tbuckley/cabot-search huggingface dataset:
Does <i>MGMT</i> (O6-methylguanine–DNA methyltransferase) have a role in metastatic Ewing sarcoma (ES) patients (pts) undergoing temozolomide (TMZ) and irinotecan (IRI)?
Authors: Emanuela Palmerini, Michela Pasello, Robin Lewis Jones, Maria Cristina Manara, Alessandro Parra, Piero Picci, Giovanni Grignani, Emanuela Marchesi, Marilena Cesari, Alessandra Longhi, Massimo Abate, Anna Paioli, Lorenzo D'Ambrosio, Franca Fagioli, Asaftei sebastian Dorin, Stefano Ferrari, Katia Scotlandi
Journal: Journal of Clinical Oncology (2017)

11030 Background: TMZ+IRI has significant activity in metastatic ES. Epigenetic silencing of the MGMT DNA gene by promoter methylation has been associated with response to TMZ in glioblastoma. Our aim was to assess if MGMT methylation 1) has a role in ES progression and 2) is predictive of response to TMZ. Methods: 1) In 10 ES cell lines presence of MGMT gene (Real-time PCR), methylation of its promoter (methylation-specific PCR) and protein expression (western blot) were assessed. MGMT protein (IHC) and methylation of its promoter was searched in 97 ES pts samples (74 localized; 23 metastatic). 2) In metastatic ES pts treated with TMZ+IRI, with pre-treatment FFPE tissue and measurable disease, the relation between RECIST response, PFS and MGMT expression (IHC) was assessed. Results: 1) The expression of MGMT gene and its protein was detected and concordant (p = 0.02) in all ES cell lines evaluated; methylation was a rare event. In ES tissue samples the methylation of the MGMT gene was found at a low intensity as compared with the unmethylated gene, but the protein expression was relatively low: 36% in localized, 65% in metastatic pts (p 0.03). 2) 24 pts (median age 19 years, range 3-50 years; F/M: 7/17) treated with TMZ + IRI from 2010 to 2015 were identified. Line of treatment: 8 patients were in 1st line; 16 ≥ 2nd line. Median n of cycles was 6 (range: 2-31). Pattern of metastases: 16 multiple sites, 4 lungs, 3 multiple sites + bone marrow, 1 bone. MGMT was positive in 63% of cases. ORR: 16.5% (1 CR , 3 PR); SD: 50% (13 pts); PD: 33.5% (7 pts). According to MGMT expression the ORR was 11% in negative and 20% in MGMT positive patients (p = 0.8). 6-mos PFS rate was 59% (38-80 %IC), no differece according to MGMT expression (pos 61% vs neg 56%, p 0.7). Conclusions: Whereas in cell lines the MGMT gene and its protein expression is a generalized event, in tissue samples MGMT protein is present in a minority of localized pts, and might be associate with tumor progression. Methylation of MGMT gene does not seem responsible for its regulation in ES, and post-transcriptional mechanisms are more likely to be involved. The presence of MGMT protein does not predict the response to TMZ + IRI in this small series.
The EMPOWER study: Promoting breast cancer screening—A randomized controlled trial (RCT) in the Childhood Cancer Survivor Study (CCSS).
Authors: Kevin C. Oeffinger, Jennifer Ford, Chaya S. Moskowitz, Joanne F. Chou, Tara O. Henderson, Melissa M. Hudson, Lisa Diller, Aaron McDonald, James Ford, Nidha Z. Mubdi, Dayton Rinehart, Chris Vukadinovich, Todd M. Gibson, Nassim Anderson, Elena B. Elkin, Kathleen Garrett, Margaret Rebull, Gregory T. Armstrong
Journal: Journal of Clinical Oncology (2016)

