tbuckley/cabot-search huggingface dataset:
Examining screening behaviors at a high-risk ovarian cancer clinic.
Authors: Courtney Lynam-Scherr, Kisha T Hope, Irene B. Helenowski, Masha Kocherginsky, Melissa Keene, Anna Everett Strohl, Charlotte Marshall-Fricker, Xiaoyue Mona Guo, Shohreh Shahabi, Lee P Shulman
Journal: Journal of Clinical Oncology (2017)

e13047 Background: Women with deleterious BRCA1/2mutations have a significantly increased lifetime risk to develop ovarian cancer. Prophylactic surgery can significantly reduce ovarian cancer risk. The Northwestern Ovarian Cancer Early Detection and Prevention Program (NOCEDPP) was established to monitor this high-risk population prior to risk-reducing surgery. For such patients, providers in the NOCEDPP recommend screening with CA-125 and transvaginal ultrasound (TVUS) biannually. The aim of this study was to examine screening rates of women who have not had surgery but attend the NOCEDPP. Methods: We reviewed electronic health records of 1,662 women who attended the NOCEDPP clinic between October 2005 – October 2015. Demographic and clinical characteristics and utilization of screening were analyzed retrospectively using descriptive statistics and Kruskal-Wallis H-tests to examine differences in screening rates by age, race, ethnicity and insurance type. Results: Of the 1,662 women initially identified, 385 had a known BRCA mutation, 303 had an appointment with at least 6 months between first and last procedure – the sample included in the final analysis. Compared with women ages 35-45 (median = 1.91) and 45+ (median = 1.18), women ages 20-35 attended the most screenings per year (median = 2.12) p = 0.001, a rate consistent with biannual recommendations. There were no significant differences in screening rate by race, ethnicity, or insurance coverage. Conclusions: Despite changes in national guidelines, providers in our high-risk clinic continue to recommend CA-125 and TVUS biannually. Our preliminary data indicates patients’ attendance is uninfluenced by race, ethnicity, or insurance coverage. Further exploration of the impact of age is warranted. Implication of findings indicate a high-risk clinic may positively impact screening behaviors above and beyond factors typically associated with non-adherence.
Global gene expression profiling of mucinous ovarian tumors and cystadenomas identifies genes of clinicopathologic importance
Authors: Fred W. A. Wamunyokoli, Tomas Bonome, Ji-Young Lee, Colleen M. Feltmate, William R. Welch, Mike Radonovich, Cindy Pise-Masison, John Brady, Ke Hao, Ross S. Berkowitz, Samuel Mok, Michael J. Birrer
Journal: Cancer Research (2006)

Proc Amer Assoc Cancer Res, Volume 47, 2006

4507 

The poor prognosis of patients with mucinous ovarian cancer remains a challenge to gynecologic oncologists, as these patients often present with aggressive chemo-resistant disease. In order to understand the molecular mechanisms contributing to the clinicopathological characteristics of mucinous ovarian carcinoma, we carried out gene expression profiling of 19 microdissected tumors (10 LMP and 9 adenocarcinoma), as well as 6 microdissected mucinous cystadenomas, using Affymetrix U133 Plus 2.0 oligonucleotide microarrays. Hierarchical clustering and binary tree prediction analysis were used to determine the relationships among normal ovarian surface epithelium, mucinous specimens, and a series of previously profiled microdissected serous tumors. PathwayAssist software was used to identify putative signaling pathways involved in the development of mucinous ovarian tumors (both LMP and adenocarcinomas). A comparison of the gene profiles between mucinous tumors and normal ovarian epithelium identified 2916 and 1765 differentially expressed in genes (p-value <0.001 with a 95% probability of identifying less than 10% false discoveries) in LMP and grade 1 and 2 adenocarcinomas, respectively. Hierarchical clustering revealed a close association between the mucinous tumors and serous adenocarcinomas, with the mucinous LMP tumors grouping independently of the serous LMP specimens. Binary tree analysis confirmed the clustering relationships for the mucinous tumors as compared to their serous counterparts. Furthermore, mucinous cystadenoma expression profiles were similar to mucinous LMP and adenocarcinomas specimens. PathwayAssist analysis identified co-regulated genes involved in drug resistance in both mucinous LMP tumors and adenocarcinomas. In addition, genes involved in cytoskeletal regulation were specifically up regulated in the mucinous adenocarcinomas. Our findings resolve the relationships among mucinous and serous tumors, and identify clinicopathologic features defining mucinous ovarian tumors
In silico analysis of a multifactorial consensus signature (ConSig) for predicting response to anthracycline (A)-based neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) patients (pts).
Authors: Natalie Heather Turner, Mattia Forcato, Simona Nuzzo, Luca Malorni, Silvio Bicciato, Angelo Di Leo
Journal: Journal of Clinical Oncology (2014)

