tbuckley/cabot-search huggingface dataset:
Symptom clusters and demographic characteristics in advanced cancer.
Authors: Aynur Aktas, Declan Walsh, Lisa A. Rybicki, Anne Fitz
Journal: Journal of Clinical Oncology (2013)

9638 Background: Little is known about demographic variations in cancer symptom clusters (SC). Our objective was to determine whether SC are associated with age, gender, race, performance status (PS), or primary cancer site. Methods: Symptoms from 1000 advanced cancer patients referred to a palliative medicine program were recorded prospectively. Among 922 patients with complete symptom data, hierarchical cluster analysis identified 7 SC. A SC was considered present if the patient had ≥50% of the symptoms in the cluster. Comparisons were made between patients with and without each cluster using the chi-square test (age &lt;65 vs. ≥65 years; gender female (F) vs. male (M); race Caucasian (C) vs. African American (AA); 10 primary site groups (PSG), or Wilcoxon rank sum test (ECOG PS 0-4). A p value &lt;0.05 indicated statistical significance. Results: 83% of patients were C, 52% ≥65 years, 56% M, and 55% had ECOG PS 3-4 Most common PSG were lung (25%), genitourinary (18%), and gastrointestinal (GI) (11%). Fatigue/anorexia-cachexia cluster was associated with race (58% AA vs. 68% C, p=0.032) and PSG (range 47% melanoma to 83% pancreas, p=0.012); Neuropsychological cluster was associated with older age (29% ≥65 vs. 39% &lt;65, p&lt;0.001) and race (22% AA vs. 36% C, p=0.001). Upper GI cluster was associated with female gender (16% M vs. 22% F, p=0.035) and PSG (range 8% Head &amp; Neck to 32% pancreas, p=0.035). Nausea/Vomiting cluster was associated with younger age (35% ≥65 vs. 43% &lt;65, p=0.010) and female gender (33% M vs. 47% F, p&lt;0.001). Aerodigestive cluster was associated with male gender (36% F vs. 44% M, p=0.010) and PSG (range 24% pancreas to 58% Head &amp; Neck, p&lt;0.001). Debility cluster was associated with race (33% AA vs. 44% C, p=0.016) and poor PS (range 17% PS0 to 54% PS4, p&lt;0.001). Pain cluster was associated with younger age (88% ≥65 vs. 92% &lt;65, p=0.028). Conclusions: We identified 7 SC whose prevalence were influenced by age, gender, race, PS, or primary cancer site. This supports the clinical relevance of the cluster concept in palliative and supportive care. Demographic characteristics may warrant different clinical approaches to patient care. Identification of these differences may help develop more effective cancer treatment and management strategies.
Prospective Comprehensive Molecular Characterization of Lung Adenocarcinomas for Efficient Patient Matching to Approved and Emerging Therapies
Authors: Emmet J. Jordan, Hyunjae R. Kim, Maria E. Arcila, David Barron, Debyani Chakravarty, JianJiong Gao, Matthew T. Chang, Andy Ni, Ritika Kundra, Philip Jonsson, Gowtham Jayakumaran, Sizhi Paul Gao, Hannah C. Johnsen, Aphrothiti J. Hanrahan, Ahmet Zehir, Natasha Rekhtman, Michelle S. Ginsberg, Bob T. Li, Helena A. Yu, Paul K. Paik, Alexander Drilon, Matthew D. Hellmann, Dalicia N. Reales, Ryma Benayed, Valerie W. Rusch, Mark G. Kris, Jamie E. Chaft, José Baselga, Barry S. Taylor, Nikolaus Schultz, Charles M. Rudin, David M. Hyman, Michael F. Berger, David B. Solit, Marc Ladanyi, Gregory J. Riely
Journal: Cancer Discovery (2017)

Tumor genetic testing is standard of care for patients with advanced lung adenocarcinoma, but the fraction of patients who derive clinical benefit remains undefined. Here, we report the experience of 860 patients with metastatic lung adenocarcinoma analyzed prospectively for mutations in >300 cancer-associated genes. Potentially actionable genetic events were stratified into one of four levels based upon published clinical or laboratory evidence that the mutation in question confers increased sensitivity to standard or investigational therapies. Overall, 37.1% (319/860) of patients received a matched therapy guided by their tumor