tbuckley/cabot-search huggingface dataset:
Phase I trial of bortezomib daily dose: Safety, pharmacokinetic profile, biological effects, and early clinical evaluation in patients with advanced solid tumors.
Authors: Rastislav Bahleda, Marie-Cécile Le Deley, Apexa Bernard, Shalini Chaturvedi, Anas Gazzah, Andrea Varga, Chi Keung, Eric Deutsch, Christophe Massard, Helgi Van De Velde, Antoine Hollebecque, Eric Angevin, Vincent Ribrag, Jean-Charles Soria
Journal: Journal of Clinical Oncology (2014)

2623 Background: Bortezomib (BTZ) is proteasome inhibitor with activity in multiple myeloma used as a weekly or twice-weekly subcutaneous regimen. BTZ showed modest activity in solid tumors, potentially related to sub-optimal tumor penetration. Methods: This is a dose escalation study to define the MTD of daily low dose schedule of BTZ given SC on days 1-5, 8-12, 15-19 of 28 day cycle based on 3+3 design. Primary objective: to establish the MTD. Secondary objectives: safety, efficacy, PK and PD. Patients ≥ 18 years with advanced solid tumors, ECOG ≤ 1, adequate organ functions, without pre-existent neuropathy were included. Biomarkers for proteasome inhibition, pre- and post-treatment tumor biopsies, circulating proteins were evaluated. Results: As of Sep 2013, 18 pts have been treated (8 M/10 F), median age 57.5 years (range 41-76). BTZ dose cohorts were (no. pts): 0.5 mg/m2 (3), 0.6 mg/m2 (11), 0.7 mg/m2(4). 11 pts received 1 cycle; 4, 2 and 1 pts received 2, 5 and 6 cycles, respectively (total 35 cycles, 13 with full doses). Three DLTs were observed in 3 pts: Sweet’s syndrome (at 0.6 mg/m2), G3 anorexia with asthenia (2 pts at 0.7 mg/m2). The most common study drug-related AEs (all grades) were fatigue (56%), thrombocytopenia (56%), rash (39%), anorexia (39%) and neuropathy (39%). 4 additional pts were enrolled at 0.6 mg/m2 considered as RP2D. Dose-normalized mean systemic exposure to BTZ was time-independent, with similar BTZ PK on day 5 and day 19. Maximum proteasome inhibition was observed at day 19 in blood, and subsequently recovered until last time point measured at day 26. Proteasome inhibition was compared in tumor/blood (n = 3) and % inhibition on day 5 varied between 0.95 – 2.01 , indicating a good correlation between tumor and blood. One PR has been observed in pt with heavily pre-treated GIST and 2 minor responses (-20%) in pt with melanoma and mesothelioma. Conclusions: Daily BTZ administration showed an acceptable safety profile, dose dependent plasma exposure, evidence of target inhibition, and preliminary signs of clinical activity. RP2D of daily above-mentioned regimen of BTZ is 0.6 mg/m2. Additional clinical, PK and PD data will be presented. Clinical trial information: eudraCT 2009-014354-15.
Outcome analysis of non-high-risk neuroblastoma patients enrolled on Children’s Oncology Group trials P9641 and A3961.
Authors: Holly Jane Meany, Edward F. Attiyeh, Arlene Naranjo, Clare Twist, Wendy B. London, Judith Villablanca, Mary Lou Schmidt, Dave Baker, Douglas R. Strother, Hiroyuki Shimada, Katherine K. Matthay, Susan Lerner Cohn, John M. Maris, Julie R. Park
Journal: Journal of Clinical Oncology (2012)