1025 Background: There are no validated predictive biomarkers for A response. While A is effective therapy in some, many breast cancer pts do not benefit. Due to the complex processes required for A-induced cytotoxicity, a prospectively defined multifactorial consig may improve prediction of A sensitivity in TNBC pts, a group whose only standard systemic treatment option is chemotherapy. Methods: ConSigs were constructed using various combinations of components (genes/gene signatures) that were based on five steps required for A function: drug penetration, nuclear topoisomerase IIα (topoIIα) protein location, increased topoIIα mRNA expression, induction of apoptosis, and immune response. The performance of each ConSig to predict pathologic complete response (pCR) in TNBC pts treated with A without taxane (T) NAC was assessed by in silico analyses of publicly available gene expression data. Correlation between ConSig expression and pCR was evaluated using ROC analyses. To assess specificity for A, ConSigs were reassessed in pts receiving A + T NAC. Results: 147 TNBC pts treated with A without T and with gene expression data derived using the same platform (Affymetrix HG-U133) were identified, 28 with pCR. Single components significantly correlated with pCR were drug penetration measured by HIF1α signature (AUC 0.64, p=0.005), nuclear topoIIα location measured by LAPT4MB mRNA (AUC 0.61, p=0.03) and immune response measured by STAT1 signature (AUC 0.65, p=0.03). The most powerful combination for prediction of A response was ConSig1, which included these three components plus topoIIα mRNA. It performed better than single components, showing higher correlation with pCR (AUC 0.71, p=5.3x10-6), high negative value (NPV) value and high odds ratio (OR) for no pCR (see Table). ConSig1 was A-specific with no correlation with response seen in pts treated with A + T. Conclusions: With further validation, ConSig1 may allow improved selection of TNBC pts for A treatment. Cohort Performance of ConSig1 NPV (95% CI) OR P value A (n=147) 93% (84%-98%) 5.53 0.001 A + T (n=301) 67% (58%-75%) 1.04 0.85
Multicenter Phase II Trial of 90Y-Ibritumomab Tiuxetan with High-Dose Chemotherapy (Busulfan/Cyclophosphamide/Etoposide) Followed by Autologous Stem Cell Transplantation in Relapsed, Refractoried, or High-Risk B-Cell NHL.
Authors: Byung Woog Kang, Jae-Cheol Jo, Shin Kim, Geundoo Jang, Sung Sook Lee, Sun Jin Sym, Jin-Sook Ryu, Won Seog Kim, Sung Soo Yoon, Cheolwon Suh
Journal: Blood (2007)
Linker-free covalent immobilization of heparin, SDF-1α, and CD47 on PTFE surface for antithrombogenicity, endothelialization and anti-inflammation
Authors: Ang Gao, Ruiqiang Hang, Wan Li, Wei Zhang, Penghui Li, Guomin Wang, Long Bai, Xue-Feng Yu, Huaiyu Wang, Liping Tong, Paul K. Chu
Journal: Biomaterials (2017)
Prognostic impact of androgen receptor (AR) and forkhead box A1 (FOXA1) in early HER2-negative primary breast cancer: A translational substudy of the prospective phase III WSG-PlanB-trial.
Authors: Tom Degenhardt, Hans Heinrich Kreipe, Oleg Gluz, Ronald E. Kates, Cornelia Liedtke, Stefan Kraemer, Michael R. Clemens, Benno Nuding, Toralf Reimer, Bahriye Aktas, Sherko Kummel, Marianne Just, Fatemeh Lorenz-Salehi, Christoph Uleer, Andrea Stefek, Volker Heyl, Rachel Wuerstlein, Ulrike Nitz, Nadia Harbeck, Matthias Christgen
Journal: Journal of Clinical Oncology (2016)

