tbuckley/cabot-search huggingface dataset:
Validation of cAMP phosphodiesterase-4D7 (PDE4D7) for its independent contribution to risk stratification in a prostate cancer patient cohort with longitudinal biological outcomes.
Authors: Jos Rijntjes, Marcia Alves de Inda, Dianne van Strijp, Eveline den Biezen-Timmermans, Anne van Brussel, Janneke Wrobel, Hans van Zon, Pieter Vos, George S Baillie, Pierre Tennstedt, Thorsten Schlomm, Miles Houslay, Chris H. Bangma, Hans Heinzer, Ralf Hoffmann
Journal: Journal of Clinical Oncology (2017)

5069 Background: In this study we present the retrospective validation of the prognostic prostate cancer biomarker PDE4D7 in predicting longitudinal biological outcomes in a historical cohort of radical prostatectomy patients. Methods: Biopsy punches from 550 patients were collected from a representative tumor area of FFPE surgical resections. RNA was extracted and PDE4D7 quantified by one-step RT-qPCR. PDE4D7 scores were calculated by normalization of PDE4D7 to the averaged expression of four reference genes. The independent prognostic value of the PDE4D7 scores were evaluated using uni- and multivariate Cox proportional hazard regression. Multivariate analyses were adjusted for clinical prognostic variables. Post-surgical outcomes tested were: PSA relapse, start of salvage treatment, progression to metastases, overall and prostate cancer specific mortality. Logistic regression was used to create a combined prognostic model of PDE4D7 with clinical risk and tested in outcome prediction. Results: The PDE4D7 score was significantly associated with time to PSA failure after prostatectomy (HR 0.53; 95% CI 0.41-0.67 for each unit increase; p &lt; 1.0E-04). After adjustment for pathology Gleason, pT stage, surgical margin status, and seminal vesicle invasion the HR was 0.55 (95% CI 0.43-0.72; p &lt; 1.0E-04). Patients with a high PDE4D7 score that were clinically classified as intermediate to high risk of progression were re-classified into a group with an average progression risk less than the average cohort risk of clinically very low risk patients. The maximum benefit, compared to Gleason score, was observed in the clinically intermediate favorable risk group. Combining clinical risk with PDE4D7 scores improved the overall risk stratification. Conclusions: The PDE4D7 score has potential to provide independent risk information and, in particular, to re-stratify patients with clinical intermediate to high risk characteristics to a very low risk profile.
The prognostic significance of exosomal marker (CD63) expression using immunohistochemistry (IHC) in patients with pancreatic ductal adenocarcinoma (PDAC).
Authors: Moh'd M. Khushman, Arun Bhardwaj, Girijesh K. Patel, Javier Laurini, Kelly Roveda, Robert Donnell, Kelley Sherling, Brittany Case, Marcus Chuan Beng Tan, Lee W. Thompson, Cindy Nelson, Mary Wyatt, Seema Singh, William R. Taylor, Ajay Singh
Journal: Journal of Clinical Oncology (2017)

