tbuckley/cabot-search huggingface dataset:
GHRH-receptor as a new targetable biomarker in breast cancer and its correlation with ER/PR/HER2 status.
Authors: Mehrdad Nadji, Norman L. Block, Andrew V. Schally, Jonathan F. Lara, Richard Alan Michaelson, Rajiv Pulinthanathu, Matthew Tortora, Suhail M. Ali, Kim Leitzel, Syed Mujtaba Rizvi, Mhd Yaser Al-Marrawi, Allan Lipton
Journal: Journal of Clinical Oncology (2015)

576 Background: In addition to its nominative function as a neurohormone acting on the pituitary, growth hormone-releasing hormone (GHRH) has been shown to modify the growth behavior of numerous cancers, including breast. GHRH is produced by tumor cells, acts in an autocrine/paracrine manner, and requires the presence of the GHRH receptor (GHRH-R) on the tumor cells to exert its effects. The aim of this study was to evaluate the relationship of GHRH-R expression in different subtypes of breast cancer (triple negative, HER2-positive and hormone receptor-positive subsets). Methods: The cohort consisted of 96 primary breast cancers. Immunohistochemistry for GHRH-R was performed on paraffin sections and the staining results were assessed semi-quantitatively from 0 (negative) to 3+ (strongly positive). Patients with 0 or 1+ GHRH-receptor expression were classified as having low expression, and 2+ or 3+ as high expression. The ER/PR/HER2 levels of each tumor were correlated with the GHRH-R IHC results. Results: 62/96 (65%) patients had hormone receptor (HR) positive (ER- and / or PR-positive), 12/84 (14%) had HER2-positive, and25/84 (30%) had triple negative breast cancers (TNBC). 92% of HER2-positive, 68% of HR-positive, and 44% of TNBC had high expression of GHRH-R. HER2-positive primaries had a significantly increased frequency of high (11/12, 92%) vs. low (1/12, 8%) GHRH-R expression compared to HER2-negative primaries (p = 0.018). There was no difference in GHRH-R expression by HR status (p = 0.38). TNBC had a significantly decreased frequency of high (11/25, 44%) vs. low (14/25, 56%) GHRH-R expression compared to non-TNBC (p = 0.041). Conclusions: GHRH-R is expressed by the majority of primary mammary carcinomas regardless of their hormone receptor status. HER2-positive tumors were more likely to express high levels of GHRH-R; TNBC expressed lower levels. This finding could potentially serve as a basis for therapeutic approaches using synthetic peptide GHRH-R antagonists that have already shown significant efficacy combined with minimal pharmacologic side effects in experimental models.
Abstract P223: Starch Digestion Related Amylase Genotypes Affect 2-year Adiposity Changes in Response to Weight-loss Diets: The Pounds Lost Trial
Authors: Yoriko Heianza, Dianjianyi Sun, Tiange Wang, George A Bray, Frank M Sacks, Lu Qi
Journal: Circulation (2017)

Background/Aim: Salivary amylase, which is encoded by the salivary gene ( AMY1 ), is responsible for digesting starchy foods into sugar, and the AMY1 shows extensive copy number variations which directly affect differences in salivary and serum amylase amount and activity. Recent evidence suggests associations of low serum amylase levels and obesity. We investigated whether the copy number related AMY1 genotypes were associated with 2-year changes of adiposity in response to weight-loss diet intervention. Methods: This study included 692 obese individuals with data on AMY1 variant rs11185098 who were randomly assigned to 1 of 4 diets varying in macronutrient contents. Changes of body weight (BW) and waist circumference (WC) over 2 years during the intervention were evaluated according to the genotype. Results: We found that changes in BW and WC were significantly different according to the AMY1 genotype (Figure). After adjustment for age, sex, ethnicity, diet groups and value for the respective outcome traits at baseline, carrying the minor A allele (which indicates higher amylase amount and activity-associated allele) of rs11185098 was significantly associated with greater reduction of BW at 6, 12, 18, and 24 months (β (SE), p value; -0.7 (0.35), 0.04; -1.21 (0.46), 0.009; -1.63 (0.52), 0.0017; -1.27 (0.49), 0.0095, respectively). Also, increasing number of allele A was associated with a greater decrease of WC at 6, 12, 18 and 24 months (p &lt;0.05 for all). The genetic effects on these outcomes did not significantly differ across the diet groups. Conclusions: Our study indicated that the genetic variant responsible for starch metabolism significantly influenced on the response to weight-loss dietary intervention. Obese individuals carrying the AMY1 genotype that associated with higher salivary amylase activity may benefit from greater weight loss and the improvement of central adiposity in response to low-calorie diet interventions.