557 Background: AR and FOXA1 have been associated with better prognosis and may play a role as molecular targets in early breast cancer (EBC). This analysis presents the largest dataset of a prospective Phase III study analyzing the prognostic impact of AR and FOXA1: WSG PlanB recruited 3198 patients with HER2-negative EBC (2009-11). Patients with HR+/HER2-, pN0-1 EBC and RS<11 were recommended to omit chemotherapy; 2448 patients were randomized for an anthracycline-taxane-based therapy (4xEC-4xDoc) vs. an anthracycline-free regimen (6xTC). Methods: Tumor samples were analyzed centrally for ER, PR, Ki67 (cut-off 20% for Luminal-B-like EBC), and histological grade. AR and FOXA1 were assessed on tissue microarrays according to the immunoreactive score (IRS), which utilizes proportion of tumor cells expressing AR (or FOXA1) and intensity of staining. An IRS score of 3 or more was considered as positive. Univariate Cox analysis was performed to evaluate the association between AR, FOXA1, AR+/FOXA1+ and event-free-survival (EFS). Results: Median follow-up was 55 months. Using the central tumor bank, AR was available for 2896 patients, FOXA1 for 2911 patients, and both markers for 2847 patients of the study. Univariate Cox analysis revealed a significant favorable impact of AR+, FOXA1+, and AR+/FOXA1+ on EFS in the whole study population (p<0.05), and in the HR+-subgroup (p=0.012, p=0.025, p=0.018). FOXA1 showed a significant association with EFS in Luminal-B-like subtype (p=0.048). Furthermore, there was a significant positive association between AR+/FOXA1+ and EFS in Luminal A disease (p=0.033). Conclusions: This WSG PlanB translational substudy showed a significant favorable impact of AR+, FOXA1+ and the combination AR+/FOXA1+ on EFS after 55 months median follow-up in all patients and within the HR+ subgroup. It may thus provide a rationale for future AR-targeted therapy approaches in EBC. Clinical trial information: NCT01049425.Distribution of AR/FOXA1. AR + AR - AR+/FOXA1 + AR or FOXA1 - FOXA1 + FOXA1 - HR + 22.9% 77.1% 19.4% 80.6% 60.7% 39.3% TNBC 4% 96% 2.5% 97.5% 6.3% 93.7% LuminalA 22.5% 77.5% 22.5% 77.5% 65.8% 34.2% LuminalB 21.6% 78.4% 18.2% 81.8% 60% 40%
Targeting myeloid derived suppressor cells: Phase 0/1 trial of low dose capecitabine + bevacizumab in patients with recurrent glioblastoma.
Authors: David M. Peereboom, Justin D. Lathia, Tyler Alban, Maksim Sinyuk, Manmeet Singh Ahluwalia, Alireza Mohammad Mohammadi, Cathy J. Brewer, Michael A. Vogelbaum
Journal: Journal of Clinical Oncology (2017)

