tbuckley/cabot-search huggingface dataset:
Phase III randomized trial of standard fractionation radiotherapy (SFX) with concurrent cisplatin (CIS) versus accelerated fractionation radiotherapy (AFX) with panitumumab (PMab) in patients (pts) with locoregionally advanced squamous cell carcinoma of the head and neck (LA-SCCHN): NCIC Clinical Trials Group HN.6 trial.
Authors: Lillian L. Siu, John N. Waldron, Bingshu E. Chen, Eric Winquist, Jim R. Wright, Abdenour Nabid, John H Hay, Jolie Ringash, Geoffrey Liu, Ana Johnson, George Shenouda, Martin Chasen, Andrew Pearce, James B. Butler, Stephen Breen, Eric Xueyu Chen, T J Childs, Alexander Montenegro, Brian O'Sullivan, Wendy R. Parulekar
Journal: Journal of Clinical Oncology (2015)

6000 Background: Concurrent administration of anti-EGFR monoclonal antibody with radiotherapy (RT) increases survival compared to RT alone in pts with LA-SCCHN. No prospective data are available comparing bioradiotherapy to standard chemoradiotherapy. Methods: Pts with TanyN+M0 or T3-4N0M0 LA-SCCHN were randomized 1:1 to receive SFX (70Gy/35 over 7 weeks) plus CIS at 100 mg/m2 intravenous (IV) for 3 doses on weeks 1, 4 and 7 (Arm A) versus AFX (70Gy/35 over 6 weeks) plus the anti-EGFR monoclonal antibody PMab at 9 mg/kg IV for 3 doses on weeks -1, 3 and 6 (Arm B). Primary endpoint was progression-free survival (PFS). A total of 320 patients were accrued from 12/2008 to 11/2011 with a median follow-up of 46.4 months (range: 0.1-64.3). Due to an observed declining event rate, the protocol was amended to analyze data with a clinical cut-off date of October 31, 2014. Results: Of 320 pts randomized, 5 did not receive protocol treatment, 156 received Arm A and 159 Arm B. Demographics: median age = 56 (range 35-80); male = 84%; ECOG 0:1 (%) = 71:29; primary site: oropharynx (81%), larynx (11%), hypopharynx (6%), oral cavity (2%); smoking history > 10 pack-years (58%). Of 259 oropharynx pts p16 status was known in 217 (84%), with 176 (81%) positive and 41 (19%) negative. A total of 93 PFS events occurred. By intention-to-treat, 2-year PFS was 73% (95% CI: 65-79%) in Arm A and 76% (95% CI: 68-82%) in Arm B, hazard ratio (HR) = 0.95; 95% CI: 0.6-1.5; p = 0.83. Upper bound of HR’s 95% CI exceeded the pre-specified non-inferiority margin. Two-year OS was 85% (95% CI: 78-90%) in Arm A and 88% (95% CI: 82-92%) in Arm B, HR = 0.89; 95% CI: 0.54-1.48; p = 0.66. By multivariable analysis, anatomic location, ECOG PS, p16 status, and T category were significant predictors of PFS (p < 0.05). Incidence of any > grade 3 non-hematologic adverse event (AE) was 88% in Arm A and 91% in Arm B (p = 0.25). QOL is reported separately. Conclusions: With a median follow-up of 46.4 months, PFS of PMab+AFX was not superior to CIS+SFX in LA-SCCHN and non-inferiority was not proven. Clinical trial information: NCT00820248.
Abstract LB-156: Delineating the pathological roles and molecular functions of histone methyltransferase G9a in hepatocellular carcinoma
Authors: Lei Wei, Felice Ho-Ching Tsang, Sandy Leung-Kuen Au, Joyce Lee, Carmen Wong, Irene Oi-Lin Ng, Chun-Ming Wong
Journal: Cancer Research (2016)

