tbuckley/cabot-search huggingface dataset:
The prognostic factors and the cause of death in patients with advanced or recurrent gastric cancer.
Authors: Sang Woo Lee, In Keun Choi, Chang Min Lee, Seung Young Kim, Jong Jin Hyun, Sung Woo Jung, Young Kul Jung, Ja Seol Koo, Jong-Han Kim, Seong-Heum Park, Seung-Joo Kim, Jun Suk Kim
Journal: Journal of Clinical Oncology (2015)

215 Background: The purpose of this study is to evaluate significant prognostic factor and compare the cause of death in patients with advanced or recurrent gastric cancer. Methods: We reviewed the medical records of 170 patients who had been diagnosed as advanced or recurrent gastric cancer between January 2006 and September 2013. The patients were divided into two groups. One group (advanced gastric cancer: AC) included 104 patients had undergone chemotherapy for advanced gastric cancer, and the other group (recurrent gastric cancer: RC) 66 for recurrence after surgical treatment. The causes of death and overall survival were compared between two groups, and the significant prognostic factors were investigated by multivariate analysis. Also, subgroup analysis was performed for 18 patients with gastrectomy for curative intent, and they were proved to have unresectable gastric cancer after surgery (non-palliative surgery for advanced gastric cancer: NS). Results: In the comparison for the causes of death, two groups showed no statistical difference, but AC group had more tendency to die because of bleeding ( p = 0.054) and infection ( p = 0.075). Overall survival of AC group did not differ from that of RC ( p = 0.901). In multivariate analysis, bone metastasis ( p = 0.013, HR = 1.923), peritoneal seeding ( p = 0.001, HR = 2.182) and the frequency of chemotherapy ( p &lt; 0.001, HR = 0.887) were significantly associated with the overall survival. In a subgroup analysis, the overall survival of NS was significantly higher than AC ( p = 0.032). Conclusions: In the patients with advanced or recurrent gastric cancer, AC might have more possibility to die because of bleeding and infection than RC. Additionally, the prognosis of patients with advanced or recurrent gastric cancer was affected by the presence of bone metastasis, peritoneal seeding and frequency of chemotherapy. Non-palliative surgery for gastric cancer might show the better prognosis than AC in the specific conditions.
A phase I study of biweekly capecitabine and the histone deacetylase inhibitors (HDACi) vorinostat in for advanced breast cancer (BC).
Authors: M. M. Abu-Khalaf, T. Kim, G. G. Chung, M. DiGiovanna, S. Radke, D. Cornfeld, L. Harris
Journal: Journal of Clinical Oncology (2011)

e13609 Background: The HDACi vorinostat (V) inhibits growth of BC cell lines and downregulates thymidylate synthase (TS), an enzyme thought to be involved in resistance to 5-fluoruracil. Methods: We designed a phase I/II clinical trial of V + capecitabine (C) for advanced BC. The primary aims are to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT) and response by RECIST criteria. Secondary aims are pharmacodynamic (PD) measures of gene signatures and candidate transcription factors in pre/post V biopsies using RNA-seq. Cohorts (Co) of 3-6 patients (pts) were enrolled and treated with escalating doses of C (1,500/1,800/2,000 mg) + V 200 mg BID on days 1-7 and 15-21 of a 28 day cycle. Pts received V on days -10, -9, -8, -7, -6 and C on day -3 to facilitate PD studies. A DLT is defined as ≥ grade 3 non-hematologic toxicity, grade 4 thrombocytopenia, grade 4 neutropenia > 5 days, grade 4 febrile neutropenia requiring hospitalization, or treatment delay of > 2 weeks due to unresolved toxicity. Results: 13 pts enrolled on phase I study: (Co1 1,500/200 mg, n= 8), (Co2 1,800/200 mg, n=5). Median age was 59 yrs (range 46-68); median number of prior therapy was 5 (range 2-9); 10 pts had ER/PR+ BC; 1 pt had HER-2+ BC; 3 pts had prior C therapy. Nine of 13 pts were evaluable for toxicity; 3 DLTS (grade 3 fatigue) occurred in Co 1 (2) and Co 2 (1). Other grade 3/4 toxicities included: 1 pt had grade 3 neutropenia, anemia, fatigue, hyponatremia, hypoalbuminemia, ataxia, infection, muscle weakness, headache and grade 4 thrombocytopenia; 1 pt had grade 3 hand/foot syndrome; 1 pt had grade 3 syncope and grade 4 hypokalemia; 1 pt had grade 3 thrombocytopenia; 1 pt had grade 3 anemia;1 pt had grade 3 neutropenia and infection; 1 pt had grade 3 neutropenia and lymphopenia; and 1 pt had grade 3 headache. Seven pts completed > 2 cycles and were evaluable for response; 3 pt had stable disease, notably 1 pt is on treatment for 27 cycles and 1 pt completed 6 cycles. Extraction/amplification/ sequencing from core biopsies shows acceptable read-mapping (45-50 % of RefSeq genes) on Illumina GA II platform. Conclusions: The MTD and recommended dose for phase II study is C1,500 mg BID and V 200 mg BID in a biweekly schedule. PD results will be presented.
Sigma1 Targeting to Suppress Aberrant Androgen Receptor Signaling in Prostate Cancer
Authors: Jeffrey D. Thomas, Charles G. Longen, Halley M. Oyer, Nan Chen, Christina M. Maher, Joseph M. Salvino, Blase Kania, Kelsey N. Anderson, William F. Ostrander, Karen E. Knudsen, Felix J. Kim
Journal: Cancer Research (2017)

