tbuckley/cabot-search huggingface dataset:
Genomic determinants of sensitivity to bipolar androgen therapy (BAT) in castrate-resistant prostate cancer (CRPC).
Authors: Michael Thomas Schweizer, Emmanuel S. Antonarakis, Mario A. Eisenberger, Peter Nelson, Jun Luo, Colin Pritchard, Samuel R. Denmeade
Journal: Journal of Clinical Oncology (2019)

200 Background: BAT is a promising treatment for CRPC and preclinical work has shown that its effects may be mediated by inducing DNA damage or cell cycle arrest. We sought to evaluate if mutations in DNA damage repair (DDR) genes or cell cycle regulators were associated with improved outcomes. Methods: Biospecimens from CRPC patients enrolled to studies testing BAT underwent germline or somatic next-generation sequencing (NGS). Samples tested included plasma (i.e. cell-free DNA) (N = 79), tumor tissue (N = 21) and saliva (N = 10). A variety of clinical grade NGS platforms were generally used. Given the concern for false negatives, we excluded cases if plasma NGS did not reveal a somatic alteration. Absence of a germline alteration was not assumed to indicate absence of somatic alterations. Comparative analyses to assess candidate biomarkers of BAT efficacy were performed. Results: Most patients received BAT following one or more next generation hormonal therapy, while 6 received BAT as first-line CRPC therapy. Of 65 cases where a germline or somatic pathogenic alteration in any gene was detected, 30 (46%) had evidence of homologous recombination deficiency (HRD), with mutations found in BRCA2 (N = 10), ATM (N = 8), CHEK2 (N = 5), PALB2 (N = 4), CDK12 (N = 3), CHD1 (N = 2), FANCA (N = 1), FANCD2 (N = 1) and BRCA1 (N = 1). TP53 alterations were also common (27/65; 42%). HRD mutations associated with increased PSA50 responses, with a trend toward improved PSA50 responses in TP53 mutated cases too (Table). In a combined analysis, men with HRD and/or TP53 mutations had improved PSA50 responses and near-significant improvement in progression free survival (PFS). Conclusions: These preliminary data suggest that BAT may be most efficacious in cancers harboring mutations in genes involved in DDR and/or cell cycle regulation. These results require prospective confirmation. [Table: see text]
Abstract 21306: Impact of Insulin Treated Diabetes Mellitus on 1 Year Outcomes After Contemporary PCI
Authors: Jaya Chandrasekhar, Samantha Sartori, Usman Baber, Shrushti Shah, Samaneh Rabieihashemi, Birgit Vogel, Serdar Farhan, Zhen Ge, Sabato Sorrentino, Madhav Sharma, Abdul Qadeer, Antonia Demopoulos, Clayton Snyder, Kasra Moazzami, Alexander Sudyn, Pedro Moreno, Jason Kovacic, Joseph Sweeney, Prakash Krishnan, Nitin Barman, George Dangas, Roxana Mehran, Annapoorna Kini, Samin Sharma
Journal: Circulation (2017)

Background: Insulin treated diabetes mellitus (ITDM) is associated with more extensive atherosclerotic disease and worse cardiovascular prognosis compared to non-ITDM patients. Hypothesis: We sought to examine 1-year outcomes in ITDM and non-ITDM patients compared to non-DM patients following contemporary percutaneous coronary intervention (PCI). Methods: We followed consecutive patients undergoing PCI at a large tertiary center from 2009-2016. Prospectively collected data were retrospectively examined. Patients were grouped based on DM and treatment status at baseline. 1-year outcomes were analyzed in a time to event manner and adjusted using multivariable Cox regression methods. Major adverse cardiovascular events (MACE) were defined as a composite of death, myocardial infarction (MI) or target vessel revascularization (TVR). Results: During the study period, 16,889 patients underwent PCI including 13.7% (n=2313) ITDM, 34.0% non-ITDM (n=5737) and 52.3% non-DM (n=8839) patients. ITDM and non-ITDM patients were younger than non-DM patients, with greater prevalence of females and non-white patients, higher body mass index and greater prevalence of prior revascularization and chronic kidney disease. ITDM patients were more likely to present with stable angina compared to others. With respect to angiographic characteristics, the prevalence of B2/C type lesions was similar between the groups. At 1-year, both ITDM and non-ITDM patients had greater risk of 1-year MACE and MI compared to non-DM patients, however ITDM patients had significantly higher rates of MACE, death, MI, and TLR ( figure ). Conclusions: The negative prognostic effect of DM following contemporary PCI is heightened in the presence of insulin treatment, compared to non-DM patients, despite use of contemporary PCI techniques and use of new generation DES.
Patients' and physicians' risk-benefit trade-off preferences for metastatic colorectacl cancer treatments.
Authors: Juan Marcos Gonzalez, Robert Morlock, Sarika Ogale, Nicolas Sommer, Joshua Posner, Axel Grothey
Journal: Journal of Clinical Oncology (2015)