10506 Background: Women treated with chest radiotherapy (RT) for childhood cancer should undergo annual surveillance mammography and breast MRI, but best methods of promoting this guideline-based screening are not established. In an RCT, we tested the role of an intervention using tailored information by mail and brief motivational telephone interview in promoting breast cancer screening in women in the U.S. and Canada. Methods: Female survivors in the CCSS treated with chest RT ≥ 20 Gy, age 25-49 years, and without a mammogram in the past 2 years were eligible. Participants (n = 204; mean age 35.8 years) were randomized 2:1 to the tailored intervention (TI) or attention control group (AC) (general health information by mail followed by heart health telephone interview), stratified by age at enrollment (25-39 vs ≥ 40) and race/ethnicity. The primary outcome was the difference in the proportion of participants completing a mammogram by 12 months as evaluated in an intent-to-treat analysis with the test. The stratum-adjusted relative risk (RR) and 95% confidence interval (CI) were estimated with Cochran-Mantel-Haenszel weights. Results: Participants in the TI and AC groups did not differ by demographic or clinical characteristics. Women in the TI group were significantly more likely than those in the AC group to report a surveillance mammogram by 12-months: 45/136 (33.1%) vs 12/68 (17.6%) [RR = 1.7; 95% CI: 1.0-2.9, p = 0.02]. The proportion of women reporting a surveillance MRI at 12-months (secondary outcome) was similar between the two groups, 16.8% (TI) compared with 13.2% (AC) [RR = 1.2; 95% CI: 0.6-2.5; p = 0.58]. In the TI group, the endorsed primary barriers for not obtaining mammography were: put it off (27%), cost (25%), doctor didn’t order it (23%), and haven’t had any problems (22%). Conclusions: The use of mailed tailored materials followed by telephone-delivered counseling increased mammography surveillance rates in female survivors at high-risk for breast cancer. However, this approach did not significantly increase the rate of breast MRI. Cost and physician ordering were important barriers that may be addressed in future studies. Clinical trial information: NCT01579552.
TCT-270 Prospective randomized comparison of paclitaxel-coated balloon versus bare-metal stent in high bleeding risk patients with de novo native coronary artery lesions
Authors: Eun-Seok Shin, Joo Myung Lee, Ae-Young Her, Scot Garg, Chang-Wook Nam, Joon-Hyung Doh, Bon-Kwon Koo, Eun-Seok Shin
Journal: Journal of the American College of Cardiology (2018)
Two years rituximab maintenance vs. observation after first line treatment with bendamustine plus rituximab (B-R) in patients with marginal zone lymphoma (MZL): Results of a prospective, randomized, multicenter phase 2 study (the StiL NHL7-2008 MAINTAIN trial).
Authors: Mathias J. Rummel, Michael Koenigsmann, Kai Uwe Chow, Wolfgang Knauf, Christian A. Lerchenmuller, Christoph Losem, Martin Goerner, Bernd Hertenstein, Thomas Decker, Arnold Ganser, Tobias Gaska, Michael Heike, Elisabeth Lange, Rudolf Weide, Wolfgang Willenbacher, Alexander Burchardt, Frank Kauff, Juergen Barth, Axel Hinke, Richard Greil
Journal: Journal of Clinical Oncology (2018)

7515 Background: Rituximab (R) maintenance is part of a standard treatment for follicular lymphoma. In MZL, however, it is not yet common practice. In this study we compared the effect of 2 years of R maintenance vs. observation after first-line treatment with B-R in patients with previously untreated MZL. Methods: Patients had stage II (bulky disease > 7 cm), III, or IV disease. Nodal and splenic MZL were included but not MALT lymphomas. Primary endpoint was progression free survival (PFS). Secondary endpoints included response rates, overall survival (OS), and toxicity. For induction patients were treated with up to 6 cycles of B-R plus 2 additional R cycles. Only patients responding to B-R were then randomized to either R maintenance (q 2 months for 2 years) or observation. Results: Median time of follow-up after registration was 76 months at the time of this analysis (February 2018). 119 patients with a median age of 65 years were evaluable for response. 108 (91%) responded to B-R induction, with 23 patients (19%) achieving a complete remission. Of 104 randomized patients, 53 (51%) were randomized to R maintenance and 51 (49%) to observation. Median age of randomized patients was 64 years, patient characteristics and toxicity were similar for both groups. PFS was superior for 2 years of R maintenance, with the median not yet reached vs. 92.2 months for observation (hazard ratio (HR) 0.35, 95% CI 0.17 – 0.76, p = 0.008). The OS rate at 6 years was 92% for R maintenance vs. 86% for observation. The difference in OS was not statistically significant (HR 0.52, 95% CI = 0.20 – 1.39). Conclusions: Our results demonstrate a statistically significant PFS improvement of a 2-year R-maintenance vs. observation after B-R induction in patients with MZL. Clinical trial information: NCT00877214.
TREETOPP: A phase 2/3 study of varlitinib plus capecitabine versus placebo plus capecitabine as second-line treatment in patients with advanced or metastatic biliary tract cancers (BTCs).
Authors: Milind M. Javle, Do-Youn Oh, Masafumi Ikeda, Shukui Qin, Wei-Peng Yong, Yee Chao, Nicola McIntyre, Chih-Yi Hsieh, Lilian Chow, Alyssa Chang, Mark McHale, Bertil Lindmark
Journal: Journal of Clinical Oncology (2018)

