tbuckley/cabot-search huggingface dataset:
A phase I study of nivolumab (anti-PD-1; BMS-936558; ONO-4538) in combination with sunitinib, pazopanib, or ipilimumab in patients (pts) with metastatic renal cell carcinoma (mRCC).
Authors: Asim Amin, Marc S. Ernstoff, Jeffrey R. Infante, Daniel Yick Chin Heng, Brian I. Rini, Elizabeth R. Plimack, David F. McDermott, Christian K. Kollmannsberger, Martin Neil Reaume, Jennifer L. Spratlin, Jennifer J. Knox, Martin Henner Voss, Sumanta Kumar Pal, Yun Shen, Arindam Dhar, Hans J. Hammers
Journal: Journal of Clinical Oncology (2013)

TPS4593 Background: Vascular endothelial growth factor receptor-tyrosine kinase inhibitors are established therapies for mRCC. However, sunitinib and pazopanib rarely elicit durable responses. Programmed death-1 receptor (PD-1) is an immune checkpoint modulator that suppresses T-cell activation by interacting with its ligands (PD-L1/2) on antigen presenting cells and some tumor cells. Nivolumab, a PD-1 receptor blocking antibody, has shown durable responses in previously treated pts with mRCC in Phase 1 and 2 trials. Ipilimumab is an immune checkpoint inhibitor (anti-CTLA-4 antibody) already approved for the treatment of advanced melanoma. We describe an ongoing Phase 1 dose-escalation and expansion study evaluating combination of nivolumab with sunitinib, pazopanib or ipilimumab in pts with mRCC. Methods: Patients with histologically confirmed mRCC are treated on 4 parallel arms: nivolumab 2.0 or 5.0 mg/kg + sunitinib standard dosing (Arm S), nivolumab 2.0 or 5.0 mg/kg + pazopanib standard dosing (Arm P), nivolumab 3 mg/kg + ipilimumab 1 mg/kg as induction (Arm I-1), and nivolumab 1 mg/kg + ipilimumab 3 mg/kg as induction (Arm I-3) with nivolumab 3 mg/kg maintenance for both arms. Arms S and P are being conducted in 2 phases: nivolumab dose-escalation phase for previously treated pts (≤18 pts/arm) and then dose-expansion phase for treatment-naïve pts (20 pts/arm) if the maximum tolerated dose is ≥5 mg/kg. Arms I-1 and I-3 are fixed-dose cohorts (20 pts/arm) including both treatment-naïve and previously treated pts. Most of the study population consists of pts with clear-cell histology; non-clear cell mRCC pts are allowed in the dose-escalation cohorts of Arms S and P. The primary objectives are to assess safety and tolerability, and to determine the recommended Phase 2 dose in pts with mRCC. The secondary objective is to assess preliminary antitumor activity (objective response rate and response duration per RECIST 1.1). Exploratory objectives are to evaluate overall survival, pharmacodynamics, and predictive biomarkers for the combinations, and pharmacokinetics and immunogenicity of nivolumab. Clinical trial information: NCT01472081.
The Transcriptional Signature of Kinases Inhibited by the Multi-Targeted Kinase Inhibitor AS703569 Is Associated with Clinical Outcome in Multiple Myeloma (MM): Anti-MM Activity of AS703569 in Preclinical Studies.
