tbuckley/cabot-search huggingface dataset:
Is it time to change the primary endpoint in clinical trials in recurrent ovarian cancer (ROC)?: Symptom burden and outcomes in patients with platinum resistant/refractory (PRR) and potentially platinum sensitive ROC receiving ≥ 3 lines of chemotherapy (PPS ≥ 3)—The Gynecologic Cancer Intergroup (GCIG) Symptom Benefit Study (SBS).
Authors: Michael Friedlander, Martin R. Stockler, Rachel O'Connell, Florence Joly, Anne Lanceley, Felix Hilpert, Aikou Okamoto, Eriko Aotani, Sandro Pignata, Paul P. Donnellan, Amit M. Oza, Elisabeth Avall-Lundqvist, Jonathan S. Berek, Katrin Marie Sjoquist, Kim Gillies, Phyllis Butow, Madeleine Trudy King
Journal: Journal of Clinical Oncology (2015)

5536 Background: The primary endpoint for clinical trials in PRR/PPS ≥ 3 ROC is progression free survival (PFS) and symptom benefit is not typically measured or reported. The primary aim of GCIG SBS is to validate a patient-reported outcome measure (PROM), the MOST (Measure of Ovarian Symptoms and Treatment concerns), to assess symptom benefit from palliative chemotherapy (PC). The SBS recruited 949 patients; the secondary aims provide insights into symptom burden, patients’ and clinician’s expectations of treatment and outcomes in a “real world” setting. Methods: Patients with PRR/PPS ≥ 3ROC completed 4 PROMs before each cycle of chemotherapy. They reported expectation of symptom improvement. Clinicians documented the indications for PC, symptoms at baseline, adverse events and estimated the number of cycles patients would receive. Results: Palliation was the major indication for chemotherapy. The mean number of prior regimens was 2.6 (range 1-10). 60% of patients had PRR and 40% had PPS > 3 ROC. At baseline, most patients were symptomatic; 75% rated at least one symptom as moderate (³5 on a 0-10 scale) and 30% rated > 5 symptoms as moderate or worse. The symptoms included pain, fatigue, anorexia, abdominal distension, dyspnea, and constipation. Many had symptoms related to prior chemotherapy (e.g. neuropathy in 28%). Most patients had high expectations of symptom benefit from chemotherapy. 36% of patients received the predicted number of cycles. 25% of patients with PRR-ROC stopped treatment in < 8 weeks mainly due to progression/death. The median number of cycles and median PFS were 4 and 5.6m in PPS≥3ROC, and 3 and 3.7m in PRR ROC respectively. Conclusions: Patients with PRR/PPS ≥ 3ROC reported a number of significant baseline symptoms. They had high expectations of symptom improvement and this should be measured. The results underscore the importance of incorporating PROMs and including symptom benefit as primary endpoints in trials in patients with PRR/PPS ≥ 3 ROC. Clinical trial information: ACTRN12607000603415.
Gastrointestinal stromal tumors: Immune protein expression and clinical outcomes.