9533 Background: Patients with non-high-risk neuroblastoma (low- and intermediate-risk) generally have an excellent event free (EFS) and overall (OS) survival with current therapy. However, within this heterogeneous patient population, there are patients that may benefit from further therapy reduction and patients that may benefit from augmented therapy. Methods: Survival tree regression analysis was performed in patients enrolled on P9641 and A3961 with OS the primary endpoint. Univariate Cox proportional hazards models determined statistically significant prognostic factors. Secondary analysis of cases with MYCN non-amplified, non-high-risk neuroblastoma classified patients by age, INSS stage, Shimada histology and genomic features to determine 5-year EFS and OS. Favorable genomics were defined as hyperdiploid tumors without 1p or 11q loss of heterozygosity (LOH). Those with LOH at 1p or 11q or with a diploid DNA index were considered unfavorable. Patients without genomic data were excluded. Results: In the survival tree analysis, ploidy and genomic features were found to be statistically significant. In the secondary analysis, patients &lt;18 months of age with stage 2 or 3, favorable histology tumors with favorable genomic profile had 5-year EFS and OS rates of 92.9±3.9% and 100% respectively. Patients with stage 2 and 3 tumors, unfavorable histology and unfavorable genomic features had EFS of 68.4±8.0% and OS of 78.4±7.0%. Patients &lt;12 months of age with stage 4 disease and either unfavorable histologic or genomic features had EFS of 69.1±5.4% and OS of 88.5±3.8%. Conclusions: Excellent outcomes in non-high-risk neuroblastoma patients with favorable histologic and genomic features suggest further reduction in therapy is possible in this cohort while maintaining survival and decreasing side effects. Select patients with unfavorable features have suboptimal OS and would benefit from modifications in therapy. Histologic and genomic criteria can be used to identify patients with non-high-risk neuroblastoma that may benefit from modifications in therapy. These data support the conduct of a cooperative group clinical trial to refine therapy for patients with non-high-risk disease.
Phase 1 trial of brentuximab vedotin in combination with gemcitabine for pediatric and young adult patients with relapsed or refractory Hodgkin lymphoma, a Children’s Oncology Group report.
Authors: Peter D. Cole, Monika Metzger, Richard A. Drachtman, Terzah M. Horton, Xiaowei Liu, Charlotte H. Ahern, Charles Minard, Elizabeth Fox, Susan Blaney, Brenda Weigel, Kara M. Kelly
Journal: Journal of Clinical Oncology (2015)

8544 Background: Salvage therapy followed by autologous stem cell transplantation improves outcomes for patients with primary refractory Hodgkin lymphoma (HL) or early relapse. Brentuximab vedotin (Bv) and gemcitabine each produce high overall response rates in this context. Compared to alternate retrieval regimens, this combination offers the advantage of avoiding agents that are associated with late treatment sequelae, such as anthracyclines, alkylators, or epipodophyllotoxins. This phase 1 trial was conducted to describe the toxicity of the combination and to define a recommended phase 2 dose (RP2D) for Bv when given with gemcitabine. Methods: Patients ≤ 30 years old with primary refractory HL or early relapse were eligible. Bv was given on day 1 of each 21-day cycle, at two dose levels (DL): DL1, 1.4 mg/kg and DL2, 1.8 mg/kg. Gemcitabine 1000mg/m2 was given on day 1 and 8. Dose limiting toxicity (DLT) was assessed during cycle 1 to define the RP2D, and response after every 2 cycles. Results: Fifteen patients have enrolled (14 evaluable for hematologic toxicity), with median age of 17 years (range 5-28). No DLTs were seen among 3 patients treated at DL1. Two of six patients experienced non-hematologic DLT at DL2: one with grade 3 hypotension and one with asymptomatic Grade 3 elevation of liver enzymes. Both had resolution of all toxicity and continued on study treatment with dose reduction of Bv to 1.2 mg/kg. An expansion cohort of six patients was enrolled at DL2; none experienced DLT. Grade 3-4 neutropenia was common (13 of 14 patients during cycle 1) but self-limited. No grade 4 non-hematologic toxicity occurred. No cases of interstitial pneumonitis or pulmonary toxicity attributable to study therapy were observed. Conclusions: Bv can be safely given in combination with gemcitabine. The RP2D of Bv is 1.8 mg/kg. The ongoing Phase 2 trial will describe the complete response rate observed within four cycles of Bv with gemcitabine. Clinical trial information: NCT01780662. Clinical trial information: NCT01780662.
Simple Protein Modification Using Zwitterionic Polymer to Mitigate the Bioactivity Loss of Conjugated Insulin
Authors: Jinbing Xie, Yang Lu, Wei Wang, Hui Zhu, Zhigang Wang, Zhiqiang Cao
Journal: Advanced Healthcare Materials (2017)