molecular profile. Excluding alterations associated with standard-of-care therapy, 14.4% (69/478) received matched therapy, with a clinical benefit of 52%. Use of matched therapy was strongly influenced by the level of preexistent clinical evidence that the mutation identified predicts for drug response. Analysis of genes mutated significantly more often in tumors without known actionable mutations nominated STK11 and KEAP1 as possible targetable mitogenic drivers.Significance: An increasing number of therapies that target molecular alterations required for tumor maintenance and progression have demonstrated clinical activity in patients with lung adenocarcinoma. The data reported here suggest that broader, early testing for molecular alterations that have not yet been recognized as standard-of-care predictive biomarkers of drug response could accelerate the development of targeted agents for rare mutational events and could result in improved clinical outcomes. Cancer Discov; 7(6); 596-609. ©2017 AACR.See related commentary by Liu et al., p. 555This article is highlighted in the In This Issue feature, p. 539.
Risks of proton pump inhibitors for patients with cirrhosis: The controversy remains
Authors: Ângelo Zambam de Mattos, Suelen Aparecida da Silva Miozzo, Cristiane Valle Tovo, Angelo Alves de Mattos
Journal: Hepatology (2017)

Potential conflict of interest: Nothing to report. To the Editor: This letter is in regard to the recently published article by Dam et al.1 The authors performed a post hoc analysis on data of patients with cirrhosis and ascites who were enrolled in three trials of satavaptan for ascites control. The study demonstrated that the use of proton pump inhibitors (PPIs) was associated with a greater risk of hepatic encephalopathy (HE; hazard ratio = 1.36, 95% confidence interval 1.01‐1.84) and spontaneous bacterial peritonitis (SBP; hazard ratio = 1.72, 95% confidence interval 1.10‐2.69).1 As highlighted by the authors, a study performed by our group reached different results regarding the association between PPIs and SBP: 22.5% of PPI users and 21.5% of PPI nonusers developed SBP (P = 0.176).2 An Argentinean study also failed to detect a significant association between PPI use and SBP.3 Despite the merits of the study by Dam et al.,1 we understand that some issues about it need further discussion. The first issue is that because it was a post hoc analysis, the authors were unaware of the PPI use status during the follow‐up. The variability of PPI use over time was pointed out as a limitation of the study by the authors themselves. Moreover, the fact that 33% of PPI users and only 14% of nonusers received lactulose at baseline1 implies that PPI users already had episodes of HE (which was supposed to be an exclusion criterion of the study) or were at a higher risk for developing it. When only lactulose nonusers were evaluated, the impact of PPI on HE was actually lost (95% confidence interval included the null value). The difference in the percentage of use of lactulose led us to believe that patients using PPIs were probably more severely ill than the others. Still, concerning lactulose, the authors considered that its use was a predictor of HE,1 which we do not agree with because we understand that patients using lactulose probably already had HE. Thus, we believe that the findings of the study by Dam et al.1 should be interpreted carefully and that more studies are required in order to abate the controversy regarding this subject. Nevertheless, we suggest that physicians avoid the indiscriminate prescription of PPIs.
Screening and Identifying of the Protein Tyrosine Phosphatase Superfamily Members Related to Chronic Myeloid Leukemia and Exploration of Its Potential Function.
Authors: Qingfeng Du, Song Zhang, Rong Li, Junmei Gong, Hongqian Zhu, Yu Wang, Feng Yao, Wei Fan, Xiaoli Liu, Shuyu Zhou
Journal: Blood (2006)
Angiogenesis factors in esophageal tumors of various histogenesis.
