tbuckley/cabot-search huggingface dataset:
Temozolamide and irinotecan in metastatic Ewing sarcoma: An Italian Sarcoma Group and Royal Marsden Hospital join study.
Authors: Emanuela Palmerini, Robin Lewis Jones, Piero Picci, Emanuela Marchesi, Roberto Luksch, Giovanni Grignani, Marilena Cesari, Alessandra Longhi, Massimo Abate, Anna Paioli, Zoltan Szucs, Lorenzo D'Ambrosio, Stefano Ferrari
Journal: Journal of Clinical Oncology (2016)

11033 Background: Treatment of patients with metastatic Ewing sarcoma (ES) remains a challenge. Pre-clinical studies and small retrospective series, mainly including pediatric patients, have demonstrated that the combination of temozolomide + irinotecan has significant antitumor activity. The aim of this pooled analysis is to identify factors influencing the activity of this combination in pediatric and adult ES patients. Methods: Patients receiving temozolomide (100 mg/m2/day, day 1-5), + irinotecan (40 mg/m2/day, day 1-5), every 21 days, for recurrent ES were eligible. Overall response rate (ORR) [complete response (CR) + partial response (PR)], stable disease (SD), 6-months progression-free survival (6-mo PFS) and 1- year overall survival (1-year OS) were assessed. Results: 52 patients treated from 2010 to 2015 were enrolled. Median age was 22 (4-65): 12 were pediatric, 40 adults. Female/Male: 17/35. ECOG performance status: 31 were ECOG 0, 21 ECOG ≥ 1. Line of treatment for metastases: 14 patients were in 1st line; 38 ≥ 2nd line. 15 cases had already been treated with busulfan and melphalan with peripheral blood stem cells support (BuMel). Pattern of metastases: 32 patients had multiple sites, 11 lung only, 6 bone only, 2 local recurrence, 2 multiple sites + bone marrow (BM). ORR in 47 patients with measurable disease, according to RECIST was 30% [CR: 2 (4%), PR: 12 (26%)]; SD: 19 (40%), PD: 14 (30%). Median number of cycles was 5 (range: 1-33). 6-mos PFS rate was 43%, significantly different according to pattern of metastases (6-mos PFS: 75% for lung only patients, 75% for bone only, 36% for multiple sites, 0% for local recurrence and 0% for multiple sites + BM, p 0.01). Prior use of BuMel, sex , ECOG, line of treatment did not affect PFS, whereas a trend for a better 6-mos PFS for adult patient was observed (6-mos PFS: adult 49% vs pediatric 27%, p 0.1). 1-year OS was 61%, significantly better for ECOG 0 (1-year OS ECOG 0 82% vs ECOG ≥ 1 37%, p 0.004), adult (1-year OS adult 65% vs pediatric 44%, p 0.05), and responding patients (1-year OS CR/PR 84% vs SD 60% vs PD 12%, p 0.001). Conclusions: Temozolomide + irinotecan is an excellent option for lung or bone only recurrent ES, especially for adult patients and ECOG 0.
Combined neoadjuvant weekly paclitaxel and trastuzumab for HER2-overexpressing breast cancer
Authors: J. Horiguchi, Y. Koibuchi, N. Rokutanda, R. Nagaoka, M. Kikuchi, A. Sato, Y. Ishikawa, H. Odawara, Y. Iino, I. Takeyoshi
Journal: Journal of Clinical Oncology (2007)

3045 Background: The purpose of this study is to determine the clinical efficacy of neoadjuvant paclitaxel and trastuzumab in women with advanced breast cancer, with or without metastatic disease. Methods: Patients with HER2-positive breast cancer (clinical stage IIB-IV) were included in this study. The patients received trastuzumab 4mg/kg loading dose intravenously then 2mg/kg weekly and concurrently paclitaxel 80mg/m 2 (Day 1, 8, 15) weekly for 4 cycles followed by surgery. Results: Preliminary results from 15 patients are reported. Of these, six patients (40%) had a clinical complete response and nine patients (60%) a clinical partial response. Fourteen of 15 patients received surgery; eight breast-conserving surgery and six modified radical mastectomy. Six patients (43%) had pathological complete response. With a median follow-up of 19 months (range, 5–32 months), these 15 patients are alive. Patients with clinical stage IIB-III breast cancer are alive without any distant metastasis. Conclusion: Combined neoadjuvant weekly paclitaxel and trastuzumab had high clinical and pathological response rates for HER2 overexpressing breast cancer. No significant financial relationships to disclose.
