tbuckley/cabot-search huggingface dataset:
Association of Caspase 8 polymorphisms with TILs and disease-free survival in primary breast cancer patients.
Authors: Pauline Wimberger, Hagen Sjard Bachmann, Jan Dominik Kuhlmann, Theresa Link, Eric Kroeber, Christoph Thomssen, Martina Vetter, Eva Johanna Kantelhardt
Journal: Journal of Clinical Oncology (2018)

e24258 Background: The minor allele of two caspase-8 polymorphisms, namely CASP8 -652 6N InsDel and CASP8 Asp302His, were shown to promote survival of T-lymphocytes and were repeatedly associated with reduced breast cancer susceptibility. However, besides some preliminary findings, clinical relevance of these polymorphisms in patients with already existing primary breast cancer is unknown. Considering an immunomodulatory and potentially tumor-protective role of these caspase-8 variants, we genotyped 785 primary breast cancer patients and correlated caspase-8 variants with i) disease-free survival (DFS) and ii) the presence of tumor infiltrating lymphocytes (TILs). Methods: Primary breast cancer samples were collected between 2009 and 2011 as part of the multicenter prospective PiA trial (NCT 01592825). The majority of patients had luminal-like tumors (75.9%), followed by triple negative (10.1%), luminal-Her2-like (9.6%) and Her2-enriched tumors (4.5%). Genotyping was performed by pyrosequencing, TILs status was assessed by hematoxylin and eosin staining. Results: The CASP8 -652 deletion was significantly associated with improved DFS in an allele-dose dependent manner (p = 0.027). Homozygosity for the -652 6N Del variant was an independent predictor for improved DFS (p = 0.005). In patients with a 302His/His genotype, there was no event of recurrence during the entire observation time. Combined analysis of diplotypes revealed an additive influence on DFS (p = 0.029). Interestingly, patients with the 302His/His variant among the unstratified patient cohort and among the luminal-like subtype alone had tumors with very low lymphocyte infiltration (0-10% TILs in 65% of cases compared to 31% of cases for other genotypes, p = 0.025). Conclusions: In line with previous epidemiological findings, we propose a prognostically favorable role of CASP8 -652 6N Del and the Asp302His variant in primary breast cancer patients. Moreover, we suggest for the first time a role of the Asp302His variant in immunosurveillance and lymphocyte infiltration of breast cancer. Our findings strongly encourage further analyze of these genetic variants as a biomarker for prognostic and immunotherapeutic considerations.
TCT-108 Long-term Survival After Hybrid Coronary Revascularization for Triple-Vessel Disease: How Does it Compare to Coronary Artery Bypass Surgery or Multi-Vessel Percutaneous Intervention?
Authors: Craig Basman, Jonathan Hemli, Michael Kim, Karthik Seetharam, Derek Brinster, Luigi Pirelli, Jacob Scheinerman, Varinder Singh, Nirav C. Patel
Journal: Journal of the American College of Cardiology (2018)
P02.05 Role of ErbB4 and its modulation as a therapeutic approach in medulloblastoma
Authors: J Aldaregia, A Olazagoitia, A Matheu, I Garcia
Journal: Neuro-Oncology (2018)

Medulloblastoma (MB) is an embryonic tumor caused by a deregulation of the cerebellum development. It is the most frequent solid tumor in childhood, classified as a grade 4 tumor by the World Health Organization (WHO). The survival rate of the patients is very variable depending on the subtype of tumor, it can range from 50% to 90%. In this context, we propose ErbB4 as a possible therapeutic target in MB. ErbB4 is a tyrosine-kinase membrane receptor implicated in development, progression, metastasis, invasion and treatment resistance in different types of cancer. In this work the expression of ErbB4 in DAOY and D283Med medulloblastoma cell lines was silenced using the interferent RNA (shRNA) technique. Different in vitro and in vivo assays were performed to measure the oncogenicity of these cells. The genetic modulation of ErbB4 promotes a decrease in cell proliferation and cellular viability, together with a statistically significant increase of apoptosis and a slight cell cycle arrest in G2/M phase. Moreover, the silencing of ErbB4 promotes a decrease in the migratory capacity. Subcutaneous injections of MB cells in FOXN1 mice have demonstrated that cells with genetic inhibition of ErbB4 exhibit a reduced capacity of tumor formation. The results of this study suggest that ErbB4 receptor has an important role in MB progression and therefore, inhibiting ErbB4 could be a potential novel therapeutic approach.
