tbuckley/cabot-search huggingface dataset:
Underdiagnosis of germline genetic prostate cancer: Are genetic testing guidelines an aid or an impediment?
Authors: Edward D. Esplin, David J Cahn, Brian Mazzarella, Christopher Michael Pieczonka, Mukaram Gazi, Laurence H. Belkoff, Sean Heron, Rishi Modh, Aaron D. Berger, David Morris, Gautam Jayram, Charles Idom, Joseph Veys, Alexander Engelman, Richard Bevan-Thomas, Mary Kay Hardwick, Kathryn E. Hatchell, Sarah M. Nielsen, Robert Luke Nussbaum, Neal D. Shore
Journal: Journal of Clinical Oncology (2021)

10504 Background: Pathogenic/likely pathogenic (P/LP) germline genetic variants are estimated to occur in 10-15% of all prostate cancer (PCa) patients. However, genetic testing for PCa patients is underutilized, partially due to complicated and restrictive testing guidelines developed at a time when the cost of testing was high. We conducted a study based in community urology clinics to determine the incidence of P/LP variants in PCa patients who met and did not meet the NCCN 2019 PCa germline genetic testing criteria. Methods: An IRB-approved, multicenter, prospective registry was initiated with 15 community and academic urologists nationwide. Eligibility criteria included patients with a PCa diagnosis unselected for personal or family history, stage or histology who had not been previously tested. Consecutive patients ages 18-90 were consented and underwent an 84-gene germline panel test. HIPAA-compliant electronic case report forms distributed to clinician collected information on patient diagnoses, NCCN testing criteria, and results-based recommendations. Results: To date, 640 enrolled patients have genetic testing results available. Overall, 69 (10.8%) patients had 72 P/LP variants detected, 15% of which were in BRCA1/2. Of the 532 patients for whom we have clinician-reported data, 293 (55%) met NCCN criteria and 239 (45%) did not. Median age was 70 (range 44-90). Overall, 11.1% (59/532) of patients with clinician-reported data had a P/LP variant. 36 (12.3%) of patients who met NCCN criteria and 23 (9.6%) of patients who did not meet criteria had a P/LP variant. The difference in P/LP rate between the two groups was not statistically significant (p=0.33). If only a conservative 12-gene PCa panel was considered, P/LP yield was 5.5% (29/532), with 8 (28%) of these patients missed by guidelines. Stratification by self-reported ethnicity was: 76% White/Caucasian (52 patients w/ P/LP), 18% Black/African American (2 patients w/ P/LP), and &lt;5% each of Hispanic or Asian. Conclusions: There was no statistically significant difference in the yield of P/LP variants between patients who met and those who did not meet NCCN PCa guidelines, reinforcing that a significant number of P/LP variants are missed if NCCN guidelines are required for genetic testing. Expanded panel testing yields more medically actionable P/LP variants than testing BRCA1/2 alone or PCa panels with 12 genes. While 18% of the cohort was Black/African American, there was a lower P/LP rate (2%) relative to other groups, indicating that more research is needed to understand genetic variation in underrepresented populations with PCa.
Long-Term Rivaroxaban for the Treatment of Acute Venous Thromboembolism in Patients with Active Cancer in a Prospective Multicenter Trial: KVTE13-01
Authors: Ho-Young Yhim, Won-Il Choi, Sung-Hyun Kim, Seung-Hyun Nam, Kyoung Ha Kim, Yeung-Chul Mun, Hun-Gyu Hwang, Doyeun Oh, Keun-Wook Lee, Eun-Kee Song, Yong Shik Kwon, Soo-Mee Bang
Journal: Blood (2017)
Cost-effectiveness of the Oncotype DX Breast Recurrence Score test in postmenopausal women with node-positive early breast cancer based on the RxPONDER trial.