Authors: Andrew M. Blakely, Andres Matoso, Thomas J. Miner
Journal: Journal of Clinical Oncology (2017)

124 Background: The immune microenvironment is emerging as an important prognostic factor with potential therapeutic targets for various malignancies. Although programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase (IDO) have been studied in some tumor types, significance of their expression in gastrointestinal stromal tumors (GISTs) is largely unknown. Methods: Tissue microarrays at an academic tertiary care center were constructed from pathology files from 1996 to 2016. Immunohistochemistry for PD-L1 and IDO was performed and correlated with tumor size, mitoses, and clinical outcomes. Tumor infiltrating lymphocytes (TILs) were counted using image analysis software. Results: 131 GISTs were analyzed. Median patient age was 64 years (range 30-89); 51.1% were male. Tumor location included 89 stomach (67.9%), 34 small bowel (26.0%), 4 colorectal (3.1%), and 4 other (3.1%). Median follow-up was 58 months. Mean tumor size was 5.6±4.5cm, range 0.5 to 24; mean mitoses were 7.2/50HPF. 19 (14.5%) metastasized to mesentery (n = 8), liver (n = 6), and elsewhere (n = 5). Mean survival was 61 months (range 7-127); 5 patients died of disease (3.8%). PD-L1 immunostain was positive in 89 (67.9%), including 11 of 19 (57.9%) malignant and 78 of 112 (69.6%) benign tumors (p = 0.4). PD-L1 positive tumors were larger (6.3±4.4 vs. 4.4±3.4 cm; p = 0.02) and had more mitoses/50HPF (8.9±5.4 vs. 3.9±3.5; p = 0.006) than PD-L1 negative tumors. IDO immunostain was positive in 116 (88.5%), including 14 of 19 (73.7%) malignant and 102 of 112 (91.1%) benign tumors (p = 0.07). There was no significant difference in size or mitotic count between IDO positive and negative tumors. Mean number of CD8-positive TILs was 168±35/mm2 and mean number of PD-L1 positive TILs was 147±28/mm2 in PD-L1 positive tumors. PD-L1 positive tumors had significantly more TILs than PD-L1 negative tumors (113±21 vs. 104±18; p &lt; 0.001). Conclusions: The majority of GISTs express PD-L1 and IDO. Expression of PD-L1 was associated with increased tumor size and higher mitotic activity. PD-L1 and IDO could play a significant role in the tumor biology of GISTs; immunotherapy targeting one or both may provide novel treatment options.
Secondary cancers in long-term survivors of primary glioblastoma.
Authors: Jung-Young Kim, Sarah Woodring, Mary Lou Affronti, Dina Randazzo, Frances McSherry, James Emmett Herndon, Eric S Lipp, Annick Desjardins, Gordana Vlahovic, Henry S. Friedman, Katherine B. Peters
Journal: Journal of Clinical Oncology (2015)

e20616 Background: Overall survival in primary glioblastoma (GBM) has been poor with 5% at 2 years, but recent advances have improved overall survival in this population. Long-term survivors (LTS), while rare, can now be identified and evaluated. Similar to LTS of other primary cancers, there is a probable risk of secondary neoplasms and this has been well-documented in not only adults with primary cancers but also in survivors of childhood cancer. Therefore, we sought to investigate the risk of secondary neoplasms from our unique cohort of primary GBM LTS. Methods: In a single-center retrospective study, we evaluated over 9,000 records from January 1, 1998 to February 8, 2010 to identify adult primary GBM patients that survived ≥ 5 yrs and these were defined as LTS. Results: As of January 28, 2014, we identified 155 LTS of primary GBM with a median OS of 11.0 years (95% CI 9.0-13.1 years) and a median follow-up of 9.6 years (95% CI 8.7-10.7 years). Among these 155 patients, we evaluated any diagnosis of cancer at least two years after the original diagnosis of primary GBM. Seventeen new and/or secondary cancers were identified in 13 LTS. Of these 17 cancers, 8 could be attributed to previous treatment with radiation and chemotherapy (skin cancer in radiation field (n = 4), leukemia (n = 2), low-grade glioma (n = 1), and sarcoma of the scalp (n = 1)). The other 9 cases included melanoma (n = 3), prostate cancer (n = 2), bladder cancer (n = 1), endometrioid adenocarcinoma (n = 1), basal cell carcinoma (n = 1), and renal cell carcinoma (n = 1). For the 13 LTS with new/secondary cancer, their mean age at GBM diagnosis was 52.9 years (sd = 11.6 years) and at new/secondary cancer was 60.0 years (sd = 11.03 years). Median time from GBM diagnosis to new/secondary cancer diagnosis was 7.8 years (range, 2.68 to 11.49 years). Conclusions: While there were few cases of new/secondary cancers, there is likely under-reporting of these cancers due to lack of long-term follow-up in LTS. We conclude that secondary cancers are a rare occurrence in GBM LTS, but despite this, continued close monitoring with appropriate specialized oncologic care is warranted. Moreover, this highlights the need for continued survivorship care of rare cancers such as primary GBM.
