bluuebunny/crossref_metadata_2025_split huggingface dataset:
A phase II trial of the DNA methyl transferase inhibitor, SGI-110 (Guadecitabine), in children and adults with SDH-deficient GIST, pheochromocytoma, and paraganglioma, and HLRCC-associated kidney cancer.
Authors: Wedekind Mary Frances , Del Rivero Jaydira , Arnaldez Fernanda Irene , Srinivasan Ramaprasad , Spencer Melissa , Steinberg Seth M. , Peer Cody J. , Figg William Douglas , Killian Jonathan Keith , Meltzer Paul S. , Linehan W. Marston , Widemann Brigitte C. , Glod John 
Published: May 2020

11540 Background: Loss of activity of the Krebs cycle component succinate dehydrogenase (SDH) complex is a mechanism of tumorigenesis in SDH-deficient cancers. Accumulation of the metabolite succinate inhibits α-ketoglutarate-dependent dioxygenases leading to DNA hypermethylation. Guadecitabine is a small molecule DNA methyltransferase inhibitor. We conducted a Phase II study to test the hypothesis that guadecitabine will impact tumor growth by reversing DNA hypermethylation in tumors with Krebs cycle abnormalities (NCT03165721). Study Objectives: Our primary objective was to assess the clinical activity of guadecitabine in patients with SDH-deficient GIST, PHEO/PGL, and HLRCC-associated renal cell carcinoma. Secondarily, we desired to evaluate the toxicities of patients on treatment with guadecitabine. Methods: We conducted a single site, open label, phase II study using a small optimal two-stage design to evaluate response in SDH-deficient GIST, PHEO/PGL, and HLRCC-associated renal cell carcinoma. Patients >12 years of age received guadecitabine subcutaneously at 45mg/m2/day for 5 consecutive days on a 28-day cycle. Activity via imaging response was assessed utilizing RECISTv1.1. Toxicities were graded using version 4.0 of the NCI Common Toxicity Criteria. All patients were included in analysis. Results: We enrolled nine patients (6F:3M) with an age range of 18-57 years. Seven patients had SDH-deficient GIST (78%), one patient with paraganglioma (11%), and one with HLRCC-associated renal cell carcinoma (11%). No patients had a complete or partial response. Five patients came off study due to progression (56%) with one death due to disease progression in the patient with HLRCC-associated renal cell carcinoma (11%). Three patients (33%) withdrew due to lack of response with stable disease. One patient was withdrawn due to investigator’s discretion (11%). Toxicities possibly, probably, or definitely related to drug included grade 3 leukopenia (11%) febrile neutropenia (11%), grade 3-4 neutropenia (22%) requiring dose reductions, grade 3 hypertension (11%), grade 2 lung infection requiring hospitalization (11%). Conclusions: In this single site, open label, phase II study in patients with SDH-deficient GIST, PHEO/PGL, and HLRCC-associated renal cell cancer guadecitabine was tolerated by the majority of patients. No complete or partial responses were observed. Clinical trial information: NCT03165721 .
Immune-checkpoint genes as predictive biomarkers of trabectedin in advanced soft-tissue sarcoma (STS): A Spanish Group for Research on Sarcomas (GEIS) translational study.