TPS4143 Background: BTCs are rare and have a poor prognosis. These cancers are often diagnosed at advanced stage with limited treatment options and poor overall survival (OS). Overexpression of epidermal growth factor receptor (EGFR), HER2, HER3, and HER4 vary from 23-57%, 4-13%, 12-23% and 59-60% of BTCs, respectively. Varlitinib is a small molecular tyrosine kinase inhibitor of EGFR, HER2 and HER4 with potent antitumor effect in preclinical BTC models. Varlitinib also demonstrated tumor shrinkage responses and durable disease stabilization in BTC patients in Phase IB study. Methods: A randomized, double-blind, placebo-controlled phase 2 (Part 1)/3 (Part 2) study to compare the efficacy of varlitinib (300 mg BID, every day) versus placebo, when combined with capecitabine (1000 mg/m2, BID for 14 days). The primary endpoints of Part 1 are objective response rate (ORR) and progression-free survival (PFS) and for Part 2 is OS. Eligible patients include those with confirmed advanced or metastatic 2nd line BTC, including intrahepatic or extrahepatic cholangiocarcinoma, gallbladder cancer and carcinoma of ampulla of Vater. Patients must have failed gemcitabine-contained 1st line systemic treatment. The target sample size is 482 patients, and enrollment has started on May 24, 2017. Safety data will be listed and summarized. Co-primary endpoints of Part 1 will be analyzed using data from an Independent Central Review of radiological data. A Hochberg procedure will be used to control the familywise type I error rate for Part 1 at the 10% level (one-sided). For Part 2, the primary endpoint, OS, will be tested at the two-sided 5% significance level. Clinical trial information: NCT03093870.
Safety of epacadostat 100 mg bid plus pembrolizumab 200 mg Q3W in advanced solid tumors: Phase 2 data from ECHO-202/KEYNOTE-037.
Authors: Omid Hamid, Todd Michael Bauer, Alexander I. Spira, David C. Smith, Anthony J. Olszanski, Ahmad A. Tarhini, Primo Lara, Thomas Gajewski, Jeffrey S. Wasser, Sandip P. Patel, Virginia F. Borges, Ani Sarkis Balmanoukian, Emmett V. Schmidt, Yufan Zhao, Mark M. Jones, Tara C. Gangadhar
Journal: Journal of Clinical Oncology (2017)

3012 Background: The immunosuppressive enzyme indoleamine 2, 3-dioxygenase 1 (IDO1) facilitates immune tolerance in cancer via T-cell suppression, and IDO1 overexpression is associated with poor survival. Epacadostat, an oral inhibitor of IDO1, has been shown to be well tolerated as monotherapy and in combination with checkpoint inhibitors. ECHO-202/KEYNOTE-037 is a phase 1/2 study evaluating the safety and efficacy of oral epacadostat plus IV pembrolizumab in patients (pts) with advanced tumors. Based on phase 1 outcomes, epacadostat 100 mg BID plus pembrolizumab 200 mg Q3W was selected for phase 2 evaluation. This analysis summarizes phase 2 safety experience in the overall population of ECHO-202/KEYNOTE-037 (pooled across tumor types) at an October 29, 2016 data cutoff. Methods: Phase 2 pts were ≥18 years of age with advanced or recurrent melanoma (MEL), non–small cell lung cancer (NSCLC), renal cell carcinoma (RCC), urothelial carcinoma (UC), triple-negative breast cancer, squamous cell carcinoma of head and neck (SCCHN), ovarian cancer, diffuse large B-cell lymphoma, or microsatellite instability–high colorectal cancer. Results: The overall safety population comprised 244 pts receiving ≥1 study treatment dose. Median age was 63 years, 52% were women, and 91% were white. As of data cutoff, 134 study pts (55%) discontinued study treatment, primarily due to disease progression (n = 97). Median exposure to study treatment was 86 days (range, 1–374 days). TRAEs occurring in ≥5% of pts were fatigue (23%); rash (16%); diarrhea and nausea (7% each); increased alanine aminotransferase, increased aspartate aminotransferase, and pruritus (6% each); and pyrexia (5%). A total of 37 pts (15%) had grade ≥3 TRAEs; the most common grade ≥3 TRAEs were increased lipase (asymptomatic) and rash (3% each). TRAEs led to discontinuation in 3% of pts. Conclusions: Epacadostat 100 mg BID plus pembrolizumab 200 mg Q3W was associated with an acceptable safety profile in pts with advanced cancers, supporting continued evaluation of the combination. The phase 3 ECHO-301/KEYNOTE-252 MEL study is ongoing and additional phase 3 studies (NSCLC, UC, RCC, SCCHN) are planned. Clinical trial information: NCT02178722.
Analysis of WNT signaling gene expression and potential role in acute myeloid leukemia (AML).
Authors: Mohsin Maqbool, Sobuhi Iqbal, Atul Sharma, Sameer Bakhshi, Sreenivas Vishnubhatla, Ashish Dutt Upadhyay, Lalit Kumar
Journal: Journal of Clinical Oncology (2016)

