tbuckley/cabot-search huggingface dataset:
Retrospective study of frequency and cost of multiple myeloma (MM) complications and treatment (Tx) related adverse events (AEs).
Authors: May Hagiwara, Sumeet Panjabi, Arati Sharma, Yaozhu (Juliette) J. Chen, Thomas E. Delea
Journal: Journal of Clinical Oncology (2016)

8060 Background: Disease-related complications and Tx related AEs (collectively “events”), such as anemia, neutropenia, thrombocytopenia, bone loss and fractures, and kidney disease affect patients with MM. Real-world data on the frequency and cost of these “events” is limited. Methods: This was a retrospective observational study using the MarketScan database. Adult patients with MM (ICD-9-CM code 203,0x) who initiated MM Tx between Jan 1, 2006 and Dec 31, 2014 were identified. Patients not enrolled continuously for 180 days pre-diagnosis until 30 days after initiation of first MM Tx were excluded. Receipt of new MM Tx or gaps >90 days between MM Txs were considered new line/s of Tx (LOT). For each patient and LOT, events and associated costs while on MM Tx were identified using diagnosis/procedure and medication claim codes. The mean cost of events per LOT was calculated. Results: A total of 12,648 patients qualified for the study (mean (SD) age 65 (12.5) y, 57% male), representing 20,869 LOT (61% 1L, 24% 2L, 9% 3L, 6% 4L+). Comorbidities preceding MM Tx included chronic pain (61%), hypertension (39%), chronic renal disease (21%), diabetes (15%), solid tumor (15%), coronary heart disease (11%), and hematologic cancer other than MM (10%). Among events studied post MM Tx, skeletal-related events (SREs) were most frequent (49% per LOT across all LOTs). Other events with a frequency ≥10% per LOT included anemia (23%), 2nd primary malignancies (21%), hypertension (20%), and febrile neutropenia (FN) (12%) (Table). The frequency of events was generally highest for 1L, except for FN and non-pneumonia infections, which were more frequent in later LOTs. Among events with frequency >10%, FN was the most costly event ($24,541/LOT) followed by SRE ($12,268/LOT). Conclusions: In pts with MM, disease-related complications and Tx related AEs are frequent and their associated costs are substantial. Frequency and costs of MM complications and Tx related AEs with frequency≥10% (N=20,869 LOTs). Frequency (%) On Tx Mean Cost/LOT ($) SREs 49 12,268 Anemia 23 5,763 2nd primary malignancies 21 7,091 Hypertension 20 2,454 FN 12 24,541 Non-pneumonia Infection 10 1,064 Vomiting 10 3,102
Antibody-interferon-alpha fusion protein (IGN002) for the treatment of b-cell non-Hodgkin lymphomas: A phase 1, first-in-human, dose-escalation trial.
Authors: Patricia Ann Young, Nam H. Dang, Loretta J. Nastoupil, Dena Minning, Michael J. Gresser, John Timmerman
Journal: Journal of Clinical Oncology (2016)

TPS3109 Background: Interferon alpha (IFNα) has anti-proliferative and pro-apoptotic effects against many cancers, including NHL, and promotes both innate and adaptive anti-tumor immunity, but the clinical utility of IFNα is hindered by dose-limiting toxicity due to systemic activation of IFN receptors. IGN002 is a novel recombinant protein comprising a chimeric IgG1 anti-CD20 antibody fused to human IFNα2b via a peptide linker. In preclinical studies against human B cell NHL, IGN002 exhibited stronger direct anti-proliferative effects, complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, and in vivo potency in xenograft models compared to rituximab (Timmerman et al, Blood 126:2762, 2015). Methods: This phase I, multicenter study (NCT02519270) was initiated in January 2016. Primary objectives are to evaluate the safety and tolerability of multiple weekly IV doses of IGN002 and determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D). Secondary objectives are to characterize the pharmacokinetics of IGN002, effects on circulating B cells, incidence of anti-IGN002 antibodies, and preliminary anti-tumor activity. Eligible patients have relapsed/refractory, measurable ( > 1.5 cm) CD20-positive NHL including diffuse large B cell, mantle cell, marginal zone, lymphoplasmacytic, follicular, transformed follicular, or primary mediastinal B-cell NHL, adequate organ functions, and ECOG PS 0-2. Exclusion criteria include small lymphocytic lymphoma/CLL; therapy with chemotherapy/small molecules, anti-CD20 antibodies or radiation within 28 days; allogeneic stem cell transplantation; CNS NHL; systemic autoimmune disease; or active infection. In the Dose-Escalation Stage, 8 cohorts of 3-6 patients will be treated at dose levels of 0.0001, 0.0003, 0.001, 0.003, 0.01, 0.03, 0.1, and 0.3 mg/kg. In Period 1, subjects will receive 2 weekly doses of IGN002, and then may receive up to 24 additional weekly doses in Period 2. In the Expansion Stage, 14 subjects will receive up to 24 weekly doses at the MTD or RP2D. These results will inform future studies of antibody-targeted IFNα therapy for NHL and other cancers. Clinical trial information: NCT02519270.
Allogeneic stem cell transplantation (Allo-SCT) for multiple myeloma (MM): The Mount Sinai experience.
Authors: Solmaz F. Afshar, Zachary Galitzeck, Mauricio Pineda-Roman, Amir Steinberg
Journal: Journal of Clinical Oncology (2017)