Authors: Vladislav Berdunov, Steve Millen, Andrew Paramore, Sarah Reynia, Nina Fryer, Jane Griffin, Nadia Georges
Journal: Journal of Clinical Oncology (2021)

534 Background: The Oncotype DX test is a predictive and prognostic multigene assay used to guide adjuvant chemotherapy in HR+/HER2- early breast cancer. The ability of the Oncotype DX test to predict the benefit of chemotherapy in node-positive early breast cancer was demonstrated in SWOG-8814. This evidence, in combination with findings from a bespoke analysis of the TransATAC study, informed an economic evaluation of the Oncotype DX test by the National Institute for Health and Care Excellence in the UK. This study examined the impact of new evidence from the RxPONDER trial on the cost-effectiveness of the Oncotype DX test in postmenopausal women with node-positive early breast cancer. Methods: The cost-effectiveness of the Oncotype DX test compared to clinical risk tools only in postmenopausal HR+/HER2- early breast cancer was estimated using a model in Microsoft Excel. The pre-RxPONDER analysis using the old cut points (RS 0-17, RS 18-30, RS 31-100) was informed by TransATAC and SWOG-8814. The model was updated with 5-year probability of distant recurrence as first site estimates based on new RS cut points (RS 0-25, RS 26-100) from RxPONDER. The impact on incremental lifetime costs and quality-adjusted life-years (QALYs) gained was examined based on the list price for the Oncotype DX test in the UK. Results: The impact of adding data from RxPONDER into the cost-effectiveness analysis is summarized in the table below. Conclusions: The RxPONDER trial demonstrated that the addition of chemotherapy to endocrine therapy had no benefit for distant recurrence in postmenopausal women with RS 0-25, regardless of clinical features, which suggests that most patients with 1-3 positive nodes can be safely spared adjuvant chemotherapy. In the model this was reflected in reduced cost of chemotherapy and higher QALYs from avoiding short and long-term adverse effects of chemotherapy. Targeted chemotherapy of a minority (17%) of patients with RS 26-100 reduced the cost of distant recurrence and improved survival based on the model results. RxPONDER provides direct evidence to inform the probability of distant recurrence with endocrine and chemo-endocrine therapy, whilst previous models have had to synthesize multiple sources of DRFI and chemotherapy treatment effect. Future studies should examine the impact of the RxPONDER findings on chemotherapy treatment decision-making in routine clinical practice.[Table: see text]
Genomic characterization of p16+ compared to p16- HNSCC patients treated with immune checkpoint inhibitors and overall survival.
Authors: Hira Ghazal Shaikh, Julie Elaine McGrath, Joanne Xiu, Brittany Nicole Hughes, Ammar Sukari, Chadi Nabhan, Wolfgang Michael Korn, Sourat Darabi, Punita Grover, Rebecca Chernock, Chukwuemeka Ikpeazu, Trisha Michel Wise-Draper
Journal: Journal of Clinical Oncology (2021)

e18024 Background: Multiple studies investigating immune checkpoint inhibitors (ICI) in head and neck squamous cell cancer (HNSCC) patients have demonstrated prolonged survival of p16+ versus p16- tumors. However, the data has been conflicting. Methods: We queried the Caris Life Sciences CODEai database to assess survival outcomes of HNSCC patients who received ICIs comparing p16+ and p16- subgroups. A standard cut-off of 2+, &gt;70% p16 staining was used. Presence of HPV16/18 genomes was tested using whole exome sequencing. Patients were considered smokers if they had &gt;15 pack-years of tobacco use. PD-L1 expression was assessed by the 22c3 antibody, ≥1 being positive. Gene mutations were evaluated using Next-Generation Sequencing (NGS) (Caris Life Sciences, Phoenix, AZ). Tumor mutational burden (TMB) was assessed by somatic nonsynonymous missense mutations. Real world overall survival (rwOS) was obtained from insurance claims data and Kaplan-Meier estimates were calculated from the date of treatment start to the date of last contact. Time on treatment (TOT) was calculated from date of start to completion of ICIs. Results: 2905 patients with HNSCC were identified in the Caris database. 41% (215/525) were smokers. Among patients who were tested for p16 and/or HPV, 32% (251/791) expressed p16 and 28% (91/236) were HPV+. The majority of p16+ tumors were oropharynx (OP) in origin (68%, 171/251). 