Abstract Liver cancer, primarily hepatocellular carcinoma (HCC), is the third leading cause of cancer mortality worldwide. In HCC, epigenetic changes including aberrant DNA methylations and histone modifications occur far more frequently than genetic alternations. However, the underlying mechanism and specific gene targets are still unknown. Using RNA-Sequencing, we identified Euchromatic histone-lysine N-methyltransferase 2 (EHMT2/G9a) as one the most significantly deregulated epigenetic regulatory genes in human HCC. G9a is a SET domain containing histone methyltransferase specific for histone H3 lysine 9 methylation. However, little is known about the functional roles of G9a in human HCC. Herein, we showed that G9a expression was frequently up-regulated in primary HCC. Up-regulation of G9a was significantly associated with multiple clinicopathological features related to HCC metastasis. We demonstrated that the frequent G9a up-regulation in HCC was attributed to the G9a gene copy number gain. In addition, we identified miR-1 as a novel post-transcriptional regulator of G9a. Loss of miR-1 significantly contributed to G9a up-regulation in human HCC. Functionally, stable knockdown (by lenti-viral based shRNA) and genetic knock-out of G9a (by CRISPR/Cas9 gene editing system) significantly suppressed HCC cell proliferation, migration and colony formation. We also demonstrated that G9a specific inhibitors, UNC0638 and BIX01294, could effectively inhibit HCC cell growth. By utilizing nude mice model, we showed that depletion of G9a drastically inhibited in vivo tumorigenicity of HCC cells. Mechanistically, we found that up-regulation of G9a epigenetically silence the expression of tumor suppressive gene RARRES3 to promote HCC tumorigenicity and metastasis. In summary, our finding suggested that up-regulation of G9a contributed to the liver carcinogenesis and could be a therapeutic target for HCC treatment. Citation Format: Lei Wei, Felice Ho-Ching Tsang, Sandy Leung-Kuen Au, Joyce Lee, Carmen Wong, Irene Oi-Lin Ng, Chun-Ming Wong. Delineating the pathological roles and molecular functions of histone methyltransferase G9a in hepatocellular carcinoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-156.
Abstract 2224: Discovery, development and characterization of a new class of therapeutic anti-PD-1 antibody
Authors: Lei Wang, Najmia Amirina, Fellix Scheuplein, Vikki Spaulding, Yanyan Wang, Sri Vadde, M. Isabel Chiu, Daniel Doty, Thomas McQuade, Bin Feng, Sheila Ranganath, Anhco “Cokey” Nguyen.
Journal: Cancer Research (2016)

Abstract Blockade of immune checkpoint (IC), such as PD-1, confers durable clinical benefit to a minority of melanoma and lung cancer patients. Challengingly, the 5-year survival rate is still below 30% in those patients, and most other solid tumors are not particularly responsive to immunotherapy. Therefore, more IC blocking mAbs are under development to meet clinical needs. Using Enumeral's unique single cell immunoprofiling platform, we developed a novel class of anti-PD-1 antibodies, named 244C8, with distinct epitope binding site than currently marketed anti-PD-1 antibodies. To evaluate the function of 244C8 on anti-tumor immunity, we employed ex vivo methods to determine responsiveness of tumor infiltrating lymphocytes (TILs), isolated from human lung cancer biopsies, to various anti-PD-1 antibodies, including our lead anti-PD1 therapeutic candidate 244C8. The results show that all anti-PD-1 antibodies tested reversed T cell exhaustion in tumor microenvironment. Further, 244C8-treated cells produced increased IFN-y compared to nivolumab, indicating a stronger anti-tumor immunity. In the settings of mixed lymphocyte reaction (MLR) and CMV antigen-recall assays, 244C8 treatment also led to higher levels of T cell activation compared to conventional anti-PD-1 antibodies. Interestingly, in both ex vivo and in vitro models, we observed a pattern of cytokine production in 244C8-treated cells that is consistently distinct from that produced by conventional/marketed anti-PD-1 antibodies, suggesting a differentiated mechanism of action. Citation Format: Lei Wang, Najmia Amirina, Fellix Scheuplein, Vikki Spaulding, Yanyan Wang, Sri Vadde, M. Isabel Chiu, Daniel Doty, Thomas McQuade, Bin Feng, Sheila Ranganath, Anhco “Cokey” Nguyen. Discovery, development and characterization of a new class of therapeutic anti-PD-1 antibody. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2224.
Abstract 5251: Chemoprevention of cadmium induced prostate carcinogenesis
Authors: Suman Suman, Trinath P. Das, Houda Alatassi, Murali K. Ankem, Chendil Damodaran
Journal: Cancer Research (2016)