Authors: Jake Delmore, David N. Cervi, Douglas McMillin, Efstathios Kastritis, Jana Jakubikova, Melissa G. Ooi, Steffen Klippel, Joseph M. Negri, Leutz Buon, Jacob Laubach, Luca Rastelli, Ann Clark, Samantha M. Sarno, Paul G. Richardson, Kenneth C. Anderson, Constantine S. Mitsiades
Journal: Blood (2009)
Vascular Invasion and Metastasis is Predictive of Outcome in Barcelona Clinic Liver Cancer Stage C Hepatocellular Carcinoma
Authors: Ali A. Mokdad, Amit G. Singal, Jorge A. Marrero, Hao Zhu, Adam C. Yopp
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: Patients with Barcelona Clinic Liver Cancer (BCLC) stage C hepatocellular carcinoma (HCC) have variable long-term outcomes. Better delineation of prognosis is important for clinical trial enrollment and clinical practice in an era of precision medicine. We hypothesized that stratification of patients with BCLC stage C HCC by presence of vascular invasion and/or metastasis improves prognostic discrimination. Methods: Using a prospectively maintained database, we identified 234 patients diagnosed with BCLC stage C HCC between 2005 and 2015. Patients were stratified into 3 groups based on tumor characteristics: (1) vascular invasion alone, (2) metastasis alone, and (3) vascular invasion and metastasis. Overall survival (OS) was compared using a Cox model. A subgroup analysis was performed based on extent of vascular invasion and site of metastasis. Results: The cohort comprised 123 patients (53%) with vascular invasion alone, 34 (15%) with metastasis alone, and 77 (33%) with both vascular invasion and metastasis. Median survival was 5.7, 3.9, and 3.0 months, respectively (P<.01). Patients with vascular invasion or metastasis alone had significantly better survival compared with those with vascular invasion and metastasis (adjusted hazard ratio [HR],0.68; 95% CI, 0.49–0.94, and HR, 0.61; 95% CI, 0.39–0.96, respectively). Compared with tumoral invasion of branch portal veins, involvement of the main portal vein was associated with worse survival (HR, 2.13; 95% CI, 1.29–3.49). OS did not differ by site of metastasis. Conclusions: Stratification of patients within the BCLC stage C staging subgroup by vascular invasion and presence of metastasis further discriminates patient prognosis. This substratification may have implications for therapy and more accurate prognostic features.
Targeting tumour markers: What makes therapy discriminating?
Authors: K. Johnson, R. Ward
Journal: Journal of Clinical Oncology (2006)

13129 Background: Therapy in inoperable non-small cell lung cancer has limited effectiveness. New therapy directed at tumour markers is attractive but limited by marker prevalence and intrinsic effectiveness. Prior work (Abstract 9639, 2005 PASCO) on 191 trials of first line therapy shows a “typical drug” needs at least a 35% difference in response rate, treatment versus control, to predict a survival gain. The current work describes the characteristics of targeted drugs likely to predict this gain at smaller differences, i.e., more discriminating drugs. We determine how much greater effects on response rate and survival, compared to the typical drug, need to be to predict this survival gain. Methods: By using 1.0, 1.1, 1.2, 2.0-fold increments in response rates over traditional therapy and the same increments for median survival up to that used for response, we defined 55 differently constructed targeted drugs. The drugs were all analysed at each of four marker prevalence rates, 5%, 20%, 50% and 100%, each analysis determining the response rate difference needed to predict a survival gain. For each analysis individual trial response rates were modified in one arm before applying linear regression. The response rate difference to predict a survival gain is the portion of the prediction band fully exceeding zero. Results: Improvements in discrimination were rare and highly sensitive to marker prevalence. Little improvement occurred for any drug with 5% or 20% prevalence, and if no survival improvement occurred, discrimination worsened (up to 90%). If both tumour response and survival were doubled, discrimination improved to 33%, 27%, 17%, and 7% for marker prevalence of 5%, 20%, 50%, or 100%, respectively. Modest changes (×1.4, ×1.6) in response and survival only improved discrimination with 100% prevalence. Clearly improved discrimination (to 20% or less) only occurred with at least ×1.8 increase in response and survival and 50% or more prevalence. Conclusions: The results show that targeting a marker only substantially improves discrimination if it doubles both tumour response rate and median overall survival and if marker prevalence is at least 50%. This approach may help rationalize aspects of drug development in oncology. No significant financial relationships to disclose.
Predictors of contralateral prophylactic mastectomy among patients with ductal carcinoma in situ (DCIS) who underwent evaluation for BRCA genetic testing.