e19520 Background: Allo-SCT has been used as a curative treatment for MM, particularly for refractory patients (pts), but outcomes across institutions have shown varying results. In this study, we examined patient-, disease-, and transplant (tx)-related variables in pts of allo-SCT for MM at Mount Sinai. Methods: Adult pts undergoing allo-SCT for MM at Mount Sinai from 2008-2015 were included in this study. Identifying variables were extracted from reports to the CIBMTR. This study was approved by the IRB, and all pts signed informed consent. Our results were compared to the 2011 CIBMTR analysis of allo-SCT for MM pts. Results: 21 pts underwent allo-SCT for MM at a median of 36 months post diagnosis (range, 12-211 mo), while the CIBMTR reported 12 mo. The median age of pts at the time of tx was 53 years (range, 38-62 yrs) with 48% White, and Hispanic, Asian or Black each 14%. Pts had one or more autologous SCT prior to allo-SCT (90%) and the median time between txs was 31.1 mo (range, 0.7-195 mo). Pts were in DS stage III (52%), and the disease was partially responsive (38%) or showed progression (33%). 81% of pts underwent nonmyeloablative/reduced-intensity conditioning, and 86% received GVHD prophylaxis. Still, 38% of pts developed acute GVHD while 19% had chronic GVHD by 1 year post-tx, lower than CIBMTR’s analysis. There was a 52% survival rate at 6 mo post SCT and 29% by year 1, considerably lower than the 46% reported by the CIBMTR. The median time to death was 5 months (range, 1-40 mo), and the main cause was primary disease (37%). At the time of analysis, 2 pts were alive with a maximum survival of 8 years post-tx. Conclusions: The Mount Sinai experience of allo-SCT for MM pts revealed overall suboptimal outcomes during the 2008-2015 study period. Our pts underwent tx much later in the disease course relative to the CIBMTR’s study. Given the noted outcomes, alternative therapies were considered in the last 4 years of our analysis, resulting in half as many allo-SCT for MM pts during the latter time period. For optimal benefit, allo-SCT in selected MM should be performed earlier in the course of disease with improved pt selection. These modifications will be implemented via participation in an upcoming BMT/CTN clinical trial at our institution.
An open-label, uncontrolled, single arm phase II trial of the PI3K inhibitor buparlisib in patients with melanoma brain metastases.
Authors: Friedegund Elke Meier, Andrea Forschner, Marlene Garzarolli, Ricarda Rauschenberg, Stefan Beissert, Claus Garbe, Thomas K. Eigentler
Journal: Journal of Clinical Oncology (2017)

TPS9595 Background: The approval of effective BRAF +/- MEK inhibitors and immune checkpoint inhibitors has revolutionized the treatment of metastatic melanoma. However, available therapies appear to be less effective on cerebral than extracerebral metastases. Hyperactivation of the PI3K-AKT survival pathway is a prominent feature of melanoma brain metastases (MBM). This trial aims to determine the activity and safety of the PI3K inhibitor buparlisib in patients (pts) with MBM. Methods: The study enrolls adults suffering from MBM not eligible for neurosurgery or/and radiosurgery. Patients must have failed prior treatment with BRAF +/- MEK Inhibitors (BRAF-V600E mutated population) and anti-PD-1 or/and anti-CTLA-4 antibodies (BRAF wild-type population), respectively. Patients are treated with buparlisib 100 mg PO daily until disease progression or unacceptable toxicity. The Simon-Two-Step design for phase 2 studies was used to determine sample size. Assuming a response rate of 12.5% in comparison to historical 10% for chemotherapy 22 (8/14) pts would be required. If there are one or fewer responses in the first 8 pts the study would stop. Prespecified activity goal for the first stage of accrual was met; currently 11/22 pts are enrolled. Clinical trial information: NCT02452294.
Short-term outcomes from a multi-institutional, phase III study of laparoscopic versus open distal gastrectomy with D2 lymph node dissection for locally advanced gastric cancer (JLSSG0901).
Authors: Sang-Woong Lee, Tsuyoshi Etoh, Tetsuji Ohyama, Noriyuki Inaki, Shinichi Sakuramoto, Kazuhiro Yoshida, Keisuke Koeda, Kei Hosoda, Chikara Kunisaki, Kazuyuki Kojima, Takashi Yasuda, Akinori Takagane, Kazunari Misawa, Takahiro Kinoshita, Kazuhito Yajima, Shuji Takiguchi, Naoki Hiki, Norio Shiraishi, Seigo Kitano
Journal: Journal of Clinical Oncology (2017)