Abstract Cadmium is known carcinogen that causes damages to multiple organs. Cadmium acts as an agonist and activates androgen receptor (AR) in prostate epithelial cells which in turn promotes the carcinogenesis of prostate. Studies have indicated that occupational exposure of cadmium is a risk factor for prostate cancer and hence there is an immediate need to prevent cadmium induced prostate cancer in occupational workers. Various reports have shown that inhibition of AR signaling by AR inhibitors suppressed cadmium induced prostate carcinogenesis. So, the present study focuses to identify dietary agent which can effectively prevent cadmium induced prostate cancer and to dissect the mechanism of action on malignant transformed cells. We have disclosed one such compound, 6-(3, 9-dihydroxy-2-prenylcoumestan (Psoralidin) (Pso) a non-toxic, orally bioavailable compound, which effectively targets only prostate cancer cells and innocuous to healthy cells. Our results have shown cadmium transformed prostate epithelial cells (CTPE) exhibits high proliferative and high colony forming ability in soft agar assays. However, treatment of CTPE cells with Pso resulted in growth inhibition, without causing toxicity to normal prostate epithelial cells (RWPE-1). Finally, in vivo experiments showed that oral administration of Pso (20 mg/kg/BW) effectively suppresses the growth in CTPE xenografts, at physiologically achievable doses without any toxicity. The pathological findings suggest that CTPE tumors exhibits epithelial and mesenchymal transition (EMT) phenotype and infiltrating margins into the surrounding muscle and adipose tissue. However, Psoralidin treated tumors showed a decrease in tumor size with a significant central necrosis (up to 60% of the tumor size). More specifically, margins of Psoralidin treated tumors are less infiltrative and becoming more well circumscribed. We have also noticed that the mesenchymal component is not present and the only viable tumor is the epithelial one after Pso treatment. Altogether, our results confirm that consumption of natural compounds such as Psoralidin may play an important role in the chemoprevention for cadmium induced prostate carcinogenesis. Citation Format: Suman Suman, Trinath P. Das, Houda Alatassi, Murali K. Ankem, Chendil Damodaran. Chemoprevention of cadmium induced prostate carcinogenesis. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5251.
A single institution retrospective review of efficacy, toxicity, and symptom burden in patients (pts) with pancreatic cancer (PaC) receiving FOLFIRINOX chemotherapy.
Authors: James Traquair Paul, Pascal J Lambert, Joel Roger Gingerich, Piotr Czaykowski, Paul Joseph Daeninck
Journal: Journal of Clinical Oncology (2014)

e15221 Background: PaC is associated with a poor prognosis. FOLFIRINOX chemotherapy improves overall survival (OS) in this disease, but may be associated with poor tolerance, and toxicity. We sought to evaluate efficacy, toxicity and symptom burden in a consecutive series of PaC pts receiving FOLFIRINOX. Methods: All pts at CancerCare Manitoba who had received ≥1 cycle of FOLFIRINOX for unresectable & metastatic PaC in the 1st line setting between February 2009 and February 2013 were identified. A retrospective health record review was undertaken to collect clinical information. Kaplan-Meier survival curves were created. Edmonton Symptom Assessment Scale (ESAS) scores were collected on available patients before, during and after treatment (tx). ESAS scores were compared using a quantile mixed regression model to detect median differences between groups. Results: We identified 37 pts, median age of 60 (36-76), of whom 24 (64.9%) were male. At presentation, 27 (73%) had metastatic disease. Primary tumor location included head 21 (56.8%), tail 9 (24.3%), body 5 (13.5%), and neck 2 (5.4%). A range of 1 to 47+ FOLFIRNOX cycles were administered (mean 14.2 and median 8). Blood work parameters were the most common reason for tx modification in 22 (59.5%) pts, with patient tolerance modifying tx in 10 (27%) pts. Oxaliplatin was removed for 13 (35.1%) pts due to neurotoxicity. Median OS was 12.0 months (36.7 – 71.1), with no difference in OS based on gender (p=0.972), tumor location (p=0.747) or extent of disease (i.e. metastatic versus locally advanced) (p=0.280). ESAS scores improved (indicating fewer symptoms) for pain (p=0.031), tiredness (p=0.046), nausea (p=0.034), drowsiness (p=0.01), appetite (p=0.003) and shortness of breath (p=0.027) in pts receiving FOLFIRINOX compared to those not receiving chemotherapy . Conclusions: At our institution FOLFIRINOX use demonstrated OS comparable to recent trials. The lower ESAS scores for pain, tiredness, nausea, drowsiness, appetite and shortness of breath in pts receiving FOLFIRINOX supports it as a tolerable tx. Whether the degree of ESAS score change is clinically significant is unknown and merits further study.
EUS-FNA for mediastinal lesions of unknown aetiology: A 4-year experience from a single centre
Authors: Vinod S. Hegade, Dinesh Saralaya, Abid Aziz, Sarah Jowett, Conrad Beckett
Journal: European Respiratory Journal (2012)