Diffuse large B-cell lymphoma in very elderly patients older than 80 years: A multicenter retrospective analysis of clinical characteristics, treatment patterns, and outcome—KCSG LY16-01.
Authors: Jung Hye Choi, Young Jin Yuh, Tae Min Kim, Hye Jin Kang, Jung Hye Kwon, Seok-Hyun Kim, Seung-Hyun Nam, Hyeok Shim, Soon-Nam Lee, Soonil Lee, So Young Chong, Jaejoon Han, Byeong Bae Park, Sung Ae Koh, Der-Sheng Sun, Hyo Jung Kim, Jun Ho Yi, Jong-Youl Jin, Yun Hwa Jung
Journal: Journal of Clinical Oncology (2017)

e19031 Background: Treatment strategy for elderly patients older than 80 years with diffuse large B cell lymphoma (DLBCL) has not been established because of treatment intolerability and lack of the data. Methods: This multicenter retrospective study was conducted to investigate clinical characteristics, treatment patterns and outcome of patients older than 80 years at the diagnosis of DLBCL from 19 institutions in Korea between 2005 and 2016. Results: A total of 194 patients were identified (men: women 93:101). Median age was 83.3 years (range 80.1-95.7). 114 (59.3%) patients had an age-adjusted international prognostic index (aaIPI) score of 2-3 and 48 (24.7%) had Charlson index with a score 4 or more. R-CHOP was given in 124 (63.9%) cases, R-CVP in 13 cases, other chemotherapy in 17 cases, radiation alone in 9 cases, and surgery alone in 2 cases. 29 (14.9%) patients did not receive any treatment. The median cycle of chemotherapy was three (range 1-10). Only 43 patients completed planed cycles of treatment. The overall response rate of 105 evaluable patients was 91.4% (CR 41.9%, PR 49.5%). 29 patients died due to treatment-related toxicity (TRT) such as pneumonia and sepsis. 13 patients died due to TRT just after 1 st cycle. Median overall survival was 14.0 months. Main causes of death were disease progression (30.8%) and treatment-related toxicities (27.1%). In multivariate analyses, overall survival was affected by aaIPI, hypoalbuminemia, elevated creatinine, and treatment. Conclusions: Age itself should not be a contraindication to treatment. However, since elderly patients show higher TRT due to infection, careful monitoring and dose modification of chemotherapeutic agents would be needed.
Integrated DNA, RNA and protein analyses for a better treatment of cancer patients.
Authors: Jean-Francois Laes, Francois Cesbron, Gregori Ghitti
Journal: Journal of Clinical Oncology (2017)

e23099 Background: Advances in the molecular profiling of tumours, together with the expanding portfolio of targeted cancer therapies have established the terrain on which personalised cancer treatment can be conducted. This expanding area of precision medicine has the potential to be offered as a routine cancer-diagnostic service. Methods: We evaluated two molecular-profiling approaches : next-generation sequencing (NGS) and a group of several assays, termed Package Plus (PP), which have been primarily designed at identifying specific clinically-relevant alterations including protein expression/activation (by immunohistochemistry), and gene-promoter methylation, gene translocations and microsatellite instability (by PCR). The molecular profiling was conducted as diagnostic service for practising oncologists, who provided formalin-fixed paraffin-embedded tumour samples (for NGS and PP) and blood samples for circulating tumour DNA (for NGS only). A subset of oncologists who received the molecular profiling results and treatment advice was then surveyed to assess whether and how the results affected their treatment plans. Results: 980 samples from 16 different cancer types were received, out of which 914 (93%) were of sufficient quality to be included in this study. Clinically-relevant (actionable) alterations that provided treatment advice were identified for the large majority (841/914; 92%) of patients using the combination of NGS and PP data, but only for a minority of (247/912; 27%) of patients using NGS data alone. Treatment advice was adhered to by the oncologist in the majority (60%) of surveyed cases, and in the cases where the advice was not followed, reasons most often cited were treatment unavailability or cost. Conclusions: Our study demonstrates the utility of a precision-medicine service based on supervised tests (protein and RNA) in combination with NGS (DNA) profiling methods for advising oncologists on appropriate cancer-treatment plans.