Phase II study of pembrolizumab in leptomeningeal carcinomatosis.
Authors: Priscilla Kaliopi Brastianos, Sanjay Prakadan, Christopher Alvarez-Breckenridge, Eudocia Quant Lee, Sara M. Tolaney, Lakshmi Nayak, Nancy U. Lin, Andrew Navia, Ivanna Bihun, Ugonma Nnenna Chukwueke, Kevin S. Oh, Michael White, Elizabeth Robins Gerstner, Donald P. Lawrence, Justine Vanessa Cohen, Anita Giobbie-Hurder, Daniel P. Cahill, Alex Shalek, Scott L. Carter, Ryan J. Sullivan
Journal: Journal of Clinical Oncology (2018)

2007 Background: Approximately 5-8% of patients with cancer develop leptomeningeal carcinomatosis (LMD). Median survival of patients with LMD is approximately 4-6 weeks and there are no effective treatment options. We performed a phase II study of pembrolizumab in LMD from any solid tumor malignancy (NCT02886585). Methods: The primary endpoint is the rate of overall survival at 3 months (OS3). A Simon two-stage design was used to compare a null hypothesis OS3 of 18% against an alternative of 43%. Ten patients were to be enrolled in the first stage. If 2 or more patients were alive at 3 months, an additional 8 patients would be enrolled. If at least 6 patients among the total of 18 patients were alive at three months, then the treatment would be deemed promising in the cohort. Serial CSF, blood samples and tumor samples were collected to elucidate the genomic and transcriptional determinants of immunotherapy response in central nervous system (CNS) lesions. Results: A total of 18 patients were accrued (15 with breast cancer, 2 with lung cancer and 1 with gastric cancer). The median follow-up of patients still alive was 2.9 months (range: 2.2 to 6.3 months). The percentage of patients with one or more grade-3 or higher adverse events that were at least possibly related to treatment is 33.3%. At the time of the data retrieval, eight (8) patients (44%) were alive at three months after enrollment (OS3). Therefore, the study met its primary endpoint. Whole exome sequencing of tissue samples and cell-free DNA from CSF and blood, as well as single-cell RNA sequencing of CSF, were carried out to track the evolution of the tumor and the immune system in the CNS and identify biomarkers of response. Genetic and transcriptomic differences within the CSF were detected between the pre- and post-treatment samples and in patients that reached OS3 compared with those that did not. Conclusions: Pembrolizumab is well-tolerated and has activity in LMD. CSF provides an opportunity to monitor the clonal evolution of tumor and the immune microenvironment in LMD. Clinical trial information: NCT02886585.
WISER survivor: Exercise and/or weight loss in breast cancer survivors.