e13507 Background: Glioblastoma (GBM) creates an immunosuppressive environment that allows tumor growth. Myeloid derived suppressor cells (MDSCs), a heterogeneous class of immunosuppressive cells, mediate immune suppression in GBMs. MDSCs are up-regulated in the blood of patients with GBM and multiple other tumor types. We have developed a novel strategy to target GBM immunosuppression using low dose 5-fluorouracil (5-FU) that, targets immune cells and does not depend on blood brain or blood tumor barrier penetration. Marked MDSC depletion occurs at 5-FU doses in mice equivalent to &lt; 10% of the normal human dosing. Goal: proof of concept that MDSC suppression in feasible in GBM pts with low-dose capecitabine [cap], an oral 5-FU analogue). Methods: Eligibility: Recurrent GBM in need of surgical resection; no prior cap or bevacizumab (bev). Cohorts of 3-6 patients receive low-dose cap 150 mg/m2/d (dose level [DL] 1) for 7 days before surgery. After surgery, patients resume cap for one cycle after which bev is added. Blood MDSC, immune cell levels, and relevant secreted factors are measured at baseline; pre- and post-op; and after the addition of bev. Tumors are assayed for MDSCs and glioma stem-like cells (GSCs). Primary endpoint: MDSC and T-Regulatory cell reduction after cap. Secondary endpoints: Tumor concentrations of MDSCs, GSCs, and T-reg cells; safety; and PFS6. Results: Three of the 4 patients enrolled have data available. All patients received 5 days of pre-op cap at DL 1 with MDSC reductions of 20, 26, and 79% from baseline. The first patient reached a reduction of 93% (measured 2 days after pre-op course) whereas the other 2 experienced return to baseline. The regulatory T cells (T-reg) also fell approximately 15, 20, and 50%, respectively. CD8 concentrations appeared to rise at the time of MDSC and T-reg reduction. No patient experienced grade 3 or higher toxicity. Conclusions: Low dose capecitabine appears to reduce MDSC concentrations with minimal toxicity. During this course T-regs also fell and CD8 concentrations rose. Dose escalation continues. (NCT02669173) (Supported by Musella Foundation, Blast GBM, Sontag Foundation, Velosano, Mylan Pharmaceuticals) Clinical trial information: NCT02669173.
Defense mechanisms and coping style at very next diagnostic period in advanced and metastatic cancer.
Authors: Anda Natalia Ciuhu, Rodica Badica, Mihaela Popescu, Mugur Radoi, Roxana Andreea Rahnea Nita, Gabriela Rahnea Nita
Journal: Journal of Clinical Oncology (2016)

e21610 Background: In 2009, the International PsychoOncology Society endorsed distress as the sixth vital sign in cancer care, cancerrelated distress is common at pivotal periods the diagnostic, treatment, recovery, and recurrence phases. Therefore, in the Fourth Edition of the Diagnostic and Statistical Manual of Mental Disorders (DSMIV), being diagnosed with a lifethreatening illness such as cancer was included for the first time as a potential traumatic event that could induce posttraumatic stress disorder (PTSD). In illness case, most often, the patient adopt primitive defense mechanisms (regression, repression, defense denial, projection) to block disease emergence in personal destiny. The adoption of more efficient defense mechanisms (intellectualization, sublimation) takes time and psychological growing up. Methods: We analyzed patients newly diagnosed in advanced or metastatic stage of cancer admitted to our department in the last 6 months. The patients had to have indication for specific treatment,either chemotherapy or radiotherapy. It has made an initial assessment of defense mechanisms and adaptation to the disease through questionnaires and open interviews conducted by psychologist. Results: 116 of 128 patients (90.625%) are sometimes defensive and only 6.25% showed strong defensive trends.Defensive mechanisms have been identified as mainly: repression 64.06%, denial 60.93% and intellectualization 57.81%. With predilection, 32 patients (25%) used as coping style the acceptance, 39,06% used the planning and 35,93% used the active coping. Conclusions: Immediately after diagnosis and initiation of specific treatment, most patients with metastatic or advanced cancer are sometimes defensive (repression, denial and intellectualization) and used coping styles like acceptance, planning and active coping. Further research with regular reassessment of patients can bring important elements on dynamic of the adjustment process, allowing identification of external intervention methods to improve the quality of life.
Prevention of Viral Infections after T Cell Depleted Allogeneic Stem Cell Transplantation By Infusion of Multi-Antigen Specific T Cell Products
Authors: Marthe C.J. Roex, Peter Van Balen, Lois Hageman, Esther Van Egmond, Sabrina A.J. Veld, Conny Hoogstraten, Ellis van Liempt, Lothar Germeroth, Hermann Einsele, Constantijn J.M. Halkes, Inge Jedema, J.H. Frederik Falkenburg
Journal: Blood (2016)
Variation in protein-coding sequence and the genetic basis of cisplatin-induced toxicities among testicular cancer survivors (TCS) in the Platinum Study.
Authors: Eric R Gamazon, Heather E. Wheeler, Robert D. Frisina, Omar El Charif, Taisei Mushiroda, Michiaki Kubo, Shirin Ardeshir-Rouhani-Fard, Darren R. Feldman, Robert James Hamilton, David J. Vaughn, Clair J. Beard, Chunkit Fung, Sophie D. Fossa, Lawrence H. Einhorn, Nancy Cox, M. Eileen Dolan, Lois B. Travis
Journal: Journal of Clinical Oncology (2016)