3591 Background: Preferences for treatment-related benefits and risks associated with metastatic colorectal cancer (mCRC) therapies may vary between patients and physicians. Methods: A literature review and clinician interviews were carried out to develop risk-benefit profiles. PFS and probabilistic adverse outcomes were described in an online discrete-choice experiment completed by patients and physicians. Participants assessed a series of 10 choices between pairs of hypothetical medication profiles . Each profile included attributes within a pre-determined range: PFS (12 months, 8 months, 6 months), severe papulopustular rash (PR) (0%, 5%, 10%, 25%), serious hemorrhage (0%, 2%, 10%, 35%), cardiopulmonary arrest (0%, 2%, 10%, 20%), and gastrointestinal perforations (0%, 2%, 10%, 20%). Choice questions were based on an experimental design with known statistical properties. Random-parameter choice models produced preference weights indicating the strength of trade-off. These weights were used to calculate the maximum acceptable risk of different adverse events associated with various mCRC therapies. Results: A total of 127 patients and 150 physicians completed the discrete-choice survey. The mean maximum level of treatment-related risk patients were willing to accept for a 4-month increase in PFS from 8 to 12 months was 16.7% (0.0%-82.9%) for PR, 13.8% (4.6%-23.2%) for gastrointestinal perforation, 10.3% (3.3%-17.1%) for serious hemorrhage and 5.1% (1.7%-8.7%) for cardiopulmonary arrest. For the same PFS improvement, physicians were willing to accept a risk of severe PR that exceeded 25% and more than 20% risk for gastrointestinal perforation, which were the maximum levels shown in the survey for each of these treatment-related adverse events. Physicians were also willing to accept 18.9% (12.3%-24.5%) risk for serious hemorrhage and 7.0% (3.0%-10.8%) for cardiopulmonary arrest for the same 4-month PFS improvement. Conclusions: The benefit-risk tradeoff data obtained in this study show potential risk-tolerance differences between patients and oncologists, highlighting the importance of understanding preferences from the patient’s perspective when making treatment decisions.
RAIG1 is a novel p53-regulated and growth-proliferative gene in human tumors
Authors: Suxing Liu, Tish Hockenberry, Asra Mirza, Iris Wei, Stuart Black, Eric Gustafson, Ferdous Gheyas, Frederick Monsma, W. Robert Bishop
Journal: Cancer Research (2004)

2540  Retinoic acid-inducible gene 1 (RAIG1), an orphan G protein-coupled receptor, was identified using differential display as induced by retinoic acid in the squamous carcinoma cell line UMSCC-22B (Cheng, Y. and Lotan, R, J. Biol. Chem., 273(52), 35008-35015, 1998). Using hierarchical cluster analysis of microarray data from breast tumor cell lines, we find that RAIG1 is classified in the cell proliferation cluster, suggesting its potential role in tumor growth. RAIG1 is expressed in G1 phase of the cell cycle in a cell-cycle-dependent manner. Taqman analysis of RAIG1 gene expression in a RNA tumor cell line panel indicated that it is over-expressed in lung, breast, colorectal, ovarian and pancreatic tumor cells. Interestingly, we observed that the expression of RAIG1 was repressed in human ovarian cancer cells at the onset of apoptosis induced by p53. There are 4 putative p53 DNA binding sites in the promoter of the RAIG1 gene. Chromatin immunoprecipitation analysis indicated that p53 binds to the promoter of RAIG1 in vivo, suggesting p53 may directly repress its expression. Moreover, the expression of RAIG1 in NIH/3T3 cells caused ligand-independent transformation and knock-down of RAIG1 gene expression in AsPc-1 pancreatic tumor cells by gene specific small-interfering RNA induced morphological change, suggesting its potential oncogenicity. Taken together, these data suggest a role for RAIG1 in tumor growth and progression.
Simultaneous T Cell Activation and Macrophage Polarization to Promote Potent Tumor Suppression by Iron Oxide‐Embedded Large‐Pore Mesoporous Organosilica Core–Shell Nanospheres
Authors: Lin Chen, Xiaobo Ma, Meng Dang, Heng Dong, Hongming Hu, Xiaodan Su, Wenfei Liu, Qing Wang, Yongbin Mou, Zhaogang Teng
Journal: Advanced Healthcare Materials (2019)

