tbuckley/cabot-search huggingface dataset:
Assessing the activity of combining PARP inhibitors (PARPi) and Nicotinamide phosphoribosyltransferase inhibitors (NAMPTi) in Ewing sarcoma (ES).
Authors: Christine Heske, Mindy I Davis, Joshua T Baumgart, Kelli Wilson, Mike V Gormally, Xiaohu Zhang, Damien Y Duveau, Rajarshi Guha, Marc Ferrer, Arnulfo Mendoza, Craig J Thomas, Lee J. Helman
Journal: Journal of Clinical Oncology (2016)

11022 Background: PARPi have emerged as an intriguing new treatment strategy for patients with ES. However, single agent activity of PARPi in preclinical in vivo models and early phase clinical trials in ES have failed to demonstrate meaningful responses, necessitating the use of rational combinations. PARP enzymes mediate DNA repair and, importantly, utilize NAD as a necessary substrate. Thus far, PARPi combination studies have focused on DNA damaging agents in anticipation of enhanced efficacy, but have been limited by toxicity. In this study, we examined PARPi combinations with NAMPTi, which block a rate-limiting step in NAD production, to assess synergistic potential in preclinical models of ES. Methods: Using a high-throughput combination screening platform, ES cell lines were profiled versus a library of more than 1900 approved and investigational drugs. Active agents were advanced into combination studies versus multiple ES cell lines. For in vivo studies, female SCID-beige mice were orthotopically injected with ES cells and randomized for drug treatment studies. Tumors were measured twice per week with calipers, and mice were weighed weekly to determine drug tolerability. Results: The combination of NAMPTi and PARPi was among the most synergistic discovered during the HTS effort. Importantly, synergy was noted for multiple NAMPTi and PARPi across multiple ES cell lines, and the effect on cell viability could be abrogated by adding nicotinamide mononucleotide (NMN), the product of the NAMPT pathway. In multiple xenograft models of ES, short-term dosing of single agent niraparib (a PARPi) showed no activity, as expected. GNE-618 (a potent NAMPTi) showed only temporary disease stabilization as a single agent. The combination, however, resulted in dramatic tumor regressions and prolonged delays in tumor regrowth. Tolerability was excellent with no toxicity-related deaths or weight loss in treated mice. Mechanistic and pharmacodynamic studies of tumors are ongoing and will be reported. Conclusions: Preclinical data suggest that combining PARPi and NAMPTi may be a promising therapeutic strategy for ES patients.
Randomized, open-label, phase 3 study of subcutaneous daratumumab (DARA SC) versus active monitoring in patients (Pts) with high-risk smoldering multiple myeloma (SMM): AQUILA.
Authors: S.Vincent Rajkumar, Peter Michael Voorhees, Hartmut Goldschmidt, Ross I. Baker, Rajesh Bandekar, Steven Kuppens, Tobias Neff, Ming Qi, Meletios A. Dimopoulos
Journal: Journal of Clinical Oncology (2018)

TPS8062 Background: Current guidelines for SMM recommend active monitoring for progression to symptomatic MM before initiating treatment as standard of care. Earlier treatment may benefit pts with SMM at high risk of progression. DARA, a CD38-targeted monoclonal antibody, is approved as monotherapy and in combination with standard of care for relapsed/refractory MM (RRMM). In a phase 1b RRMM study, a SC co-formulation of DARA with recombinant human hyaluronidase (rHuPH20; DARA SC) showed low infusion reaction rates and similar response rates to those seen with intravenous (IV) DARA in RRMM. Given the encouraging single-agent activity of IV DARA observed in a phase 2 SMM study (12-month PFS rate: 95%), we hypothesized that DARA SC may delay progression of high-risk SMM to MM compared with active monitoring. Methods: AQUILA is an ongoing, phase 3, randomized, open-label, multicenter study of DARA SC (1,800 mg DARA + rHuPH20 [2,000 U/mL] administered by manual injection (15 mL) over approximately 5 minutes at alternating abdominal locations QW for Cycles 1 and 2, Q2W for Cycles 3-6, and Q4W thereafter for up to 39 cycles or 36 months; 28-d cycles) versus active monitoring (no study medication). Eligible pts (≥18 y) have had a confirmed diagnosis of SMM for ≤5 y, have factors indicating a high risk of progression (clonal bone marrow plasma cells [BMPCs] ≥10% + ≥1 of the following: serum M protein ≥30 g/L, IgA SMM, immunoparesis with reduction of 2 uninvolved Ig isotypes, serum involved:uninvolved free light chain ratio ≥8- < 100, or clonal BMPCs > 50%- < 60% with measurable disease), and have an ECOG performance status of ≤1. The primary endpoint is PFS as assessed by an independent review committee. Secondary endpoints include time to biochemical or diagnostic (SLiM-CRAB) progression, ORR, complete response rate, duration of and time to response, time to first-line treatment for MM, progression-free survival on first-line treatment for MM (PFS2), incidence of MM with adverse prognostic features, and OS. Disease will be evaluated per International Myeloma Working Group response criteria. Approximately 360 pts will be randomized (1:1) to the 2 arms. Clinical trial information: NCT03301220.
