tbuckley/cabot-search huggingface dataset:
Risk of skin rash with the proteasome inhibitor bortezomib: Updated systematic review and meta-analysis.
Authors: Emily Christine Case, Shenhong Wu, John F. Gerecitano, Mario E. Lacouture
Journal: Journal of Clinical Oncology (2012)

9092 Background: Rash is a common, adverse event to the novel proteasome inhibitor bortezomib (Velcade). Indicated for the treatment of multiple myeloma and mantle cell lymphoma, bortezomib is the first proteasome inhibitor approved by regulatory agencies. Because the incidence of bortezomib-induced skin rash varies widely in published manuscripts, we performed a systematic literature review and meta-analysis to determine the incidence and overall risk. Methods: We searched PubMed and Web of Science databases and abstracts presented at the American Society of Clinical Oncology and The American Society of Hematology annual meetings (1998 to July 2011) to identify relevant clinical studies. Eligible studies included prospective clinical phase II and phase III trials, with data on the incidence of rash in patients taking 1.3mg/m 2 , 1.5mg/m 2 , or 1.6 mg/m 2 of bortezomib intravenously either weekly or twice weekly. The incidence of rash and relative risk (RR) were calculated using random-effects or fixed-effects model, depending on the heterogeneity of included studies. Results: A total of 2,616 patients with various hematologic and solid malignancies from 35 clinical trials were included for analysis. Among patients receiving twice weekly bortezomib, the summary incidence of all-grade and high-grade rash were 18.8 % (95% CI: 14.9% to 23.5%) and 3.6 % (95% CI: 2.3% to 5.7%), respectively. We found no significant increase in all grade rash incidence with higher doses of bortezomib: 19.3 % (95% CI: 15% to 24.5%) and 20.8% (95% CI: 11.6% to 34.4%) for doses of 1.3 mg/m 2 and 1.5 mg/m 2 , respectively. In addition, bortezomib was associated with an increased risk in both all grade (RR: 19.70, 95% CI: 8.73 to 44.44, p&lt;0.001) and high-grade rash (RR: 5.35, 95% CI: 2.16 to 13.29, p&lt;0.001), compared to controls. Weekly bortezomib is associated with lower risk of rash compared to twice weekly dosing (incidence 3.9% versus 18.8%, p=0.001). Conclusions: Bortezomib is associated with a significant risk of developing rash with a higher risk among patients receiving twice weekly dosage. Management of rash to bortezomib is critical to prevent a negative effect on quality of life and dose modifications, both of which affect clinical outcome.
Efficacy and safety of cladribine: Subcutaneous versus intravenous administration in hairy cell leukemia.
Authors: Tarek Yakout Mohamed, Mosaad El Gammal, Alfred Elias Namour, Raafat Ragaie Abdel Malek, Ola Khorshid
Journal: Journal of Clinical Oncology (2013)

7013 Background: Hairy cell leukemia (HCL) is rare B-cell lymphoproliferative disorder. Its treatment has evolved from splenectomy with time to failure (TTF) of 19 months to Cladribine that increased complete remission (CR) rate to 90%, with only small percentage of patients relapsing at 30 months. Cladribine (CDA) is originally administered intravenously as continuous infusion for 7 days; Subsequently, it was administered subcutaneously. This study aims at comparing efficacy and toxicity of Subcutaneous (SC) versus Intravenous (IV) administration of CDA in treatment of HCL. Methods: This retrospective study included HCL patients presented to National Cancer Institute and Nasser Institute, Cairo, Egypt, during period 2004-2010. Included patients received CDA as 1st or 2nd line with minimum follow up of 12 months. All files were reviewed for baseline clinical &amp; laboratory parameters, route of administration, response, adverse events and survival. Results: This study included 49 eligible patients, 41 patients received CDA as 1 st line treatment, while 8 patients as 2 nd line. Eighteen patients were treated by continuous IV infusion whereas 31 patients by SC injections. Both groups were comparable regarding baseline clinical and laboratory parameters with no statistically significant difference. At median follow up period of 33.5 months, complete remission rate was 94% in IV group versus 97% in SC group (p=0.691); median TTF for IV group was 52.9 months while that for SC group was not reached (p=0.035). The median time to achieve CR in both arms was similar. By analyzing different factors affecting TTF using multivariate analysis, route of administration proved to be the only statistically significant factor (P=0.006). Regarding adverse events, there was no difference between both groups in hematological toxicities. IV route was associated with a significant higher incidence of mucositis (p=0.02) and viral infections (p=0.01). Hepatotoxicity and neurotoxicity were higher in SC group but difference was not statistically significant. Conclusions: SC administration of cladribine is an alternative route to IV in treatment of HCL with similar response rate, longer time to treatment failure and better tolerability.
Microsatellite instability and survival after adjuvant chemotherapy among stage II and III colon cancer patients: results from a population-based study
Authors: A. Elizabeth, L. Jansen, B. Hendrik, M. Kloor, K. Tagscherer, W. Roth, D. Boakye, E. Herpel, C. Grüllich, J. Chang-Claude, H. Brenner, M. Hoffmeister
Journal: Annals of Oncology (2019)
Physiological Biomimetic Culture System for Pig and Human Heart Slices
Authors: Qinghui Ou, Zoë Jacobson, Riham R.E. Abouleisa, Xian-Liang Tang, Sajedah M. Hindi, Ashok Kumar, Kathryn N. Ivey, Guruprasad Giridharan, Ayman El-Baz, Kenneth Brittian, Benjamin Rood, Ying-Hsi Lin, Samuel A. Watson, Filippo Perbellini, Timothy A. McKinsey, Bradford G. Hill, Steven P. Jones, Cesare M. Terracciano, Roberto Bolli, Tamer M.A. Mohamed
Journal: Circulation Research (2019)