Development of a disease-specific measure of quality of life in myelodysplastic syndromes (MDS): The “QUALMS-1”.
Authors: Gregory Alan Abel, Stephanie Lee, Richard M. Stone, David P. Steensma, Nancy Young, Alice Houk, B Taylor Hastings, Yolanda Martins, Robert Klaassen
Journal: Journal of Clinical Oncology (2012)

6103 Background: Studies assessing the quality of life (QoL) experienced by patients with MDS have almost universally relied upon generic measures; however, disease-specific QoL tools can allow for more sensitive assessments of the impact of changes in disease status. Methods: Using a clinical impact method of instrument development, individual and combined focus groups were conducted with 32 members of our institution’s MDS community (patients, their caregivers, and health care providers) to identify MDS-relevant QoL domains and associated question topics. Participants’ rankings of the importance of the domains and question topics were compared, collapsing patients/caregivers into one group and physicians/other providers into another. A draft scale was constructed taking a greater number of questions from the more highly-ranked domains. Results: “Fatigue” was ranked as the most important domain (see table). None of the 12 domains were ranked significantly differently by patients/caregivers versus providers. The two groups ranked 5 of 60 question topics differently: “Too tired for routine tasks” (providers higher; p= .05); “limited availability of support beyond the family” (providers higher; p= .02); “organizing life around transfusion/MD appointments” (providers higher, p= .03); “bruising” (patients/caregivers higher, p= .05) and “anger over diagnosis” (providers higher, p= .03). Conclusions: A high level of agreement in the rankings of domains and question topics between MDS patients/caregivers and providers suggests that the QoL experience of MDS patients is consistently compromised. The resulting 38-item draft QUALMS-1 tool is now being piloted (cognitive debriefing and behavioral coding) in a new cohort of MDS patients, with the ultimate goal of validation in a multi-institutional setting. [Table: see text]
T-Cell Mineralocorticoid Receptor Controls Blood Pressure by Regulating Interferon-Gamma
Authors: Xue-Nan Sun, Chao Li, Yuan Liu, Lin-Juan Du, Meng-Ru Zeng, Xiao-Jun Zheng, Wu-Chang Zhang, Yan Liu, Mingjiang Zhu, Deping Kong, Li Zhou, Limin Lu, Zhu-Xia Shen, Yi Yi, Lili Du, Mu Qin, Xu Liu, Zichun Hua, Shuyang Sun, Huiyong Yin, Bin Zhou, Ying Yu, Zhiyuan Zhang, Sheng-Zhong Duan
Journal: Circulation Research (2017)

Hypertension remains to be a global public health burden and demands novel intervention strategies such as targeting T cells and T-cell-derived cytokines. Mineralocorticoid receptor (MR) antagonists have been clinically used to treat hypertension. However, the function of T-cell MR in blood pressure (BP) regulation has not been elucidated.We aim to determine the role of T-cell MR in BP regulation and to explore the mechanism.Using T-cell MR knockout mouse in combination with angiotensin II-induced hypertensive mouse model, we demonstrated that MR deficiency in T cells strikingly decreased both systolic and diastolic BP and attenuated renal and vascular damage. Flow cytometric analysis showed that T-cell MR knockout mitigated angiotensin II-induced accumulation of interferon-gamma (IFN-γ)-producing T cells, particularly CD8+ population, in both kidneys and aortas. Similarly, eplerenone attenuated angiotensin II-induced elevation of BP and accumulation of IFN-γ-producing T cells in wild-type mice. In cultured CD8+ T cells, T-cell MR knockout suppressed IFN-γ expression whereas T-cell MR overexpression and aldosterone both enhanced IFN-γ expression. At the molecular level, MR interacted with NFAT1 (nuclear factor of activated T-cells 1) and activator protein-1 in T cells. Finally, T-cell MR overexpressing mice manifested more elevated BP compared with control mice after angiotensin II infusion and such difference was abolished by IFN-γ-neutralizing antibodies.MR may interact with NFAT1 and activator protein-1 to control IFN-γ in T cells and to regulate target organ damage and ultimately BP. Targeting MR in T cells specifically may be an effective novel approach for hypertension treatment.