7023 Background: The canonical Wnt signaling plays an essential role in leukemic stem cells and regulates self-renewal and cell differention. Dysregulation of Wnt signaling activation is thought to contribute to the acute myeloid leukemia (AML) pathogenesis by enhancing self renewal. Beta-Catenin is the core component of canonical Wnt signaling and is regulated by the important molecules like APC and Axin of the pathway. Despite extensive investigation of the WNT genes expression profile in various tumors, little is known about the Beta-Catenin, APC and Axin expression and their prognostic role in AML. The aim of the present study was to determine the potential implications of WNT signaling gene expression and their impact on survival in de novo AML patients. Methods: Gene expression profile of various Wnt signaling molecules; B-Catenin, APC and Axin was done. We investigated the mRNA expression of B-Catenin, APC and Axin genes in bone marrow and/or blood samples by quantitative real time polymerase chain reaction using SYBR-Green chemistry and analysis was done by ΔΔCT Method. 18S RNA and B2M genes were used as reference genes. Results: In Total, 117 de novo non M3 AML patients were included for the gene expression profile and analyzed for their clinicopathologic features. Gene expression results were compared with 40 healthy controls. Median age for entire cohort (n = 117) was 17 years (Range 1-58 years). FLT3-ITD mutation was positive in 11(9.5%) patients. B-catenin showed a significantly increased mRNA expression with a 5.15 fold rise (p < 0.05) and APC and Axin showed non significant increase of mRNA expression with a 4.2; 2.15 fold rise as compared to healthy controls respectively (p = 0.75, & p = 0.17). Only B-catenin over expression was significantly associated with poor OS survival at median followup of 17 months and having less CR rates (p = 0.02). There was no significant correlation of APC and Axin over expression with survival and no correlation of any Wnt genes vs baseline clinical characteristics like Hb, TLC, plts, FLT3-ITD mutations. Conclusions: Our results suggest the WNT signaling activation existence in AML patients and suggest that B-Catenin along with other molecules could be the key component in the pathogenesis in AML.
P53 status in primary tumor predicts efficacy of first-line abiraterone and enzalutamide in castration-resistant prostate cancer patients.
Authors: Benjamin Louis Maughan, Liana Guedes, Kenneth M. Boucher, Gaurav Rajoria, Zach Liu, Szczepan Klimek, Roberto Zoino, Emmanuel S. Antonarakis, Tamara L. Lotan
Journal: Journal of Clinical Oncology (2017)

5064 Background: We tested whether tissue-based analysis of p53 and PTEN genomic status, measured predominantly in primary tumor samples, may be predictive for sensitivity to abiraterone and enzalutamide in castration resistant prostate cancer (CRPC). Methods: We performed a retrospective analysis of 309 consecutive patients with CRPC treated with first-line abiraterone or enzalutamide. Of these, 116 men (38%) had available tumor tissue for analysis, and formed the basis of this study. Deleterious TP53 missense mutations and PTEN deletions were interrogated using genetically validated immunohistochemical assays for p53 protein nuclear accumulation and PTEN protein loss. OS and PFS were compared between patients with and without p53 and/or PTEN alterations. Results: 46% of evaluable cases had PTEN loss and 27% had p53 nuclear accumulation. 45% (53/118) of cases underwent targeted next generation sequencing and p53 nuclear accumulation was 91% sensitive and 90% specific for underlying TP53 missense mutation. OS and PFS did not differ significantly according to PTEN status but were associated with p53 status. Median OS was 15.8 months (95% CI, 15.8–23.9) and 28.7 months (95% CI, 28.7–42.7) for men with and without p53 nuclear accumulation, respectively (HR 1.98; P = 0.007). Median PFS was 5.5 months (95% CI, 3.53–10.5 months) and 10.2 months (95% CI, 7.37–13.3 months) in men with and without p53 nuclear accumulation, respectively (HR 1.73; P = 0.013). In multivariable analyses, p53 status was independently associated with both OS (HR 2.13; P = 0.016) and PFS (HR 1.83; P = 0.034). This effect was also seen in the subset of patients with prostatectomy tissue only. In patients with p53 nuclear accumulation median PFS (p &lt; 0.001) and median OS (p &lt; 0.001) were decreased compared to wild-type patients. No effect was seen with PTEN loss in either PFS (p = 0.12) or OS (p = 0.50). Conclusions: p53 status may be a biomarker of sensitivity to novel hormonal therapies in CRPC. PTEN was not a biomarker of sensitivity in our study. These results require prospective validation.
Treatment of essential thrombocytopenia patients intolerant/ resistant to hydroxyurea: A physician survey.
Authors: Bijan Nejadnik, John Mascarenhas, Karen M Rappaport, Biao Lu, Bruno M Gagnon, Srdan Verstovsek
Journal: Journal of Clinical Oncology (2017)