Authors: KATHRYN H. SCHMITZ, Angela DeMichele, Lorraine T Dean, Andrea B. Troxel, David B Sarwer
Journal: Journal of Clinical Oncology (2016)

TPS10140 Background: With nearly 200,000 new invasive breast cancer diagnoses yearly and a nearly 90% 5 year survival rate, the number of survivors is expected to grow steadily. The primary challenges faced by these women can be divided into two broad categories: 1) persistent adverse effects of treatment and 2) recurrence. Research supports a key role for exercise and weight loss in controlling these survivorship challenges. The overarching goal of the WISER Survivor Trial is to examine the efficacy of exercise and/or weight loss to improve breast cancer-related lymphedema (BRCL) AND to reduce risk for recurrence, as evaluated by levels of biomarkers hypothesized to be along the causal pathway between energy balance and recurrence. Methods: Eligible participants were female breast cancer survivors who had completed treatment at least six months prior to randomization, BMI > 25 but < 50, stable BCRL, age < 80, ability to walk 6 min. unaided, no plans for curative or reconstructive surgery during the study, no self-report of weight lifting or > 90 weekly minutes of aerobic activity in prior 12 months. Recruitment of 351 women was completed in 38 months. The majority of participants (74%) were recruited through letters sent by tumor registries. Exercise prescription: 2x weekly resistance training and walking 180 min/wk. Participants meet with trainers weekly for six weeks, followed by monthly sessions to one year. Adjustable dumbbells shipped directly to participant homes facilitate adherence to the home based exercise program. Weight loss intervention: 24 weekly group behavioral counseling sessions with a registered dietitian, including 20 weeks of meal replacement programming. Weight loss groups continue to meet monthly through the end of the one year intervention. Outcomes include changes in arm swelling as measured by perometry and changes in biomarkers for recurrence, including markers of growth factors, inflammation, and oxidative stress. All participants have completed 6 month assessments. Adherence to the exercise protocol has been consistently over 80%. A total of 228 women have completed the trial, with another 50 still undergoing follow-up. Data collection is expected to be complete by June 2016, with results to be reported in 2017. Clinical trial information: NCT01515124.
Utility of surveillance imaging in stage III non-small cell lung cancer (NSCLC) patients: A SEER-Medicare analysis.
Authors: Manish K. Thakur, Julie Ruterbusch, Ann G. Schwartz, Jennifer Lynn Beebe-Dimmer, Andreana N Holowatyj, Antoinette J. Wozniak, Shirish M. Gadgeel
Journal: Journal of Clinical Oncology (2016)

8531 Background: Around 22% of NSCLC patients have stage III disease at diagnosis and their 5-year survival is about 27%. Though current NCCN guidelines recommend surveillance imaging every 6-12 months for 2 years, the utility of surveillance imaging in detecting tumor recurrences early as opposed to at the time of clinical evidence of recurrence is unclear. Thus, we conducted a retrospective analysis of stage III NSCLC patients using the SEER-Medicare database to assess the rate of surveillance imaging and its association with survival. Methods: Stage III NSCLC patients diagnosed from 2007 through 2011 who survived at least 4 months after receiving treatment with curative intent were eligible for inclusion in the study. Surveillance was defined as receipt of chest CT and/or PET scans between 4 to 6 months after the completion of treatment. Receipt of surveillance imaging by clinical and demographic factors was assessed using either chi-square or Mantel-Haenszel trend tests. Survival was assessed using Kaplan Meier curves, log-rank tests, and Cox proportional hazards regression. Results: Of the 14,965 stage III NSCLC patients diagnosed during the study period, 2,358 patients received treatment with curative intent and survived long enough for inclusion into the study. Of these patients, only 34% received surveillance scans, but the proportion increased significantly during the study period (30% in 2007 to 37% in 2011, p-trend = 0.0022). There were no differences seen in the receipt of imaging surveillance by demographic characteristics (age, sex, race/ethnicity). Overall survival was significantly higher for those who received a surveillance scan (31 months) compared to those who did not (26 months, p = 0.0011). When adjusted for clinical and demographic variables significantly associated with overall survival, the survival benefit persisted (HR 0.79, 95% CI 0.71-0.87). Conclusions: In this retrospective study, surveillance imaging after definitive treatment in stage III NSCLC patients was associated with improved survival. While just 34% patients received a scan, surveillance uptake improved over the 5-year study period. These data suggest that surveillance imaging has clinical utility.
Treatment patterns for metastatic melanoma in US community oncology clinical practice: A retrospective observational study.