Intraoperative radiotherapy (IORT) impairs surgical wound-stimulated breast cancer cell invasion
Authors: G. Baldassarre, B. Belletti, J. S. Vaidya, S. D'Andrea, M. Roncadin, T. Perin, M. G. Trova, E. Candiani, A. Veronesi, A. Colombatti, S. Massarut
Journal: Journal of Clinical Oncology (2007)

21139 Background: Risk of local recurrence after complete excision of breast cancer is higher in the area around the original tumor, suggesting that wound healing may be implicated. Methods: We collected blood samples (BS) before surgery and wound fluid (WF) in the 24 hours after breast conserving surgery from 50 patients. Twenty five of these patients were also treated with TARGeted Intraoperative radioTherapy (TARGIT, 20Gy to tumor bed surface in one session), immediately after the surgical excision. The ability of the BS and WF to stimulate growth and motility of a panel of normal and mammary carcinoma cells was studied. A proteomic approach was used to analyze the expression pattern of WF and BS. Results: We assayed five cell lines in a transwell based assay using individual patient BS and wound fluids WF as potential chemo-attractants. WF strongly attracted cells from all 5 types of breast cancer cell lines that we tested including MDA- MB 231, MCF-7, MDA-MB 453, T47D and SKBR-3. The WF attracted the cells better than both the respective BS. Importantly, in all tested cell lines TARGIT significantly impaired the ability of WF to attract cancer cells (p=0.03 MDA-MB 231 and MCF-7. p=0.01 for MDA-MB 453, and SKBR-3). Moreover, while BS did not stimulate 3D motility over the control WF strongly stimulated 3D movement of MDA-MB 231 and MDA-MB- 453 cells. This stimulatory effect was abrogated in the WF taken from patients who had received TARGIT (p=0.01 for MDA-MB 231 and p&lt;0.0001 for MDA-MB 453). Similar results were obtained when cell proliferation was evaluated using the same cell lines and BS or WF samples. Finally, proteomics analyses demonstrated that TARGIT modifies the expression levels of several key proteins involved in tumor cell growth and dissemination. Conclusion: TARGIT delivered to the tumor bed alters the cytokines and growth factors expression patterns in the surgical wound and abrogates its stimulatory effect on cancer cell growth and motility. This novel mechanism of action of radiotherapy could partly explain the very low recurrence rates found in large pilot studies of this technique and open new avenues for peri-operative therapies. No significant financial relationships to disclose.
Intracranial hemorrhage in patients with atrial fibrillation receiving anticoagulation therapy
Authors: Renato D. Lopes, Patrícia O. Guimarães, Bradley J. Kolls, Daniel M. Wojdyla, Cheryl D. Bushnell, Michael Hanna, J. Donald Easton, Laine Thomas, Lars Wallentin, Sana M. Al-Khatib, Claes Held, Pedro Gabriel Melo de Barros e Silva, John H. Alexander, Christopher B. Granger, Hans-Christoph Diener
Journal: Blood (2017)
Early negative circulating EBV DNA as prediction of survival in extranodal NK/T-cell lymphoma, nasal type (ENKL).