Preclinical testing of cardiotoxicity and efficacy of novel heart failure therapies faces a major limitation: the lack of an in situ culture system that emulates the complexity of human heart tissue and maintains viability and functionality for a prolonged time. To develop a reliable, easily reproducible, medium-throughput method to culture pig and human heart slices under physiological conditions for a prolonged period of time. Here, we describe a novel, medium-throughput biomimetic culture system that maintains viability and functionality of human and pig heart slices (300 µm thickness) for 6 days in culture. We optimized the medium and culture conditions with continuous electrical stimulation at 1.2 Hz and oxygenation of the medium. Functional viability of these slices over 6 days was confirmed by assessing their calcium homeostasis, twitch force generation, and response to β-adrenergic stimulation. Temporal transcriptome analysis using RNAseq at day 2, 6, and 10 in culture confirmed overall maintenance of normal gene expression for up to 6 days, while over 500 transcripts were differentially regulated after 10 days. Electron microscopy demonstrated intact mitochondria and Z-disc ultra-structures after 6 days in culture under our optimized conditions. This biomimetic culture system was successful in keeping human heart slices completely viable and functionally and structurally intact for 6 days in culture. We also used this system to demonstrate the effects of a novel gene therapy approach in human heart slices. Furthermore, this culture system enabled the assessment of contraction and relaxation kinetics on isolated single myofibrils from heart slices after culture. We have developed and optimized a reliable medium-throughput culture system for pig and human heart slices as a platform for testing the efficacy of novel heart failure therapeutics and reliable testing of cardiotoxicity in a 3-dimensional heart model.
Association of Obesity With Multiple Sclerosis Risk and Response to First-line Disease Modifying Drugs in Children
Authors: Brenda Huppke, David Ellenberger, Hannah Hummel, Wiebke Stark, Markus Röbl, Jutta Gärtner, Peter Huppke
Journal: JAMA Neurology (2019)