Authors: Moura David Silva , Hindi Nadia , Lopez-Alvarez Maria , Sanchez-Bustos Paloma , Carrasco-Garcia Irene , Santos-Fernandez Paloma , Martinez-Delgado Paula , Lacerenza Serena , Blanco-Alcaina Elena , Mondaza-Hernandez Jose Lucinio , Gutierrez Antonio , Alvarez Rosa Maria , Cordeiro Magda , De Sande González Luis Miguel , Marquina Gloria , Cano Juana Maria , Cruz Jurado Josefina , Valverde Morales Claudia Maria , Martinez-Trufero Javier , Martin Broto Javier 
Published: May 2020

11546 Background: Despite several second-line options are accessible for the treatment of advanced STS, there is a lack of predictive biomarkers available to support the rational selection of these drugs. Trabectedin specifically targets mononuclear cell lineage (macrophages and monocytes) that ultimately could inhibit tumor angiogenesis. Moreover, trabectedin seems to induce the expression of immune-checkpoint proteins (e.g. PD-L1); however, the predictive value of these factors remains unknown. We present the analyses of immune-checkpoint genes ( CD274, CD86, CTLA4, HAVCR2, LAG3 and PDCD1) and CD163, CD4, CD68 and CD8A expression as potential predictive factors of response to trabectedin in a subset of STS patients of the GEIS registry. Methods: Selection criteria included patients with STS, pretreated with at least 2 lines in the advanced setting (one line being trabectedin), with paraffin block available and ethic committee’s approval. Direct transcriptomics was performed using HTG Molecular Oncology Biomarker Pathway panel (HTG Molecular Diagnostics, Inc.; Tucson, AZ, USA), following manufacturers’ instructions. Data analyses were performed taking into account the median Log2 of expression of each gene and by correlating it with progression-free survival (PFS) for trabectedin, and overall survival measured from the starting date of trabectedin treatment (OS). Results: Among 387 registered patients, fitting with the inclusions criteria, 139 cases were used for gene expression analyses, as the discovery set. Patients had median age of 52 years, 54% were females and had a median follow-up from diagnosis of 44 months. High expression of CD274 (PD-L1) was significantly associated with better PFS of trabectedin (5.4 vs. 3.0 months; p= 0.006). Similar results were obtained with high expression of CTLA4 and LAG3: 6.0 vs 3.1 months; p = 0.005 and 5.4 vs 2.7 months; p = 0.042, respectively. Expression of CTLA4 and LAG3 showed no significant impact in OS; whereas CD274 high expression showed a trend towards better OS (17.9 vs 10.2 months; p = 0.077). Also, no significant correlation was achieved for CD163, CD4, CD68, CD8A, CD86 and HAVCR2; PDCD1 (PD-1) showed a trend towards better PFS of trabectedin, p = 0.114. Conclusions: The expression of selected immune-checkpoint genes exhibited a potential predictive value for trabectedin in advanced STS. Validation studies (at the transcriptional and protein level) are currently ongoing to confirm their potential predictive role.
Comparison of different systemic therapeutic regimes in resectable high-risk soft tissue sarcoma: Results of a network meta-analysis.
Authors: Haussmann Jan , Budach Wilfried , Boelke Edwin , Tamaskovics Balint , Djiepmo Njanang Freddy Joel , Corradini Stefanie , Kammers Kai , Wessalowski Ruediger , Matuschek Christiane 
Published: May 2020

11549 Background: The treatment of high-risk soft tissue sarcoma of the trunk or the extremities consists of surgical resection with risk-adapted radiation therapy. Further treatment options which can significantly improve local and systemic tumor control including chemotherapy are not well established. Due to the heterogeneity of disease different systemic approaches as well as their application during different time points have been attempted. Methods: We conducted a literature search for randomized clinical trials in the treatment of localized, resectable high-risk soft tissue sarcoma comparing different treatment modalities according to the PRISMA guidelines. We extracted published hazard ratios and number of events for the endpoints of overall and disease-free survival (OS; DFS) as well as local and distant recurrence-free interval (LRFI; DRFI). The different modalities were compared in a network meta-analysis against the defined standard treatment surgery ± radiotherapy using the inverse-variance heterogeneity model (ivhet) with the help of the Microsoft Excel add-in Meta-XL V5.3. Results: The literature search identified 25 studies including 3489 patients. The network analysis showed that adjuvant chemotherapy (adjCTx) results in a significant improvement in overall survival (HR = 0.86; CI-95%: 0.75-0.97; p = 0.017) compared to the standard treatment of surgery ± radiatherapy alone. Combined treatment with regional hyperthermia and neoadjuvant chemotherapy (HTx+nadjCTx) also improves OS (HR = 0.45; CI-95%: 0.20-1.00; p = 0.049). Preoperative chemotherapy alone (nadjCTx) as well as perioperative chemotherapy (periopCTx) resulted both in non-statistically significant improvements in OS (HR = 0.61; CI-95%: 0.29-1.29; p = 0.195) and (HR = 0.48; CI-95%: 0.15-1.55; p = 0.218). Histology-tailored neoadjuvant chemotherapy (tNaCTx) also showed no effect on overall survival (HR = 1.08; CI-95%: 0.45-2.61; p = 0.868). The analysis of DFS, LRFI and DRFI disclosed a similar pattern between the different treatment regimens. Conclusions: The addition of cytotoxic chemotherapy in resectable high-risk soft tissue sarcomas provides a measurable benefit in overall survival. Shifting of systemic therapy to the neoadjuvant setting and combination with regional hyperthermia might be favored. Predictive clinical and molecular markers are needed to evaluate and limit potentional risks prospectively going forward.