e15730 Background: Exosomes are important mediators of intercellular communication, and play pivotal roles in cancer progression, metastasis and chemoresistance. Exosomal membranes are enriched in endosomes-specific tetraspanins (CD63 and CD9). In patients with PDAC, positive correlation between CD9 expression and overall survival (OS) was reported. However, CD63 expression was conserved in all patients without reported prognostic significance. Here, we explored the prognostic significance of CD63 expression using IHC in patients with PDAC of mixed gender and racial background. Methods: Between 2012 and 2016, 49 patients with PDAC treated at Mitchell Cancer Institute had available tissue (pancreatic resected tissue/biopsy [N = 29] or metastatic site biopsy liver, omentum or bone (N = 20)) for CD63 staining using IHC. Two pathologists independently scored the expression of CD63. Staining intensity was graded from 1-3. Staining percentage was estimated in 10% increments. Mean Quick-score (Intensity X Percentage of staining) was calculated. Unpaired t test was used for statistical analysis. Results: Median age was 64 years (range 42-85). 53% are males. 67% white, 27% African Americans (AA) and 6% are other ethnicities. 41% had stage IV disease while 49% had stage I, II and III. Tumor involved the head (51%), body (20%) and tail (29%). The mean CD63 Q score is slightly higher in AA compared to white (157 vs 149, P = 0.76). The mean CD63 Q score is higher in the pancreatic tissues compared to metastatic sites tissues (185 Vs 102, P = 0.0002). In our cohort, patients with mean CD63 Q score &gt; = 140 had longer median OS compared to patients with mean Q score of &lt; 140 (19 months Vs 3 months, P = 0.0003) and progression free survival (PFS) (12 months vs 1 month, P = 0.0043). Conclusions: In our cohort of patients with PDAC, there was no racial difference in CD63 expression between white and AA. The expression of CD63 is higher in the pancreas compared to metastatic sites (liver, omentum and bone). There is positive correlation between CD63 expression and PFS and OS. To our knowledge, this is the first study to show prognostic significance of CD63 expression in patients with PDAC using IHC.
A phase II trial of older adults with metastatic breast cancer (MBC) receiving nab-paclitaxel: Melding the fields of geriatrics and oncology.
Authors: Enrique Soto Perez De Celis, Suzette Blanchard, Joanne E. Mortimer, Peggy Burhenn, Christina Haeyoung Yeon, Yuan Yuan, Daneng Li, Vani Katheria, James Ross Waisman, Thehang H. Luu, George Somlo, Anne M. Noonan, Ty Lee, Nimit Sudan, Samuel Chung, Anait Arsenyan, Abrahm Levi, Jennifer Choi, Andrea Rubalcava, Arti Hurria
Journal: Journal of Clinical Oncology (2017)

10035 Background: The Institute of Medicine and ASCO identified key research priorities to improve the evidence base of older adults with cancer, including the need for therapeutic phase II trials. Here we present a phase II study of nab-paclitaxel in older patients (pts) with MBC, incorporating geriatric oncology principles in the study design. Methods: Pts age ≥65 years with MBC and 0-1 chemotherapy (CT) lines received nab-paclitaxel (100 mg/m 2 , 3 wks on, 1 wk off). Pts completed a geriatric assessment (GA) pre-CT including measures of function, comorbidity, cognition, nutrition, and psychosocial status. A CT toxicity (tox) risk score was calculated for each pt (Hurria et al. JCO 2011 and 2016). Relationships between tolerability (no. courses, hospitalizations, dose reductions, and grade (G) ≥3 tox attributed to CT) and risk score were assessed using generalized linear models, Student’s t tests, and Fisher’s exact test. Response rate (RR) and progression free survival (PFS) were evaluated. Results: 40 pts (mean age 73 [65-87]) were accrued from 06/12 to 01/16. Median no. of cycles was 6 [0-33], RR was 35% (95% CI 21-52%) and PFS was 6.5 months (95% CI 5.5-NR). 58% (n = 23) of pts had G ≥ 3 tox and 30% (n = 12) were hospitalized due to CT. G 2/3 neuropathy and G 3/4 neutropenia occurred in 10% of pts (n = 4), with no cases of febrile neutropenia. Based on the CT tox risk score, 53% (n = 21), 38% (n = 15), and 10% (n = 4) were low, intermediate, and high risk. As a continuous variable, doubling in the risk score was associated with a reduction in courses completed of 4.5 (se = 1.4, p = 0.003). Lower mean log 2 risk scores were found in pts that did not require hospitalization (diff = -0.59, 95% CI -1.00, -0.18; p = 0.007), or did not have a dose reduction (diff = -0.46, 95% CI -0.85, -0.06; p = 0.02). G ≥ 3 tox was found in 38% of low, 73% of intermediate and 100% of high risk pts, with combined intermediate/high risk pts experiencing significantly more G ≥ 3 tox (OR 5.8, 95% CI 1.3-33.1; p = 0.01). Conclusions: This phase II trial of older pts with MBC receiving nab-paclitaxel incorporated geriatric principles in an oncology trial. Incorporating the GA and CT tox risk score can help weigh the risks and benefits of therapy in older adults. Clinical trial information: NCT01463072.
TCT-688 Effect of renin-angiotensin system blockade in long term outcomes following transcatheter aortic valve implantation: Results from the retrospective cohort of the RASTAVI study
Authors: Ignacio Amat-Santos, Pablo Catala, Antonio Munoz-Garcia, Luis Nombela-Franco, None Vincente Serra, Ander Regueiro, Fernando Rivero, Jose Antonio Fernandez Diaz, Victor Jimenez Diaz, Cesar Moris, Ana Revilla-Orodea, Luis Varela-Falcon, Manuel Carrasco
Journal: Journal of the American College of Cardiology (2018)
Analysis of the association between the toll-like receptors 2 and 9 and the emotional status of the elderly cancer patient.
Authors: Letícia telles Sales, Jurema Telles O Lima, Marina Santaliz De Godoy Moreno, Gabriela Delgado Soriano, Luiz Claudio Santos Thuler, Maria Julia Gonçalves Mello, Kleber das neves Jatahy, Guacyra Magalhaes Pires, Luiz barros Baptista, Leuridan Torres
Journal: Journal of Clinical Oncology (2018)