Authors: Elena Mikhaylovna Frantsiyants, Oleg Ivanovich Kit, Evgeniy N. Kolesnikov, Natalia D. Cheryarina, Larisa Kozlova, Yulia A. Pogorelova
Journal: Journal of Clinical Oncology (2017)

87 Background: Study of biological nature of tumors can provide important information on the malignant process course and contribute to the drug therapy development. The purpose of the study was to analyze levels of some growth factors in tissues of malignant esophageal tumors of various histogenesis. Methods: Levels of VEGF-А and its receptor sVEGF-R1, VEGF-С and its receptor sVEGF-R2, EGF, IFR-1, IFR-2 and TGF-β1 were studied by the ELISA using standard test-systems in tissue samples obtained from 39 patients: 27 – esophageal squamous cell carcinoma (ESCC), 12 – esophageal adenocarcinoma (EA). All patients had stage II disease (G2, pTNM). Results: Development of the pathogenic vascularization mechanism in ESCC and EA tissues was found to have both similar and different characteristics associated with the expression of growth factors. Similarities included activation of VEGF-А, VEGF-С, VEGF-R1, VEGF-R3, TGF-β1 and EGF in tissues of malignant tumors despite their histogenesis, while differences involved IGF-I and IGF-II content. A strong positive correlation between levels of VEGF-А and IGF-1 (r = 76; p &lt; 0.01), but not IGF-II, was registered in EA tissues only, while in ESCC we found the negative correlation between VEGF-А and IGF-1(r = - 81; p &lt; 0.01) and VEGF-А and IGF-2 (r = -79; p &lt; 0.01). The same was observed for VEGF-С: a strong positive correlation with IGF-1(r = 79; p &lt; 0.01), but not with IGF-II in EA, and a strong negative correlation with IGF-1(r = - 83; p &lt; 0.01) and IGF-2 (r = -87; p &lt; 0.01) in ESCC. EGF appears to be the only VEGF-А and VEGF-С inductor in ESCC, as a strong correlation with it was noted: r = 75 (p &lt; 0.01) and r = 77 (p &lt; 0.01) respectively, while activators of angio- and lymphogenesis factors in EA were presented by IGF-1 and EGF (r = 76 at p &lt; 0.01 and r = 79 at p &lt; 0.01 with VEGF-А and VEGF-С, respectively). Conclusions: Apparently, the two histological types of esophageal cancer are two different diseases with their own pathogenesis, prognosis and therefore approach to the targeted therapy.
A phase Ib trial of an anti-idiotypic vaccine for Lewis Y (IGN 301) administered subcutaneously in patients with refractory solid tumors
Authors: S. G. Thakkar, P. Heeger, B. Wacker, M. Roddy, G. Waxenecker, G. Himmler, H. Loibner, P. Elson, R. Bukowski
Journal: Journal of Clinical Oncology (2004)

2586 Background: The Lewis Y (LeY) antigen is expressed on 60–90% of solid tumors with limited expression on normal tissue. This property has attracted interest to use LeY antigen as a vaccine in cancer immunotherapy. Use of an anti-idiotypic antibody (IGN 301) as an immunogenic surrogate for the LeY antigen is hypothesized to elicit a strong IgG response. We are conducting a phase I trial of IGN 301 to determine the safety, immunologic effects and antitumor activity with and without GM-CSF or IFN-α2b. Methods: Twenty-eight patients with solid tumor refractory to standard therapy enrolled in 2 cohorts. Cohort 1 received vaccine alone and cohort 2 received vaccine plus colony stimulating factor (GM-CSF). The immunogenicity of IGN 301 was assessed by measurement of the total humoral immune response. Seroconversion was assayed by ELISA and defined as a serum Ig titer of at least 1:100 against the murine type anti-idiotypic antibody used as vaccine antigen in IGN 301. T-cell reactivity was assessed by ELISPOT. Peripheral blood lymphocytes (PBLs) were isolated by Ficoll centrifugation and then tested for reaction against IGN 301, LeY and a series of positive and negative controls. Results: No patient experienced greater than grade 2 toxicity. Cohort 1 had a 64% seroconversion rate (9/14 patients) and cohort 2 had 60% (3/5 patients). T-cell reactivity was more frequent in cohort 1 (43%) versus cohort 2 (14%). The most frequent response observed was a Th1 phenotype (IFN-γ response). Only one patient from all evaluable was observed to have a Th2 (IL-4) response. Conclusions: IGN 301 was well tolerated without significant toxicities. Immunization induced a high rate of antibody seroconversion. Elicited T-cell immune response was predominantly Th1 phenotype. Further evaluation will assess the role and toxicity of IFN-α2b administration as an adjuvant with this vaccine. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Igeneon Igeneon
Rapid characterization of candidate loss of function genes in primary organoid culture.