Phase Ib study of decitabine in combination with gemcitabine in treatment of advanced soft tissue and bone sarcomas.
Authors: Monga Varun , Dodd Rebecca , Scherer Amanda , Gutierrez Wade Robert , Tanas Munir , Mott Sarah L. , Milhem Mohammed M. 
Published: May 2020

11550 Background: Sarcomas are a heterogeneous group of tumors and are associated with high rates of metastases leading to poor prognosis. Numerous epigenetic changes including hypermethylation have been identified in several sarcoma subtypes. Restoration of normal methylation patterns using DNA hypomethylating agent when combined with chemotherapy has shown to slow tumor growth in preclinical studies. Low continuous dosing of hypomethylating agent has epigenetic modulating effect with less toxicity. We conducted a Phase 1b study evaluating safety & tolerability and identifying the recommended phase 2 dose (RP2D) of subcutaneous (SQ) decitabine (DEC) given with fixed dose infusion gemcitabine (GEM) in patients with advanced soft tissue sarcomas (STS) and bone sarcomas. Methods: Eligible patients at least age 18 yrs with metastatic histologically confirmed STS or bone sarcoma after progression on one line or if refused adriamycin for STS were included. Prior GEM use was permitted. A modified 3+3 dose escalation design was used exploring two dose cohorts of DEC, 0.1 and 0.2 mg/kg SQ administered on a twice weekly schedule for three weeks and GEM given as 900 mg/m2, IV over 90 min on days 1, 8 & 15 of a 28-day cycle. Treatment was continued until disease progression or unacceptable toxicity. Dose limiting toxicity (DLT) was defined as any drug related non-hematological grade 3 or 4 toxicity per CTCAE v4.0. Disease assessment was performed every 8 weeks using RECIST v1.1. Results: 31 patients (25 STS & 6 bone sarcomas) were enrolled of which 7 were non-evaluable. There were 12 evaluable patients in each dosing cohort. Of the total 744 adverse events (AE) 17.2% were grade 3/4 and most were neutropenia without neutropenic fever. 45.7% AEs were possibly (44.6%) or probably (1.1%) attributed to DEC use. The toxicities were not significantly different between DEC doses. No DLTs were observed. One patient died due to progressive disease. Conclusions: Combination of fixed dose infusion GEM with low dose subcutaneous DEC is moderately toxic. Most toxicities were hematological. While there were few responses, the RP2D of DEC selected was 0.1 mg/kg as it showed prolonged disease stabilization. Clinical trial information: NCT02959164 . [Table: see text]
Effect of integrating machine learning mortality estimates with behavioral nudges to increase serious illness conversions among patients with cancer: A stepped-wedge cluster randomized trial.
Authors: Manz Chris , Parikh Ravi Bharat , Evans Chalanda N. , Chivers Corey , Regli Susan B , Changolkar Sujatha , Bekelman Justin E. , Small Dylan , Rareshide Charles A.L. , O'Connor Nina , Schuchter Lynn Mara , Shulman Lawrence N. , Patel Mitesh S. 
Published: May 2020

12002 Background: Most patients with cancer die without a documented serious illness conversation (SIC) about prognosis and goals. Interventions that increase SICs between oncology clinicians and patients may improve goal-concordant care and end-of-life outcomes. Methods: In this stepped-wedge cluster randomized trial (NCT03984773), we tested the effect of an intervention delivering machine learning-based mortality estimates with behavioral nudges to oncologists to increase SICs among patients with cancer. The clinician-focused intervention consisted of 1) weekly emails providing individual SIC performance feedback (number of SICs in the past month) and peer comparisons; 2) a list of patients scheduled for the next week with a ≥10% predicted risk of 6 month mortality by a validated machine learning prognostic algorithm, and 3) automated opt-out text prompts on the patient’s appointment day to consider an SIC. Eight medical oncology clinics were randomized to receive the intervention in a stepped-wedge fashion every four weeks for a total of 16 weeks. Medical oncology clinicians were included if they were trained to use the SIC Guide (Ariadne Labs, Boston MA). Patients were included if they had an outpatient encounter with an eligible clinician between June 17 and November 1, 2019. The primary outcome was the percent of patient encounters with a documented SIC. Intention to treat analyses adjusted for clinic and wedge fixed effects and clustered at the oncologist level. Results: The sample consisted of 78 clinicians and 14,607 patients. The mean age of patients was 61.7 years, 55.7% were female, 70.4% were white, and 19.6% were black. The percent of patient encounters with an SIC was 1.2% (106/8536) during the pre-intervention period and 4.0% (401/10,152) during the intervention period. In intention to treat adjusted analyses, the intervention led to a significant increase in SICs (adjusted odds ratio, 3.7; 95% CI, 2.5 to 5.4, P value < 0.0001). Conclusions: An intervention consisting of machine learning mortality estimates and behavioral nudges to oncology clinicians increased SICs by three-fold over 16 weeks, a significant difference.This is one of the first studies evaluating a machine learning-based behavioral intervention to improve serious illness communication in oncology. Secondary analyses (completed April 2020) will clarify whether this intervention leads to a sustained increase in SIC rates and improves goal-concordant care and end-of-life outcomes. Clinical trial information: NCT03984773 .