Suppression of androgen receptor (AR) activity in prostate cancer by androgen depletion or direct AR antagonist treatment, although initially effective, leads to incurable castration-resistant prostate cancer (CRPC) via compensatory mechanisms including resurgence of AR and AR splice variant (ARV) signaling. Emerging evidence suggests that Sigma1 (also known as sigma-1 receptor) is a unique chaperone or scaffolding protein that contributes to cellular protein homeostasis. We reported previously that some Sigma1-selective small molecules can be used to pharmacologically modulate protein homeostasis pathways. We hypothesized that these Sigma1-mediated responses could be exploited to suppress AR protein levels and activity. Here we demonstrate that treatment with a small-molecule Sigma1 inhibitor prevented 5α- dihydrotestosterone-mediated nuclear translocation of AR and induced proteasomal degradation of AR and ARV, suppressing the transcriptional activity and protein levels of both full-length and splice-variant AR. Consistent with these data, RNAi knockdown of Sigma1 resulted in decreased AR levels and transcriptional activity. Furthermore, Sigma1 physically associated with ARV7 and ARv567es as well as full-length AR. Treatment of mice xenografted with ARV-driven CRPC tumors with a drug-like small-molecule Sigma1 inhibitor significantly inhibited tumor growth associated with elimination of AR and ARV7 in responsive tumors. Together, our data show that Sigma1 modulators can be used to suppress AR/ARV-driven prostate cancer cells via regulation of pharmacologically responsive Sigma1-AR/ARV interactions, both in vitro and in vivoCancer Res; 77(9); 2439-52. ©2017 AACR.
A phase II/III study of sotatercept (ACE-011), an activin antagonist, for chemotherapy-induced anemia in patients with metastatic non-small cell lung cancer treated with first-line platinum-based chemotherapy.
Authors: H. Raftopoulos, A. Laadem, M. Puccio, R. D. Knight
Journal: Journal of Clinical Oncology (2011)

TPS235 Background: Chemotherapy-induced anemia (CIA) is often encountered in treating lung cancer patients. Erythropoiesis-stimulating agents are FDA approved for treating CIA; however, there are concerns about negative effects on survival and/or tumor progression in certain populations, including patients with non-small cell lung cancer (NSCLC). Sotatercept is a human fusion protein consisting of the extracellular domain of activin receptor IIA linked to the IgG1 Fc domain that has been shown to increase release of mature erythrocytes into circulation in nonclinical studies. Early phase clinical trials support further development of sotatercept for the treatment of CIA. Methods: This is a single-blind, randomized, phase IIa, dose ranging study (Part 1) followed by a phase IIb/III, double-blind, randomized, placebo-controlled study (Part 2) of sotatercept for the treatment of CIA in adults with metastatic NSCLC treated with first-line platinum-based chemotherapy. Patients with hemoglobin ≥6.5 to <11.0 g/dL, ECOG Performance status of 0–2, life expectancy of >3 months, and adequate renal function are eligible to enroll. In Part 1, 90 patients will be randomized to sotatercept (15, 30, or 45 mg SC every 42 days for up to 4 doses) to determine an effective dose having a hematopoietic response in the treatment of CIA in advanced NSCLC. Part 2 will be performed in 2 stages. In the first stage, 180 patients will be randomized to sotatercept or placebo. An interim assessment based on transfusion rate at 4 months will be performed. In stage 2, 570 additional patients will be randomized to achieve full accrual based on a positive futility assessment. During both Part 1 and 2, response rate, time to progression, progression-free and overall survival, safety, pharmacokinetics, duration of hematopoietic response, and quality of life will be assessed. Exploratory analyses will be performed to assess effects on bone metabolism, dose-response relationship, activin A expression, circulating tumor cell enumeration, and renal function biomarkers. The trial will be open for enrollment in 2011 (ClinicalTrials.gov NCT01284348).
Differences between women’s preferred and actual experience with ‘shared decision-making’: A mixed method study.
Authors: Deborah Ejem, J Nicholas Dionne-Odom, Danny Willis, Peter Kaufman, Laura Urquhart, Marie Bakitas
Journal: Journal of Clinical Oncology (2016)