e17074 Background: Toll-Like Receptors (TLRs) are important in oncology research due to its role in the activation of various biological factors, inflammation and its influence on tumor progression. Changes in innate immunity have also been shown to be related to depression. prostate cancer patients have a higher risk of depression than the general population.Objective: analyze the expression of the Toll-like Receptors (TLR) 2 and 9 in prostate cancer elderly patients (≥60 years), associating its expression with the emotional status. Methods: Between 2015 and 2017, a prospective cohort with 68 elderly prostate cancerpatients collected clinical and sociodemographic variables. 19 elderly male patients without any personal or familiar history of cancer were included as a control group. Thedetermination of the expression of TLR2 and TLR9 was performed by flow cytometry.Statistical analysis was performed using GraphPad Prism 7. Risk of depression was determined Geriatric Depression Screening Scale (GDS15). Results: When comparing the prostate cancer and control groups, there are significant differences between the expression of TLR2 and TLR9 (p = 0,0385 and p < 0,0001). There are significant differences between the expression of TLR2 and TLR9 between oncological patients with or without risk of depression (p < 0,0001 and p = 0,0039). Conclusions: There is an association between risk of depression and higher expression of TLR2 in leucocytes and a further study of its role as predictor of risk of depression in elderly patients is fundamental. The relationship between prostate cancer and higher expression of TLR9 in leucocytes should also be further studied, to better evaluate its role as a predictor of prognosis in elderly patients with prostate cancer.
Commentary: Trends in Quantitative Cancer Risk Assessment
Authors: Samuel C. Morris
Journal: Environmental Health Perspectives (1991)

Quantitative cancer risk assessment is a dynamic field, more closely coupled to rapidly advancing biomedical research than ever before. Six areas of change and growth are identified: expansion from models of cancer initiation to a more complete picture of the total carcinogenic process; trend from curve-fitting to biologically based models; movement from upperbound estimates to best estimates, with a more complete treatment of uncertainty; increased consideration of the role of susceptibility; growing development of expert systems and decision support systems; and emerging importance of risk communication.
Can preoperative breast MRI help predict DCIS recurrence?
Authors: Brian S. Johnston, Averi E Kitsch, Karthik Ramesh, Larissa A. Korde, Sara H. Javid, Janie M. Lee, Susan Peacock, Constance Dobbins Lehman, Savannah C. Partridge, Habib Rahbar
Journal: Journal of Clinical Oncology (2016)