Nanomaterial-based immunotherapy stimulating T cell activation or tumor-associated macrophage (TAM) conversion holds great promise for promoting tumor suppression. Herein, a novel nanoplatform, iron oxide-embedded large-pore mesoporous organosilica nanospheres (IO-LPMONs), is prepared for the first time to simultaneously activate cytotoxic T cells and polarize macrophages for potent tumor immunotherapy. The IO-LPMONs have large mesopores (6.3 nm) and inorganic-organic hybrid shells, which contribute to a high payload (500 µg mg-1 ) of the antigen ovalbumin (OVA). The IO-LPMONs effectively deliver OVA to dendritic cells (DCs) and activate DCs. Subsequently, high activation of both CD4+ and CD8+ effector antigen-specific T cells is achieved for powerful antitumor effects. Moreover, the IO-LPMONs also act as an immune modulator to polarize TAMs from an immunosuppressive M2 to a tumor-killing M1 phenotype, which induces efficient apoptosis of tumor cells. The combined T cell activation and macrophage polarization strategy based on the IO-LPMONs elicits remarkable combined antitumor effects in vivo, showing great promise for tumor treatment.
Evaluating the frequency and functional consequences of epigenetic mutations on outcome derived from urothelial tumor sequencing in non-muscle invasive bladder cancer (NMIBC).
Authors: Paloma Cejas, Stephanie A. Mullane, Eliezer Mendel Van Allen, Justine A. Barletta, Michaela Bowden, Mary-Ellen Taplin, Mark Pomerantz, Toni K. Choueiri, David J. Kwiatkowski, Henry Long, Joaquim Bellmunt
Journal: Journal of Clinical Oncology (2015)

e15519 Background: Recent sequencing of BC genome by TCGA has revealed recurrent mutations in chromatin modifying genes, implicating epigenetic factors in bladder tumorigenesis. TCGA data was muscle invasive BC (MIBC) and limited data is available on the mutation patter in NMIBC. We investigated the frequency and the impact of epigenetic alterations on recurrence and progression in NMIBC. Methods: Paired normal/tumor samples from clinically annotated NMIBC have undergone whole exome sequencing (WES). The pattern of chromatin remodeling genes mutations (CRM) were compared to TCGA. We have focused on histone-modifications namely H3K4me2, via an optimized ChIP-Seq protocol for FFPE samples. We correlated the impact of CRM correlation with patient outcomes. Results: 60 NMIBC patient samples have undergone WES. Preliminary results in 27 patients are available with, 17 having paired tumor/normal analysis. Based on a preliminary analysis, CRM have been observed at a similar frequencies between TCGA and our NMIBC cohort: KMT2D (27%vs30%), ARID1A (25%vs10%), KDM6A (24%vs22%), and EP300 (15%vs20%). In addition, MLL3, MLL, CREBBP, CHD7, and SRCAP were all mutated in > 10% of samples. Four tumor samples with extreme phenotype have successfully undergone H3K4me2 ChIP-Seq and results show high quality data,distinct from other tumors studied (colorectal, germ cell, breast, prostate) and shows H3K4me2 signal around BC genes. Analysis of the full cohort is ongoing. Conclusions: NMIBC exhibits a different mutations pattern in chromatin-modifying genes compared to MIBC. We have successfully performed ChIP-seq, to identify the histone methylation differences in NMIBC with different outcome. Results of the impact of mutations/epigenetic alterations on recurrence and progression will be presented.
Prognosis of Japanese patients with metastatic renal cell carcinoma who underwent subsequent systemic therapy due to prior failure of VEGF-TKI therapy.
Authors: Nobuo Shinohara, Wataru Obara, Katsunori Tatsugami, Sei Naito, Tomomi Kamba, Masayuki Takahashi, Takashige Abe, Koji Oba, Seiji Naito
Journal: Journal of Clinical Oncology (2015)