Apatinib in patients with adenocarcinoma of stomach or gastroesophageal junction: A prospective, multicenter, non-interventional study (Ahead-G202).
Authors: Chunmei Bai, Diansheng Zhong, Xiu-Bao Ren, Ruixing Zhang, Likun Liu, Nan Du, Mudan Yang, Junyan Yu, Zhanzhao Fu, Aimin Zang, Junping Zhang, Jianfeng Diao, Yuchuan Ren, Jinghua Gao, Huaqing Wang, Jun Guo, Lei Zhang, Liwen MA, Junmei Jia, Guozhong Li
Journal: Journal of Clinical Oncology (2018)

e16047 Background: This study observed the efficacy and safety of apatinib in patients with advanced gastric adenocarcinoma, helping elucidate the optimal initial dose in the real world with wider inclusion criteria. Methods: This trial enrolled patients(pts) from 32 centers in China who had disease progression after at least two lines of systemic chemotherapy, or pts who were considered to be benefit from the treatment. Pts received oral apatinib 500 mg once daily, and dose could be adjusted according to the pts’ physical condition and the doctors’ experience. The tumor response was determined according to RECIST 1.1 criteria; the adverse events (AEs) were graded using CTCAE version 4.0. Results: Between Mar 2015 and Dec 2017, 391 pts were identified to have received apatinib. The median age was 62 years and the ratio of male to female was about 2:1(266:125). Among the eligible pts, 145 received apatinib at an initial dose of 250 mg (Group A), 228 received at the dose of 425-500 mg (Group B), and only 18 received at the dose of 750-850 mg (Group C). There were 272 pts received survival analysis and 186 among them received efficacy evaluation. 15 pts had partial response (PR) and 124 pts had disease stability (SD), achieving an ORR of 8.1% and a DCR of 74.7%. The mPFS and mOS were 3.5 months and 6.8 months respectively. 98 pts in Group A and 157 pts in Group B received survival analysis, and there was no difference in age, gender, ECOG and treatment line. Although there was no significant difference between the mPFS of group A and group B (3.0 vs 3.9 months; p = 0.15), Group B presented a prolongation of mOS compared to group A (7.1 vs 5.8 months; p = 0.04). All the 391 pts received safety analysis. Most common AEs were hypertension (43.3%), fatigue (31.8%), hand-foot skin reactions (18.6%), proteinuria (20.2%), diarrhea (8.4%) and bleeding (6.6%). The grade 3 to 4 AEs were hypertension (6.6%), hand-foot skin reactions (3.3%) and fatigue (3.0%). Conclusions: In the real world, pts were most likely given apatinib by the dose of 500mg or less. The dose of 425-500mg showed similar efficacy to Phase Ⅲ clinical trial (850mg), while the mOS of 250mg was shorter. No new adverse events had been identified in this trial. Clinical trial information: NCT02668380.