BRCA mutations and outcome in epithelial ovarian cancer (EOC): Experience in ethnically diverse groups.
Authors: Tamar Safra, Wei-Chu V Lai, Tara Berman, Lucia Borgato, Elsa Reich, Maria Alvear, Franco Muggia, Sharon Pelles-Avraham
Journal: Journal of Clinical Oncology (2012)

5078 Background: EOC patients with BRCA mutations have been reported to have better prognosis than non-hereditary (NH) matched cases, an advantage shown especially in the Ashkenazi-Jewish (AJ) population. We have analyzed our experience in our ethnically diverse patient cohort from NYC, Israel and Italy. Methods: A retrospective chart review of patients diagnosed with Stage IC-IV EOC between 1995-2008 at the NYU Cancer Institute, Tel Aviv Sourasky MC and Padova Clinical Cancer Centers. Out of &gt;700 patients, 183 were tested for BRCA mutations and evaluated. Results: Median age was 55.5 (range 31–83 years). Out of 183, 86 are carriers of BRCA1/2 mutations and 97 tested negative, 67 and 19 are carriers of BRCA1 and BRCA2 mutation respectively. Carrier frequency in EOC population is 46% (45/97) in AJ's and 48% (41/86) in non-AJ's. AJ patients had the following BRCA1 mutations: 185delAG (29), 5382insC (5), unknown (UK) (2) and BRCA2 mutations: 6174delT (8), UK (1). Non-AJ's were divided by ethnicities into non-AJ, Caucasian, African-American, Hispanic, Middle Eastern or unknown. Non-AJ Jewish patients had BRCA1 mutations in 185delAG (7) and BRCA2 in 6174delT (1), UK (1). Non-Jewish Caucasians exhibited the widest variation of mutation types, with the following BRCA1 sites: 185delAG, K1702X (5223A&gt;T), E1373X, 3829delT, 185delAT, IVS11+1G&gt;A, 5385insC, 5083del19&gt;stop1670, 1720delAF&gt;stop536, 1806C/T&gt;Igu536Ter, del ex1a-2, cod1486ex14:4575delAstop1504, 5563G7A;Trp1815stop, 5181delGTT(Val1688del) and UK and the following BRCA2 sites: 6174delT (2), 5301insA (1), 802delAT (1), cod2960ex22:9106C/t (1), cod68ex3:432delAstop79 (1), 7408A/T;Arg2394stop (1). One African-American patient with BRCA1 at 1294del40, 1 Hispanic BRCA1 at 185delAG. OS was significantly prolonged for BRCA carriers at 93.6 months versus 63.2 months [95% CI: 44.5-91.7] (p=0.0016) for NH. Conclusions: Our data reports a wide variety of BRCA mutations in an ethnically diverse EOC population and confirms that BRCA mutations carriers have a better prognosis with a longer median survival compared to NH population. A larger cohort might manifest prognostic differences between the different types of mutations.
Clinical implication of inflammation-based prognostic score and perioperative nutrition control in pancreatic cancer.