e15615 Background: The present study was conducted to clarify the prognosis of Japanese patients who failed prior VEGF-TKI therapy and to investigate prognostic factors in these patients. Methods: Of 389 consecutive patients for whom treatment was started between 2008 and 2010 at 23 hospitals in Japan, 171 patients who failed prior VEGF-TKI therapy and received other types of VEGF-TKIs (sunitinib, sorafenib, axitinib) or mTOR inhibitors (everolimus, temsirolimus) as a subsequent therapy were the subject of the present study. The endpoints were progression-free survival (PFS) and overall survival (OS) after the start of subsequent therapy. Relationships between overall survival and potential prognostic factors at the start of subsequent therapy were assessed using the Cox proportional hazard model. Median follow-up was 12.4 months (range 1-50.5). Results: Of 171 patients, VEGF-TKIs were administered in 98 patients (sunitinib 56, sorafenib 32, axitinib 10) and mTOR inhibitors were administered in 73 patients (everolimus 64, temsirolimus 9). Median OS in the entire cohort of 171 patients was 16.5 months. The median PFS and OS were 6.4 and 15.1 months and 6.3 and 18.5 months in the VEGF-TKI group and mTOR inhibitor group, respectively. There were no significant differences in PFS and OS between the 2 groups. In multivariate analysis, two factors at the start of subsequent therapy were identified as independent poor prognostic factors for OS: ECOG-PS of 1 or more (HR, 2.09; 95%CI 1.12-3.37), and CRP/albumin ratio more than 0.15 (HR, 3.01; 95%CI 1.69-5.36). Each patient was assigned to one of three risk groups: favorable risk (0 factors, n = 40), in which median OS was 29 months; intermediate risk (1 factor, n = 52), in which median OS was 16 months; and poor risk (2 factors, n = 50), in which median OS was 8 months (p = 0.0000006). Conclusions: The present study showed for the first time the prognosis of Japanese patients with metastatic RCC who failed prior VEGF-TKI therapy. Furthermore, we identified two independent prognostic factors and developed a new prognostic classification for these patients.
Active and Ultra-Large Von Willebrand Factor Is Significantly Elevated in Patients with Immune Thrombotic Thrombocytopenic Purpura
Authors: Wenjing Cao, Alicia Veninga, Elizabeth M. Staley, Adam Miszta, Nicole Kocher, Lance Williams, Marisa B. Marques, Bas de Laat, X. Long Zheng
Journal: Blood (2018)
A single typical trichoscopic feature is predictive of tinea capitis: a prospective multicentre study
Authors: F. Dhaille, A.‐S. Dillies, F. Dessirier, P. Reygagne, M. Diouf, T. Baltazard, F. Lombart, V. Hébert, M. Chopinaud, L. Verneuil, C. Becquart, E. Delaporte, C. Lok, G. Chaby
Journal: British Journal of Dermatology (2019)

Specific trichoscopic signs of tinea capitis (TC) were first described in 2008. The accuracy of this diagnostic tool has not been evaluated. To assess the diagnostic accuracy of trichoscopy. A prospective, multicentre study was done between March 2015 and March 2017 at the dermatology departments of four French university medical centres. Patients with a presumed diagnosis of TC were included. Trichoscopy was considered to be positive if at least one specific trichoscopic sign was observed. Trichoscopy results were compared with the gold standard for diagnosis of TC (mycological culture). One hundred patients were included. Culture was positive for 53 patients and negative for 47. The sensitivity of trichoscopy was 94% [95% confidence interval (CI) 88–100], specificity was 83% (95% CI 72–94), positive predictive value was 92% and negative predictive value was 86%. Comma hairs, corkscrew hairs, zigzag hairs, Morse‐code‐like hairs and whitish sheath were significantly more frequent in patients with a positive mycological culture (P < 0·001). Comma hairs were more frequent in patients with Trichophyton TC (P = 0·026), and zigzag hairs were more frequent in patients with Microsporum TC (P < 0·001). Morse‐code‐like hair was not observed in any patients with Trichophyton TC and therefore appears to be highly specific for Microsporum TC. The presence of a single trichoscopic finding is predictive of TC. Trichoscopy is a useful, rapid, painless, highly sensitive tool for the diagnosis of TC – even for dermoscopists with little experience of trichoscopy. It enhances physicians' ability to make treatment decisions. What's already known about this topic? Tinea capitis (TC) must be confirmed by a mycological culture that may take up to 6 weeks, delaying treatment. Specific trichoscopic signs of TC were first described in 2008, but the accuracy of trichoscopy for diagnosing TC has not previously been evaluated. What does this study add? The present series is the largest yet on the use of trichoscopy in the diagnosis of TC. Our results demonstrated that the presence of a single feature (comma hair, corkscrew hair, zigzag hair, Morse‐code‐like hair or whitish sheath) is predictive of TC. Trichoscopy is painless and highly sensitive. Morse‐code‐like hair appears to be highly specific for Microsporum TC.
Validation of the Functional Assessment of Cancer Therapy-Breast (FACT-B) quality of life instrument.
Authors: Elizabeth A Hahn, Eisuke Segawa, Karen Kaiser, David Cella, Benjamin D. Smith
Journal: Journal of Clinical Oncology (2015)