Effect of risk communication on anxiety, breast cancer worry and risk perception in women at high risk of breast cancer.
Authors: Zhuoer Xie, Neil Wenger, Liliana Johansen, David Elashoff, Jacqueline Trent, Kristina Lee, Celia Kaplan, Lisa Madlensky, Tracy M. Layton, Antonia Petruse, Arash Naeim
Journal: Journal of Clinical Oncology (2018)

e22129 Background: Breast cancer risk assessment models and guidelines are designed to prevent breast cancer in high risk women. However, the effect of communicating a high risk status on the psychosocial health of a general population of women undergoing breast screening is less known. As part of the Athena Breast Health Network, where patients’ risk data (Gail model) were collected during mammography, this pilot study sent risk communications(RC) to a subset of high risk women to examine the effect of RC. Methods: Women were screened for high risk at two mammography sites, for practical reasons RC was initiated at one site before the other. Subjects at the No RC (N = 24) and the RC site (N = 100) completed surveys including PROMIS Anxiety Scale, Breast cancer worry (BCW) and risk perceptions (RP) at baseline and at 5 weeks. The RC subjects received a RC and a survey to measure negative affect state (NAS) between time points. Study outcomes were compared between time points within each group with paired t-tests or Wilcoxon signed-rank tests as appropriate. Outcomes were compared between groups via two sample T tests and Wilcoxon rank-sum tests. Linear regression was used to examine the association between Anxiety and BCW. Results: Mean NAS was 13.8 (lower than general population) with SD 5.4. No significant changes in Anxiety, BCW and RP were observed within groups, nor were differences seen between groups (shown in Table, presented as mean±SD and p-value). However, subjects in RC group thought more about breast cancer [BCW item 1] (1.7 vs. 1.4, p = 0.02). Moreover, BCW was significantly associated with Anxiety at baseline (r = 0.5, p < 0.001). Conclusions: Breast cancer worry was associated with anxiety. No evidence was found that risk communication worsened subjects’ anxiety, breast cancer worry, and risk perception. Further, risk communication made people think more about breast cancer, which may help focus high risk women on important available preventative services. Anxiety BCW RP RC No RC p RC No RC p RC No RC p Baseline 53±7.9 55±8.9 0.31 7.2±2.2 7.4±2.6 0.9 51.7±24.8 49.3±23 0.7 5 week 51.9±8.9 52.3±10.8 0.87 6.8±1.5 6.3±2 0.1 42.5±26 43.5±22.8 0.1 Changes -0.9±0.8 -2.7±1.8 0.3 -0.4±0.3 -1.1±0.5 0.26 -8.5±2.2 -8.7±4.2 0.9
Long-term treatment-free remission (TFR) following frontline (1L) nilotinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP): ENESTfreedom 144-wk results.