87% (970/1111) of tumors expressed PD-L1 and 16% (216/1362) had TMB ≥10/Mb. TP53 (54%, n=1115/2076) and CDKN2A (17%, n=281/1649) were the most common mutations. When compared to p16-, the p16+ group had a higher prevalence of TMB ≥10/Mb (26% vs 17%) and RB1 mutations (21% vs 4%) but lower number of smokers (15% vs 34%) and TP53 mutations (32% vs 58%). Similar to previous reports, p16+ oropharynx squamous cell carcinoma (OPSCC) patients survived longer than p16- patients, rwOS, 47 vs. 20 months (HR=0.55, p = 0.014) respectively. Among patients who were treated with ICIs, p16+ and p16- non-OP HNSCC, rwOS was not reached (NR) for both groups at follow up of 22 months while TOT for p16+ and p16- respectively, was 3.5 vs. 2.7 months, HR 0.507, p=0.039. No statistically significant difference was found in rwOS (19.3 vs. 24 months, HR 1.8, p=0.27) or TOT (3.7 vs. 4.1 months, HR 0.78, p=0.38) between p16+ and p16- OPSCC groups treated with ICIs, respectively. Conclusions: P16+ non-OP HNSCC patients receiving ICIs were found to remain on treatment longer compared to p16- patients which was not reproduced in the OPSCC subgroup. Randomized controlled trials are needed to verify p16 as a prognostic marker for ICI therapy.[Table: see text]
Exploring molecular profiles and survival in hormone receptor-positive uterine serous carcinoma.
Authors: Amaranta Craig, Annelise M. Wilhite, Sharon Wu, Joanne Xiu, Gina Mantia-Smaldone, Enrique Hernandez, Jubilee Brown, Nathaniel L. Jones
Journal: Journal of Clinical Oncology (2021)

5579 Background: Hormone receptor (HR) positivity has been reported as a good prognostic indicator in endometrial cancer. This study investigated estrogen receptor (ER) and progesterone receptor (PR) positivity as indicators of platinum response and improved survival in uterine serous carcinoma (USC), and determined differences in molecular profiles between these tumors and hormone receptor negative tumors. Methods: Tumor profiling was done with immunohistochemistry (IHC), next generation sequencing (NGS), and whole transcriptome sequencing (WTS). PD-L1 expression was determined by IHC using SP-142 (cut-off &gt;1%). Microsatellite instability (MSI) status was evaluated with IHC and NGS, and tumor mutational burden (TMB) by totaling somatic mutations per tumor (high if &gt; 10 mutations/ MB). Immune-cell fraction was determined with QuantiSeq. We used insurance claims data to calculate Kaplan-Meier estimates for overall survival (OS). Statistical significance was determined with chi-square and Wilcoxon rank sum test and adjusted for multiple comparisons. Results: 2806 USC tumors were available for molecular profiling with 717 HR+/966 HR-, 1559 ER+/1059 ER- and 805 PR+/1809 PR-. Median OS for HR+ patients was longer than patients who were HR- regardless of treatment (1152 v 797 days; hazard ratio 0.68, 95% CI 0.58-0.80, p &lt; 0.01). This OS benefit of HR positivity remained for patients receiving platinum therapy (1134 v 889 days; hazard ratio 0.75, 95% CI 0.58-0.98, p &lt; 0.01). HR+ status trended towards improved OS in those treated with hormone therapy (407 vs 771 days, hazard ratio 0.78, 95% CI 0.59-1.02, p = 0.07). In addition to increased androgen receptor expression (54.2 vs 6.2%, p = &lt; 0.001), PTEN mutations were more common in the HR+ group (10.3 vs 5.1%, p = 0.016). This resulted in in more frequent alterations of the PI3K pathway when compared to HR- tumors 64.5 vs 52.2%, p = &lt; 0.001). PD-L1, TMB, and MSI status were similar between the two cohorts. Checkpoint inhibitor gene expression was notable for higher IDO expression in the HR+ group, but lower CD80, CD86, HAVCR2, IFNG, and PDC1 expression. The immune micro-environment was notable for less B-cells and M1 macrophages, but more M2 macrophages. Breaking the ER and PR positive cohort down to individual expression of each gene resulted in similar OS and molecular findings. Conclusions: HR positivity is associated with improved survival in allcomers with USC and those treated with platinum therapy, and there was a trend to improved OS with hormone therapy. More data is needed to determine if HR status is a prognostic marker for IO treatment response. This cohort had a distinct molecular profile compared to HR- tumors.
