6 and sVCAM-1. Peak CAR T cell in blood and serum cytokine levels were generally comparable in higher vs lower risk pts defined as TP53 mutated (n = 6/36) vs unmutated (n = 30/36), or high vs low Ki-67 proliferation index (PI; ≥ 30% [n = 40/49] and &lt; 30% [n = 9/49]), consistent with the comparable clinical efficacy of KTE-X19 in these subgroups. Conclusions: PD profile of KTE-X19 associated with efficacy (MRD status at 1 mo) and treatment-related NE. In contrast to approved therapies, KTE-X19 showed comparable pharmacology and clinical outcomes in pts with higher vs lower risk MCL defined by TP53 mutation or Ki-67 PI. Clinical trial information: NCT02601313 .