Authors: Jerald P. Radich, Tamas Masszi, María Teresa Gómez Casares, Andrzej Hellmann, Jesper Stentoft, Eibhlin Conneally, Valentin García Gutierrez, Norbert Gattermann, Phillipp D. Le Coutre, Bruno Martino, Susanne Saussele, Francis J. Giles, David M. Ross, Giuseppe Saglio, Manu Sondhi, Suddhasatta Acharyya, Shalini Chaturvedi, Véronique Bédoucha, Andreas Hochhaus
Journal: Journal of Clinical Oncology (2018)

7063 Background: ENESTfreedom (NCT01784068) is a phase 2 study evaluating TFR following 1L nilotinib in newly diagnosed CML-CP pts. We previously reported 48- and 96-wk TFR rates of 51.6% and 48.9%. Long-term data (144-wk; data cutoff, Oct 11, 2017) on TFR durability are now available. Methods: Pts with MR4.5 (BCR-ABL1 ≤ 0.0032% on International Scale [BCR-ABL1IS]) and ≥ 2 y of 1L nilotinib entered a 1-y consolidation phase; pts with sustained deep molecular response were eligible for TFR. Treatment was restarted after loss of major molecular response (MMR; BCR-ABL1IS ≤ 0.1%). Results are from the 144-wk analysis, in which all pts completed ≥ 144 wk of TFR, restarted nilotinib, or discontinued the study. Results: At data cutoff, 89 of 190 pts entering the TFR phase remained in TFR (144-wk TFR rate: 46.8%, 95% CI 39.6-54.2%). 94 pts (49.5%) discontinued TFR due to loss of MMR (91 restarted nilotinib), and 7 (3.7%) discontinued TFR for other reasons. 4 pts in TFR at 96 wk were no longer in TFR at 144 wk (3 had first loss of MR4.5 within 8 wk in TFR). Of 91 pts who restarted nilotinib, 90 (98.9%) and 84 (92.3%) regained MMR and MR4.5, respectively (1 discontinued the study without MMR, 5 discontinued with MMR but not MR4.5, 1 remained in reinitiation phase with MMR but not MR4.5). Of 84 pts who regained MR4.5, 70 (83.3%) had stable MR4.5 48 wk later, 11 (13.1%) discontinued the study < 48 wk after regaining MR4.5, and 3 (3.6%) remained in reinitiation phase with < 48 wk of follow-up after regaining MR4.5. No pt had disease progression. 10 pts died (consolidation, 2; TFR, 1; reinitiation, 4; discontinuation, 3), none of causes attributable to CML. 144-wk treatment-free survival rate was 48.7% (95% CI 41.4-55.6%). Among 94 pts remaining in TFR for > 96 wk, any-grade musculoskeletal pain–related AE rates were 16.0%, 40.4%, 9.6%, and 4.3% in the consolidation phase and first, second, and third 48 wk of TFR, respectively; cardiovascular event rates were low across these periods. Conclusions: These results suggest the durability and safety of TFR following 1L nilotinib, with a 144-wk TFR rate of 46.8%. There were no disease progressions, and musculoskeletal pain appeared transient. Clinical trial information: NCT01784068.
Carfilzomib, bendamustine, and dexamethasone (KBd) in advanced multiple myeloma: The EMN09-trial.
Authors: Martin Gramatzki, Andreas Guenther, Massimo Offidani, Monika Martha Engelhardt, Vittorio Montefusco, Francesca Patriarca, Emanuele Angelucci, Marco Salvini, Wolfram Pönisch, Stefano Spada, Silvia Gentili, Ralph Wäsch, Natalie Schub, Paolo Corradini, Hermann Einsele, Pieter Sonneveld, Mario Boccadoro, Francesca Maria Gay
Journal: Journal of Clinical Oncology (2018)

8019 Background: Various new agents have been introduced recently to treat relapsed/refractory multiple myeloma (RRMM), yet the chronification of the disease requires additional options for patients (pts) in advanced stages. Here, effectiveness and tolerability are important. Many advanced pts have received little chemotherapy but may suffer from peripheral neuropathy (PN). Carfilzomib (K) is a potent novel proteasome inhibitor not inducing significant PN. K was combined with bendamustine (B) to achieve synergistic effects. KB with low-dose dexamethasone (d) was tested in RRMM pts in a phase 1/2 trial (NCT02056756). Methods: 63 RRMM pts with ≥2 lines of prior therapy received KBd. Therapy consisted of 8 28-day courses of B at 70 mg/m2 day 1,8; K at 27 mg/m2 (initially 20 mg/m2) day 1,2,8,9,15,16; d at 20 mg on every treatment day plus day 22,23. Responding pts received Kd maintenance every 14 days until PD. In the phase 1, a dose escalation in 6 pts to K at 36 mg/m2 was attempted but led to 2 dose limiting toxicities. Thus, the phase 2 was conducted with K at 27 mg/m2. Results: Pts had a median age of 66 years (range 37-79) and presented with RRMM in a median of 5.2 years after diagnosis. They were extensively pretreated, with a median of 4 prior lines (range 2-9) and 75% had previously received autologous stem cell transplantation, 87% bortezomib and 86% immunomodulatory drugs. At least VGPR rate was 32%, including 18% CR/sCR/nCR; 19% of pts achieved PR, 41% SD, 8% PD. Median PFS was 11.6 months, median OS 24.0 months. 1-year PFS was 72% in standard-risk and 35% in high-risk cytogenetics pts. Infections, particularly pneumonia, cardiac and thromboembolic adverse events (AEs) were the most frequent non-hematological AEs of grade ≥3; 51% of pts experienced ≥1 severe AE. Also the hematological toxicity was manageable. Conclusions: KBd was effective and well-tolerated in advanced RRMM pts requiring treatment rather late in the course of their disease. This cost-effective combination therapy with K at the 20/27 mg/m2 and B at 70 mg/m2 can be applied in an outpatient setting, with no significant nausea, hair loss or PN. Yet, cardiopulmonary and vascular signs need attention and infection prophylaxis is mandatory in these immunosuppressed pts. Clinical trial information: NCT02056756.