Authors: Daniel James Hart, Ameen Abdulla Salahudeen, Sean de la O, Kyuho Han, David Morgens, Michael Bassik, Calvin Jay Kuo
Journal: Journal of Clinical Oncology (2017)

77 Background: Genome scale sequencing efforts have identified chromosomal deletions and non-synonymous mutations as putative drivers of gastro-intestinal cancer. There is a need to rapidly validate these drivers in robust models. The culture of primary, non-transformed tissues in vitro as three-dimensional organoids that accurately recapitulate organ structure and physiology serves as an ideal model for such validation, and many other applications in biology. Methods: Mouse wild type and p53 flox/flox upper digestive tract tissue containing epithelial and mesenchymal components were cultured in an air-liquid interface and subjected to adenovirus expressing either a functional control or Cre recombinase. Resultant organoids were passaged at confluency until dysplasia was evident in histology. A lentiviral shRNA (loss-of-function) screen was then conducted, where proliferative activity was measured with barcode reads from the pooled library. Results: p53-null organoids showed histology consistent with human gastrointestinal cancer. These organoids were also able to form small tumors when injected subcutaneously into immune-deficient mice. The pooled lentiviral shRNA screen functionally validated candidate drivers. Conclusions: Gastrointestinal organoids are a suitable model for the introduction of oncogenic mutations in a tractable and replicable format. In future work we will validate loss-of function and gain-of-function screens with CRISPRi/a libraries, and replicate these screens in human gastrointestinal organoids.
Metastatic NSCLC: Treatment patterns, outcomes, and costs of newer agents.
Authors: Adrian G. Sacher, Lisa W. Le, Anthea Lau, Craig Earle, Natasha B. Leighl
Journal: Journal of Clinical Oncology (2012)

7606 Background: New therapies for metastatic NSCLC have improved survival in clinical trials. The increased cost of these agents has led to variable drug funding and treatment across jurisdictions. Here we review patterns, real-world outcomes and costs of metastatic NSCLC treatment in the province of Ontario. Methods: All patients diagnosed with metastatic NSCLC from 2005-2009 were identified from the Ontario Cancer Registry with demographic, histologic and mortality data. Treatment records from the Ontario New Drug Funding Program and centralized treatment database were linked. Statistical analysis involved Wilcoxon rank sum, Kruskal-Wallis, Cochran-Armitage trend and likelihood ratio tests where appropriate. Results: 8113 metastatic NSCLC patients were identified. The median age was 68; 39% had adenocarcinoma, 14% squamous carcinoma and 43% histology not otherwise specified. Most were treated in regional cancer centers (92%). The majority (76%) did not receive systemic therapy; 23% received first-line chemotherapy, most commonly platinum doublets. More patients received systemic therapy over time (19% in 2005 v 26% in 2009, p &lt;0.0001). Older patients (p &lt;0.0001) and those with squamous histology (p &lt;0.0001) were less likely to receive systemic therapy. Center of diagnosis did not affect the likelihood of treatment (p=0.46). The median time from diagnosis to death was significantly greater among patients selected to receive chemotherapy (9.3 v 3.2 months, p &lt;0.0001), and with cisplatin/gemcitabine compared to other doublets (10.7 v 8.2 months, p=0.004). 31% of treated patients received second-line chemotherapy, predominantly with docetaxel (52%) or pemetrexed (41%). Pemetrexed use increased significantly over time (8% in 2005 v 71% in 2009, p&lt;0.0001), as did the mean drug cost of second-line therapy ($5939/patient in 2005 v $10,057 in 2009). A longer median survival was also seen with pemetrexed in adenocarcinoma (17.9 v 15.2 months for docetaxel, p =0.02). Conclusions: Most metastatic NSCLC patients do not undergo systemic treatment. First- and second-line treatment outcomes in this population-based study were similar to clinical trials, confirming better outcomes with new agents at greater cost.