Apatinib plus vinorelbine: A novel combination of all-oral regimen in heavily pretreated patients with metastatic HER2-negative breast cancer.
Authors: Peng Yuan, Anjie Zhu, Jian Yue, Binghe Xu
Journal: Journal of Clinical Oncology (2018)

e13096 Background: Antiangiogenic therapy in combination with chemotherapy is effective in control advanced breast cancer. Apatinib is an oral highly potent tyrosine kinase inhibitor targeting vascular endothelial growth factor receptor 2(VEGFR-2). Phase II clinical trials of Apatinib single agent exihited objective response in heavily pretreated, metastatic breast cancer with manageable toxicity. This study aims to investigate the efficacy and safety of the oral vinorelbine-Apatinib combination in pre-treated metastatic breast cancer. Methods: This single arm prospective study enrolled patients with HER2 negative advanced breast cancer, pretreated with anthracycline and taxanes, and who failed in the metastatic setting at least one prior chemotherapy regimen. The primary end point was PFS. Secondary end points included objective response rate (ORR), clinical benefit rate (CBR), OS and safety. Patients were treated with apatinib 500/425 mg daily plus oral vinorelbine 60-80 mg/m2 day1,8,15, q3W. Initial dose was chosen according to the general status. Patients eligible were evaluated by CT or MRI scan every 2 cycles until disease progression. Adverse events (AEs) were assessed and graded in accordance with the Common Terminology Criteria for AEs, version 4.0. Results: 40 patients were enrolled with a median age of 55 (30-70) years. 19/31 patients experienced dose modification or transient discontinuation during treatment. 4 patients stopped receiving oral vinorelbine due to severe AEs and continued to receive apatinib monotherapy. Of all 40 patients, median PFS was 5.2 months (95% CI, 3.7-6.7). 31 patients were eligible for efficacy analysis. ORR was 16.1% (5/31). CBR was 38.7% (12/31). The most common grade 3/4 treatment-related AEs were hypertension (25.0%), gastrointestinal reaction (22.5%), pain(12.5%), myelosuppression(10.0%), fatigue (5.0%) and mucosal inflammation (5.0%). Conclusions: The all-oral therapy of apatinib plus vinorelbine presented objective efficacy in heavily pretreated advanced HER2-negative breast cancer, with acceptable and manageable toxicity. Clinical trial information: NCT02768415.
<i>CYP2C19</i>-guided voriconazole prophylaxis in neutropenic AML patients.