Abstract GMM-026: AMPLIFICATION OF USP13 DRIVES OVARIAN CANCER METABOLISM
Authors: Cecil Han
Journal: Clinical Cancer Research (2019)

Abstract Dysregulated energetic metabolism has been recently identified as a hallmark of cancer. Although mutations in metabolic enzymes hardwire metabolism to tumourigenesis, they are relatively infrequent in ovarian cancer. More often, cancer metabolism is re-engineered by altered abundance and activity of the metabolic enzymes. Here we identify ubiquitin-specific peptidase 13 (USP13) as a master regulator that drives ovarian cancer metabolism. USP13 specifically deubiquitinates and thus upregulates ATP citrate lyase and oxoglutarate dehydrogenase, two key enzymes that determine mitochondrial respiration, glutaminolysis and fatty acid synthesis. The USP13 gene is co-amplified with PIK3CA in 29.3% of high-grade serous ovarian cancers and its overexpression is significantly associated with poor clinical outcome. Inhibiting USP13 remarkably suppresses ovarian tumor progression and sensitizes tumor cells to the treatment of PI3K/AKT inhibitor. Our results reveal an important metabolism-centric role of USP13, which may lead to potential therapeutics targeting USP13 in ovarian cancers. Citation Format: Cecil Han. AMPLIFICATION OF USP13 DRIVES OVARIAN CANCER METABOLISM [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-026.
Demographic Factors Associated With Non-Guideline–Based Treatment of Kidney Cancer in the United States
Authors: Jeffrey M. Howard, Karabi Nandy, Solomon L. Woldu, Vitaly Margulis
Journal: JAMA Network Open (2021)

<h3>Importance</h3> Significant demographic disparities have been found to exist in the delivery of health care. Demographic factors associated with clinical decision-making in kidney cancer have not been thoroughly studied. <h3>Objective</h3> To determine whether demographic factors, including sex and race/ethnicity, are associated with receipt of non-guideline–based treatment for kidney cancer. <h3>Design, Setting, and Participants</h3> This retrospective cohort study was conducted using data from the National Cancer Database for the years 2010 through 2017. Included patients were individuals aged 30 to 70 years with localized (ie, cT1-2, N0, M0) kidney cancer and no major medical comorbidities (ie, Charlson-Deyo Comorbidity Index score of 0 or 1) treated at Commission on Cancer–accredited health care institutions in the United States. Data were analyzed from November 2020 through March 2021. <h3>Exposures</h3> Demographic factors, including sex, race/ethnicity, and insurance status. <h3>Main Outcomes and Measures</h3> Receipt of non-guideline–based treatment (undertreatment or overtreatment) for kidney cancer, as defined by accepted clinical guidelines, was determined. <h3>Results</h3> Among 158 445 patients treated for localized kidney cancer, 99 563 (62.8%) were men, 120 001 individuals (75.7%) were White, and 91 218 individuals (57.6%) had private insurance. The median (interquartile range) age was 58 (50-64) years. Of the study population, 48 544 individuals (30.6%) received non-guideline–based treatment. Female sex was associated with lower adjusted odds of undertreatment (odds ratio [OR], 0.82; 95% CI, 0.77-0.88;<i>P</i> &lt; .001) and higher adjusted odds of overtreatment (OR, 1.27; 95% CI, 1.24-1.30;<i>P</i> &lt; .001) compared with male sex. Compared with White patients, Black and Hispanic patients had higher adjusted odds of undertreatment (Black patients: OR, 1.42; 95% CI, 1.29-1.55;<i>P</i> &lt; .001; Hispanic patients: OR, 1.20; 95% CI, 1.06-1.36;<i>P</i> = .004) and overtreatment (Black patients: OR, 1.09; 95% CI, 1.05-1.13;<i>P</i> &lt; .001; Hispanic patients: OR, 1.06; 95% CI, 1.01-1.11,<i>P</i> = .01). Individuals who were uninsured, compared with those who had insurance, had statistically significantly