Authors: Nao Takano, Suguru Yamada, Tsutomu Fujii, Mitsuru Tashiro, Nobutake Tanaka, Daishi Morimoto, Go Ninomiya, Yukiko Niwa, Hideki Takami, Naoki Iwata, Masamichi Hayashi, Mitsuro Kanda, Chie Tanaka, Daisuke Kobayashi, Goro Nakayama, Hiroyuki Sugimoto, Masahiko Koike, Michitaka Fujiwara, Yasuhiro Kodera
Journal: Journal of Clinical Oncology (2017)

390 Background: Systemic inflammation and nutrition status are considered to influence survival in cancer patients. A variety of systemic inflammation-based prognostic scores have been explored; however, there has been no study to clarify which score could best reflect survival in resected pancreatic cancer patients. Methods: Between 2002 and 2016, 422 consecutive patients who underwent curative resection of pancreatic cancer were enrolled. The Glasgow Prognostic Score (GPS), modified GPS (mGPS), neutrophil to lymphocyte ratio (NLR), platelet to lymphocyte ratio (PLR), prognostic index (PI), and prognostic nutritional index (PNI) scores for each patients were calculated. Survival of each score was evaluated, and correlations between the score selected on the basis of the prognostic significance and various clinicopathological factors were analyzed. On the other hand, the nutrition markers (pre-albumin, transferrin, and retinol-binding protein) of 30 patients who received the enteral nutrition during the perioperative period were also evaluated. Results: In the analysis of the GPS, the median survival time (MST) was 29.4 months for score 0, 25.5 for score 1, and 17.7 for score 2 ( p&lt; 0.001), and mGPS was also found to be significant ( p= 0.003). On the contrary, there were no significance in MST between other scores (NLR, PLR, PI, or PNI). Multivariate analysis revealed that lymph node metastasis, positive peritoneal washing cytology, and a GPS score of 2 were significant prognostic factors. There was also statistically significant correlation between the GPS score and tumor location (head), tumor size ( &gt; 2.0cm), bile duct invasion, and duodenal invasion. In terms of nutrition status, the postoperative nutrition markers of 30 patients managed by enteral nutrition tended to recover earlier than 79 patients managed by intravenous nutrition. Conclusions: Our results demonstrated that the GPS could be an independent predictive marker and was superior to other inflammation-based prognostic scores in patients with resected pancreatic cancer. The results also suggested that perioperative nutrition support and infection control would improve survival of pancreatic cancer patients.
Primary chest wall soft tissue sarcomas: predictors of survival following surgical resection in a large population cohort.
Authors: Sadiq Rehmani, Adnan M Al-Ayoubi, Raja Michael Flores, Faiz Y. Bhora
Journal: Journal of Clinical Oncology (2015)

10571 Background: Primary soft tissue sarcomas (STS) of the chest wall are rare entities with limited information regarding treatment and oncological outcomes. The aim of this study is to evaluate the outcomes of surgical treatment in malignant primary chest wall STS and identify factors affecting survival using the Surveillance, Epidemiology, and End Results (SEER) database. Methods: We conducted a retrospective analysis using the SEER database (1988 -2010) and queried for all patients with primary chest wall STS. Only adult patients with histologically confirmed single primary tumor undergoing curative surgical resection were included in the study. Primary outcome was overall survival; covariates included demographics, tumor pathology, radiation and type of surgical procedure as coded in SEER (Simple/Partial or Total/Radical). Chi-square tests were performed to analyze categorical variables. Kaplan-Meier and Cox regression analyses were used to evaluate overall survival. Results: A total of 1053 cases of surgically resected, histologically confirmed, primary chest wall STS were identified. Mean age was 56 years and male to female ratio was 1.33:1. Out of 1053, 57% patients underwent Simple/Partial resection while 43% underwent Total/Radical. A total of 42% patients received radiation therapy. The mean overall survival of the entire cohort was 126.6 (± 8.284) months. After adjusting for covariates using Cox’s proportional hazards regression, higher tumor grade (grade3: HR = 4.934 {CI: 2.599-9.365}, p < 0.001; grade4: HR = 4.895 {CI: 2.629-9.117}, p < 0.001) and tumor size (5-10 cm: HR = 1.77 {CI: 1.216-2.560}, p < 0.005; > 10cm: HR = 3.72 {CI: 2.538-5.458}, p < 0.001) were found to be independently associated with poor survival. Conclusions: Primary chest wall soft tissue sarcomas are uncommon tumors. Using the SEER database, we present the largest cohort reported to date. In this analysis, both advanced tumor grade and size are poor predictors of survival. Further studies are required to validate these findings and to direct adjuvant therapy.