Patients’ expectations of oncologists and primary care providers (PCPs) in addressing reproductive and sexual health.
Authors: Ying Wang, Leo Chen, Winson Y. Cheung
Journal: Journal of Clinical Oncology (2014)

9584 Background: The risk of infertility and sexual dysfunction from cancer therapy is inadequately discussed at the time of cancer diagnosis (Wang et al, ASCO 2013) even though these issues can cause significant distress. Our aims were to survey young cancer patients to 1) ascertain their expectations of physicians in addressing these concerns and 2) characterize how patients’ expectations modify the likelihood of having discussions about reproductive and sexual health. Methods: Patients aged 20 to 39 diagnosed with solid tumors from 2006 - 2008, evaluated at any 1 of 5 regional cancer centers in British Columbia and alive at >/= 2 years after diagnosis were surveyed to determine their views about oncologists’ and PCPs’ responsibilities for reproductive and sexual health. Survey responses were paired with tumor and treatment characteristics from patients’ medical records. Using logistic regression, we explored for associations between expectations and whether or not patient-physician conversations had occurred. Results: A total of 453 patients (response rate 57%) were included: median age was 35 years, 29% were men, 88% had ECOG 0, and 78% reported being in a relationship. Tumor sites included breast (50%), testicular (27%), gynecological (17%) and colorectal (6%). Patients expected their PCPs to be more involved than their oncologists in addressing fertility and sexual function (82% vs. 76% and 73% vs. 49%, respectively). However, only 55% and 7% of individuals actually engaged in conversations about these issues with their physicians. In multivariate models, higher patient expectations of oncologists’ involvement in reproductive and sexual health did not correlate with greater likelihood of having a discussion (OR 1.22 p=0.49 and OR 0.99 p=0.98, respectively). Conversely, increased patient expectations of their PCPs correlated with receipt of a discussion about fertility (OR 2.44 p=0.01) but not about sexual function (OR 0.62 p=0.15). Conclusions: Patients prefer to address their reproductive and sexual health concerns with their PCPs. Whereas most discussions appear to be driven by physician factors, fertility conversations with PCPs can be facilitated by increased patient engagement.
Genetic polymorphisms’ influence in outcome of metastatic renal cell cancer patients treated with VEGF-targeted agents.