34 Background: Women with metastatic breast cancer (MBC) face numerous treatment and ACP decisions along their illness trajectory. We aimed to explore the treatment and ACP decision-making processes and decision support needs of women with MBC. Methods: Convergent, parallel mixed methods study (9/08-7/09). Sample included women with MBC managed by 3 breast oncologists at the Norris Cotton Cancer Center, Lebanon, NH. Participants completed a semi-structured interview and standardized decision-making instruments (decision control preferences) at study enrollment (T1; n = 22) and when they faced a decision point or 3 months later (T2; n = 19), whichever came first. Results: Participants (n = 22) where all white, averaged 62 years and were mostly married (54%), retired (45%), had a ≥ bachelor’s degree (45%), and had incomes &gt; $40,000 (50%). On the control preferences scale, most women reported a preference for a ‘shared decision’ with clinician (T1 = 14 (64%) vs T2 = 9 (47%)) compared to making the decision themselves (T1 = 6 (27%) vs T2 = 6 (32%)), or delegating the decision to their doctor (T1 = 2 (9%) vs T2 = 4 (21%)). In semi-structured interviews about their actual treatment decision-making experience, women described experiencing a passive or delegated rather than a shared decision-making process. Conversely, women described a much more active ACP decision-making process that was often shared with family rather than their oncologists. Conclusions: Women selected a “shared” process using a validated tool; however their descriptions of the treatment decision-making processes were inconsistent with their actual experience, which was a more passive process in which they followed the oncologists’ treatment suggestions.
Prospective phase II trial of GTX in metastatic pancreatic cancer: Laboratory and clinical studies.
Authors: Robert Fine, Yoomi Lee, William H. Sherman, Anthony Paul Gulati, Paul Eliezer Oberstein, Kyung Chu, Dawn Tsushima, Kelley B Mowatt, Beth Schrope, James A Lee, John Allendorf, John A Chabot, Stephen M. Schreibman
Journal: Journal of Clinical Oncology (2013)

209 Background: We found that in pancreatic cancer (PC) cells, when gemcitabine, docetaxel, capecitabine (GTX) are given in a sequence and time specific manner, it 1) increased Bax, Bak, Fas and decreased Bcl-2 and Bcl-XL expression; 2) increased hENT-1 expression &gt;8 fold, which increased intracellular gemcitabine accumulation by 220%; 3) specifically inhibited MEK to ERK phosphorylation (p-MEK) by &gt;70%. Methods: From this pre-clinical data, we developed the GTX regimen utilizing: capecitabine 750 mg/m 2 /BID capped at 2500mg/day for days 1-14; on days 4 and 11 gemcitabine at 750mg/m 2 given over 75mins (FDR), followed by docetaxel at 30mg/m 2 . Week 3 is off all drugs. Forty four patients with previously untreated metastatic PC were enrolled and followed until death. ECOG PS was: 0(2%), 1(63%), 2(35%), and median age was 60 (33-72). Over 85% of patients had &gt;3 liver metastases. Results: Median response rate (RR) was 38% with 14% CR in metastatic or primary sites and 40% stable disease using RECIST 1.0 indices. Median PFS was 6.9 months and median OS was 14.5 months. After failing GTX, 80% of patients received our second line synergistic regimen called ICM (irinotecan 80mg/m 2 and cisplatin 25mg/m 2 on days 1 and 8, and mitomycin C 5mg/m 2 on day 1 only, out of a 28 day cycle). The 6, 12, 18, 24, 30 and 36 month survival on GTX was 77, 59, 35, 16, 14 and 7%, respectively. Grade3/4 toxicities were: leukopenia (32%), neutropenia (29%), febrile neutropenia (3%), anemia (12%), thrombocytopenia (12%), diarrhea (5%), HFS (3%), fatigue (8%), and mucositis (8%). GTX inhibited MEK to ERK phosphorylation (P-MEK). We performed IHC (0-4+) for P-MEK in 16 patients and found high P-MEK (3-4+) correlated with an 85% RR while low P-MEK (0-1+) correlated with a 90% rate of PD to GTX. Conclusions: GTX is an effective regimen for metastatic PC with durable RR, PFS, OS rates, and acceptable toxicities. IHC for P-MEK seems to be a good biomarker to identify subsets of patients who will respond to GTX. GTX is a rationally designed regimen derived from lab studies. GTX increases pro-apoptotic and decreases anti-apoptotic proteins, inhibiting MEK to ERK in the MAPK pathway. Clinical trial information: NCT00996333.
Metformin (Met): A cost-effective adjunct therapy with enzalutamide (Enza) for metastatic castrate-resistant prostate cancer (mCRPC)?
Authors: Jordan Hill, Mike Paulden, Christopher McCabe, Peter Venner, Brita Lavender Danielson, Scott A. North, Nawaid Usmani
Journal: Journal of Clinical Oncology (2016)