Statin and aspirin use and risk of VTEs in ovarian cancer patients.
Authors: Hedy S Rennert, Gad Rennert, Ofer Lavie, Shlomi Sagi, Michele Leviov, Mariana Steiner, Ayelet Shai
Journal: Journal of Clinical Oncology (2013)

5576 Background: Deep vein thrombosis and pulmonary embolism - venous thromboembolic events (VTEs) - are associated with significant morbidity and increased risk of mortality in cancer patients. Ovarian cancer patients are at a particularly increased risk for VTEs. Statins and aspirin have been shown to reduce the risk of VTEs in the general population in randomized trials. However, the effect of these medications on the incidence of VTEs in ovarian cancer patients has not been studied. Methods: Patients diagnosed with ovarian cancer between years 2000 and 2011 were identified through the Israeli Cancer Registry (ICR). Patients insured by Clalit Health Services, the largest HMO in Israel, were included. Data regarding medication use, chronic diseases and VTE diagnosis were extracted from the computerized database. Patients taking Warfarin or Low Molecular Weight Heparin for 3 months or longer were excluded. Statistical analysis was performed using SPSS (v 18). Use of medications was analyzed as a time dependent covariate in a Cox regression model. Results: Of 1,886 patients 179 (9.5%) had a VTE during a median follow up of 3.13 years. 95 patients (5%) had a VTE 2 years after diagnosis of ovarian cancer. In a multivariate analysis use of chemotherapy and stage 3 or 4 at presentation were associated with an increased risk for VTE's 2 years after diagnosis. Age was associated with a trend for increased risk. Statins were used by 43.2% of the patients, and 31.9% used aspirin. Aspirin use was associated with a reduced incidence of a VTE, which was borderline statistically significant (p=0.054). Statin use did not affect the incidence of VTE's in the group of ovarian carcinoma patients. Conclusions: Our results suggest that in patients with ovarian cancer aspirin use is a possible protector from deep vein thrombosis and pulmonary embolism. Prospective trials are warranted to assess the benefit of aspirin and statins for prevention of VTE's in the high risk population of ovarian cancer patients. [Table: see text]
Long-term survival with <sup>90</sup>yttrium ibritumomab tiuxetan and rituximab as treatment for relapsed or refractory diffuse large B-cell lymphoma.