Polymer–protein conjugation has been extensively explored toward a better protein drug with improved pharmacokinetics. However, a major problem with polymer–protein conjugation is that the polymers drastically reduce the bioactivity of the modified protein. There is no perfect solution to prevent the bioactivity loss, no matter the polymer is conjugated in a non‐site specific way, or a more complex site‐specific procedure. Here the authors report for the first time that when zwitterionic carboxybetaine polymer (PCB) is conjugated to insulin through simple conventional coupling chemistry. The resulting PCB–insulin does not show a significant reduction of in vitro bioactivity. The obtained PCB–insulin shows two significant advantages as a novel pharmaceutical agent. First, its therapeutic performance is remarkable. For PCB–insulin, there is a 24% increase of in vivo pharmacological activity of lowering blood glucose compared with native insulin. Such uncommonly seen increase has rarely been reported and is expected to be due to both the improved pharmacokinetics and retained bioactivity of PCB–insulin. Second, the production is simple from manufacturing standpoints. Conjugation procedure involves only one‐step coupling reaction without complex site‐specific linkage technique. The synthesized PCB–insulin conjugates do not require chromatographic separation to purify and obtain particular isoforms.
Waiting to Clamp Cords Reduces Anemia in High-Risk Infants
Authors: Anita Slomski
Journal: JAMA (2017)

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Use of neoadjuvant chemotherapy in advanced ovarian cancer.
Authors: Larissa Meyer, Angel Cronin, Charlotte C. Sun, Michael A. Bookman, Robert Allen Burger, Mihaela C. Cristea, Jennifer J. Griggs, Charles F. Levenback, Gina Mantia-Smaldone, Ursula Matulonis, Joyce C. Niland, David M. O'Malley, Alexi A. Wright
Journal: Journal of Clinical Oncology (2015)

5563 Background: In 2010, a randomized trial demonstrated no difference in survival in advanced ovarian cancer patients treated with neoadjuvant chemotherapy (NAC) or primary debulking surgery (PDS). We examined the use and effectiveness of NAC in clinical practice over time. Methods: Prospective cohort study of women with stage IIIC/IV ovarian cancer treated at National Comprehensive Cancer Network (NCCN) institutions between 2003-2012. We examined the use (N = 961) and outcomes (N = 414) of NAC + interval debulking (IDS) +/- adjuvant chemotherapy versus PDS +/- adjuvant chemotherapy. Propensity score matching was used to balance observed confounders between groups in the outcomes analyses and trial participants excluded. Cox regression, logistic regression, and Fisher’s exact test were used to examine overall survival, residual disease, and perioperative morbidity in the matched sample. Results: Use of NAC+IDS increased from 0-39% between 2003-2010, and rose to 53% (stage IIIC) and 58% (stage IV) in 2011-2012. Adoption of NAC+IDS varied by institution from 0%-29% (stage IIIC, P < 0.001) and 13%-48% (stage IV, P = 0.04). After propensity-score adjustment, NAC+IDS was associated with lower survival in stage IIIC disease, compared with PDS (median 31 vs. 50 months, hazard ratio [HR] 1.54, 95% confidence interval [CI] 1.05-2.24), and comparable survival in stage IV disease (median 43 vs. 32 months, HR 0.78, 95% CI 0.50-1.22). NAC+IDS was associated with higher odds of an R0 resection [odds ratio (OR): 2.26, 95% CI 1.28-3.98, stage IIIC; OR 4.03, 95% CI 1.73-9.38, Stage IV), and fewer ostomies (adjusted rates: 3% vs. 9%, P = 0.11, stage IIIC and 3% vs. 11%, P = 0.06, stage IV). Readmission rates were lower in NAC+IDS, compared with PDS (adjusted rates: 2% vs. 16% for stage IIIC and 2% vs 15% for stage IV, both P < 0.001). Conclusions: NAC+IDS use increased significantly at NCCN centers between 2003-2012. In this observational study, overall survival was comparable in patients with stage IV disease, and NAC+IDS was associated with lower ostomy rates and perioperative morbidity in stage IIIC and IV disease. NAC+IDS was associated with decreased survival in patients with stage IIIC disease, however additional selection bias may remain after propensity-score matching.
STEAM: A randomized, open-label, phase 2 trial of sequential and concurrent FOLFOXIRI-bevacizumab (BEV) versus FOLFOX-BEV for the first-line (1L) treatment (tx) of patients (pts) with metastatic colorectal cancer (mCRC).
Authors: Johanna C. Bendell, Benjamin R. Tan, James Andrew Reeves, Henry Q. Xiong, Rita Laeufle, Michelle Byrtek, Nicolas Sommer, Herbert Hurwitz
Journal: Journal of Clinical Oncology (2014)