Authors: Chaoyong Liang, He Huang, Chengcheng Guo, Ying Tian, Xueying Li, Mengping Zhang, Huang Ming Hong, Xiaohong Fu, Xiaoting Lin, Shanshan Li, RM BEI, Zhao Wang, Xiaojie Fang, Tongyu Lin
Journal: Journal of Clinical Oncology (2014)

8562 Background: Predictive tumor markers are essential for extranodal NK/T cell lymphoma, nasal type (ENKL), which pursues an aggressive clinical course with poorer prognosis. This prospective study was conducted to evaluate the dynamic monitoring value of circulating EBV DNA concentration for the prediction of ENKL. Methods: From Jan 2006 to Aug 2012, plasma samples from 113 ENKL pts were collected before and/or every 2 cycles of chemotherapies for circulating EBV DNA measurement by a real-time PCR assay. Results: The positive rate of circulating EBV DNA was 61.9% (70/113) with a median concentration of 1.21×103copies/ml. After two cycles of chemotherapies, 45 pts were tested circulating EBV-DNA and 53.33% (24/45) pts became negative EBV-DNA candidates. There were 87.5% (21/24) pts obtained complete remission at the end of the treatment, comparing as 42.86% (9/21) in the still positive EBV-DNA groups(P= 0.002). There was a tendency that the pts whose circulating EBV-DNA became negative after two cycles would have better prognosis (5-year OS: 75% vs 46%, P=0.074). The similar situation of CR rate and OS happened in the EBV-DNA detection of completion of total chemotherapies. The more advance of the stage, the higher concentration of EBV-DNA was found. When divided the positive group as low and high-dose ones by the cut-off value as 2×104copies/ml, the CR rate of the high-dose group was much lower and the 5-year OS was significantly better than the low-dose group and the negative group.7 of 13 relapsed pts of >1×103copies/ml EBV-DNA at the time of recurrent, and the survival outcome was dismal for them compared to the other 6 pts of ≤1×103copies/ml(5- year OS: 0% vs 80%, P=0.001). Conclusions: Circulating EBV-DNA level can predict the efficacy of treatment as a dynamic marker of ENKL. Pts with early positive detection of EBV-DNA after 2 cycles of chemotherapy maybe received more aggressive treatments.
Insurance status as a strong predictor of outcome in triple-negative breast cancer (TNBC): A multi-institutional retrospective study.
Authors: Tithi Biswas, Shreya Prasad, Timothy Zagar, Jimmy Efird, Sarah E. James, Paul R. Walker, Rachel Elizabeth Raab, Lisa A. Carey, Lawrence B. Marks
Journal: Journal of Clinical Oncology (2013)

1069 Background: TNBC accounts for about 15-20% of all breast cancer. TNBC has particularly aggressive clinical course and accounts for a disproportionate number of breast cancer relapses and deaths in early stage disease. TNBC also have worse prognosis especially in African American (AA) women compared with white women. This retrospective study aims to investigate various clinical and demographic prognostic factors in TNBC. Methods: 476 TNBC patients who were treated at Eastern Carolina University and University of North Carolina, CH between 4/96 and 9/11 were included in this analysis. We collected data on age, race, grade, lymphovascular invasion (LVI), stage, treatments including surgery, chemotherapy, radiation, chemotherapy drugs, insurance type and year of treatment. Overall Survival (OS) was computed from the date of diagnosis to the date of death or last FU. For disease free survival (DFS), patients were scored if they failed either locally or distally. The Cox proportional-hazards regression model was used to compute hazard ratios. Results: The median age was 52 years (21-88 years) with median FU of 3.7 years. 49% women were white race followed by AA 223 (47%) and Hispanic or other race (5%). Stage (p&lt;0.001), grade (p=0.02), surgery (p&lt;0.0001), adjuvant chemotherapy (p=0.025), LVI (p=0.05) and type of insurance were significant predictor of OS. Similarly, stage (p&lt;0.0001), surgery (p&lt;0.0001), LVI (p=0.03) and insurance were significant predictors for DFS. On multivariate analysis, stage, surgery and adjuvant chemotherapy remained statistically significant predictors. Medicaid vs. Private Insurance also remained a significant detriment of survival (OS: HR=3.6, p&lt;0.0001; DFS: HR=2.8, p&lt;0.0001) as did having No Insurance for OS (HR=2.0, p=0.0074). Conclusions: To our knowledge, this is a largest retrospective study showing type of insurance to be a strong predictor of outcome in this very specific breast cancer subtype which remained significant after adjusting all other variables. Further insight is needed to determine the cause of this finding.