Authors: Eric D. Whitman, Frank Xiaoqing Liu, Xiting Cao, Amin Haiderali, Amy Pickar Abernethy
Journal: Journal of Clinical Oncology (2016)

e21052 Background: The landscape of systemic therapy for advanced melanoma has been changing quickly, beginning in March 2011 with ipilimumab approval, followed by approvals of BRAF/MEK inhibitors, and in late 2014, the anti-programmed death 1 (PD1) agents, pembrolizumab and nivolumab. This retrospective observational study examined the evolution of contemporary treatment patterns for metastatic melanoma (mMel, stage IV). Methods: We utilized electronic health records (EHR) from a national sample of US community practices in the Flatiron Health oncology database. Eligible patients were ≥ 18 years old and initiated first-line (1L) therapy for mMel from 1/1/2013, to 3/31/2015. Additionally, we studied patients with mMel prescribed pembrolizumab from 9/1/2014, and those prescribed nivolumab from 12/1/2014, through 8/31/2015. The three cohorts were followed through 9/30/2015. Results: The main cohort included 726 patients with mMel, of median age 66 years and 67% male. Of 695 (96%) tumors tested for BRAF mutation, 45% were BRAF mutant, 53% BRAF wild-type, and 2% indeterminate. Forty 1L regimens were administered, the most common being ipilimumab (49%) and vemurafenib (17%). The most commonly prescribed 2L regimens were pembrolizumab (22%), ipilimumab (19%), dabrafenib plus trametinib (15%), and nivolumab (10%). Treatment regimens changed dramatically after 3Q2014. For 1L, ipilimumab-based and BRAF inhibitor regimens were administered less frequently in both BRAF-mutant and BRAF wild-type cohorts, of whom 45% and 60%, respectively, received an anti-PD1 agent in 3Q2015. For 2L, use of anti-PD1 agents increased to 59% in 3Q2015, while ipilimumab use fell from 30% in 3Q2014 to 11% in 3Q2015. In the anti-PD1 cohorts, pembrolizumab was prescribed in 1L (60/161; 37%), 2L (46%), and 3L or later (17%), likewise nivolumab (39/102 [38%], 31%; 30%, respectively), both most commonly prescribed as monotherapy. Conclusions: Our study results illustrate the rapidly changing landscape of therapy for mMel. The immediacy of information provided by EHR-based datasets enables the study of current treatment patterns to guide future decisions about optimal therapies for mMel.
Investigation of the clinicopathological features of vulva cancer: A retrospective survey of the JGOG Net Work study.
Authors: Shin Nishio, Takeo Shibata, Satoshi Yamaguchi, Hiroyuki Kanao, Atsumi Kojima, Munetaka Takekuma, Akiko Tozawa, Hideki Tokunaga, Etsuko Miyagi, Hisamori Kato, Kazuko Kurihara, Toru Yanase, Mikio Mikami, Toru Sugiyama
Journal: Journal of Clinical Oncology (2017)

e17029 Background: Vulvar cancer is a rare malignancy in women. During the past 30 years, large surveys of vulva cancer have not been performed in Japan. We therefore conducted a multicenter study to clarify the clinicopathological features of vulva cancer in Japan. Methods: In this multicenter retrospective cohort study, the clinical data of patients with vulva cancer were surveyed. The medical records of patients with vulvar cancer patients treated between 2001 and 2010 were retrospectively reviewed after obtaining approval from the Institutional Review Board of each institution. Survival analysis was performed using Kaplan-Meier curves. The effects of the clinical factors on overall survival were investigated using a Cox regression model. Results: A total of 1082 patients treated in 108 centers were studied. The median age was 72 years (range, 20 to 96). The disease stage was stage I in 415 patients (38.3%), stage II in 249 (23%), stage III in 255 (23.6%), and stage IV in 163 (15.1%) (FIGO 2009). The diagnosis was squamous cell carcinoma in 779 patients (72%), Paget’s disease in 158 (14.6%), adenocarcinoma in 63 (5.8%), and others in 82 (7.6%). Positive lymph nodes were found in 237 patients (21.9%). The median tumor diameter was 35 mm (range, 1 to 180). The 5-year overall survival was 86% in stage I, 74.7% in stage II, 48.2% in stage III, and 39.3% in stage IV (P &lt; 0.001), and that according to histology was 63.9% in squamous cell carcinoma, 57.1% in adenocarcinoma, 79.7% in Paget’s disease, and 85.4% in others. The hazard ratio was 0.51 in patients with a histology of Paget’s disease or others (vs. squamous cell carcinoma or adenocarcinoma; P = 0.001; 95% CI, 0.35-0.75), 2.14 in patients with a the number of positive lymph nodes 2 or more (vs. 0 or 1; P &lt; 0.001; 95% CI, 1.50-3.05), 2.10 in patients with a tumor diameter of ≥35mm (vs. &lt; 35mm; P = 0.001; 95% CI, 1.36-3.25). Conclusions: Treatment outcomes in Japanese patients with vulvar cancer were similar to those reported previously. However, squamous-cell carcinoma, adenocarcinoma, positive lymph nodes, and bulky tumors were associated with poor outcomes. Multidisciplinary treatment might be required in patients with these characteristics. Clinical trial information: UMIN000017080.
