tbuckley/cabot-search huggingface dataset:
Evaluating the NCCN Clinical Criteria for Recommending<i>BRCA1</i>and<i>BRCA2</i>Genetic Testing in Patients With Breast Cancer
Authors: Caiqian Cropper, Ashley Woodson, Banu Arun, Carlos Barcenas, Jennifer Litton, Sarah Noblin, Diane Liu, Minjeong Park, Molly Daniels
Journal: Journal of the National Comprehensive Cancer Network (2017)

Background: Mutations in the BRCA1 and BRCA2 genes predispose individuals to a significantly elevated risk for breast and ovarian cancers. Identification of these individuals allows for proper screening, management, and testing of at-risk relatives. NCCN has established clinical criteria for recommending BRCA1/2 testing. Patients and Methods: A retrospective chart review of 1,123 patients with breast cancer was performed to evaluate the positive predictive values (PPVs) of 14 individual criteria for predicting BRCA1/2 mutations. Results: Two criteria had PPVs significantly below 10%. Only 2 of 115 patients who were recommended for testing based solely on the criterion of “diagnosed with breast cancer at ≤45 years of age” had pathogenic mutations at a PPV of 1.6% (95% CI, 0.2%–6.0%). Additionally, 0 of 37 individuals who underwent testing based on the criterion, “diagnosed with breast cancer at any age with ≥2 close blood relatives with breast cancer at any age” tested positive (95% CI, 0%–9%). Overall, meeting >1 criterion has a PPV of 12%, whereas meeting only 1 criterion has a PPV of 3.2% (95% CI, 1.6%–5.7%), significantly below 10% (P<.0001) for predicting BRCA1/2 positivity. Conclusions: Patients with breast cancer meeting >1 criterion constitute a population significantly enriched for BRCA1/2 mutations, whereas those meeting only 1 criterion test positive at a rate similar to unselected patients with breast cancer. These data will inform ongoing discussions regarding how to best implement BRCA1/2 genetic testing.
Wireless Monitoring Program of Patient-Centered Outcomes and Recovery Before and After Major Abdominal Cancer Surgery
Authors: Virginia Sun, Sinziana Dumitra, Nora Ruel, Byrne Lee, Laleh Melstrom, Kurt Melstrom, Yanghee Woo, Stephen Sentovich, Gagandeep Singh, Yuman Fong
Journal: JAMA Surgery (2017)

A combined subjective and objective wireless monitoring program of patient-centered outcomes can be carried out in patients before and after major abdominal cancer surgery.To conduct a proof-of-concept pilot study of a wireless, patient-centered outcomes monitoring program before and after major abdominal cancer surgery.In this proof-of-concept pilot study, patients wore wristband pedometers and completed online patient-reported outcome surveys (symptoms and quality of life) 3 to 7 days before surgery, during hospitalization, and up to 2 weeks after discharge. Reminders via email were generated for all moderate to severe scores for symptoms and quality of life. Surgery-related data were collected via electronic medical records, and complications were calculated using the Clavien-Dindo classification. The study was carried out in the inpatient and outpatient surgical oncology unit of one National Cancer Institute-designated comprehensive cancer center. Eligible patients were scheduled to undergo curative resection for hepatobiliary and gastrointestinal cancers, were English speaking, and were 18 years or older. Twenty participants were enrolled over 4 months. The study dates were April 1, 2015, to July 31, 2016.Outcomes included adherence to wearing the pedometer, adherence to completing the surveys (MD Anderson Symptom Inventory and EuroQol 5-dimensional descriptive system), and satisfaction with the monitoring program.This study included a final sample of 20 patients (median age, 55.5 years [range, 22-74 years]; 15 [75%] female) with evaluable data. Pedometer adherence (88% [17 of 20] before surgery vs 83% [16 of 20] after discharge) was higher than survey adherence (65% to 75% [13 of 20 and 15 of 20] completed). The median number of daily steps at day 7 was 1689 (19% of daily steps at baseline), which correlated with the Comprehensive Complication Index, for which the median was 15 of 100 (r = -0.64, P < .05). Postdischarge overall symptom severity (2.3 of 10) and symptom interference with activities (3.5 of 10) were mild. Pain (4.4 of 10), fatigue (4.7 of 10), and appetite loss (4.0 of 10) were moderate after surgery. Quality-of-life scores were lowest at discharge (66.6 of 100) but improved at week 2 (73.9 of 100). While patient-reported outcomes returned to baseline at 2 weeks, the number of daily steps was only one-third of preoperative baseline.Wireless monitoring of combined subjective and objective patient-centered outcomes can be carried out in the surgical oncology setting. Preoperative and postoperative patient-centered outcomes have the potential of identifying high-risk populations who may need additional interventions to support postoperative functional and symptom recovery.