1537 Background: Due to its exquisite cisplatin-sensitivity, testicular cancer is a model for the curable malignancy. However, the long-term toxicities of cisplatin-based treatment can be devastating, including chemotherapy-induced peripheral neuropathy (CIPN) and ototoxicity. Methods: Using whole exome sequencing (n = 194) and replication genome-wide association study (n = 300), we investigated the contribution of common (minor allele frequency [MAF] ≥ 5%) and low-frequency (1% < MAF < 5%) coding variants to CIPN and ototoxicity. We characterized protein-truncating variants (nonsense, frameshift, essential splice site) and missense variants predicted to be deleterious, particularly, in genes previously associated with peripheral neuropathy and Mendelian disorder-associated hearing loss. We performed the gene-based test SKAT with adjustment for genomic ancestry and cumulative cisplatin dose. Results: We identified protein-truncating variants exome-wide, including in the previously reported hearing loss genes Connexin 26 and CHD7. Application of SKAT to all variants in known autosomal hearing loss protein-coding genes (n = 41) from the Deafness Gene Mutation Database revealed a significant set-level association (p = 0.003) with ototoxicity. The top ototoxicity-associated genes from the exome-wide analysis were HOXA2, a gene associated with Microtia, hearing impairment, and cleft palate (MHICP), and MIR320A, a modulator of AQP4, a protein in the inner ear essential to hearing. CIPN-associated genes from our analysis (p < 0.001) showed greater enrichment for significant gene-level associations with ototoxicity (p < 2.2x10-16), suggesting polygenic pleiotropy for toxicity phenotypes. Conclusions: Our study, which includes the largest germline whole exome sequencing performed on TCS to date, offers key insights into the genetic architecture of cisplatin-induced toxicities and has important implications for the design of future pharmacogenetic studies of chemotherapy-induced adverse effects. Identified genes with pleiotropic effect on multiple toxicities warrant further study.
Clinical characterization of DNA mismatch repair deficiency (MMR-D) in endometrial cancer (EC).
Authors: Karen Anne Cadoo, Christina Tran, Deborah DeLair, Angela G. Arnold, Asad Ashraf, Elizabeth Lin Jewell, Noah D. Kauff, Kara Long, Jennifer Jean Mueller, Mark E. Robson, Maria Schiavone, Magan Trottier, Robert A. Soslow, Kenneth Offit, Carol Aghajanian, Zsofia Kinga Stadler
Journal: Journal of Clinical Oncology (2016)