Authors: Nisreen Elsayegh, Angelica M. Gutierrez-Barrera, Kimberly I. Muse, Heather Lin, Diana L. Turco, Jennifer Keating Litton, Henry Mark Kuerer, Banu Arun
Journal: Journal of Clinical Oncology (2012)

1549 Background: Patients with DCIS are at increased risk for developing contralateral breast cancer (CBC). Therefore, an increasing number of women with DCIS are electing for contralateral prophylactic mastectomy (CPM). In a previous study involving 2072 women with DCIS, 13.5% chose CPM. In this study, we aimed to evaluate factors associated with CPM in patients with DCIS who underwent genetic counseling for BRCA. Methods: 165 women with pure DCIS, who underwent genetic counseling, were included in the study. Patients’ characteristics were obtained from a prospectively maintained research database at UT M.D. Anderson Cancer Center. Univariate and multivaraite logistic regression analysis were used to determine predictive factors associated with CPM. Patients’ characteristics included age, marital and educational status, tumor markers, nuclear grade, family history with breast (BC) and ovarian cancer (OC), race, Ashkenazi Jewish ancestry, and BRCA genetic test results. Results: Out of 165 patients, 17(10.3%) were found to have a BRCA deleterious mutation. 44(26.7%) underwent CPM. Younger patients (median ≤ 45 yr) were more likely to elect for CPM than older patients (p= 0.0098). Patients who tested positive for a BRCA mutation were more likely to elect for CPM than those who tested negative or were not tested (p= 0.0001). Patients who had a family history of OC (15 (57.7%) were more likely to choose CPM than those who did not (p= 0.0004). These three factors remained significant in the multivariate model (p &lt;0.008). Marital and educational status, tumor markers, nuclear grade, and family history of breast cancer were not significant predictors of CPM. Conclusions: The rate of CPM in patients with DCIS is high. Factors associated with increased likelihood of undergoing CPM include family history of OC, age, and BRCA positivity. Further studies are needed to evaluate patients perception of CBC risk, and if this may play a role in the high number of CPM.
Abstract 9918: Respiration Increases Ventricular Filling at Rest and Exercise via Pulmonary Compliance: A Clinical and Computational Modeling Study
Authors: Ethan Kung, Alexander Van De Bruaene, Guido Claessen, Andre La Gerche, Alison Marsden, Pieter De Meester, Sarah Devroe, Jan Bogaert, Piet Claus, Hein Heidbuchel, Werner Budts, Marc Gewillig
Journal: Circulation (2015)

Introduction: Due to the absence of a sub-pulmonary ventricle, the Fontan circulation is sensitive to respiration-induced changes in intrathoracic pressure. However, the importance of a ‘respiratory pump’ in creating forward flow remains controversial. We aim to investigate the effects and mechanisms of respiration on ventricular filling at rest and exercise using clinical data and computational modeling. Hypothesis: We assess the hypotheses that (1) changes in intrathoracic pressure due to respiration would aid ventricular filling and output and (2) this effect would be maintained or enhanced during incremental exercise. Methods: Ten Fontan patients (6 male, 20±4 years) underwent ungated cardiac magnetic resonance imaging at rest and during supine bicycle exercise (3 incremental intensities) to evaluate systemic ventricular volumes. Patient-specific computational simulations using a lumped-parameter network model of Fontan exercise elucidated resting and exercise physiology in details for each patient at each metabolic state tested. Results: Compared to expiration, inspiration increased EDVi (98±16 to 103±15 mL/m2;P=0.001), SVi (55±9 to 59±9 mL/m2;P=0.001) and cardiac index (3.9±0.7 to 4.2±0.8 L/min/m2;P=0.002), but did not affect ESVi (P=0.096). Respiratory-dependent SVi did not change significantly during incremental exercise (3±2% to 5±3%; P=0.084). Computational modeling showed highest caval vein flow return during end-inspiration, and peak SV during expiration, exposing a phased time-delay mechanism at work. Removal of respiration in simulations corresponded to decreases in cardiac index of 0.39±0.037 L/min/m2. Conclusions: Inspiration increased ventricular filling at rest and exercise by similar amounts. A phased time-delay between highest caval vein flow and highest SV suggests an indirect mechanism where respiration aids ventricular filling via pulmonary compliance.