A validation study of stratification by the 55-gene classifier for assessing recurrence risk in stage II colon cancer: The 55 STAR study (UMIN23879).
Authors: Shigeki Yamaguchi, Kazuo Hase, Eiji Shinto, Eiji Oki, Mototsugu Shimokawa, Megumi Ishiguro, Masaru Morita, Tetsuya Kusumoto, Naohiro Tomita, Yojiro Hashiguchi, Masafumi Tanaka, Shinobu Ohnuma, Sachiyo Tada, Tomoko Matsushima
Journal: Journal of Clinical Oncology (2018)

3526 Background: Cancer subtypes classified by DNA microarray data have shown excellent abilities in predicting patient prognosis; in particular, consensus molecular subtypes (CMSs) are regarded as the most robust classification system with clear biological interpretability. Recently, we performed unsupervised clustering analysis using a public database and selected the expression of 55 gene to construct a discriminant model with the aim of classifying colon cancer (CC) into three subtypes: “microsatellite instability (MSI)-like”, “chromosomal instability (CIN)-like”, and “stromal”; the recurrence rates of these subtypes were shown to be different (p = 0.001). In this study, we conducted a retrospective, multi-institutional study to validate the quality of a novel 55-gene classifier (55GC) for Stage II CC and compared 55GC subtypes with the CMS categories. Methods: We collected formalin-fixed, paraffin-embedded cancer specimens from 232 patients with Stage II CC who underwent curative surgery (R0) without adjuvant chemotherapy at 10 institutions between 2009 and 2012. Tissue sections were prepared from each specimen and subjected to DNA microarray measurement. Results: Using the 55GC, patients were classified as having the MSI-like subtype in 27%, CIN-like in 41%, and stromal in 32% of the cases. The 5-year recurrence-free survival (RFS) rate of patients with the MSI-like, CIN-like, and stromal subtype cancers was 88.5%, 83.3%, and 71.2%, respectively (stromal vs. others: p = 0.0049). Multivariate analysis by Cox's proportional hazard model revealed that stromal subtype (hazard ratio, 2.3; p = 0.0063), pT4, and the number of lymph nodes examined ( < 12) were independent poor prognostic factors. The overall concordance rate between 55GC and CMS was 72%: 29% (18/62) of the MSI-like subtype, 79% (75/95) of the CIN-like subtype, and 98% (74/75) of the stromal subtype were judged as CMS1, CMS2/3 and CMS4, respectively. The 5-year RFS rate of patients with CMS1, CMS2/3 and CMS4 was 100%, 86.3%, and 73.0%, respectively (CMS4 vs. others: p = 0.005). Conclusions: 55GC is a useful and reproducible grading system for recurrence risk stratification of Stage II CC.