11552 Background: Ductal carcinoma in situ (DCIS) is a pre-invasive breast cancer that may be overtreated due to lack of reliable clinical and pathological prognostic features. Recently, breast MRI parameters, including signal enhancement ratio (SER) and normal tissue background parenchymal enhancement (BPE), have shown promise as breast cancer risk biomarkers. We aimed to assess whether preoperative MRI (pMRI) features can predict DCIS recurrence after treatment. Methods: We retrospectively identified all patients diagnosed with DCIS who underwent pMRI from 2004 through 2013 and recurred after ( > 6 months) definitive surgical treatment. For each index case, a DCIS control patient who did not recur was identified, matched on clinical (age ± 4 years; BRCA status; menopausal status; prior chemoprevention), pathology (nuclear grade; necrosis; ER/PR), and treatment (surgical margins [ < 1, 1-9, or ≥ 10mm]; endocrine therapy; radiation therapy) features. On pMRI, lesion kinetics (enhancement volume; percent enhancement; SER) and normal tissue features (amount of fibroglandular tissue; BPE) were quantitatively measured for each case. Differences in MRI parameters between cases and controls were assessed by Wilcoxon signed rank test, and parameter performance was explored by calculating areas under the receiver operating characteristic curve (AUC). Results: Recurrences were identified in 14/415 (3.4%) women with DCIS who underwent pMRI. Matched controls were identified for 11 cases; thus, 22 patients were included. For the 11 included index cases, median age was 46 (range[r]: 33-78) years and median time to recurrence was 14 months (r: 6-60 months). Median follow-up time for control cases was 92 months (r: 42-130 months). Compared to matched controls, DCIS recurrence cases exhibited significantly greater BPE (55.1% ± 21 vs. 38.6% ± 13; p = 0.01; AUC = 0.75), lesion volume (11.2 cm3 ± 11 vs. 1.9 cm3± 1.5; p = 0.004; AUC = 0.88), and lesion peak SER (1.5 ± 0.3 vs. 1.2 ± 0.3; p = 0.03; AUC = 0.82). Conclusions: In this study, patients with recurrent DCIS had higher BPE, lesion volume, and lesion SER on pMRI compared to matched non-recurrent controls. These MRI biomarkers show promise for decreasing DCIS overtreatment and warrant further study in larger cohorts.
PI3KCA mutation as an independent pronostic factor in anal squamous cell carcinoma treated by abdomino-perineal resection: Evidence from a retrospective cohort of 148 patients.
Authors: Wulfran Cacheux, Etienne Rouleau, Petros Tsantoulis, Adrien Briaux, Pascale Mariani, Marion Richard-Molard, Bruno Buecher, Virginie Dangles-Marie, Sophie Richon, Julien Lazartigues, Emmanuelle Jeannot, Fereshteh Farkhondeh, Anne De La Rochefordiere, Marie-Christine Falcou, Arnaud Roth, Sergio Roman-Roman, Emmanuel Mitry, Ivan Bieche, Astrid Lievre
Journal: Journal of Clinical Oncology (2016)

e15060 Background: A better understanding of the molecular profile of the anal squamous cell carcinomas (ASCCs) is necessary to consider new therapeutic approaches, and the identification of prognostic and predictive factors for response to treatment. Methods: We retrospectively analyzed tumors from ASCC patients for mutational analysis of KRAS, NRAS, HRAS, BRAF, PI3KCA, MET, TP53 and FBXW7 genes. Results: Specimen from 148 patients were analyzed: 96 treatment-naive tumors and 52 recurrences after initial radiotherapy (RT) or chemoradiotherapy (CRT). Mutations of KRAS, PIK3CA, FBXW7 and TP53 genes was present respectively in 3 (2.0%), 30 (20.3%), 9 (6.1%) and 7 tumors (4.7%). The distribution of the mutations was similar between treatment-naive and relapse tumors, except for TP53 mutations being more frequent in recurrences (p= 0.0005). In patients treated with abdomino-perineal resection (APR) after relapse (n = 38, median follow up of 218 months), overall survival was significantly correlated with HPV16 status (p= 0.048), gender (p= 0.045) and PIK3CA mutation (p= 0.037). PIK3CA status retained its prognostic significance in Cox multivariate regression analysis (p= 0.025). Conclusions: Our study identified PIK3CA mutation as an independant prognostic factor in ASCC recurrence treated by APR, suggesting a potential benefit from adjuvant treatment and the evaluation of targeted therapies with PI3K/Akt/mTor inhibitors in PI3KCA-mutated patients.
Abstract 20081: Distinct Signaling Pathways Mediate Phosphorylation of Sarcomeric Proteins in the Right and Left Ventricle of the Failing Heart
Authors: Arpad Kovacs, Mark T Waddingham, Detmar Kolijn, Judit Barta, Attila Tóth, Zoltán Papp, Sophie van Linthout, Carsten Tschöpe, Wolfgang A Linke, Nazha Hamdani
Journal: Circulation (2017)