Risk of cardiovascular disease in women with and without a history of breast cancer: The Pathways Heart Study.
Authors: Greenlee Heather , Iribarren Carlos , Neugebauer Romain , Rana Jamal S , Nguyen-Huynh Mai , Cheng Richard , Shi Zaixing , Izano Monika , Laurent Cecile , Lee Valerie S. , Roh Janise M. , Shen Hanjie , Santiago-Torres Margarita , Hershman Dawn L. , Kushi Lawrence H. , Kwan Marilyn L. 
Published: May 2020

12016 Background: Breast cancer (BC) survivors are at increased risk of cardiovascular disease (CVD) following diagnosis, as compared to women without BC. To provide a population-based estimate of CVD risk in BC survivors, we compared risk of CVD events in women with and without BC history enrolled in the Kaiser Permanente Northern California (KPNC) integrated health system. Methods: Data were extracted from KPNC electronic health records. All invasive BC cases diagnosed between 2005-2013 were identified and matched 1:5 with non-BC controls on birth year, race/ethnicity and KPNC membership at date of BC diagnosis. Cox regression models were used to assess differences in the hazard of four major CVD events (ischemic heart disease (IHD), heart failure (HF), cardiomyopathy, and stroke). Models were adjusted for factors known to influence risk of breast cancer or CVD.Other CVD events included arrhythmia, cardiac arrest, carotid disease, myocarditis/pericarditis, transient ischemic attack, valvular disease, and venous thromboembolism (VTE). We additionally examined subgroups of cases who received chemotherapy, radiation, and endocrine therapy, and their controls. Results: A total of 14,942 women with a new diagnosis of invasive BC were identified and matched to 74,702 women without BC history. On average, women were 62.0 years, 28.3 kg/m2BMI, 64.9% non-Hispanic white. Among all cases and controls, there were no significant differences in hazard of developing IHD, cardiomyopathy, and stroke; there was a borderline difference in HF (HR: 1.08, 95% CI: 0.99, 1.19). Cases were more likely to have a cardiac arrest (HR: 1.39, 95% CI: 1.09, 1.78) and develop VTE (HR: 1.97, 95% CI: 1.74, 2.23). Women treated with chemotherapy were more likely than controls to develop HF (HR: 1.44, 95% CI: 1.21, 1.72), cardiomyopathy (HR: 2.01, 95% CI: 1.02, 3.98), and VTE (HR: 3.15, 95% CI: 2.62, 3.79). Women who received radiation therapy were more likely to develop carotid disease (HR: 5.49, 95% CI: 1.22, 24.66) and VTE (HR: 1.65, 95% CI: 1.35, 2.03) than controls. Women who received endocrine therapy were more likely to experience a cardiac arrest (HR: 1.49, 95% CI: 1.07, 2.09) and develop VTE (HR: 1.70, 95% CI: 1.42, 2.03) than controls. Conclusions: Women with BC were at increased risk of heart failure, cardiomyopathy, cardiac arrest, VTE and carotid disease. These risks varied by cancer treatment, with higher risk in those who received chemotherapy. Future studies should explore the effects of chemotherapy class and radiation dose exposure on diverse CVD endpoints in BC survivors.
Temporal trends in opioid prescribing patterns among oncologists in the Medicare population.