e17753 Background: The FACT-B is widely used in international clinical trials and health services research. The purpose of this project was to evaluate reliability and validity for Version 4 of the FACT-B. Methods: De-identified data were obtained from an ongoing breast cancer treatment trial. Participants completed the FACT-B and other patient-reported outcomes (PRO) measures at Baseline, and 6 and 12 months after completing radiation. Physicians assessed cosmetic outcome and NCICTC adverse events. Internal consistency reliability was estimated with Cronbach's coefficient alpha. Construct, criterion and responsive validity were evaluated with correlations and analysis of variance. Effect sizes were calculated as mean differences divided by the Baseline SD or change score SD. Since this trial is ongoing, missing data were considered missing at random. Results: The numbers of participants were: Baseline (n= 280), 6 months (n= 263), and 12 months (n= 220). Slightly more than half were age 60 or older, most were Non-Hispanic White, and most had invasive breast cancer. Internal consistency reliability coefficients were 0.70 or greater for most FACT-B subscales. At 12 months, mean scores for most FACT-B scales were higher (better) for those with a physician-rated cosmetic assessment of excellent compared to poor/fair/good (p< 0.05), and effect sizes were 0.306 to 0.384. Most mean FACT-B scores were significantly higher for those with Grade 0-1 NCICTC toxicities compared to those with Grade 2-3 (p< 0.05), and effect sizes were 0.321 to 0.522. Correlations between most FACT-B subscales and the Body Image Scale (BIS) were medium to large (-0.34 to -0.55). Most FACT-B mean scores differed across BIS change groups (p< 0.05). Conclusions: Measurement science relies on an accumulating body of evidence examining key properties in different contexts. This report provides new information about the FACT-B (Version 4) which exhibited good reliability and validity in this sample of 280 English-speaking women participating in a clinical trial for breast cancer treatment. PRO measures, such as the FACT-B, can provide important information for assessing the overall burden of cancer and the effectiveness of interventions.
The effect of urologic oncology fellowship training on type and yield of prostate biopsy.
Authors: Molly Elmer DeWitt-Foy, Ahmed El-Shafei, Wendy Melissa Coronado, Robert Abouassaly
Journal: Journal of Clinical Oncology (2019)

135 Background: Prostate biopsy is a commonly performed procedure done in the evaluation of elevated prostate specific antigen (PSA), abnormal digital rectal exam (DRE), or for patients with a known prostate cancer diagnosis on active surveillance. The diagnostic yield of prostate biopsy is related to patient factors including age and race, but may also be correlated with provider factors, including clinical experience and training. We aim to determine the relationship between urologic oncology fellowship training (UOFT) and years of training with diagnostic yield of prostate biopsy. Methods: A retrospective review was conducted of patients who underwent prostate biopsy across the Cleveland Clinic between 2000 and 2018. Biopsies done by urologists with and without UOFT were detailed via descriptive statistics and with appropriate (chi square, Student t) tests. Logistic regression was performed, adjusting for last PSA, age, race, and type of biopsy. Results: A total of 11,255 biopsies performed by 129 urologists had complete information for review. The average patient age at biopsy was 65 years. The mean number of years in practice was 16 with a range from &lt; 1 to 46 (SD 11.26). Of 129 urologists 16 (12.4%) had completed a urology oncology fellowship. Those with UOFT were more likely to use MRI guidance for biopsy (7.73% v 2.89%). Overall, 35.5% of all biopsies were positive for prostate cancer, with a significantly higher rate of positive biopsy for urologists with UOFT (40.7% v 32.43%, OR 1.4, p &lt; 0.0001). Having completed greater than 5 years of clinical practice was correlated with greater odds of positive biopsy (OR 1.170, p &lt; 0.0001), but significance of this association was lost when adjusting for oncology fellowship. UOFT remained a significant predictor of diagnostic yield even when adjusting for most recent PSA, age and race of patient, provider years in practice, and type of biopsy (MRI v transrectal ultrasound). Conclusions: Urologic oncology fellowship training is associated with a higher diagnostic yield on prostate biopsy, and a higher uptake of MRI guided biopsy. Higher rate of positivity on biopsy may be attributable to more nuanced patient selection for biopsy or to biopsy technique.