TPS3652 Background: Recent randomized trials investigating 5-fluorouracil [5-FU]/leucovorin [LV]/oxaliplatin/irinotecan (FOLFOXIRI) with bevacizumab (BEV) for the first-line (1L) treatment (tx) of metastatic colorectal cancer (mCRC) patients (pts) showed improved progression-free survival (PFS) and overall response rate (ORR) vs. 5-FU/LV/irinotecan (FOLFIRI) with BEV (Falcone et al, ASCO 2013) and improved PFS, ORR, and resection rate of metastases vs. 5-FU/LV/oxaliplatin (FOLFOX) with BEV (Bridgewater et al, ESMO 2013). Toxicity may be a limitation of the regimen; alternating tx with FOLFOX and FOLFIRI (sequential FOLFOXIRI) may improve the tolerability of treating 1L pts with all three agents. The efficacy and safety of FOLFOXIRI-BEV have yet to be investigated in the US, and the impact of maintenance and of BEV tx beyond disease progression (PD) following FOLFOXIRI-BEV is unknown. Methods: The STEAM study (NCT01765582) is a randomized, open-label, US-based, phase 2 trial investigating sequential or concurrent FOLFOXIRI-BEV vs. FOLFOX-BEV and maintenance tx in pts with previously untreated mCRC. Key eligibility criteria include unresectable mCRC and age 18–75 years. Pts are randomized 1:1:1 to concurrent FOLFOXIRI-BEV, sequential FOLFOXIRI-BEV (alternating FOLFOX and FOLFIRI q4w), or FOLFOX-BEV q2w during a four to six month induction phase (BEV 5 mg/kg in each arm). After induction, pts receive 5-FU/LV + BEV (5 mg/kg) q2w or capecitabine + BEV (7.5 mg/kg) q3w as maintenance tx until PD. After PD, pts receive second-line (2L) 5-FU–based chemotherapy (physician’s choice) with BEV (dose equivalent of 2.5 mg/kg/week) until 2L PD. Pts are stratified by extent of metastatic disease (liver-limited vs non–liver-limited), primary tumor location (right- vs left-sided), and study center. Primary objectives are to evaluate 1L ORR (concurrent FOLFOXIRI-BEV vs FOLFOX-BEV), 1L PFS (concurrent and sequential FOLFOXIRI-BEV vs FOLFOX-BEV), and safety. Secondary objectives include resection rate, rate of conversion to resectable disease, time to 2L PFS, and overall survival (concurrent and sequential FOLFOXIRI-BEV vs FOLFOX-BEV). The study has enrolled 109 of a planned 280 pts to date. Clinical trial information: NCT01765582.
Return of individual research results: Policies and experiences of cancer genomic researchers.
Authors: Lynn G. Dressler, Nikolajs Zeps, Allison Mary Deal, Janell Markey, Bartha Knoppers
Journal: Journal of Clinical Oncology (2014)

11025 Background: Although it is not the intent of the International Cancer Genomics Consortium (ICGC) or The Cancer Genome Atlas (TCGA) studies to return individual research results (RIRR), clinically relevant results will be discovered. Debate about RIRR are well described in the literature, however little information exists regarding researcher experiences and institutional policies. Methods: The ICGC Ethics and Policy Committee developed an anonymous survey that was distributed electronically or by hardcopy to genomic researchers participating in ICGC and TCGA, asking about perspectives, experience and policy relevant to RIRR. Analysis was limited to researchers conducting human cancer genomic research. Results: 111/164 (66%) surveys were eligible for analysis. Compared to non US researchers, US researchers were significantly less likely to report a responsibility to consider whether a research result would have clinical relevance for the subject (83% v 57%; p=0.011). Fifty-one percent of researchers reported finding clinically relevant results important for the subject to know. The 3 most common findings were susceptibility to cancer/other chronic disease (46%); pharmacogenomic (42%), and Mendelian Disease (20%). Forty percent reported returning results to physicians (40% at least 1X; 15% > 5X) or individual research subjects (28% at least 1x). Most (80%) agreed that a result should be validated before return, yet there was no agreement even on how to analytically validate results. Regarding institutional policy, 28% reported an RIRR policy existed, including 9% whose policy was not to return results; 12% reported no policy; and 50% did not know if a policy existed. 17% reported that the informed consent (IC) never addresses RIRR; 30% reported the IC always addresses RIRR and 30% did not know what the IC addressed. Conclusions: Regardless of study intent, clinically relevant research results are being found and returned to physicians and individual research subjects. A critical need exists to develop consistent approaches for validating research results; raise researcher awareness of institutional policies and develop practical guidance for researchers involved in international collaborations.
Development of a Hypoxic Radiosensitizer‐Prodrug Liposome Delivery DNA Repair Inhibitor Dbait Combination with Radiotherapy for Glioma Therapy
Authors: Hongmei Liu, Yifan Cai, Yafei Zhang, Yandong Xie, Hui Qiu, Lei Hua, Xuejiao Liu, Yuling Li, Jun Lu, Longzhen Zhang, Rutong Yu
Journal: Advanced Healthcare Materials (2017)