Aim: Endoscopic ultrasound guided fine needle aspiration (EUS-FNA) allows access to the posterior mediastinum and tissue acquisition under real-time ultrasound guidance through the oesophageal wall. The aim of this study was to report the experience of mediastinal EUS-FNA in a large UK tertiary centre. Methods: The study included all patients who underwent mediastinal EUS-FNA in our institution from January 2008 to December 2011. Patient and procedure related data were collected from endoscopy reports. Cytology and microbiology culture reports were compared to the final clinical diagnoses made during the follow-up. We calculated sensitivity, specificity, positive and negative predictive value (PPV&NPV) of mediastinal EUS-FNA for most common conditions. Results: 195 patients (n=195, males 65%, mean age 58.6) underwent mediastinal EUS-FNA during the study period. Mean size of the lesions was 15.82mm (range 3.9-43) in short axis and 28.23mm (range 8-60) in long axis. Sub-carinal lymph nodes (LN) were the commonest (145/195, 70.3%) target lesion.

View this table:

Table 1:Overall and condition specific results of mediastinal EUS-FNA





Conclusion: Our large series shows that mediastinal EUS-FNA has high sensitivity and specificity for malignancy and sarcoidosis. With overall high sensitivity & specificity, it should be a useful tool in the assessment of mediastinal pathology.
Sir Frederick Gowland Hopkins (1861-1947)
Journal: JAMA (1970)

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The effect of antihypertensive drug treatment on mortality in the presence of resting electrocardiographic abnormalities at baseline: the HDFP experience. The Hypertension Detection and Follow-up Program Cooperative Research Group.
Journal: Circulation (1984)

The Hypertension Detection and Follow-up Program (HDFP) reported a significant reduction in 5 year mortality from all causes in its intensively treated stepped care group compared with its referred care group (p less than .01). In stratum I (mean baseline diastolic blood pressure 90 to 104 mm Hg) mortality in the stepped care group was 20.3% lower than that in the referred care group (p less than .01). For persons in this stratum not on antihypertensive drugs at baseline and free of major target organ damage, mortality in the stepped care group was 28.6% lower than that in the referred care group (p less than .01). Publication of the results of Multiple Risk Factor Intervention Trail (MRFIT), indicating possibly increased mortality in special intervention hypertensive participants with resting electrocardiographic (ECG) abnormalities, prompted further analyses of the HDFP data to determine whether stepped care drug treatment in stratum I patients with resting ECG abnormalities was associated with a similar outcome. Of the 7825 HDFP participants in stratum I, 5173 met MRFIT eligibility criteria and qualified as a subgroup comparable to the MRFIT "mild" hypertensives, 1963 with and 3210 without evidence of resting ECG abnormalities at baseline. In the subgroup without resting ECG abnormalities, mortality rates for coronary heart disease, major cardiovascular diseases, and for all causes were consistently lower in the stepped care group than in the referred care group. This finding was consistent with the MRFIT results.(ABSTRACT TRUNCATED AT 250 WORDS)
Prevalence of somatic mutations in risk genes including <i>BRCA1/2</i> in consecutive ovarian cancer patients (AGO-TR-1 study).
Authors: Eric Hahnen, Klaus H. Baumann, Andre Heimbach, Alexander Reuss, Christian Jackisch, Jan Hauke, Tjoung-Won Park-Simon, Lisa Katharina Richters, Lars Christian Hanker, Sandra Kroeber, Jacobus Pfisterer, Heidrun Gevensleben, Andreas Schnelzer, Dimo Dietrich, Stephanie Schneider, Stefan Kommoss, Frederic Marme, Katharina Prieske, Rita K. Schmutzler, Philipp Harter
Journal: Journal of Clinical Oncology (2016)