Indomethacin to inhibit AKR1C3 intracrine androgen production and sensitizes prostate cancer (PCa) to enzalutamide.
Authors: Chong-xian Pan, Chengfei Liu, Primo Lara, Christopher P. Evans, Marc Dall'Era, Stanley Yap, Wei Lou, Allen Gao
Journal: Journal of Clinical Oncology (2017)

161 Background: Enzalutamide (Enza) improves the treatment of metastatic castration-resistant PCa (mCRPC). Acquired resistance is the most common cause of treatment failure. Our objective was to determine mechanisms of resistance to Enza and develop novel therapy to overcome resistance. Methods: Enza-resistant PCa cells were established through continuous culture of C4-2B cells with Enza. Global gene expression array and western blots were used to assess gene expression in cell lines and validated in clinical specimens using Oncomine and GEO databases. The therapeutic effects of indomethacin were determined in cell culture and in mice carrying CWR22Rv1 xenografts. A Phase I/II clinical trial with Enza plus indomethacin has been approved by IRB. Results: Steroid biosynthesis pathways, especially AKR1C3, were significantly elevated in Enza resistant cells and was associated with high production of androgens. AKR1C3 was also highly expressed in metastatic and recurrent CaP and in Enza-resistant xenograft tumors. Overexpression of AKR1C3 conferred resistance to Enza. Inhibition of AKR1C3 expression by its specific shRNAs or AKR1C3 enzymatic activity by indomethacin re-sensitized Enza-resistant CaP cells to Enza treatment both in vitro and in vivo. Combination of indomethacin and Enza resulted in significant inhibition of Enza-resistant tumor growth. Indomethacin treatment in one patient with mCRPC induced tumor shrinkage and PSA decrease. In a Phase I/II trial funded by the Department of Defense, patients with mCRPC, good performance status (ECOG 0-2) and vital organ function, and no history of Enza or indomethacin treatment will be recruited. The co-primary objective is to assess the toxicity and prostate-specific antigen (PSA) response ( ≥ 50% reduction). We will also assess the overall response as determined by the Prostate Cancer Working Group 2 criteria, progression-free survival and molecular correlative studies. Conclusions: AKR1C3 activation is a critical resistance mechanism associated with Enza resistance. Indomethacin targets AKR1C3 and intratumor androgen synthesis, and can be potentially used as a therapeutic agent for mCRPC. Clinical trial results will be presented. Clinical trial information: to be registered.
Developmental alterations in Huntington's disease neural cells and pharmacological rescue in cells and mice
Authors: Ryan G Lim, Lisa L Salazar, Daniel K Wilton, Alvin R King, Jennifer T Stocksdale, Delaram Sharifabad, Alice L Lau, Beth Stevens, Jack C Reidling, Sara T Winokur, Malcolm S Casale, Leslie M Thompson, Mónica Pardo, A Gerardo García Díaz-Barriga, Marco Straccia, Phil Sanders, Jordi Alberch, Josep M Canals, Julia A Kaye, Mariah Dunlap, Lisa Jo, Hanna May, Elliot Mount, Cliff Anderson-Bergman, Kelly Haston, Steven Finkbeiner, Amanda J Kedaigle, Theresa A Gipson, Ferah Yildirim, Christopher W Ng, Pamela Milani, David E Housman, Ernest Fraenkel, Nicholas D Allen, Paul J Kemp, Ranjit Singh Atwal, Marta Biagioli, James F Gusella, Marcy E MacDonald, Sergey S Akimov, Nicolas Arbez, Jacqueline Stewart, Christopher A Ross, Virginia B Mattis, Colton M Tom, Loren Ornelas, Anais Sahabian, Lindsay Lenaeus, Berhan Mandefro, Dhruv Sareen, Clive N Svendsen
Journal: Nature Neuroscience (2017)
Using adjacent to tumor samples as normal controls in molecular investigations: Are we missing the earliest biomarkers?