Phase II study of eribulin in combination with gemcitabine for the treatment of patients with locally advanced or metastatic triple negative breast cancer: ERIGE trial on behalf of the Gruppo Oncologico Italiano di Ricerca Clinica (GOIRC).
Authors: Antonino Musolino, Rosa Porzio, Daniela Rubino, Antonio Frassoldati, Alessia Caldara, Alessio Schirone, Stefania Gori, Federico Piacentini, Rossana Berardi, Alba Ariela Brandes, Giovanna Cavazzini, Jennifer Foglietta, Federica Villa, Benedetta Pellegrino, Roberta Camisa, Renata Todeschini, Michele Tognetto, Nadia Naldi, Daniela Baldari, Filippo Montemurro
Journal: Journal of Clinical Oncology (2017)

1095 Background: There are no well-established chemotherapy regimens for metastatic triple negative breast cancer. The combination of a microtubule inhibitor (eribulin) with a nucleoside analog (gemcitabine) may synergistically induce tumor cell death, especially in tumors like triple negative breast cancers (TNBC) characterized by high cell proliferation, aggressive tumor behavior, and chemo-resistance. Methods: We performed an open-label, national multicenter phase 2 study evaluating the combination of eribulin (0.88 mg/m 2 ) plus gemcitabine (1000 mg/m 2 ) on day 1 and 8, q21 as either first- or second-line treatment of locally advanced or metastatic TNBC. The Simon's optimal two-stage design was used for estimating objective response rate (ORR) as study primary endpoint. A prospective, molecular correlative study was carried out on germinal DNA of study population to assess the role of germinal DNA polymorphisms and BRCA mutations in predicting efficacy and toxicity of the combination regimen. Results: From July 2013 to September 2016 , 83 (37 in the first stage, 46 in the second one) assessable patients were enrolled. Median age at baseline was 56 years. Sixty-six and 17 patients were in first or second-line treatment, respectively. All patients were previously treated with an anthracycline and/or a taxane. With regard to the first stage of study enrolment, patients received a median number of 6 cycles of treatment. The ORR (CR+PR) was 43.24% (90% CI 29.3-58.0) and the clinical benefit rate (CR+PR+SD) was 64.9% (90% CI: 50.1%-77.8%). The most common grade 3/4 AEs ( &gt; 10% of patients) were neutropenia without febrile neutropenia and liver toxicity. Grade 1/2 AEs were fatigue, anemia, thrombocytopenia, diarrhea, alopecia, peripheral neuropathy, and oral mucositis. Conclusions: The combination of eribulin and gemcitabine shows promising activity and a moderate toxicity profile in metastatic TNBC. More mature toxicity and outcome data of the final study population and correlation with genome analysis will be presented at the meeting. Clinical trial information: 2012-003505-10.