Authors: James Kevin Hicks, Kevin Shahbazian, Rod E. Quilitz, Rami S. Komrokji, Timothy Edward Kubal, Jeffery Lancet, Yanina Pasikhova, Dahul Qin, Wonhee So, Ana P Velez, Howard L. McLeod, John N. Greene
Journal: Journal of Clinical Oncology (2018)

6594 Background: Acute myeloid leukemia (AML) patients who have prolonged neutropenia are at increased risk of morbidity and mortality due to invasive fungal infections. Voriconazole (VCZ), an effective antifungal prophylactic, is metabolized by the polymorphic CYP2C19 enzyme. Approximately 25% of individuals are genetically predicted to be CYP2C19 rapid metabolizers, thus at increased risk of breakthrough fungal infections due to low VCZ concentrations. We implemented a quality improvement pilot utilizing CYP2C19 genotype to optimize prophylactic VCZ dosing. Methods: AML patients with prolonged neutropenia are eligible for CYP2C19 genotyping (Luminex xTAG CYP2C19 Kit v3). Phenotypes are assigned per Clinical Pharmacogenetics Implementation Consortium guidelines. CYP2C19-guided recommendations for our quality improvement pilot are as follows: avoidance of VCZ in ultrarapid metabolizers, VCZ 300 mg twice daily (BID) for rapid metabolizers, and VCZ 200 mg BID for all other phenotypes. Therapeutic drug monitoring (TDM) is performed at the discretion of the medical team (goal trough concentration of 1-5.5 mcg/ml). Results: To date, 193 AML patients have undergone CYP2C19 genotyping; 3 (1.6%) ultrarapid, 50 (25.9%) rapid, 78 (40.4%) normal, 55 (28.5%) intermediate, and 7 (3.6%) poor metabolizers were observed. 154 patients (79.8%) received VCZ for prophylaxis, 11 (5.7%) for treatment, and 28 (14.5%) did not receive VCZ. Of the 154 patients receiving prophylactic VCZ, 137 (89%) were dosed per CYP2C19-guided recommendations. Pre-intervention (VCZ 200 mg BID) and post-intervention (VCZ 300 mg BID) VCZ trough concentrations were compared. Only 36.4% (4/11) of CYP2C19 rapid metabolizers receiving VCZ 200 mg BID achieved the goal trough concentration, whereas 75% (21/28) of rapid metabolizers receiving VCZ 300 mg BID achieved the goal trough concentration. CYP2C19-guided VCZ dosing resulted in trough concentrations in the target range for 70.1% (47/67) of all patients. Conclusions: Implementation of CYP2C19 genotyping to guide VCZ prophylactic dosing is feasible, with 70.1% of all patients having a VCZ goal trough concentration. Future analysis will determine if CYP2C19-guided VCZ dosing prevents breakthrough fungal infections.
COVA4231, a potent CD3/CD33 bispecific FynomAb with IgG-like pharmacokinetics for the treatment of acute myeloid leukemia
Authors: Kristina Klupsch, Vanessa Baeriswyl, Roland Scholz, Joana Dannenberg, Roger Santimaria, David Senn, Elena Kage, Adrian Zumsteg, Isabella Attinger-Toller, Ulrike von der Bey, Susann König-Friedrich, Fanny Dupuy, Wibke Lembke, Clara Albani, Severin Wendelspiess, Lucijana Dinkel, Dorina Saro, Robert W. Hepler, George S. Laszlo, Chelsea J. Gudgeon, Julian Bertschinger, Simon Brack, Roland B. Walter
Journal: Leukemia (2018)
Abstract B10: Radiomics signatures on the region defined by using multi-window CT to improve detection lung cancer screening
Authors: Hong Lu, Wei Mu, Yoganand Balagurunathan, Jin Qi, Mathew Schabath, Robert James Gillies
Journal: Clinical Cancer Research (2018)

Abstract Purpose: To evaluate the utility of defining a region using complementary information provided by different CT windows on the lung nodules to predict malignancy. Methods: We obtained 50 cases from National Lung Screening Trial (NLST) with 23 malignant and 27 benign patients. We segmented lung nodules using lung and mediastinal window independently and obtained the difference region (3D). About 260 quantitative radiomics features were exacted on the voxels segmented from different windows and the difference region. We used support vector machines (SVM) to build a predictive model to identify malignancy. We compared the effectiveness of the multi-window based features against single-lung window features using a 2-fold cross validation. Results: We find several radiomics features in the difference region to be predictive of malignancy; the best univariate features was Run_Length_Nonuniformity differnce region had an AUC of 0.911.The best feature in the lung window was defined by Sum_Entropylung window, which had an AUC of only 0.825. While using cross-validataion (2-fold) we obtained a mean accuracy of 80.97% and an AUC of 0.8 (specificity and sensitivity of 0.887 and 0.712). Compared to single-window, the best predictive features had accuracy of 78.17% and AUC of 0.772 (specificity and sensitivity of 0.876 and 0.667). Conclusions:The multi-window based radiomics features, especially the features from difference area, can improve diagnostic performance in differentiation of benign and malignant lung nodules to great extent. Citation Format: Hong Lu, Wei Mu, Yoganand Balagurunathan, Jin Qi, Mathew Schabath, Robert James Gillies. Radiomics signatures on the region defined by using multi-window CT to improve detection lung cancer screening [abstract]. In: Proceedings of the Fifth AACR-IASLC International Joint Conference: Lung Cancer Translational Science from the Bench to the Clinic; Jan 8-11, 2018; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2018;24(17_Suppl):Abstract nr B10.