Does Bisphosphonate-Induced Osteonecrosis of the Jaw (BONJ) Preclude Intensive Chemotherapy? Oral and Infectious Toxicities Associated with Autotransplantation In Patients with BONJ.
Authors: Prakash Varadarajan, Juan Toro, Robert M. Craig, Deanna Schneider, Ju-Hsien Chao, David Haile, Cesar O. Freytes
Journal: Blood (2010)
Phase I study of a novel humanized anti-CD20 antibody, BM-ca, in patients (pts) with relapsed or refractory indolent B-cell non-Hodgkin lymphoma (B-NHL) pretreated with rituximab.
Authors: Kensei Tobinai, Michinori Ogura, Dai Maruyama, Tatsuya Suzuki, Yukio Kobayashi, Toshiki Uchida, Suguru Fukuhara, Takashi Oyama, Tomoharu Fukuzaki, Yasuhiko Komatsu
Journal: Journal of Clinical Oncology (2013)

8551 Background: BM-ca is a novel humanized type-I/II anti-CD20 antibody, which is effective against rituximab-resistant cell line RC-K8, and has more potent anti-cell-proliferation activity than rituximab or ofatumumab when combined with cancer chemotherapeutics. The aim of this study was to evaluate the safety, efficacy, and PK profile of BM-ca in pts with indolent B-NHL. Methods: A total of 12 pts {age: median 61 (50-73), number of prior regimens: median 2 (1-13)} with indolent B-NHL relapsed after or refractory to rituximab-containing therapy underwent treatment by IV infusion of BM-ca weekly for 4 weeks at a dose of 5, 10, or 15 mg/kg. Initially, 3 pts were to undergo BM-ca therapy at a dose of 5 mg/kg using the conventional 3+3 dose escalation design. To minimize infusion reactions (IRs), pts were pretreated with acetaminophen and d-chlorpheniramine maleate. Allopurinol and/or hydrocortisone were also administered if necessary. Infusion was started at 50 or 100 mg/h and was gradually increased to a maximum of 400 mg/h. Since no DLTs were observed, all 12 pts completed weekly 4 doses of BM-ca. Results: The most frequent AE was IRs (11 of 12 pts), which occurred mostly in the first infusion, and the highest grade of AE was neutropenia (grade 4 in one pt of 15 mg/kg after the last infusion). Anti-BM-ca antibodies were not detected. Of the 12 pts examined, 2 achieved CR (10 mg/kg) and 2 PR (15 mg/kg); these 4 pts had follicular histology. The remaining 8 pts including one each of extranodal marginal zone, nodal marginal zone, and small lymphocytic histology were judged to achieve SD. The CR states in 2 pts continued at least &gt;14 and &gt;11 months, respectively. The PK properties of BM-ca were comparable to those of other naked anti-CD20 antibodies including rituximab (AUC and C max were proportional to the doses; V dss ≈4 L; t 1/2 ≈750 h). Since at 10 mg/kg the response was the best and no grade 4 AE observed, 10 mg/kg was suggested as a recommended phase II dose. Conclusions: Four weekly IV administration of BM-ca up to 15 mg/kg was well tolerated and safe with promising preliminary anti-lymphoma activity in pts with indolent B-NHL. Further evaluation is warranted. Clinical trial information: 000004805.