higher adjusted odds of undertreatment (OR, 2.63; 95% CI, 2.29-3.01;<i>P</i> &lt; .001) and lower adjusted odds of overtreatment (OR, 0.72; 95% CI, 0.67-0.77;<i>P</i> &lt; .001). <h3>Conclusions and Relevance</h3> This study found that there were significant disparities in treatment decision-making for patients with kidney cancer, with increased rates of non-guideline–based treatment for women and Black and Hispanic patients. These findings suggest that further research into the mechanisms underlying these disparities is warranted and that clinical and policy decision-making should take these disparities into account.
Publication Productivity and Bibliometric Profiling of Graduating General Surgery Chief Residents
Authors: Torbjorg Holtestaul, Ian Jones, Zachary Colburn, Daniel Nelson, Timothy Vreeland, Jason Bingham, Christopher Yheulon
Journal: JAMA Surgery (2021)

This cross-sectional study assesses the publication productivity of graduating general surgery residents as well as factors associated with a chief resident’s academic research output.
Abstract NT-096: FABCLAVINE, A SECONDARY METABOLITE FROM XENORHABDUS BUDAPESTENSIS AS THERAPY AGAINST OVARIAN CANCER
Authors: Arvinder K Kapur, Mayur Kajla, Susan Paskewitz, Pooja Mehta, Geeta Mehta, Manish S Patankar
Journal: Clinical Cancer Research (2019)

Abstract Ovarian cancer is the fifth most common cause of cancer-related deaths in women in the United States. Most women with ovarian cancer present with advanced disease. Even though initial response to surgery and chemotherapy is generally positive, many patients relapse with chemoresistant disease. We are especially interested in finding natural products that have anti-neoplastic activity against relapsed disease. Here, we report fabclavine, a secondary metabolite from Xenorhabdus budapestensis as novel anti-cancer agent. Fabclavine was isolated and purified from cell-free supernatants of Xbu cultures. In a two-step procedure, active compounds were first precipitated from the supernatant with acetone and subsequently purified via reverse phase chromatography. Proliferation assays conducted on several ovarian cancer cell lines such as OVCAR3, OVCA433, ID8, IOSE, show that fabclavine inhibits the cancer cell proliferation at nanomolar (250-400 nM) concentration but has no effect on IOSE at that concentration. The ovarian cancer cell line OVCA33 when tested in proliferation assay showed, they are sensitive to fabclavine at a ten-fold lower concentration than cisplatin. Besides proliferation assay in 2D culture, we also tested the effect of fabclavine in 3D culture of ovarian cancer cell lines. The results indicate, fabclavine was equally effective in 3D culture and killed 40-50% of the cells in spheroids. In addition, fabclavine was also tested against cancer stem cells isolated from ovarian cancer patient and grown in 3D culture and it inhibited the growth of stem cells by 45%. Treatment of ovarian cancer cell lines with Fabclavine indicated DNA damage and an increase in cleaved caspase 3 and Annexin V binding, confirming that this agent was killing the OVCAR3, ID8 and OVCA433 cancer cell lines via apoptosis. Further experiments are underway to determine the apoptosis pathway (intrinsic or extrinsic) activated by fabclavine. Here we are describing for the first time a novel agent which is water soluble, active at low concentration and conveniently purified from cell free supernatant of bacterial culture. These properties of fabclavine makes it an excellent molecule to develop as therapy against ovarian tumors. Citation Format: Arvinder K Kapur, Mayur Kajla, Susan Paskewitz, Pooja Mehta, Geeta Mehta, Manish S Patankar. FABCLAVINE, A SECONDARY METABOLITE FROM XENORHABDUS BUDAPESTENSIS AS THERAPY AGAINST OVARIAN CANCER [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr NT-096.