Introduction: Altered signaling pathways play a central role in sarcomeric dysfunction in the pathophysiology of heart failure (HF). Hypothesis: Treatment options for HF are still limited maybe because of distinct remodeling processes and molecular mechanisms in the right (RV) and left ventricle (LV) of the failing heart. Methods: Post-MI rats and HF patients with reduced ejection fraction were compared to sham-operated and healthy controls, respectively. LV and RV sarcomeric protein phosphorylation, protein kinase activity, phosphodiesterase (PDE) expression, myofilament calcium sensitivity (pCa50) and cardiomyocyte passive tension (Fpassive) were quantified. Results: In HF rats LV pCa50 was higher compared to control, and was higher in the LV vs. RV. This goes along with decreased TnI phosphorylation in the LV and RV, and decreased MyBP-C phosphorylation but only in the RV. PDE2A, 3A and 9A expressions were increased, while PDE5A remained unaltered in the LV. Unexpectedly, all these PDEs were decreased ...
Dissecting genetic heterogeneity in stage III cutaneous malignant melanoma with spatially resolved transcriptomics.
Authors: Hanna Eriksson, Kim Thrane, Jonas Maaskola, Johan Hansson, Joakim Lundeberg
Journal: Journal of Clinical Oncology (2018)

e21587 Background: Cutaneous malignant melanoma (melanoma) demonstrates high mutational load with extensive inter- and intra-tumoral genetic heterogeneity and complex interactions between the tumor and the tumor microenvironment (TME). Further insights into underlying mechanisms are crucial for understanding tumor progression and response to treatments Methods: We adapted the Spatial Transcriptomics (ST) technology for Stage III melanoma lymph node biopsies and successfully generated sequencing data of transcriptomes from over 2,200 tissue domains Results: By using a strategy for deconvolution along with traditional approaches for dimensionality reduction of transcriptome-wide data, we visualized the transcriptional landscape within the tissue and identified gene expression profiles linked to histological entities. Furthermore, our unsupervised data also demonstrate the more complex spatial intra-tumoral composition of the melanoma metastases which was not evident by morphological annotation. Each biopsy presents distinct gene expression profiles with examples of multiple melanoma signatures co-existing within a single tumor region as well as shared profiles for lymphoid tissue characterized according to their spatial location and gene expression profiles. Interestingly, we demonstrated that the lymphoid area in close proximity of the tumor region displays a specific expression pattern which may reflect the TME, a key component to understand tumor progression. Conclusions: By applying the ST technology to generate gene expression profiles, a new landscape of the melanoma metastases becomes evident. This should inspire further analyses to understand the multiple components of tumor progression and therapy outcome in a spatial context.
RNAseq analysis of the sorafenib phase III DECISION trial in differentiated thyroid cancer (DTC): Correlation with clinical outcome.
Authors: Jaume Capdevila, Ignacio Matos Garcia, Francesco M Mancuso, Carmela Iglesias, Paolo Nuciforo, Carles Zafon, Hector G. Palmer, Zighereda Ogbah, Laura Muiños, Carol Elaine Pena, Marcia S. Brose, Martin Schlumberger, Ana Vivancos
Journal: Journal of Clinical Oncology (2017)