Emerging Potential Roles of Lysyl-Oxidase-like 2 Stimulates Cancer Associated Fibroblasts Promoting Myelofibrosis of Myeloproliferative Neoplasms
Authors: Xiaoli Liu, Na Xu, Chengyun Pan, Xuan Zhou, Qifa Liu, Ru Feng, Jing Sun, Hongsheng Zhou
Journal: Blood (2016)
Abstract 252: Doxorubicin-induced H9c2 Cell Death is Mediated by Excessive Mitochondrial Fission and Mitophagy
Authors: Michael P Catanzaro, Ashley Weiner, Amanda Kaminaris, Satoru Kobayashi, Qiangrong Liang
Journal: Circulation Research (2015)

Doxorubicin (DOX) is a widely used antineoplastic agent that can cause heart failure. DOX cardiotoxicity is closely associated with mitochondrial damage. Mitochondrial fission and mitophagy are quality control mechanisms that help maintain a pool of healthy mitochondria. However, too much mitochondrial fission and/or mitophagy may compromise cell viability. Indeed, Mdivi-1, an inhibitor of the fission protein Drp1, can attenuate DOX-induced cardiac injury, suggesting that mitochondrial fragmentation may play a role in DOX cardiotoxicity. Using genetic gain- and loss-of function approaches, we determined whether mitochondrial fragmentation and/or mitophagy contribute to DOX-induced cardiomyocyte death. H9c2 cardiac myoblast cells were transfected with siRNA targeting Drp-1 before DOX administration. Mitochondrial morphology was examined with confocal microscopy after infection of the cells with the adenovirus encoding mitochondria-targeted fluorescent protein MitoDsRed. Morphometric analysis demonstrated that Drp-1 knockdown markedly diminished DOX-induced mitochondrial fragmentation as shown by form factor, aspect ratio, and mean mitochondrial size. This led to reduced cardiomyocyte death as revealed by the percentage of propidium iodide (PI)-positive cells and the cleavage of caspase-3 and Poly ADP ribose polymerase (PARP). Not surprisingly, Drp-1 knockdown also attenuated DOX-induced mitophagy flux as assessed by the dual fluorescent mitophagy reporter mt-Rosella. Further, knockdown of Parkin, a key regulator of mitophagy, dramatically diminished DOX-induced H9c2 cell death. Although Drp1 overexpression did not markedly increase DOX-induced cell death, Parkin overexpression predisposed H9c2 cells to DOX toxicity. Together, these results suggest that DOX-induced cardiotoxicity may be due to excessive mitochondrial fragmentation and accelerated mitochondrial degradation through autophagy. Strategies that limit mitochondrial fission and mitophagy within the physiological range may help reduce DOX cardiotoxicity. However, further studies are clearly warranted to make sure that these strategies will not compromise the antitumor efficacy of DOX.
Pembrolizumab (pembro) + chemotherapy (chemo) as neoadjuvant treatment for triple negative breast cancer (TNBC): Preliminary results from KEYNOTE-173.
Authors: Peter Schmid, Yeon Hee Park, Eva Muñoz-Couselo, Sung-Bae Kim, Joohyuk Sohn, Seock-Ah Im, Esther Holgado, Yang Wang, Thao Dang, Gursel Aktan, Javier Cortés
Journal: Journal of Clinical Oncology (2017)

556 Background: Pembro has shown efficacy and acceptable safety in pts with previously treated metastatic TNBC. The phase Ib KEYNOTE-173 study (NCT02622074) evaluated pembro + chemo as neoadjuvant therapy for locally advanced TNBC. We present cohorts A and B. Methods: Women aged ≥18 y with locally advanced, nonmetastatic TNBC; ECOG PS 0/1; and no prior chemo, targeted therapy, or immunotherapy within 12 mo were eligible. Dosing in A was single-dose pembro followed by 4 cycles of pembro Q3W + nab-paclitaxel (Np) weekly followed by 4 cycles of pembro + doxorubicin + cyclophosphamide Q3W. Dosing in B was the same as in A but with carboplatin Q3W added