4029 Background: The safety of laparoscopic gastrectomy for advanced gastric cancer is controversial. We conducted a multi-institutional, randomized controlled trial to compare short- and long-term outcomes of laparoscopic distal gastrectomy (LAP) with D2 lymph node dissection for advanced gastric cancer in comparison to open distal gastrectomy (OP) in Japan (UMIN000003420). We herein demonstrate short-term outcomes of this trial. Methods: Patients with potentially curable gastric cancer (T2-T4, N0-2 and M0) by distal gastrectomy were eligible for inclusion. Between November 2009 and July 2016, 507 patients were randomly assigned to either the LAP group (n = 252) or the OP group (n = 255). Only credentialed surgeons in both the procedures from 37 Japanese institutions participated in the study. The primary endpoint was 5-year relapse free survival. Secondary endpoints were 5-year overall survival, adverse events and short-term clinical outcomes. Results: According to study protocol, 47 patients among the total eligible patients were excluded because of distant metastasis or tumor extension intraoperatively. The remaining 460 patients underwent distal gastrectomy with D2 lymph node dissection and were analyzed as per protocol. Estimated blood loss was lower in LAP than in OP (30 vs. 150 ml, P &lt; 0.001) and operative time was longer in LAP than in OP (291 vs. 205 min, P &lt; 0.001). Post-operative analgesics use was less in LAP than in OP (38.3 vs. 53.6 %, P = 0.001), and first day of flatus was shorter in LAP than in OP (2 vs. 3 days, P &lt; 0.001). There were no significant differences in all grade intra-operative complications (LAP 0.9% vs. OP 2.6%, P = 0.285). In addition, there were no significant differences in grade 3 and higher post-operative complications between the two groups (LAP 3.1% vs. OP 4.7%, P = 0.473). Hospital mortality was 0.4 % in each group. Conclusions: Credentialed surgeons could safely perform laparoscopic distal gastrectomy with D2 lymph node dissection for locally advanced gastric cancer. The laparoscopic approach could be accepted without increasing major surgical complications in this setting. Clinical trial information: 000003420.
Semi-automated platform for efficient and accurate annotation and interpretation of somatic variants in cancer.
Authors: Meaghan Russell, Julie Y Tse, Angeliki Pantazi, Andrew Bjonnes, Shermin Pei, Dana Vuzman, Jane Jiang, Maria Lvova, Jennifer E. Ring, Stephen Lyle, Shyamal Dilhan Weeraratne
Journal: Journal of Clinical Oncology (2018)

e18597 Background: Rapid advances in NGS technology have enabled high throughput generation of data allowing for more comprehensive approaches to precision medicine and improved cancer patient care. However, efficient and timely variant interpretation and reporting to guide physicians’ therapeutic decisions remains an unmet need. Manual interpretation of variants is onerous, unreproducible, and non-scalable. At the same time, full automation of highly-nuanced clinical interpretation without human intervention is still at a nascent stage and has high error rates. Herein, we describe development of a semi-automated platform that augments accuracy and efficiency of clinical interpretation and reporting by over 20-fold. Methods: To facilitate accurate and efficient variant interpretation and clinical reporting we developed and validated GENEKEEPER (KEW, Inc.; Cambridge, MA), a cloud-based knowledgebase and reporting tool. The underlying database architecture seamlessly integrates patient sequence data with numerous resources including, the internal knowledgebase, trial registries, professional guidelines, and other public databases. The internal knowledgebase includes over 40,000 variants from > 3,000 patient tumor specimens, annotated by PHD/MD expert analysts to be consistent with the AMP guidelines. Results: In an analysis of 20 sequenced tumors, curated using our platform, we noted a 10-fold increase in efficiency and 2-fold increase in accuracy as compared to manual curation. We also observed a near 100% congruency of reported clinical trials and therapies between different curators. The flexible architecture enabled facile implementation of AMP guidelines to enhance standardization and accuracy of variant interpretation. Overall the platform demonstrated a 20-fold increase in efficacy in report generation. Conclusions: Semi-automated curation platforms promote precision and efficacy in analyzing and reporting clinically relevant variants to guide informed treatment decisions. GENEKEEPER significantly reduces the laboriousness of manual curation and will empower clinical laboratories to exponentially scale-up NGS operations.
Neoadjuvant chemotherapy versus chemoradiation prior to esophagectomy: Impact on rate of complete pathologic response and survival in esophageal cancer patients.
Authors: Albert C. Lockhart, Pamela Parker Samson, Cliff Grant Robinson, Jeffrey D. Bradley, Varun Puri, Stephen R. Broderick, G Alexander Patterson, Bryan F Meyers, Traves Crabtree
Journal: Journal of Clinical Oncology (2016)