Aplastic Anemia in the Context of Hemolytic Paroxysmal Nocturnal Hemoglobinuria: Feasibility of Antibody-Based Intensive Immunosuppression during Eculizumab Treatment
Authors: Simona Pagliuca, Flore Sicre de Fontbrune, Serena Marotta, Anna Paola Iori, Marie Robin, Gérard Socié, Regis Peffault de Latour, Antonio M Risitano
Journal: Blood (2016)
Long noncoding RNA lncKdm2b is required for ILC3 maintenance by initiation of Zfp292 expression
Authors: Benyu Liu, Buqing Ye, Liuliu Yang, Xiaoxiao Zhu, Guanling Huang, Pingping Zhu, Ying Du, Jiayi Wu, Xiwen Qin, Runsheng Chen, Yong Tian, Zusen Fan
Journal: Nature Immunology (2017)
The prognostic B2-Score for metastatic breast cancer: An external evaluation of 852 patients.
Authors: Achim Wöckel, Regine Wolters, Igor Novopashenny, Lukas Schwentner, Rolf Kreienberg, Wolfgang Janni, Manfred Wischnewsky, Anne Regierer
Journal: Journal of Clinical Oncology (2014)

1103 Background: The B2-Score is an individual, quantitative assessment of the likelihood of overall survival for advanced breast cancer patients based on routine parameters easily accessible in daily clinical care. Although major progress has been made, the optimal therapeutic management of the individual patient is still unknown. Besides elaborative molecular classification of tumors simple clinical measures such a prognostic score may be helpful to further individualize optimal breast cancer care. This study is a further external evaluation of this score. Methods: This German multicenter [17 certified breast cancer centers] retrospective cohort study called BRENDA (Quality of breast cancer care under evidence-based guidelines) included 10.119 advanced breast cancer patients. In the Cox regression model, hormone receptor (HR) status, the specific site of metastasis, and metastatic-free interval (MFI) were associated with survival from first relapse. Results: Medianage at primary diagnosis was 63 yrs (range 22-96), median MFI was 17 mths (range 0-200). 78.2% were HR-positive. 88.8% were M0 at primary diagnosis. 73.6% of the M0- patients were treated non-guideline adherent with respect to primary adjuvant therapy. 18% had 2 or more guideline violations. Median [mean] of B2Score was 11 (range 3-38) [12.1; STD 6.4]. 40.0% were low risk, 27.3% intermediate risk and 32.7% high risk. 5 years cumulative survival was 37% (95% CI 31%-44%) for low risk, 25% (95% CI 18%-31%) for intermediate risk and 11% (95% CI 7%-16%) for high risk. Cox-Mantel Hazard Ratio for intermediate risk was 1.34 (p=0.007; 95% CI 1.08-1.66) and for high risk 2.30 (p=<0.001; 95% CI 1.89-2.81) compared to low risk. Conclusions: The B2-Score classified these patients into 3 risk groups with highly significant different overall survival, confirming the prognostic value of this score. More than 70% of the advanced breast patients in this study—originally M0—were treated nonguideline adherent with respect to adjuvant therapy.
Regulatory Role of RNA Chaperone TDP-43 for RNA Misfolding and Repeat-Associated Translation in SCA31
Authors: Taro Ishiguro, Nozomu Sato, Morio Ueyama, Nobuhiro Fujikake, Chantal Sellier, Akemi Kanegami, Eiichi Tokuda, Bita Zamiri, Terence Gall-Duncan, Mila Mirceta, Yoshiaki Furukawa, Takanori Yokota, Keiji Wada, J. Paul Taylor, Christopher E. Pearson, Nicolas Charlet-Berguerand, Hidehiro Mizusawa, Yoshitaka Nagai, Kinya Ishikawa
Journal: Neuron (2017)
Proteomic characterization of human multiple myeloma bone marrow extracellular matrix
Authors: S V Glavey, A Naba, S Manier, K Clauser, S Tahri, J Park, M R Reagan, M Moschetta, Y Mishima, M Gambella, A Rocci, A Sacco, M E O'Dwyer, J M Asara, A Palumbo, A M Roccaro, R O Hynes, I M Ghobrial
Journal: Leukemia (2017)
Correlation of expression of microRNA miR-21 with prognostic characteristics in gastric cancer.