Decision making and informed consent among participants in novel phase 1 trial designs.
Authors: Katherine Elizabeth Reeder-Hayes, Megan Roberts, Elizabeth Claire Dees
Journal: Journal of Clinical Oncology (2016)

e21548 Background: Cancer patients in phase 1 clinical trials may be at risk of misunderstanding the objective of the trial (therapeutic misconception) or their own likelihood of benefit from participation (therapeutic optimism). These concerns are complicated by the changing design of phase 1 oncology trials, including more targeted therapies and standard of care drugs combined with experimental compounds. Few data are available on the decision making process and understanding of patients participating in this new generation of phase 1 trials. Methods: We embedded a qualitative semi-structured interview within a phase 1b clinical trial of a novel Pi3kinase inhibitor combined with a standard chemotherapy agent, capecitabine. Patients (n = 18) had advanced breast cancer with one to three prior lines of therapy. Topics included factors influencing the decision to participate, understanding of trial purpose, and personal goals related to participation. Data were audio-recorded and dually coded using atlas.ti software. Results: Individuals outside the phase 1 trial team, including local oncologists and family members, were key advocates for participation. A minority of patients (39%) correctly identified trial objectives as related to safety and dosing, despite written consent documentation of these objectives. Even among patients who understood trial objectives, many identified therapeutic benefit as a personal goal, although hope of cure was rarely mentioned. Appealing aspects of study design included the use of capecitabine and the targeted nature of the investigational drug. The trial was generally regarded as having more potential benefit than standard therapy alone, but the possibility of added toxicity was not a focus for most patients. Altruism was a secondary motivator of participation. Conclusions: Participants in this phase 1b oncology trial including a targeted agent and a standard of care drug had significant but not unrealistic hopes for therapeutic benefit. Although the type of therapeutic benefit anticipated by most patients appeared reasonable, continued findings of poor understanding of study objectives, similar to studies from prior decades, suggest room for improvement in consenting procedures.
Efficacy and safety of pomalidomide as a replacement therapy for lenalidomide for relapsed/refractory multiple myeloma patients refractory to a lenalidomide-containing combination regimen.