Authors: Jairam Vikram , Yang Daniel X. , Pasha Saamir , Soulos Pamela R. , Gross Cary Philip , Yu James B. , Park Henry Soo-Min 
Published: May 2020

12022 Background: In the wake of the United States (U.S.) opioid epidemic, there have been significant governmental and societal efforts to curb opioid prescribing. However, it is unknown whether these efforts have affected prescribing among oncologists, whose patient population often requires narcotics for symptom management. We investigated temporal patterns in opioid prescribing for Medicare patients among oncologists. Methods: We queried the Centers for Medicare and Medicaid Services Part D prescriber dataset to identify independently practicing physicians between January 1, 2013 and December 31, 2017. We used population-averaged multivariable negative binomial regression to estimate the association between time and per-provider opioid prescribing rate, defined as number of opioid claims (original prescriptions and refills) per 100 patients, among oncologists and non-oncologists on both a national and statewide level. All models were adjusted for provider characteristics and annual total patient count per provider. Results: The final study sample included 20,513 oncologists and 711,636 non-oncologists. From 2013 to 2017, the national opioid prescribing rate declined by 19.3% (68.8 to 55.5 opioid prescriptions per 100 patients; P< 0.001) among oncologists and 20.4% (50.7 to 40.3 prescriptions per 100 patients; P< 0.001) among non-oncologists. During this timeframe, 40 U.S. states experienced a significant ( P< 0.05) decrease in opioid prescribing among oncologists, most notably in Vermont (-43.2%), Idaho (-34.5%), and Maine (-32.8%). In comparison, all 50 states exhibited a significant decline ( P< 0.05) in opioid prescribing among non-oncologists. In 5 states, opioid prescribing decreased more among oncologists than non-oncologists, including Oklahoma (-24.6% vs. -7.1%), Idaho (-34.5% vs. -17.8%), Utah (-31.7% vs. -18.7%), Texas (-19.9% vs. -14.7%), and New York (-24.0% vs. -19.7%) (all P< 0.05). Conclusions: Between 2013 and 2017, the opioid prescribing rate decreased by approximately 20% nationwide among both oncologists and non-oncologists. These findings raise concerns about whether opioid prescribing legislation and guidelines intended for the non-cancer population are being applied inappropriately to patients with cancer and survivors.
FDA analysis of ECOG performance status and safety outcomes.
Authors: Singh Harpreet , Gong Yutao , Roy Pourab , King-Kallimanis Bellinda , Bhatnagar Vishal , Pazdur Richard , Kluetz Paul Gustav 
Published: May 2020

12024 Background: Patients with poor performance status are often excluded from clinical trials. The FDA has published several guidances on modernizing oncology clinical trial eligibility criteria to more accurately reflect the patient population. Many patients receiving novel oncology therapeutics are heavily pretreated, and often have comorbidities, organ dysfunction, and frailty syndromes. Little is known about the safety of novel therapeutics in patients with poor performance status. Methods: Data from six randomized trials (n=4465) leading to registration for several solid tumor and malignant hematologic cancers, including multiple therapeutic mechanisms of action, such as EGFR TKI’s, immune checkpoint inhibitors (ICI), and chemotherapy, were pooled. Cumulative incidence of Grade 3-5 adverse events and serious adverse events at Days 30, 90, and 180 were evaluated based on ECOG 0-2. Rates of treatment discontinuation by ECOG was also examined. Results: Cumulative incidence of toxicity events at days 30, 90, and 180 are shown in Table. Patient dropout rates due to death were 3.9%, 6.7%, and 10.9%; dropout rates due to disease progression were 66.5%, 66.6% and 56.9%; and dropout rates due to reasons other than progression or death were 29.7%, 26.7% and 32.1% for ECOG PS 0, 1 and 2, respectively. Conclusions: This FDA exploratory analysis of safety outcomes in registration trials based on ECOG suggests increasing rates of adverse events and rates of treatment discontinuation due to death with worsening performance status. Discontinuation rates due to disease progression and other reasons did not appear to be worse for ECOG 2 compared to 0-1. These findings were consistent across therapies (targeted therapy, ICI, chemotherapy). All trials in the analysis led to FDA approval, thus inclusion of patients with ECOG 2 did not adversely affect the trial outcome for this set of FDA approved agents. ECOG performance status eligibility criteria should be evaluated and modified on a frequent basis during drug development. Additional analysis of trials which enroll patients with ECOG 2 is needed. [Table: see text]