Authors: Jian-Chun Cai, Lin-Pei Wang, Ya-Ling Tang
Journal: Journal of Clinical Oncology (2012)

e14629 Background: MicroRNAs may play an important role in earlt stage gastric cancer. Methods: We studied the expression of MicroRNAs in gastric cancer to understand the expression characteristics of one of the key MicroRNAs miR-21 using 65 cases of early-stage gastric cancer identified from our cancer center records between October 2007 and March 2010. First, we used an MicroRNA array (miRCURY LNA Array) that contained 1,348 known probes and compared the expression profile of these MicroRNAs in six cases of gastric cancer specimen with their surrounding normal tissues. We then studied the expression of miR-21 and correlated it with the histologic characteristics of the 65 cases by RT-PCR. Results: The expression of seven MicroRNAs (miR-374b*, miRPlus-E1212, miR-338-5p, miR-297, miR-21, miR-135b, and miR-18a) was significantly up-regulated, while nine MicroRNAs (miR-29b-2*, miR-1260, miRPlus-E1241, miR-S1-5p, miR-148a, miR-29c, miR-647, miR-196b*, ebv-miR-BART5) significantly down-regulated. Because miR-21 was highly overexpressed in gastric cancer compared to its normal surrounding tissue, we next studied if the expression of miR-21 in sixty-five cases of gastric cancer was associated with clinical and histologic characteristics of early stage gastric cancer. We found that the increased expression of miR-21 was correlated with poorly differentiated histology (high grade), T3-4 stage and nodal involvement. The average level of miR-21 expression was two to five folds higher in the cases that are poorly differentiated, T3-4 stage, or with lymph node involvement compared to the cases that were well or moderately differentiated, T1-2 stage or with negative nodal involvement. The high-grade gastric cancers were associated with the highest level of miR-21 compared to the surrounding normal tissues. These results suggest that miR-21 is a potential biological marker indicative of the aggressiveness nature of this malignancy. Conclusions: Our results demonstrate that expression of several MicroRNAs may play important roles in the development and progression of gastric cancer and the increased expression of miR-21 is associated with poor prognostic characteristics.
Gene expression profiling to predict recurrent Dukes' B colon cancer
Authors: Y. Wang, T. Jatkoe, Y. Zhang, M. G. Mutch, D. Talantov, J. Liang, H. L. McLeod, D. Atkins
Journal: Journal of Clinical Oncology (2004)

9555 Background: The 5yr survival rate of Dukes' B colon cancer patients is 75%. Identification of patients at high risk of recurrence in this group would improve staging and the use of adjuvant chemotherapy. In this study, we used DNA chip technology to systematically identify new prognostic markers for tumor relapse in Dukes' B colon cancer patients. Methods: Using Affymetrix U133a GeneChip, RNA samples from 74 Dukes' B colon cancer patients were analyzed. 31 of these patients were selected because they developed tumor relapse in <3 yrs while 43 patients remained disease-free for >3 yrs after surgery. Two supervised class prediction approaches were used in order to identify gene markers that can best discriminate the relapse and the disease-free patients. A multivariate Cox proportional hazards model was built to predict recurrence. Results: Gene expression profiling of 74 patients identified a 23-gene signature that can be used to predict recurrence in Dukes' B patients. This signature was validated in the testing set of 36 independent patients. The performance accuracy is 78% (28/36). 13/18 relapse patients and 15/18 disease-free patients were predicted correctly giving an OR=13 (95% CI: 2.6, 65; p=0.003). The log rank test indicated a significant difference in disease-free time between the predicted relapse and disease-free patients (P=0.0001). Conclusions: This study shows that gene expression profiling provides a successful strategy to identify molecular markers that can be used to in a classification model of colon cancer recurrence. The clinical value of these markers is that the patients at a high predicted risk of relapse (13-fold risk) could be up-staged to receive adjuvant therapy, similar to Dukes' C patients. Our data highlights the feasibility of a prognostic assay that could help to focus more intensive treatment for localized colon cancer. Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Johnson & Johnson Johnson & Johnson Johnson & Johnson