6083 Background: In DECISION, sorafenib significantly impacted progression-free survival (PFS) and response rate (RR) in radioactive-iodine refractory DTC. The aim of this biomarker study was to identify RNA expression profiles related with PFS, overall survival (OS) and RR and to describe the expression profiles of DTC histologies. Methods: Of the 417 patients in the trial, 247 had sufficient formalin fixed paraffin embedded archival tumor material for RNAseq. We generated on average 77 million paired-end reads for each sample on HiSeq2000 (Illumina). RNAseq reads were mapped against the human reference genome (GRCh38) with STAR (v2.5.1b) using ENCODE parameters. 125 samples had sufficient quality to be included in the analysis. Results: The analysis subset included 68 sorafenib and 57 placebo patients (PFS 10.3 vs 7.4 months, HR: 0.62 CI 95% 0.38-0.99, p = 0.046). Unsupervised clustering using the 100 most variable genes identified 3 groups: BRAF-like (included most of the BRAF-mutated tumors), RAS-like (included most of the RAS mutated tumors) and non-BRAF-non-RAS-like group (included most wild-type tumors). These groups, based on the mutational profile, can be correlated with tumor type: the papillary BRAF-mutant, the follicular wild-type, and a third group with papillary, follicular and poorly differentiated with predominant RAS mutations. A Student t-test comparing papillary and follicular histologies revealed a signature of 283 genes with significantly different expression that, within the papillary tumors, identifies a subset with an expression profile more similar to follicular. No RNA signatures correlating with benefit from sorafenib were identified. Conclusions: While papillary and follicular thyroid cancers have significantly different RNA expression profiles, a subset of papillary has been identified with an expression profile more similar to follicular. In addition, a unified RAS-like expression profile spans subsets of papillary, follicular, and poorly differentiated thyroid cancers, suggesting that tumor biology can be similar across histologies. Clinical trial information: NCT00984282.
Abstract 12515: Short- and Long-term Prognosis of Adaptive Servo Ventilation Therapy for Patients With Heart Failure With Preserved Ejection Fraction
Authors: Atsushi Umeyama, Noriaki Takama, Toda Kazuyoshi, Masahiko Kurabayashi
Journal: Circulation (2016)

Introduction: In Japan, Adaptive Servo Ventilation (ASV) is usually used for heart failure patients with sleep disordered breathing. However, SERVE-HF trial showed that ASV therapy could not reduce mortality and morbidity in patients with heart failure with reduced ejection fraction (HFrEF) in addition to optimized medical care in spite our data conflicting findings concerning these results. However, there is no data whether ASV therapy shows effectiveness and safety for patients with heart failure with preserved ejection fraction (HFpEF). Hypothesis: Our aim is to estimate short- and long-term prognosis of ASV therapy for patients with HFpEF compared with standard optical medical therapy. Methods: After medical therapy was optimized, a total of 157 consecutive HFpEF patients were divided into 2 groups. Fifty-six patients were tried to initiate ASV therapy (Group A), and 101 patients were categorized into optimal medical therapy (Group M). We estimate the short- (1-year) and long-term (average observational period: 1140±778 days) prognosis of ASV therapy for patients with HFpEF. Results: Short-term prognosis showed that ASV was equally effective and safe therapy for patients with HFpEF (Survival rate: Group A: 94.6%, Group M: 93.07%, p=0.699) (Figure 1A). On the other hands, long-term prognosis showed that ASV therapy had a tendency to fall into high fatal cardiovascular event rate (Group A: 19.6%, Group M: 9.9%, p=0.086) (Figure 1B). Especially, Group A with high central sleep apnea {central apnea index (CAI) ≧10/h} showed significant higher fatal cardiovascular event rate (CAI ≧10/h: 35.7%, CAI &lt;10/h: 14.3%, Group M: 9.9%, p=0.029) (Figure 1C). Conclusions: Our results showed that short-term ASV therapy was effective and safe for patients with HFpEF compared with optimal medical therapy. On the other hands, long-term ASV therapy had limited effectiveness against HFpEF.