Authors: James R. Berenson, Alexa Cohen, Tanya M. Spektor, Ashkan Lashkari, Roy Mackintosh, Alberto Bessudo, Michael Oren Robinson, Haresh S. Jhangiani, Nashat Y. Gabrail, Ibrahim Nakhoul, Samir V. Kubba, Jeffrey D. Neidhart, Tina Maluso, Regina A. Swift, Robert A. Vescio
Journal: Journal of Clinical Oncology (2018)

e20012 Background: Pomalidomide (POM) is a third–generation immunomodulatory drug shown to be safe and effective for the treatment of relapsed/refractory multiple myeloma (RRMM) patients (pts) previously treated with bortezomib and lenalidomide (LEN). POM in combination with dexamethasone has been shown to overcome resistance and to be effective not only in RRMM pts but also in high risk myeloma cases. In this trial, we are evaluating the efficacy, safety and tolerability of POM replacing LEN for pts who were refractory to a LEN and steroid-containing regimen. Methods: This is a multicenter, open-label and non-randomized study. Pts who have failed a combination regimen containing LEN were treated with POM along with all of the other drugs previously used in the regimen. POM administered orally (dose is determined based on the previous regimen) on days 1-21 of a 28-day cycle, whereas other drugs are administered using the same schedule(s), dose(s) and drug combination as the last LEN-containing regimen. The planned enrollment on the study will be 45 pts. Results: To date, a total of 35 pts have been enrolled. The median age of pts was 68 years (range, 51-80 years), and 22 (63%) were males. Pts had received a median of 3 prior treatments (range, 1-8). Of the 35 pts, 17 and 18 pts received 4 mg or 2 mg of POM as their starting dose. The median follow-up time for all pts is 5.4 months (range, 1.6-7.4). Amongst evaluable pts (n = 35) the overall response rate (ORR) was 29% (CR [9%], VGPR [6%], PR [14%]), and clinical benefit rate (CBR) was 34% (MR [6%]). Fifty-four percent showed stable disease (SD) while 11% exhibited disease progression (PD). Overall ORR and CBR are expected to increase with further follow up among pts who have been recently enrolled on this trial. The median progression free survival was 7.6 months. Common ≥ Gr 3 AEs were neutropenia (29%), hyponatremia (6%), worsening anemia (6%) and thrombocytopenia (6%). Conclusions: We show thatPOM replacement for LEN among RRMM pts who are refractory to a LEN and steroid-containing regimen that includes at least one other agent achieves clinical activity in some pts. Clinical trial information: NCT02188368.
Clinical outcome and characteristics of patients with cervical cancer submitted to renal replacement therapy.
Authors: Diego Reis, Eduardo Rocha, Tatiane Cristine Ishida
Journal: Journal of Clinical Oncology (2017)

e21627 Background: Cervical cancer is the 2nd most prevalent and 4th cause of cancer-related death in Brazil among women. It may cause renal failure due to tumoral growth, the treatments, among other causes. Purpose: To evaluate the clinical outcome and the risk of death in patients with cervical cancer hospitalized submitted to hemodialysis, to describe the clinical characteristics of these patients. Methods: Retrospective observational study. Patients diagnosed with cervical cancer, hospitalized, submitted to renal replacement therapy were identified in a single institution (n = 92). Risk of death was estimated using Kaplan-Meier analysis. The Cox proportional hazards regression model was used to determine the risk of death on the basis of: cancer staging, disease activity, Performance status at admission, oncological surgery before hemodialysis subgroup. Results: 92 patients with cervical cancer hospitalized were submitted to intermittent hemodialysis between January 2007 and December 2008. Data was available for all the 92 patients. Median age at diagnosis 47.8 years (25.4-95.1), 73.9% was diagnosed stage III/IV, 95% had disease progression/ active disease before hemodialysis. 84 patients (91%) were dead at the moment of analysis (Cut-off date 30/03/2010), median interval between first hemodialysis and death 1.1 months (0-24.8). The main cause of death was postrenal kidney failure (82.6%). In multivariate analysis, stage II/III/IV (compared with stage I) and disease progression/active disease were the only independent prognostic factors associated with increased risk of death (HR = 3.149; 95% CI, 1.765 to 5.610; P = .001 and HR = 4.205; 95% CI, 1.002 to 17.65; P = .05). Conclusions: Women with advanced disease and active disease/ disease progression have a significant increased risk of death compared with those with stage I, stable disease/ disease in remission. Prospective studies are warranted to investigate the benefit hemodialysis in patients with cervical cancer.