Medicines for Treatment Intensification in Type 2 Diabetes and Type of Insulin in Type 1 and Type 2 Diabetes in Low-Resource Settings: Synopsis of the World Health Organization Guidelines on Second- and Third-Line Medicines and Type of Insulin for the Control of Blood Glucose Levels in Nonpregnant Adults With Diabetes Mellitus
Authors: Gojka Roglic, Susan L. Norris
Journal: Annals of Internal Medicine (2018)

The World Health Organization developed these guidelines to provide guidance on selection of medicines for treatment intensification in type 2 diabetes and on use of insulin (human or analogue) in type 1 and 2 diabetes. The target audience includes clinicians, policymakers, national diabetes program managers, and medicine procurement officers. The target population is adults with type 1 or 2 diabetes in low-resource settings in low- or high-income countries. The guidelines also apply to disadvantaged populations in high-income countries.The recommendations were formulated by a 12-member guideline development group and are based on high-quality systematic reviews identified via a search of several bibliographic databases from 1 January 2007 to 1 March 2017. The GRADE (Grading of Recommendations Assessment, Development and Evaluation) system was used to assess the quality of the evidence and the strength of the recommendations. The guideline was peer-reviewed by 6 external reviewers.Give a sulfonylurea to patients with type 2 diabetes who do not achieve glycemic control with metformin alone or who have contraindications to metformin (strong recommendation, moderate-quality evidence).Introduce human insulin treatment to patients with type 2 diabetes who do not achieve glycemic control with metformin and/or a sulfonylurea (strong recommendation, very-low-quality evidence).If insulin is unsuitable, a dipeptidyl peptidase-4 (DPP-4) inhibitor, a sodium-glucose cotransporter-2 (SGLT-2) inhibitor, or a thiazolidinedione (TZD) may be added (weak recommendation, very-low-quality evidence).Use human insulin to manage blood glucose in adults with type 1 diabetes and in adults with type 2 diabetes for whom insulin is indicated (strong recommendation, low-quality evidence).Consider long-acting insulin analogues to manage blood glucose in adults with type 1 or type 2 diabetes who have frequent severe hypoglycemia with human insulin (weak recommendation, moderate-quality evidence for severe hypoglycemia).
Changes in the microbiome induced by adjuvant chemotherapy for breast and gynecological cancer and their association with weight gain.
Authors: Ayelet Shai, Maya Morr, Atara Uzan, Omry Koren
Journal: Journal of Clinical Oncology (2018)

e22113 Background: Adjuvant chemotherapy for breast cancer is associated with weight gain and glucose intolerance. Obesity increases the risk of cardiovascular morbidity and might increase the risk of disease recurrence. In recent years the role of the intestinal microbiome in human physiology is being uncovered. The microbiome has been shown to influence metabolism and weight gain. We aimed to identify changes in the intestinal microbiome following adjuvant chemotherapy in women and to test their association with weight gain. Methods: Women treated with adjuvant chemotherapy for breast and gynecological malignancies were recruited. Fecal samplesweretaken prior to treatment, after 3-4 cycles and after treatment. Weight was measured atthese time points. Information regarding use of antibiotics and nutritional changes was systematically collected. Gut microbiota was analyzed using 16S rRNA gene sequencing. Results: Fifteen patients were recruited (13 breast cancer, 2 ovarian cancer). 5 gained 1 kg or more during treatment. Antibiotic use was not associated with weight gain. Beta diversity based on uniFrac analysis significantly changed between pre, during and post treatment samples (p = 0.002). Significant increase in the relative abundance of bacterial species from the orders Lactobacillae, Clostridiales, Pasteurellaies and Turicibacterales was seen in samples taken during chemotherapy relative to pre treatment samples. When comparing patients that did and did not gain weight we observed that Ruminococcus bromii was more abundant in pre treatment samples of patients that did not gain weight while other species from the order Clostridiales were more abundant in pre treatment samples of women that did. Alpha diversity decreased during treatment only in patients that gained weight and this difference was of borderline significance (p = 0.07). Conclusions: The composition of the microbiome changed in women during adjuvant chemotherapy for breast and ovarian cancer. We found differences in microbiome content and diversity between patients that gained weight and those that did not. Analyses with a larger sample size are needed to confirm these observations.