to pembro + Np. Concentrations were pembro 200 mg; doxorubicin 60 mg/m 2 ; cyclophosphamide 600 mg/m 2 ; Np 125 mg/m 2 in A, 100 mg/m 2 in B; and carboplatin AUC 6 (1 cycle = 21 d). DLTs were assessed at cycles 1-3 and 6-7. Dose levels were deemed toxic if ≥3 of the first 6 pts or ≥4 of 10 pts had DLTs. Surgery was 3-6 wk after treatment completion/discontinuation. Primary end points were safety and recommended phase 2 dose of pembro combined with chemo. Key efficacy end points were pathological CR (pCR) rate, defined as ypT0/Tis, ypN0, and ypT0 ypN0, and ORR (RECIST v1.1, investigator). pCR analyses included all pts. Results: By Jan 6, 2017, 10 pts were in each cohort. Median age was 53 y (range 32-71); most pts had invasive ductal histology (90%), primary tumor stage ≥T2 (90%), and nodal involvement (75%). DLTs (myelosuppression) occurred in 7 pts (3 in A, 4 in B) and were unrelated to pembro. Gr 3-4 treatment-related AEs (TRAEs) occurred in 8 pts in A and 10 pts in B; none were fatal. One pt in A and 2 pts in B discontinued for a TRAE (2 ALT elevations with pembro; 1 DVT with chemo). Overall ORR (CR+PR) before surgery was 80% (90% CI, 49-96) in A and 100% (90% CI, 74-100) in B. ypT0/Tis pCR rate was 70% (90% CI, 39-91) in A and 100% (90% CI, 74-100) in B; ypT0 ypN0 pCR rate was 50% (90% CI, 22-78) in A and 90% (90% CI, 61-100) in B; and yT0/Tis ypN0 pCR rate was 60% (90% CI, 30-85) in A and 90% (90% CI, 61-100) in B. Conclusions: Preliminary data suggest that pembro + chemo as neoadjuvant therapy for TNBC results in manageable toxicity and promising antitumor activity. Clinical trial information: NCT02622074.
Antitumor activity of trabectedin and lurbinectedin in germline BRCA2 carriers with metastatic breast cancer (MBC) as compared to BRCA1 carriers: Analysis of two phase II trials.
Authors: Judith Balmana Gelpi, Jan Antoni Lubinski, Banu Arun, Tomasz Byrski, Melinda L. Telli, Steven J. Isakoff, Cristian Fernandez, Pilar Lardelli, Carmen Maria Kahatt, Arturo Soto-Matos, Suzette Delaloge
Journal: Journal of Clinical Oncology (2017)

574 Background: BRCA 1/2-associated breast cancer share homologous recombination deficiency, but also have independent and potentially actionable roles. Novel drugs with innovative mechanism of action, lacking cross-resistance with other used agents are needed for BRCA 1/2 MBC. Trabectedin (TR) and its analog, lurbinectedin (L), have shown to be active in BRCA 1/2 MBC. This study was sought to determine if there was a difference in activity of these agents between BRCA1 and 2 carriers. Methods: Safety and efficacy in MBC BRCA 1/2 were analyzed in 2 separate phase II trials of single agent TR and L. Results: 88 patients were evaluated: 34 with TR, 54 with L. Median age: 46 and 43, respectively. Median (range) prior chemotherapy lines: TR, 4 (1-10); L, 2 (0-5). Clinical responses were seen in the 2 trials (see table) and were higher in BRCA2 than in BRCA1 (33% vs 9% with TR and 61% vs 26% with L). Main adverse event was myelosuppression (grade 3-4 neutropenia / thrombocytopenia / febrile neutropenia: TR, 62.1%/24.3%/10.8% L, 66.7%/20.4%/20.4%). Non-hematological toxicity was mostly grade 1-2: fatigue, nausea/vomiting and high transaminases (grade 3/4 TR, 40.5%, L 18.5%). Conclusions: Remarkable activity of trabectedin and lurbinectedin as single agents was observed in BRCA 2 associated MBC. This finding warrants further investigation. One potential mechanistic rationale is the role of both lurbinectedin and BRCA 2 in transcription. Safety was acceptable and manageable in both studies. Clinical trial information: NCT01525589. [Table: see text]
Thyroid hormone replacement and the risk for colorectal cancer.