340 Background: Several new therapies have changed the landscape of prostate cancer (PCa) treatment, primarily due to their effectiveness in treating patients with mCRPC. Enza has garnered much attention, but is relatively expensive (~$3175/month). Met is less expensive (~$8.00/month) and has been used for decades to treat patients with non-insulin dependent diabetes. Two recent large population-based studies of PCa have demonstrated that diabetics taking Met had improved PCa specific and overall survival compared to those not taking Met. As a result, we hypothesized that Met has the potential to be a cost-effective adjunct therapy to Enza, although it is not currently used as such. Methods: We constructed a Markov-based decision analytic model to compare the cost-effectiveness of Enza alone versus Enza combined with Met. Through expert elicitation, we assumed that adding Met to Enza increases its efficacy by 15%. All other costs, utilities, and transition probabilities were derived from existing literature or expert elicitation. Effectiveness was measured using quality-adjusted life years (QALYs). Costs and QALYs were considered over a lifetime horizon and discounted at 5% per annum. Cost-effectiveness was considered using a willingness to pay threshold of $50 000/QALY. Results: Adding Met to Enza increases expected lifetime costs per patient by $83 651, and improves the expected effectiveness of treatment by 3.74 QALYs, compared to Enza alone. The incremental cost-effectiveness ratio is $22 374/QALY. Accounting for parameter uncertainty, adding Met to Enza has a 72% probability of being cost-effective. Conclusions: Although Met is not currently used as an adjunct therapy to Enza, doing so would likely be cost-effective provided it is as effective as we have assumed in our model. Additionally, our results indicate that the combination of Enza and Met could be among the most cost effective interventions in oncology. However, given the uncertainty around the effectiveness of such an adjunct therapy, our results support the need for further clinical trials to provide more robust evidence of the effectiveness of such a combination therapy in clinical practice.
Pre-morbid anthropometric measurement and its impact on outcome in early-stage breast cancer in midwestern Ireland.
Authors: Keith Ian Quintyne, Bernie Woulfe, Rajnish K. Gupta
Journal: Journal of Clinical Oncology (2013)

45 Background: Obesity has become a grave public health concern of global proportions, especially in many developed counties. Clinical obesity may be defined as a body mass indeed (BMI) of greater than or equal to 30kg/m 2 . Within recent times, growing interest has been seen for the relationship between obesity and cancer; with it being identified as a significant risk factor. It has also been appreciated that it is one of the greatest modifiable risk factors for malignancy. Obesity at the time of diagnosis of early-stage breast cancer (EBC) has been associated with poor outcome, especially breast-cancer specific survival. The potential mechanism for this has been linked to several factors including: associated adverse disease features; hormonal influences; co-morbidities that can interfere with therapy; and other yet unknown pathways. We herein report our experience on patients with newly diagnosed EBC and related pre-morbid anthropometric data and its impact on their outcome in an ambulatory Medical Oncology practice in Mid-Western Ireland. Methods: Study period: 01/01/2001 – 31/12/2010. Retrospective data was derived from (1) MWCC Oncology database, (2) pathology reports, and (3) patient files. Data was collated and entered into an Access database and exported into IBM SPSS Statistics 20 version for statistical analysis. Results: One thousand and forty-one (1,041) patients with EBC were identified and analysed. Median age: 55 years (23 – 87 years). Median follow-up: 5.04 years. BMI distribution revealed: Underweight (&lt;18.5kg/m 2 ): 1%; Normal (18.5 – 25kg/m 2 ): 33%; Overweight (25.1 – 30kg/m 2 ): 39%; and Obese (&gt;30kg/m 2 ): 27%. It was noted that obese patients had disproportionately later age of presentation, larger tumours, ductal carcinoma on histology and a smoking history (including current and former smokers). Obese patients accounted for 50% of the non-cancer related deaths observed. Obese patients showed poorer survival in all categories, but it was only statistically significant for non-cancer related deaths. Conclusions: Pre-morbid anthropometric data has shown that obese patients had poorer outcome, and highlights that potential intervention can have impact on improving outcome in EBC.
Early impact of the Affordable Care Act (ACA) on financial worry.
Authors: Amy J. Davidoff, Xin Hu, Helen M. Parsons, Zhiyuan Zheng
Journal: Journal of Clinical Oncology (2016)