Gliomas are highly radioresistant tumors, mainly due to hypoxia in the core region of the gliomas and efficient DNA double‐strand break repair. However, the design of a radiosensitizer incorporating the two above mechanisms is difficult and has rarely been reported. Thus, this study develops a hypoxic radiosensitizer‐prodrug liposome (MLP) to deliver the DNA repair inhibitor Dbait (MLP/Dbait) to achieve the simultaneous entry of radiosensitizers with two different mechanisms into the glioma. MLP/Dbait effectively sensitizes glioma cells to X‐ray radiotherapy (RT). Histological and microscopic examinations of dissected brain tissue confirm that MLP effectively delivers Dbait into the glioma. Furthermore, the combination of MLP/Dbait with RT significantly inhibits growth of the glioma, as assessed by in vivo bioluminescence imaging. These findings suggest that MLP is a promising candidate as a Dbait delivery system to enhance the effect of RT on glioma, owing to the synergistic effects of the two different radiosensitizers.
Positive association of gastric cancer surgery outcome with surgeon specialization in a Shanghai high-volume general hospital.
Authors: Zhenbin Shen, Yihong Sun, Cong Wang, Naiqing Zhao, Weidong Chen, Xuefei Wang, Hongshan Wang, Yong Fang, Fenlin Liu, Zhaoqing Tang, Yanna Wang, Haojie Li, Yongzhe Piao, Laura Chu, Lisa Wang, Wei Dong, Xinyu Qin
Journal: Journal of Clinical Oncology (2012)

4092 Background: Numerous studies suggest positive relationship between hospital volume and cancer treatment outcomes, the surgeon’s experience and specialty training may also be important. This was examined in a high volume hospital in Shanghai among patients who underwent gastric cancer (GC) surgery. Methods: Data on consecutive patients (pts) undergoing R0 or R1 GC resection in Zhongshan hospital between January 2003 and June 2010 were collected and analyzed. Follow-up on pts who were non-Shanghai residents were less complete therefore excluded. Post-operative mortality, pathologic results and survival outcome for pts treated by surgical training, i.e., sub-specialized vs., non-specialized, were obtained. Survival was calculated by the Kaplan-Meier method and Log-rank test was used to determine statistical significance. To determine whether sub-specialty surgical training was an independent factor for overall survival (OS), univariate and multivariate analyses were performed using Cox proportional hazards regression. Results: Total 5,046 pts underwent R0 or R1 GC resection were identified.1594 pts had complete covariate data, survival information and were included in the study. Of them, the sub-specialized group included 217 cases treated by 3 surgeons, while the non-specialized group included 1377 cases treated by 52 surgeons. 5-year cumulative OS was higher in the sub-specialized group (62.9% vs. 54.6%, p=0.032). Multivariate analysis showed that tumor stage(p&lt;0.001), location of tumor (p=0.003), vascular invasion (p&lt;0.001) and surgeon (HR=1.54, p=0.001) were all associated with OS. The incidence of positive margin was higher in non-specialized group (2.0% vs. 2.7%, p&lt;0.001) and the probability of retrieved lymph nodes less than 15 was more in non-specialized group (25.9% vs. 7.3%, p&lt;0.001). Postoperative mortality was also higher in non-specialized group than in specialized group(1.5% vs. 0.9%, p&lt;0.001). Conclusions: In high volume general hospital, sub-specialty training is desirable in gastric cancer surgery, the quality of gastric cancer surgery can be further improved by sub-specialty training leading to better treatment outcome.