Authors: Jon E. Arnason, Katarina Luptakova, Jacalyn Rosenblatt, Jeffrey Zwicker, James D. Levine, Vassiliki Boussiotis, Michelle Kim, David Avigan, Robin Joyce
Journal: Journal of Clinical Oncology (2013)

8558 Background: Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) are salvaged with high dose chemotherapy followed by autologous stem cell rescue. Ibritumomab tiuxetan is an anti-CD20 antibody conjugated to the radionuclide 90 yttrium. 90Y ibritumomab tiuxetan has demonstrated clinical efficacy in DLBCL with a favorable toxicity profile relative to transplant. Methods: This phase II trial investigated the overall response rate (ORR), event free survival (EFS), overall survival (OS) and toxicity of treatment with ibritumomab followed by rituximab in patients with relapsed or refractory DLBCL, not candidates for transplant. Patients were treated with an initial dose of rituximab (250 mg/m 2 ) followed one week later by ibritumomab (0.4 mCi 90 Y/kg or 0.3 mCi 90 Y/kg based on plateles) followed by 4 weekly doses of rituximab (375mg/m 2 ). All non-progressing patients received maintenance rituximab (375 mg/m 2 ) weekly for 4 doses every 6 months for 4 cycles. Results: 25 patients were enrolled. Median age was 79 (range 45-95). 12 of 25 (48%) had stage 3 or 4 disease. 13 (52%) had 2 or more prior regimens. At 12 weeks 5 patients (21%) had a complete response (CR), 3 (13%) a partial response, 2 (8%) stable disease and 14 (58%) progressed for an ORR of 32% (8/25). At best response 7 patients obtained a CR. Median EFS was 2.5 months. Median OS was 8.1 months. No patient who obtained CR later relapsed, with follow up of 18.3-100.1 months. Deaths unrelated to treatment occurred in remission in 5 patients. 2 patients remain free of disease at 67.4 and 100.1 months. 11 (65%) patients had grade 3 or 4 thrombocytopenia, but no significant bleeding was observed. 9 (36%) patients had grade 3 non-hematologic toxicity. Grade 1 and 2 fatigue occurred in 41%. Patients who progressed through a rituximab containing regimen were at high risk of early progression. Conclusions: The ORR of ibritumomab as salvage therapy for DLBCL compares favorably to other regimens with acceptable toxicity. Those patients with disease refractory to rituximab are not likely to benefit. For a subset of patients not candidates for salvage with autologous transplant, this treatment can produce a durable remission. Clinical trial information: NCT00110149.
Effect of stimulation of natural killer cells with an anti-CD137 mAb on the efficacy of trastuzumab, cetuximab, and rituximab.
Authors: Holbrook Edwin Kohrt, Roch Houot, Kipp Weiskopf, Matthew Goldstein, Peder Lund, Ferenc Scheeren, Debra Czerwinski, A. Dimitrios Colevas, Wen-Kai Weng, Michael F. Clarke, Robert W. Carlson, John Sunwoo, Thomas Tedder, Lieping Chen, Ronald Levy
Journal: Journal of Clinical Oncology (2012)

2514 Background: Antibody-dependent cell-mediated cytotoxicity (ADCC), mediated by natural killer (NK) cells, plays an important role in the efficacy of monoclonal antibodies (mAb)s. CD137 is a costimulatory molecule expressed on immune cells following activation, including NK cells. We hypothesize that as the antitumor efficacy of mAbs is due to ADCC, their activity can be enhanced by stimulation of NK cells with an anti-CD137 agonistic mAb. Methods: Upregulation of CD137 on NK cells was assessed using CD20+lymphoma, HER2+breast, and EGFR+head and neck cell lines and primary patient samples. NK cell degranulation, cytokine release and cytotoxicity were assessed by CD107a mobilization, IFN-γ secretion, and chromium release. Mechanism of synergy was explored by cell depletion in an immune competent mouse model. Xenotransplanted models were used to demonstrate anti-tumor activity and sufficiency of an innate immune response. Results: NK cells in human primary patient samples do not express CD137 at baseline, however CD137 is highly upregulated when encountering mAb-coated tumor cells. MAb-induced NK cell degranulation and cytotoxicity are enhanced by anti-CD137 agonistic mAb. In a murine lymphoma model, anti-CD137 mAb significantly enhances anti-tumor activity of anti-CD20 mAb leading to complete tumor resolution and prolonged survival. NK cell depletion completely abrogates the therapeutic effect. In seven xenotransplant models, sequential administration of rituximab, trastuzumab or cetuximab plus anti-CD137 mAb provided superior reduction in tumor burden and prolonged overall survival. In a phase 0 biomarker study, level of CD137 expression on circulating and intratumoral NK cells was influenced by disease burden, prior treatment, FcγRIII polymorphism, and time since mAb therapy. Conclusions: Our results demonstrate the synergy of anti-CD137 mAb and a tumor-targeting mAb by stimulation of mAb-activated NK cells with anti-CD137 mAb to enhance ADCC. These results support a novel, sequential antibody approach against CD20+B cell, HER2+breast, and EGFR+head and neck malignancies by targeting first the tumor and then the host immune system.