CARG-2020, an oncolytic artificial virus co-delivering three immunomodulators, to regress and cure established tumors in mice.
Authors: Bijan Almassian, Bhaskara R Madina, Ju Chen, Marie M Krady, Xianyong Ma, Timur O Yarovinsky, Valerian Nakaar, Kepeng Wang
Journal: Journal of Clinical Oncology (2021)

e14560 Background: Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in humans. Treatment of late-stage CRC remains ineffective, even with the use of latest immunotherapies. Oncolytic viruses have shown limited use for the treatment of cancers, and further improvement of these agents with immune-modulating activities may prove crucial for patients with CRC and other malignancies. To this end, we developed CARG-2020 as an artificial virus for infectious diseases and immuno-oncology (AVIDIO) that employs virus-like vesicles (VLV). VLVs, which are membrane-encapsulated RNA replicons, are oncolytic and can deliver multiple genes resulting in the modulation of several independent immune pathways. Methods: The AVIDIO platform is comprised of in vitro evolved RNA-dependent RNA polymerase from an alphavirus, Semliki Forest virus, and envelope glycoproteins from vesicular stomatitis virus, which together form VLVs. Unarmed or empty vector (VLV), VLV armed with IL-12 (VLV-IL-12) and a VLV that simultaneously expresses IL-12, a dominant-negative form of IL-17 receptor A (dn-1L17RA) and shRNAs targeting PD-L1 (CARG-2020), were given intratumorally to test their therapeutic potential against established (500-600mm 3 ) MC38 tumors in mice. We used tumor growth measurements and analyses of tumor-infiltrating cells after consecutive treatments with these agents to monitor their antitumor and immunomodulatory activities, respectively. Results: Both VLV-IL-12 and CARG-2020 regressed the tumors to undetectable levels in most mice harboring syngeneic MC38 tumors when given intratumorally. CARG-2020, carrying IL-12, dn-IL17RA and PD-L1 shRNA, exerts broader spectrum of immuno-responses and higher number of complete response rates compared with VLV-IL-12. Treatment of primary tumors with VLV-IL-12 or CARG-2020 also significantly repressed the growth of secondary tumors on the other flank of mouse’s body, suggesting an effective systemic immunity elicited by these two agents against the same type of tumors. In addition to the marked local and systemic activation of Th1 cells and CD8 + T cells by both vectors, CARG-2020 also downregulated PD-L1 expression in tumors, and suppressed expression of IL-17A-activated chemokines CXCL1 and CXCL2 that are known to promote cancer development and therapy resistance. Conclusions: As an oncolytic RNA replicon, AVIDIO platform-derived CARG-2020 encodes IL-12, dn-IL-17RA and PD-L1 shRNAs which are expressed concurrently within the same vector. CARG-2020 modulates IL-12, IL-17RA and PD-L1 signaling, and exerts broad immune modulation in tumor microenvironment. Treatment with CARG-2020 eliminates the majority of grafted large tumors in mice, and is effective against both primary and distal tumors. Based on this impressive efficacy results, further development of CARG-2020 in colorectal patients is warranted.
Cardiorenal Syndrome in Thalassemia Patients
Authors: Sorasak Makmettakul, Adisak Tantiworawit, Suree Lekawanvijit, Arintaya Phrommintikul, Thanawat Rattanathammethee, Sasinee Hantrakool, Chatree Chai-Adisaksopha, Ekarat Rattarittamrong, Lalita Norasetthada
Journal: Blood (2017)