Authors: Fabio Augusto Barros Schutz, Kathryn P. Gray, Mark M Pomerantz, Michael B. Atkins, Michelle S. Hirsch, David F. McDermott, Megan Lampron, Andrew Percy, Gwo-Shu Mary Lee, Jonathan E. Rosenberg, Sabina Signoretti, Philip W. Kantoff, Matthew Freedman, Toni K. Choueiri
Journal: Journal of Clinical Oncology (2012)

4635 Background: Single nucleotide polymorphisms (SNP) in critical signaling pathways may impact the outcome of metastatic renal cell cancer (mRCC) patients (pts) treated with VEGF targeted agents. Methods: Germline DNA was extracted from 263 pts of European-American ancestry enrolled in a prospective protocol with full baseline and follow up clinical data. A total of 113 common SNPs within select genes involved in RCC pathogenesis, angiogenesis and drugs metabolism were genotyped and associations sought with clinical outcome. The primary endpoint was progression free survival (PFS), defined as time from VEGF targeted therapy to progression or death. Cox model tested for the association between SNPs with PFS in univariate and multivariate model that adjusted for age, gender, type of VEGF inhibitor and MSKCC risk score. The false discovery rate (pFDR) was used to control for the number of tests performed. Results: The median follow-up time was 51.6 months (mo), 81% of pts had progression or death events. All patients were treated with an approved VEGF targeted agent (bevacizumab, sunitinib, sorafenib or pazopanib). Fifty three percent (140/263) of pts were treated with sunitinib. Two SNPs, one in HIF2α and one in VEGFR2, showed a significant association with the risk of progression. Compared to the dominant genotype (frequency 83%, median PFS 10.1mo), the VEGFR2 rs2305948 variant genotype (frequency 17%) showed a superior PFS (median 19.2mo) corresponded to an adjusted hazard ratio (HR) of 0.56 (95%CI: 0.37-0.84; p=0.005). Similarly and compared to the dominant genotype (frequency 94%, median PFS 10.6mo), the HIF2α rs11687512 variant genotype (frequency 6%) had a superior PFS (median 26.5mo) with an adjusted HR of 0.33 (95%CI 0.16-0.68; p=0.002). The analysis adjusted for age, gender, type of VEGF targeted therapy (Sunitinib vs. others) and MSKCC risk score. False discovery rate was &lt;20% with both SNPs. Conclusions: Inherited variants may influence the PFS of pts with mRCC treated with VEGF targeted agents. Validation of these findings in an independent cohort is required. If validated, these results could help identifying subset of pts that are more likely to remain progression free on treatment.
Effect of anti-CTLA-4 antibody treatment on T-cell repertoire evolution in treated cancer patients.
Authors: Edward Cha, Yafei Hou, Mark Klinger, Craig Cummings, Malek Faham, Antoni Ribas, Lawrence Fong
Journal: Journal of Clinical Oncology (2013)

3020 Background: CTL-associated antigen 4 (CTLA-4) is an immune checkpoint expressed by T cells. While treatment with anti-CTLA-4 antibody can induce clinical responses in advanced cancer patients, its effects on the breadth of the T cell response is unknown. Methods: We used a sequencing-based method, LymphoSIGHT, to assess T cell repertoire diversity in 46 patients with metastatic castration resistant prostate cancer or metastatic melanoma. Peripheral blood mononuclear cells were obtained from patients prior to and during treatment with anti-CTLA-4 antibody. mRNA was amplified using locus-specific primer sets for T cell receptor (TCR) beta, and the amplified product was sequenced. Sequence reads were used to quantitate absolute TCR frequencies using standardized clonotype determination algorithms with normalization by spiked reference TCR sequences. Following clonotype quantitation, repertoire differences between serial samples were assessed by the Morisita index, a statistical measure of population dispersion. Results: 97 paired samples were assessed, of which 46 (47%) had increases and 22 (23%) had decreases in TCR diversity by more than 2-fold. By comparison, none of 9 untreated sample pairs underwent more than a 2-fold change in diversity (P = 0.005, Fisher’s exact test, two tailed). TCR repertoire differences between monthly samples were markedly higher than for time-matched controls. After the first treatment, median Morisita index between samples was 0.197 for treated samples versus 0.039 for untreated (P = 0.0005, Mann-Whitney U test). The median number of clones that significantly changed in abundance was 421 for treated versus 45 for controls. In patients with multiple time points, this rapid clonotype evolution continued through treatment. Despite this global turnover in repertoire, a subset of high frequency clones, including CMV-specific T cells, remained relatively constant over the course of the study. Conclusions: CTLA-4 blockade increases the global rate of T cell clonotype turnover and influences TCR diversity. This evolution of the TCR repertoire may reflect a mechanism by which CTLA-4 blockade enhances tumor-specific T cells over time.