1522 Background: MMR-D, characterized by loss of protein expression of MMR protein(s) (MLH1, MSH2, MSH6, PMS2) by immunohistochemistry (IHC) occurs in 20-25% of ECs & serves as a screening test for Lynch Syndrome (LS). MMR-D may be somatic, characterized by MLH1/PMS2 protein loss & presence of MLH1 promoter hypermethylation (MLH1-HM+) or may result from a germline mutation in a MMR gene (LS). However, a proportion of MMR-D EC patients (pts) have absence of an identifiable germline alteration & absence of MLH1-HM and are referred to as having “Lynch-like syndrome” (LLS). Clinical & family history (hx) of LLS in EC remains poorly characterized. Methods: Database review identified all MMR-D EC pts who were evaluated at MSKCC 2007-2015. Electronic medical records & progeny pedigrees were reviewed. Statistics performed via GraphPad Prism v. 6, Mann Whitney U compared median age, Fishers exact test was performed on remaining variables. Results: Of 226 MMR-D EC cases, 101 (45%) had MLH1/PMS2 loss with MLH1-HM+, 69 (31%) had LS & 56 (25%) LLS. IHC in LS pts demonstrated loss of: MSH2/MSH6, 36 (52%); MLH1/PMS2, 14 (20%); PMS2, 8 (12%); MSH6, 11 (16%) & in LLS pts: MSH2/MSH6, 23 (41%); MLH1/PMS2, 8 (14%); PMS2, 4 (7%); MSH6, 21 (38%). Germline mutations in LS pts included: MLH1, 14 (20%); MSH2, 33 (48%); MSH6, 16 (23%); PMS2, 9 (13%). Patient & family hx characteristics of LS & LLS pts are provided in the table. Conclusions: The majority of LLS EC pts have IHC MSH2/MSH6 or MSH6 loss & appear to have a weaker personal & family cancer hx compared with LS EC pts. The biology & clinical implications of MMR-D in this group is unknown & somatic mutational profiling is being undertaken to explore alternative mechanisms for MMR-D, results will be presented. LS N=69 LLS N=56 P Median age at EC (range) 50 (35-65) 53 (28-69) 0.03 N (%) N(%) Personal Hx Any second primary cancer (SPC) 35 (51) 14 (25) <0.001 LS-associated SPC 27 (39) 8 (14) <0.001 Family Hx 1o relative colon cancer 41 (59) 5 (9) <0.001 <age 50 22 (32) 0 <0.001 1o relative EC 24 (35) 3 (5) <0.001 <age 50 13 (19) 1 (2) <0.001 Any relative with LS cancer 65 (94) 35 (63) <0.001 Met Amsterdam criteria 40 (58) 6 (11) <0.001 Met Bethesda criteria 27 (39) 8 (14) <0.001 Met Bethesda criteria if EC <50 yr included 48 (70) 25 (45) <0.001
Estrogen receptor α phosphorylated at Ser<sup>167</sup>: Distribution and prognostic implications in endometrial cancer.
Authors: Yoshio Yoshida
Journal: Journal of Clinical Oncology (2012)

e15539 Background: Both ligand-dependent and ligand-independent activation of estrogen receptor (ER)α is modulated by receptor phosphorylation, which is enhanced by ligand binding. Similar to Akt, ERα is activated through phosphorylation at Ser 167 , resulting in activation of the ERα-dependent pathways that are involved in endometrioid endometrial cancer (EEC) pathogenesis. It is known that the mammalian target of rapamycin (mTOR)/p70 S6 kinase 1 (S6K1) and mitogen-activated protein kinase (MAPK)/p90 ribosomal S6 kinase (RSK) signaling pathways coordinately regulate phosphorylated- (p-) ERα. The purpose of this study was to determine the importance of Ser 167 phosphorylation in EEC progression. Methods: Immunohistochemical staining of primary EEC surgical specimens (n=103) was carried out using antibodies specific for p-ERα and for p-Akt, p-mTOR/S6K1 and p-MAPK/RSK. and for p-Akt, p-mTOR/S6K1 and p-MAPK/RSK. Results: Patients positive for nuclear Ser 167 phosphorylation had significantly shorter relapse free survival. Althoughthe result was not significant, levels of nuclear p- tended to be higher in advanced-stage ECC patients. Nuclear p-ERα was significantly positively correlated with p-MAPK and p-S6K1. Conclusions: The amount of nuclear ERa Ser 167 phosphorylation is associated with p-MAPK and p-S6K1, and may be important in EEC progression and outcome.