The Psychopharmacology of Effort-Related Decision Making: Dopamine, Adenosine, and Insights into the Neurochemistry of Motivation
Authors: John D. Salamone, Mercè Correa, Sarah Ferrigno, Jen-Hau Yang, Renee A. Rotolo, Rose E. Presby
Journal: Pharmacological Reviews (2018)

Effort-based decision making is studied using tasks that offer choices between high-effort options leading to more highly valued reinforcers versus low-effort/low-reward options. These tasks have been used to study the involvement of neural systems, including mesolimbic dopamine and related circuits, in effort-related aspects of motivation. Moreover, such tasks are useful as animal models of some of the motivational symptoms that are seen in people with depression, schizophrenia, Parkinson's disease, and other disorders. The present review will discuss the pharmacology of effort-related decision making and will focus on the use of these tasks for the development of drug treatments for motivational dysfunction. Research has identified pharmacological conditions that can alter effort-based choice and serve as models for depression-related symptoms (e.g., the vesicular monoamine transport-2 inhibitor tetrabenazine and proinflammatory cytokines). Furthermore, tests of effort-based choice have identified compounds that are particularly useful for stimulating high-effort work output and reversing the deficits induced by tetrabenazine and cytokines. These studies indicate that drugs that act by facilitating dopamine transmission, as well as adenosine A<sub>2A</sub> antagonists, are relatively effective at reversing effort-related impairments. Studies of effort-based choice may lead to the identification of drug targets that could be useful for treating motivational treatments that are resistant to commonly used antidepressants such as serotonin transport inhibitors.
Pacritinib (PAC) vs best available therapy (BAT) in myelofibrosis (MF): Long-term follow-up of patient-reported outcomes (PROs) in the phase III PERSIST-1 trial.
Authors: Ruben A. Mesa, Claire N. Harrison, Francisco Cervantes, James P. Dean, Lixia Wang, Tanya Granston, Yoojung Yang, Alessandro M. Vannucchi, Adam Mead
Journal: Journal of Clinical Oncology (2016)

7067 Background: MF is a life-threatening hematologic malignancy that can markedly impact patient (pt) quality of life. PERSIST-1 compared PAC vs BAT, excluding JAK2 inhibitors, in pts with MF, regardless of baseline (BL) platelet (plt) count. At wk 24, a significantly greater proportion of PAC- vs BAT-treated pts achieved ≥ 35% spleen volume reduction (ITT: 19.1% vs 4.7%, p = 0.0003, 1º end point) and ≥ 50% reduction in Total Symptom Score (TSS; ITT: 24.5% vs 6.5%, p < 0.0001) by the Myeloproliferative Neoplasm Symptom Assessment Form (MPN-SAF). This analysis examines PROs at wk 48. Methods: Pts (N = 327) were randomized 2:1 to oral PAC 400 mg qd or BAT. Eligibility criteria included: DIPSS Int-1, Int-2, or high-risk MF; ANC > 500/µL; no restriction on BL plt or hemoglobin; splenomegaly ≥ 5 cm. Pts had BL TSS ≥ 13 by MPN-SAF, each symptom was rated from 0 (absent) to 10 (worst imaginable). In agreement with the FDA, the protocol was amended to incorporate the updated MPN-SAF 2.0; 6 common symptoms from the original MPN-SAF and MPN-SAF 2.0 were used in a combined analysis to assess pt symptom burden. Pts could crossover from BAT to PAC after wk 24 or upon disease progression prior to wk 24. Analysis was based on pts with TSS assessments at BL and wk 48. Results: Among evaluable pts remaining on initial treatment (Tx) at wk 48, 46% and 17% of PAC- or BAT-treated pts, respectively, achieved ≥ 50% reduction in TSS (41% and 10% at wk 24). Among evaluable pts who crossed over from BAT to PAC, 15% and 31% achieved ≥ 50% reduction in TSS at 24 and 36 wks from crossover, respectively. From BL to wk 24, significant reductions in common symptoms were reported with initial PAC Tx; for all but bone pain, additional reductions in mean percent change were seen from wk 24 to wk 48 (Table). Conclusions: In pts with MF, PAC Tx led to durable improvements in PROs with additional symptom recovery over time, including with PAC Tx after crossover from BAT. Clinical trial information: NCT01773187.Initial Tx Wk 24 Wk 48 PAC (n = 146) BAT (n = 73) PAC (n = 99) BAT (n = 6) Mean % change from BL in Individual Symptom Scores Worst fatigue/tiredness –21 48 –25 5 Early satiety –35 4 –42 86 Abdominal discomfort –26 82 –30 48 Night sweats –53 101 –55 96 Pruritus –33 39 –52 198 Bone pain –24 4 –14 –65
Genetic correlates of therapeutic toxicities of stage III colon carcinoma patients treated with adjuvant FOLFOX+/-cetuximab (NCCTG N0147, Alliance).
Authors: Polly A. Newcomb, Wei Sun, Xinwei Hua, Barbara L. Banbury, Amanda I. Phipps, Jonathan Kocarnik, Tabitha A. Harrison, Qian Shi, Frank A. Sinicrope, Stephen N. Thibodeau, Emily Chan, Sharlene Gill, Richard M. Goldberg, Morton S. Kahlenberg, Suresh Nair, Anthony Frank Shields, Balkrishna N. Jahagirdar, Ulrike Peters, Steven R. Alberts, Andrew T. Chan
Journal: Journal of Clinical Oncology (2017)

3604 Background: Limited research has investigated the role of variation in the host genome as a determinant of colon carcinoma (CC) outcomes, including toxicity due to therapeutic agents. We examined the relationship between germline genetic factors and treatment-associated serious adverse events (SAEs) in a population of CC patients in which treatment was standardized and follow-up for outcomes was uniformly conducted. Methods: Using existing biospecimens from CC patients with resected stage III disease in a phase III randomized trial of FOLFOX adjuvant chemotherapy with and without cetuximab (NCCTG N0147), genome-wide genotyping arrays were conducted for 2200 patients for a total of ~20 million single nucleotide polymorphisms (SNPs). Using logistic regression models we assessed SNP-specific associations with SAEs, utilizing a discovery-based approach to search the genome in an unbiased manner. Detailed information on SAEs was collected using the Common Toxicity Criteria for Adverse Events (CTCAE, v3.0). Analyses evaluating associations with specific classes of common grade ≥3 SAEs were performed, including gastrointestinal toxicities, neutropenia, and paresthesias. A threshold of P &lt; 5x10 -8 was used to denote genome-wide significance. Results: Among patients who received FOLFOX, several SNPs on chr 15 near the ANP32A gene and on chr 2 near the CD207 gene were statistically significantly associated with grade ≥3 neuropathy. The strongest SNP-specific associations in these regions were in the range of odds ratio (OR) = 1.3, P = 2.8×10 −10 and OR = 1.5, P = 2.7×10 −10 , respectively. Conclusions: Findings from this genome-wide analysis demonstrate the potential importance of germline genetic variation in influencing CC patients’ experience of specific toxicities to FOLFOX regimens. These results highlight two genomic regions of potential interest for understanding the biological mechanism for such toxicities, although further evaluation and replication is needed. Support: U10CA180821, U10CA180882, U10CA180820, U10CA180863, U10CA180888, CCSRI 021039, R01CA176272, Eli Lilly &amp; Co, Pfizer, Sanofi. Clinical trial information: NCT00079274 .