Authors: Shimon Ben Boursi, Kevin Haynes, Ronac Mamtani, Yu-Xiao Yang
Journal: Journal of Clinical Oncology (2014)

1600 Background: The association between thyroid hormones and cancer risk was evaluated in several studies with conflicting results. While thyroid hormones can stimulate cancer growth, hypothyroid function can lead to reduced risk and a more favorable outcome in cancer patients. Aim: To evaluate the risk for colorectal cancer (CRC) in patients treated with thyroid hormones replacement. Methods: We conducted a nested case-control study using The Health Improvement Network (THIN), a large population-based medical records database from the United Kingdom (UK) that contains information on 11.7 million patients with follow up of up to 18 years. Study cases were defined as those with any medical code of CRC. Subjects with known familial colorectal cancer syndromes or IBD were excluded from the study. For every case, 4 eligible controls matched on age, sex, practice site, and duration of follow-up before index date were selected using incidence density sampling. Exposure was defined as any thyroid hormone therapy at least 6 month before index date. The odds ratio (OR) and 95%CI were estimated using conditional logistic regression analysis adjusted for BMI, alcoholism, smoking history, Diabetes mellitus and chronic NSAIDs use. Results: 22,023 CRC patients and 85,981 controls were identified with a mean follow up time of 6 years before index date (SD 3.53). The adjusted OR for CRC associated with use of thyroid hormones was 0.87 (95%CI 0.82-0.93, p<0.0001) and remained reduced 5 and 10 years after initiation of therapy (OR 0.84, 95%CI 0.78-0.91 and 0.83, 95%CI 0.74-0.92 respectively). There was no change in OR when analyzing all durations of therapy, including patients treated for less than 6 months (OR 0.88, 95%CI 0.82-0.93). Conclusions: Patients using thyroid hormone replacement drugs have a statistically significant reduction in CRC risk. Further research is required in order to evaluate whether this effect is secondary to the primary thyroid disease or direct effects of therapy.
Abstract AP13: NF-KAPPAB CLASSICAL VERSUS ALTERNATIVE PATHWAYS SUPPORT DISTINCT POPULATIONS OF OVARIAN CANCER TUMOR-INITIATING CELLS
Authors: Carrie D. House, Elizabeth A. Jordan, Christina M. Annunziata
Journal: Clinical Cancer Research (2017)

Abstract Ovarian cancer is the most lethal gynecological malignancy in the United States with high morbidity and mortality due to recurrence and chemoresistance. Our data suggest tumor-initiating cells (TICs) play an important role in disease biology. We previously showed that a subset of ovarian cancer cells depends on NF-kappaB signaling, and that expression of NF-kappaB proteins is associated with poor survival. Given that NF-kappaB expression correlates with a poor outcome in ovarian cancer, and NF-kappaB activity supports drug resistance and tumorigenicity, we hypothesize that NF-kappaB supports a TIC program responsible for ovarian cancer relapse. To investigate this pathway in TICs, we designed a novel method to enrich for TICs from cell lines and patient samples by culturing non-adherent, floating cells in stem cell conditions defined by low attachment flasks and serum free media. Preliminary data confirm that these cells have higher stem cell marker expression, are chemoresistant, and are more tumorigenic in nude mice compared to their adherent counterparts. These TIC-enriched culture conditions enhance NF-kappaB expression and activity. More specifically, alternative NF-kappaB signaling through the RelB transcription factor supports TIC populations by regulating aldehyde dehydrogenase (ALDH), an enzyme with high activity in TICs. Using an inducible shRNA targeting RelB we show that spheroid formation, ALDH expression and activity, chemoresistance, and tumorigenesis in both subcutaneous and intrabursal xenograft models, significantly decreased in the absence of RelB. Interestingly, loss of classical NF-kappaB signaling, through an shRNA targeting the RelA transcription factor, was less effective in targeting TICs, but more effective at targeting a proliferative subpopulation with high Ki67 staining. We conclude that classical and alternative NF-kappaB signaling support ovarian tumor cells with distinct phenotypes and the collaboration of these pathways may be critical for supporting tumor repopulation following chemotherapy. Current studies will measure system level changes induced by these shRNAs, and identify a gene signature specific to each NF-kappaB pathway in ovarian TICs. Clarifying the nuances of NF-kappaB signaling in TICs will increase our understanding of ovarian cancer recurrence and further focus therapeutic strategies to prevent relapse. Citation Format: Carrie D. House, Elizabeth A. Jordan, Christina M. Annunziata. NF-KAPPAB CLASSICAL VERSUS ALTERNATIVE PATHWAYS SUPPORT DISTINCT POPULATIONS OF OVARIAN CANCER TUMOR-INITIATING CELLS [abstract]. In: Proceedings of the 11th Biennial Ovarian Cancer Research Symposium; Sep 12-13, 2016; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(11 Suppl):Abstract nr AP13.