4054 Background: At this time, short-and long-term outcomes among locally advanced esophageal cancer patients receiving neoadjuvant chemotherapy versus chemoradiation therapy prior to esophagectomy remain poorly characterized with conflicting findings among various institutions. Methods: Esophageal cancer patients receiving either neoadjuvant chemotherapy or chemoradiation prior to esophagectomy were identified using the National Cancer Data Base (NCDB). Univariate analysis compared patient, tumor, and postoperative outcome characteristics. Logistic regression was performed to identify variables associated with achieving pCR. Kaplan-Meier analysis was performed to compare overall median survival by neoadjuvant therapy type and pCR status. Finally, a Cox proportional hazards model was fitted to identify variables associated with increased mortality hazard. Results: From 2006 – 2012, 916/7,338 (12.5%) of patients received neoadjuvant chemotherapy while 6,422 (87.5%) received neoadjuvant chemoradiation. Neoadjuvant chemoradiation patients were more likely to achieve pCR (17.2% versus 6.4%, p < 0.001) and less likely to have positive margins (5.6% versus 11.5%, p < 0.001) than neoadjuvant chemotherapy patients, with no difference in 30- or 90-day mortality. Achieving pCR was associated with improved overall median survival (59.5 months ± 4.0 versus 30.1 months ± 0.76 for those with persistent disease, p < 0.001). On logistic regression, neoadjuvant chemoradiation therapy was independently associated with achieving pCR (Odds Ratio 2.75, 2.01 – 3.77, p < 0.001). Despite improvement in pCR rate with neoadjuvant chemoradiation, neoadjuvant therapy type was not independently associated with long-term survival (HR 1.12, 95% CI 0.97 – 1.30, p = 0.12). Conclusions: While neoadjuvant chemoradiation is more successful in downstaging esophageal cancer prior to esophagectomy, this therapy was not independently prognostic for improved long-term survival. Other factors affecting long-term survival among pathologic complete responders and among patients with persistent disease should be investigated to clarify this association.
Mutational analysis and safety/efficacy in a phase 2 multi-center investigation of ABI-009 (<i>nab</i>-rapamycin) in patients with advanced malignant perivascular epithelioid cell tumors (PEComa).
Authors: Andrew J. Wagner, Richard F. Riedel, Brian Andrew Van Tine, Rashmi Chugh, Kristen N. Ganjoo, Lee D. Cranmer, Seth Pollack, Kamalesh Kumar Sankhala, Erlinda Maria Gordon, Vinod Ravi, Jason L. Hornick, David J. Kwiatkowski, Berta Grigorian, Neil Desai, Mark Andrew Dickson
Journal: Journal of Clinical Oncology (2018)