e18565 Introduction: Hydroxyurea (HU) is deemed first-line cytoreductive therapy for patients with essential thrombocythemia (ET) at high-risk for vascular complications with 20-25% of patients developing HU intolerance/ resistance (HUIR). Up to one-third of patients taking anagrelide, often the 2 nd line drug of choice, are also unable to tolerate its side effects (cardiovascular and gastrointestinal). A review of the medical literature suggests widespread support for individualized treatment plans in ET with multiple options, including HU, anagrelide, interferon and busulfan, but little is known about physician practice. Methods: We contracted with a research company to perform an internet survey of 20 academic and 20 community hematologists to assess treatment practices for HUIR ET patients. We assumed a 25% rate of resistance to anagrelide. Results: Academic and community physicians reported 22% and 25% HUIR rates, respectively. An estimated 60% and 44% of HUIR patients in academic and community settings, respectively, would undergo treatment with an agent other than anagrelide (interferon, busulfan, or ruxolitinib) in 2 nd or 3 rd line treatments. Physicians not using anagrelide as 2 nd line therapy also would not use it as 3 rd line therapy. Anagrelide is used more frequently in the community setting. Conclusions: About 50% of HUIR patients are treated with agents other than anagrelide as 2 nd / 3 rd line therapy. Reasons for practice variation in the treatment of ET remain poorly understood. [Table: see text]
Basal physical inactivity as an independent risk factor for early death in elderly cancer patients: A prospective Brazilian cohort study with 608 patients.
Authors: Jurema Telles O Lima, Maria Julia Gonçalves Mello, Anke Bergmann, Mirella Rebello Bezerra, Zilda Cavalcanti, Letícia telles Sales, Luiz Claudio Santos Thuler
Journal: Journal of Clinical Oncology (2017)

e21534 Background:With the aging of the population, cancer in the elderly people is becoming an increasingly common and complex health problem, particularly in low-middle-income countries, where physical inactivity and obesity have also been challenging and correlated with cancer and aging. The aim of this study is to determine whether the baseline physical inactivity per International Physical Activity Questionnaire(IPAQ) is an independent factor of premature death in the first six months.Methods: prospective cohort study of elderly patients (≥ 60 years). Participants with a recent diagnosis of cancer were from eight community hospitals and one cancer center in Northeast Brazil and were recruited during their first medical appointment at the outpatient oncologic clinic. Sociodemographic and clinical variables were determined and baseline comprehensive geriatric assessment (CGA) was conducted including IPAQ and Time Up and Go test. Data were analyzed using multivariate Cox proportional hazards models, overall survival was estimated using the Kaplan–Meier method and survival curves were compared using the Log rank test. Results:From 2015-2016, 608 patients, mean age 71.9 (SD ±7.4; range 60-96), 50.7% male, were enrolled. Main diagnoses were prostate cancer (29.1%), digestive system cancer (25.5%) and breast cancer (16.0%). 40.3% were considered obese/overweight (BMI ≥ 27). 42.1% were considered physically inactive per IPAQ. The mean of the Time Up and Go test on the physically inactive group by IPAQ was of 13.11s (SD ± 6.5), and of 22.72s (SD± 16.7) on the physically active one. After adjustment for age, site of cancer and cancer stage, the multivariate regression Cox model showed that being physically inactive is an independent predictor for early death (HR = 2.35, 95% CI: 1.50‒ 3.66, p &lt; 0.001).Conclusions:Physical inactivity at admission was identified as a significant predictor of risk for premature death in elderly cancer patients. The evaluation of the physical activity should be incorporated into regular geriatric assessment of elderly cancer patients.
TCT-81 The Comparative Effectiveness and Safety of Impella Versus Intra-Aortic Balloon Pump in Patients who Underwent Percutaneous Coronary Intervention: Insights from the Blue Cross Blue Shield of Michigan Cardiovascular Consortium (BMC2)
Authors: Devraj Sukul, Milan Seth, Akshay Khandelwal, George Hanzel, Ryan Madder, Hiroshi Yamasaki, Hameem Changezi, Thomas Earl, Hitinder Gurm
Journal: Journal of the American College of Cardiology (2018)