5544 Background: The mutation status of BRCA1/2 and other ovarian cancer (OC) predisposition genes is a valuable prognostic and predictive factor and widely used for clinical decision making. However, data on the prevalence of clearly somatic BRCA1/2alterations is sparse. Methods: We performed a consecutive cohort study of primary and recurrent OC patients by paired next generation sequencing (NGS) analysis of OC related genes using DNA derived from blood (Harter et al., co-submitted abstract) and FFPE tumor samples by a customized Agilent SureSelect XT gene panel. Analyses were complemented by detecting large genomic rearrangements (LGRs) in BRCA1/2 (MLPA). At the time of the data cut, 353 patients were analyzed (199 cases with first diagnosis and 154 with platinum sensitive relapse). Data analysis was restricted to likely deleterious variants (IARC class 4/5). Only variants present in the tumor sample but not in the corresponding blood sample were considered somatic. The minimum allele read frequency was set to 10%. Results: In this cohort (n = 353), 21.8% patients showed pathogenic germline mutations in BRCA1 (n = 59), BRCA2 (n = 17), or both (n = 1). Another 6.8% of the patients (n = 24) carried deleterious germline mutations in non-BRCA1/2 predisposition genes (Harter et al.). All class 4/5 germline mutations identified by NGS were confirmed in the corresponding tumors, with generally increased allele read frequencies. Germline LGRs were solely present in BRCA1 (n = 7) and confirmed in the tumor samples by MLPA. Deleterious somatic BRCA1/2 mutations were detected in 4.0% of the cases (9 BRCA1; 5 BRCA2). Another 1.1% (n = 4) carried somatic mutations in other DNA repair genes (ATM, PALB2, RAD51D, FANCM). Somatic TP53 mutations were found in 78.8% (n = 278) of the tumors, another 6.2% carried somatic mutations in PIK3CA (n = 16) and PTEN (n = 6). Conclusions: The prevalence of deleterious somatic BRCA1/2 mutations (4.0%) was lower than described (Pennington et al., 2014). Deleterious somatic mutations in other predisposition genes involved in DNA repair were rare (1.1%). In total, 84.9% of the class 4/5 mutations in BRCA1/2 or other predisposition genes identified in the tumor samples were of germline origin. Clinical trial information: NCT02222883.
Abstract 4955: Isolation and characterization of circulating tumor cells (CTCs) in breast and prostate cancer: Comparison of Harpoon CTC assay performance with the CellSearch CTC Test
Authors: Mark Connelly, David Chianese, Carrie Morano, Thai Bui, Shemeeakah Powell, Noel Ngoubilly, Renouard Sanders, Tom Barber, Ravi Kapur, Shyamala Maheswaran, Mehmet Toner, Daniel Haber
Journal: Cancer Research (2016)

Abstract Circulating tumor cells (CTCs) can provide important information about a patient's prognosis. Currently, the CELLSEARCH® CTC Test (hereafter referred to as CS) is the only US Food and Drug Administration-cleared assay for isolating and enumerating CTCs. This technology uses a CTC antigen-dependent method to isolate CTCs that may limit its ability to detect CTCs with low or no epithelial cell adhesion molecule (EpCAM) expression. We evaluated the Harpoon CTC Isolator and Chip, which uses an antigen-independent, negative depletion method to enrich CTCs from patient blood samples. As a result of the negative depletion method, the final Harpoon Product (ie, CTC-enriched cell suspension) contains CTCs that express cytokeratin (CK) and EpCAM (canonical CTCs) as well as those with low or no expression of these antigens (non-canonical CTCs). After isolation, CTCs were spun onto microscope slides and imaged using a Vectra Multispectral Imaging System. We obtained performance data on an initial prototype Harpoon assay (Harpoon + Vectra [Hrp+Vec]) and compared CTC enumeration between Hrp+Vec and CS using blood samples from 36 breast and prostate cancer patients. From 7.5 mLs of blood, the Hrp+Vec assay recovered 79.0% to 93.5% of canonical EpCAM+/CK+ CTCs recovered by CS. The Hrp+Vec assay also successfully detected non-canonical CTCs (EpCAM-/CK+ or EpCAM+/CK-) in these samples. At the CS clinical cutoff for prognostic value, where ≥5 CTCs is associated with poor prognosis, the Hrp+Vec assay was 97% concordant with CS. Hrp+Vec also detected CTCs in 12.5% (2/16) more patient samples than CS. Finally, a consensus analysis of all Vectra scan results (including both canonical and non-canonical CTCs) demonstrated that the Hrp+Vec assay detected between 90.5% and 108.9% of the number of CTCs as identified by CS. These results indicate that, when compared with CS, the prototype Hrp+Vec assay detected CTCs with similar efficiency and identified more samples as CTC-positive in these breast and prostate cancer patients. Importantly, the Hrp+Vec assay did enrich non-canonical CTCs thought to be missed by CS, and ongoing efforts are aimed to further characterize these cell populations. Citation Format: Mark Connelly, David Chianese, Carrie Morano, Thai Bui, Shemeeakah Powell, Noel Ngoubilly, Renouard Sanders, Tom Barber, Ravi Kapur, Shyamala Maheswaran, Mehmet Toner, Daniel Haber. Isolation and characterization of circulating tumor cells (CTCs) in breast and prostate cancer: Comparison of Harpoon CTC assay performance with the CellSearch CTC Test. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4955.