TPS11589 Background: PEComas are rare mesenchymal tumors with a female predominance, composed of epithelioid cells that show a focal association with blood vessel walls and usually express both melanocytic and smooth muscle markers. The prognosis of advanced malignant PEComa is poor, with a median survival of 12-17 months. There have been no prospective trials for PEComa. Case reports have shown that PEComas are often associated with the loss of tumor suppressor genes TSC1 or TSC2 which results in downstream activation of the mTOR complex, making mTOR inhibition a promising therapeutic strategy. ABI-009, albumin-bound rapamycin nanoparticle, is a novel mTOR inhibitor that can utilize albumin-mediated transport pathways to achieve enhanced tumoral drug delivery. This is the first prospective open-label multicenter study to assess mutational status and safety/efficacy of an mTOR inhibitor for advanced PEComa. Methods: At least 30 patients naive to mTOR inhibitors, with pathologically confirmed malignant PEComa that is either metastatic or locally advanced and for which surgery is not a recommended option, will be enrolled. ABI-009 at 100 mg/m2 IV, is given weekly for 2 out of 3 weeks (21-day cycle) until disease progression or unacceptable toxicity. The primary endpoint is overall response rate (ORR) assessed with CT/MRI scans via RECIST v1.1. This sample size will be sufficient to exclude an inactive regimen ( < 15% ORR) with 95% confidence. Secondary endpoints are duration of response, 6-month progression-free survival (PFS), median PFS, median overall survival, and safety. Patient tumor mutational analysis, including exome sequencing of 300 genes including TSC1/2 and mTOR pathway genes, and circulating DNA analysis, will be performed. Exploratory endpoints include PK/PD relationships for safety and/or efficacy endpoints, and correlative studies with baseline TSC mutational analysis and tumor biomarkers. The study is ongoing as of February 2018. Clinical trial information: NCT02494570.
Inhibition of the Wnt/β-catenin pathway to promote T-cell immunity and survival in a syngeneic mouse model of ovarian cancer.
Authors: David W Doo, Angelina Londono, Selene Meza-Perez, Ashwini A. Katre, Sara J Cooper, John Michael Straughn, Donald J. Buchsbaum, Lyse Norian, Troy Randall, Rebecca Christian Arend
Journal: Journal of Clinical Oncology (2018)

5566 Background: The Wnt/β-catenin pathway downregulates protective immunity mediated by intra-tumoral CD8+T cells, resulting in immune exclusion across cancer types. WNT974 inhibits the enzyme porcupine, which controls Wnt ligand secretion. Our objective was to evaluate the effects of Wnt inhibition on tumor growth, immune response, and survival in a syngeneic mouse model of ovarian cancer (OVCA). Methods: C57BL/6 mice were injected subcutaneously (SC) or intraperitoneally (IP) with 7 x 106 ID8 mouse OVCA cells. After 28 days, WNT974 or vehicle control was administered by oral gavage for up to 28 days. SC tumors were measured with calipers and tumors were harvested for NanoString gene expression profiling. Mice with IP tumors were kept to evaluate survival, or sacrificed after 14 days of treatment and omental tumor weights and ascites volume were measured. Flow cytometry was used to evaluate the immune response in IP tumors. Results: In the SC model, treatment with WNT974 reduced tumor size compared to vehicle control at day 60 (22.4 vs. 41.0 mm2, p = 0.0001). A gene signature of T cell infiltration was upregulated in SC tumors of WNT974-treated mice (p = 0.038). In the IP model, ascites volume (0.06 vs. 5.95 mL, p = 0.019) and number of ascites cells (2.60 x 107 vs. 7.45 x 107 cells, p = 0.019) were decreased after treatment with 14 days of WNT974. Analysis of the omental tumors revealed an increased ratio of CD8+ T cells to T regulatory cells in the WNT974-treated mice (2.90 vs. 1.67, p = 0.024), as well as an increased number of dendritic cells (23,613 vs. 8,332 cells, p = 0.045). A higher frequency of CD8+ T cells were found to express granzyme B (91.8 vs. 26.6%, p < 0.0001) and TNF-α (31.1 vs. 0.84%, p < 0.0001) after treatment with WNT974. Survival was significantly improved in the WNT974-treated group (p = 0.007). Conclusions: Using a syngeneic OVCA mouse model, treatment of ID8 tumor-bearing mice with WNT974 decreased tumor growth and ascites and prolonged survival. This effect coincided with an upregulated anti-tumor immune response, suggesting that the Wnt/β-catenin pathway may be an important immunomodulatory target in ovarian cancer.
TCT-110 Incidence, predictors, and outcomes of DAPT disruption due to non-compliance versus bleeding after PCI: insights from the PARIS Registry
Authors: Kamilia Moalem, Usman Baber, Jaya Chandrasekhar, Bimmer Claessen, Samantha Sartori, Melissa Aquino, George Dangas, Antonio Colombo, Annapoorna Kini, C. Michael Gibson, Mitchell Krucoff, Alaide Chieffo, David Moliterno, Bernhard Witzenbichler, Stuart Pocock, Roxana Mehran
Journal: Journal of the American College of Cardiology (2018)
Bcor insufficiency promotes initiation and progression of myelodysplastic syndrome
Authors: Shiro Tara, Yusuke Isshiki, Yaeko Nakajima-Takagi, Motohiko Oshima, Kazumasa Aoyama, Tomoyuki Tanaka, Daisuke Shinoda, Shuhei Koide, Atsunori Saraya, Satoru Miyagi, Ichiro Manabe, Hirotaka Matsui, Haruhiko Koseki, Vivian J. Bardwell, Atsushi Iwama
Journal: Blood (2018)