Improved posttransplant mortality after share 35 for liver transplantation
Authors: Allison J. Kwong, Aparna Goel, Ajitha Mannalithara, W. Ray Kim
Journal: Hepatology (2017)

The Share 35 policy was implemented in June 2013 to improve equity in access to liver transplantation (LT) between patients with fulminant liver failure and those with cirrhosis and severe hepatic decompensation. The aim of this study was to assess post‐LT outcomes after Share 35. Relevant donor, procurement, and recipient data were extracted from the Organ Procurement and Transplantation Network/United Network for Organ Sharing database. All adult deceased donor LTs from January 1, 2010, to March 31, 2016, were included in the analysis. One‐year patient survival before and after Share 35 was assessed by multivariable Cox proportional hazards analysis, with adjustment for variables known to affect graft survival. Of 34,975 adult LT recipients, 16,472 (47.1%) were transplanted after the implementation of Share 35, of whom 4,599 (27.9%) had a Model for End‐Stage Liver Disease (MELD) score ≥35. One‐year patient survival improved from 83.9% to 88.4% after Share 35 ( P &lt; 0.01) for patients with MELD ≥35. There was no significant impact on survival of patients with MELD &lt;35 ( P = 0.69). Quality of donor organs, as measured by a donor risk index without the regional share component, improved for patients with MELD ≥35 ( P &lt; 0.01) and worsened for patients with lower MELD ( P &lt; 0.01). In multivariable Cox regression analysis, Share 35 was associated with improved 1‐year patient survival (hazard ratio, 0.69; 95% confidence interval, 0.60‐0.80) in recipients with MELD ≥35. Conclusion: Share 35 has had a positive impact on survival after transplantation in patients with MELD ≥35, without a reciprocal detriment in patients with lower acuity; this was in part a result of more favorable donor–recipient matching. (H epatology 2018;67:273‐281).
Effect of Race and Ethnicity on Outcomes With Drug-Eluting and Bare Metal Stents
Authors: Robert S. Kumar, Pamela S. Douglas, Eric D. Peterson, Kevin J. Anstrom, David Dai, J. Matthew Brennan, Peter Y.M. Hui, Michael E. Booth, John C. Messenger, Richard E. Shaw
Journal: Circulation (2013)

Black, Hispanic, and Asian patients have been underrepresented in percutaneous coronary intervention clinical trials; therefore, there are limited data available on outcomes for these race/ethnicity groups.We examined outcomes in 423 965 patients in the National Cardiovascular Data Registry CathPCI Registry database linked to Medicare claims for follow-up. Within each race/ethnicity group, we examined trends in drug-eluting stent (DES) use, 30-month outcomes, and relative outcomes of DES versus bare metal stents. Overall, 390 351 white, 20 191 black, 9342 Hispanic, and 4171 Asian patients > 65 years of age underwent stent implantation from 2004 through 2008 at 940 National Cardiovascular Data Registry participating sites. Trends in adoption of DES were similar across all groups. Relative to whites, black and Hispanic patients undergoing percutaneous coronary intervention had higher long-term risks of death and myocardial infarction (blacks: hazard ratio, 1.28; 95% confidence interval, 1.24-1.32; Hispanics: hazard ratio, 1.15; 95% confidence interval, 1.10-1.21). Long-term outcomes were similar in Asians and whites (hazard ratio, 0.99; 95% confidence interval, 0.92-1.08). Use of DES was associated with better 30-month survival and lower myocardial infarction rates compared with the use of bare metal stents among all race/ethnicity groups except Hispanics, who had similar outcomes with DES or bare metal stents.Black and Hispanic patients undergoing percutaneous coronary intervention had worse long-term outcomes relative to white and Asian patients. Compared with bare metal stent use, DES use was generally associated with superior long-term outcomes in all racial and ethnic groups, although these differences were not statistically significant in Hispanic patients.