44 Background: We examined changes in financial worry for working-aged cancer survivors compared to individuals without a cancer history (controls) after ACA-mandated health insurance enrollment and caps on cost-sharing were implemented in 2014. We hypothesized that cancer survivors would be more likely to report financial worry, and that ACA implementation would reduce financial worry. Methods: We pooled data from the 2013-2014 National Health Interview Survey for adults aged 21-64 years. Cancer survivors were identified based on self-report of ever being told by a physician that they had cancer (excluding non-melanoma skin cancer). Reports of worry about eight financial matters were dichotomized as “very worried” vs. “less worried”; a summary measure captured reports of being “very worried” about any item. Linear probability regressions assessed the impact of being a cancer survivor and the post-ACA period on high financial worry, controlling for demographics and health status. Interaction terms between cancer and post-ACA tested for differential ACA effects for cancer survivors. Results: Compared to controls (n = 50,304), cancer survivors (n = 2,192) were more likely to report being very worried about finances pre-ACA (46.7% vs. 39.6%) and post-ACA (42.3% vs. 36.0%). The ACA was associated with an adjusted 3.9 (CI: 2.9-4.9) percentage point (PPT) decrease in the probability of financial worry overall. Being a cancer survivor was associated with increased likelihood of being very worried about finances overall (PPT = 3.5, CI: 0.8-6.2), medical costs associated with a serious illness (PPT = 3.4, CI: 0.9-5.9) and normal healthcare (PPT = 3.4, CI: 1.1-5.7), having enough money for retirement (PPT = 2.4, CI: 0.0-4.8), and being able to maintain an enjoyable standard of living (PPT = 2.5, CI: 0.3-4.7). The ACA did not affect financial worry for cancer survivors differently than for controls. Conclusions: The ACA was associated with small but significant reductions in financial worry for working-aged adults, with similar effects for cancer survivors and controls. Cancer survivors were more likely to report financial worry, and worried about both paying for healthcare and the ability to maintain an adequate financial position in the short and longer run.
A qualitative investigation of mindfulness practice to support advance care planning (ACP).
Authors: Shelley A. Johns, Ann H. Cottingham, Kathleen A. Beck-Coon, Paul R. Helft
Journal: Journal of Clinical Oncology (2016)

15 Background: Despite ongoing attempts to increase ACP in the U.S, a national longitudinal study of patients with cancer found no significant change in participation in end-of-life (EOL) discussions or living will completion between 2000-2012. A key barrier to ACP includes emotional discomfort talking about EOL care preferences. Mindfulness practices facilitate emotional regulation through present-centered awareness and non-reactive coping. In this pilot, an intervention combining mindfulness training, mindful communication skill development, and information about ACP was hypothesized to increase ACP in patients with cancer. Methods: The Mindfully Optimizing Delivery of End-of-Life Care (MODEL Care) intervention provided 12 hours of training to 13 patients with advanced-stage cancer and their family CGs (n = 13 dyads). Training included breath awareness, sitting meditation, mindful movement (yoga), mindful communication, and ACP information. Patients reported on participation in ACP behaviors at baseline and 4 weeks post intervention. Patients and CGs participated in semi-structured qualitative interviews after MODEL Care that were recorded, transcribed, and coded for key themes. Results: Compared to baseline, patients made notable improvement in ACP behaviors, including having goals of care conversations with their oncologist (p = .03) and family CG (p = .06). Qualitatively, patients and CGs reported an improved ability to “pause” and effectively manage tender emotions, coupled with improved communication and connection between patient and caregiver: “It kind of reminded us both that we need to make a conscious effort to ensure communication occurs on important things”; “We’ve been more in sync than we ever have been.” Moreover, MODEL Care reportedly facilitated thinking about the future to “do what we need to do” and “get things prepared." Conclusions: The MODEL care intervention improved patient and CG ability in areas foundational to ACP engagement: reduced emotional reactivity, communicating about difficult issues, and understanding relevance of ACP. Findings support the potential use of mindfulness training to support ACP for adults with cancer and their family CGs. Clinical trial information: NCT02367508.