Authors: Williams Fernandes Barra, Fabiano Moreira, Arthur Ribeiro-dos-Santos, Sidney Santos, Andrea KCR Santos, Samia Demachki, Monica B Assumpcao, Andre Salim Khayat, Carolina Barauna Assumpcao, Ana Karyssa Anaissi, Geraldo Ishak, Pedro Antonio Mufarrej Hage, Paulo P Assumpção
Journal: Journal of Clinical Oncology (2017)

80 Background: Recently, some papers aiming to warn the scientific community regarding possible misinterpretation due to using adjacent to tumor sample tissues as normal controls were published The main motivation for these alerts was the observation of important molecular alterations in tissues nearby a cancer, although been collected from non-tumor areas. Nevertheless the cancer field hypothesis has been recognized many years ago; this concept was not incorporated to current practice in molecular investigations. In this work we aim to investigate potential implications of using adjacent to tumor sample tissues as normal controls. Methods: Gastric Cancer (GC) and Adjacent Tissues (AT) paired fresh samples of 16 patients, and 16 samples from non-cancer patients (NC) were analyzed. miRNA sequencing was performed using Illumina Miseq platform. Statistical analysis was performed in R using DESeq2 tool to identify differential expressed miRNAs. Results: Comparing GC with NC tissue samples, we observed 21 miRNAs differentially expressed (p-value &lt; 0.05 and |Log2(Fold-Change)| &gt; 2), eight were down-regulated and 13 were up-regulated in GC. Comparing AT with NC tissue samples, 16 miRNAs were differentially expressed, two were down-regulated and 14 were up-regulated in AT. In both comparisons, GC and AT samples clustered together and clearly separated from NC samples. Comparing GC with AT samples, hsa-miR-196a-5p was significantly down-regulated in GC. Conclusions: AT tissues harbor molecular alterations distinguishing them from non-cancer patient’s samples. Combined analyses of the groups clearly demonstrated that AT resembles much more cancer profile than NC patient’s tissue prolife. Using AT samples as controls might impair the discovery of possible initial molecular events identifiable exclusively by using samples from non-cancer patients. The current strategy of molecular investigation must be revised.
Retrospective study of ramucirumab in patients with advanced gastric cancer.
Authors: Daisuke Sakai, Toshihiro Kudo, Aya Kato, Koji Tanaka, Yasuhiro Miyazaki, Tomoki Makino, Tsuyoshi Takahashi, Yukinori Kurokawa, Makoto Yamasaki, Shuji Takiguchi, Masaki Mori, Yuichiro Doki, Taroh Satoh
Journal: Journal of Clinical Oncology (2017)

199 Background: Ramucirumab is a human, monoclonal antibody that specifically blocks activation of vascular endothelial growth factor (VEGF) Receptor. Ramucirumab with paclitaxel have shown the efficacy, and is recommended as second line chemotherapy in the gastric cancer treatment guideline in Japan. June 2015, ramucirumab was approved in Japan. Methods: We retrospectively investigated the efficacy and safety of ramucirumab in the patients with advanced gastric cancer in our institution from July 2015 to September 2016. Results: 50 patients were eligible. 11 patients were administered as ramucirumab monotherapy, and 39 patients were in combination with paclitaxel. 22 patients were administered as 2nd line treatment and 24 patients as third or more lines. Progression free survival and overall survival of all assessable patients was 2.4 months (95% CI: 1.8 - 4.6) and 6.0 months (95% CI: 4.6 - 9.2), respectively. PFS in subgroup of 2nd line and combined with paclitaxel (n = 20) was 7.0 months. Response rate in patients who had mesuarable lesion was 22.8 %. Major grade 3/4 adverse events were Leukopenia (59.1%), Neutropenia (68.2 %), febrile neutropenia (9.1%), and GI perforation (2.0 %). Conclusions: Ramucirumab seemed to be effective and safe in clinical setting against advanced gastric cancer.