Obesity reportedly increases the risk of pediatric multiple sclerosis (MS), but little is known about its association with disease course.To investigate the association of obesity with pediatric MS risk and with first-line therapy response among children with MS.This single-center retrospective study used the medical records and database at the Center for MS in Childhood and Adolescence, Göttingen, Germany. The study included 453 patients with relapsing-remitting pediatric MS and body mass index (BMI) measurement taken within 6 months of diagnosis. Onset of the disease occurred between April 28, 1990, and June 26, 2016, and the mean disease duration was 38.4 months. Data were collected from July 14, 2016, to December 18, 2017.Data on BMIs were stratified by sex and age using German BMI references and compared with the BMI data of 14 747 controls from a nationwide child health survey for odds ratio (OR) estimates. Baseline magnetic resonance imaging findings, intervals between first and second MS attacks, annualized relapse rates before and during treatment with interferon beta-1a or -1b and glatiramer acetate, frequency of second-line treatment, and Expanded Disability Status Scale (EDSS) scores were compared between nonoverweight (BMI≤90th percentile), overweight (BMI>90th-97th percentile), and obese (BMI>97th percentile) patients.In total, 453 patients with pediatric MS were included, of whom 306 (67.5%) were female, and the mean (SD) age at diagnosis was 13.7 (2.7) years. At diagnosis, 126 patients (27.8%) were overweight or obese, with obesity associated with statistically significant twofold odds of MS in both sexes (girls OR, 2.19; 95% CI, 1.5-3.1; P < .001 vs boys OR, 2.14; 95% CI, 1.3-3.5; P = .003). Obese patients, compared with nonoverweight patients, had statistically significantly more relapses on first-line treatment with interferon beta and glatiramer acetate (ARR, 1.29 vs 0.72; P < .001) and a higher rate of second-line treatment (21 [56.8%] of 37 vs 48 [38.7%] of 124; P = .06). Baseline neuroimaging, interval between first and second MS attacks, pretreatment relapses, and EDSS progression scores were not correlated with BMI.In this study, increased pediatric MS risk appeared to be associated with obesity, and obese patients did not respond well to first-line medications; altered pharmacokinetics appeared to be most likely factors in treatment response, suggesting that achieving healthy weight or adjusting the dose according to BMI could improve therapy response.
A pediatric phase I trial and pharmacokinetic (PK) study of erlotinib (ERL) followed by the combination of ERL with temozolomide (TMZ): A Children’s Oncology Group Study
Authors: R. I. Jakacki, J. Tersak, S. Blaney, M. Krailo, M. Hamilton, J. Dancy, R. Gilbertson, A. Ingle, P. C. Adamson
Journal: Journal of Clinical Oncology (2006)

9015 Background: EGFR is potently inhibited by ERL. Aberrant cell signaling via the EGFR family has been implicated in the development of several human cancers, including certain pediatric solid tumors. Methods: A phase I dose escalation study in children with refractory solid tumors was conducted to define the maximal tolerated dose (MTD) and dose limiting toxicities (DLTs) of single agent ERL, determine the tolerability of the combination of ERL and TMZ, and to determine the PK of ERL. Pts received single agent ERL qd × 28 d followed by ERL qd continuously in combination with TMZ 180 mg/m 2 /day × 5d. Cycles were repeated q 28 d. ERL was initially administered using the IV formulation given orally. The tablet form was subsequently studied at the MTD to further evaluate PK. Results: 46 pts (36 fully evaluable for toxicity) median age 11.5 yrs (range 3–20 yrs), were enrolled in cohorts of 3–6 pts at ERL doses of 35, 50, 65, 85 and 110 mg/m 2 /d. At the 110 mg/m 2 /day dose level, 2/4 pts had DLT (1 rash, 1 hyperbilirubinemia). In the expanded cohort at the MTD of 85 mg/m 2 /d, (n=21), 3 pts had DLT (2 rash, 1 diarrhea). Non-DLTs observed during the single agent cycle included diarrhea (n=14), rash (n=9), hyperbilirubinemia (n=7), neutropenia and/or thrombocytopenia (n=5). 1 pt with a soft tissue sarcoma had a minor response after 28d of single agent ERL, continuing to a PR by cycle 4. 3 pts (2 neuroblastoma, 1 neurocytoma) had prolonged responses (13–20+ months) to the combination. Oral administration of the IV formulation resulted in a higher Cmax and a lower Cmin compared to the adult data using tablets. Median apparent clearance was 2.85 (range 1.61–6.37) L/hr/m 2 with a terminal half of 8.45 (5.1–27.1) hr. No PK interaction was observed between ERL and TMZ and the combination was well tolerated. Conclusions: The pediatric recommended phase 2 dose of ERL of 85 mg/m 2 /day, either alone or in combination with TMZ, is well tolerated in children. A COG phase 2 trial is planned. [Table: see text]
Preoperative PD1 checkpoint blockade and receptor activator of NFkB ligand (RANKL) inhibition in non-small cell lung cancer (NSCLC) (POPCORN).
Authors: Elizabeth Stephanie Ahern, Annette Cubitt, Emma Ballard, Michele W.L. Teng, William C. Dougall, Mark J. Smyth, Brett Gordon Maxwell Hughes
Journal: Journal of Clinical Oncology (2019)

TPS129 Background: Preclinical studies indicate Receptor Activator of NF-κB Ligand (RANKL) blockade improves anti-tumor efficacy of immune checkpoint blockade (ICB). Clinical trials combining denosumab (anti-RANKL mAb) with ICB are underway in various cancers although the hypothesized mechanism of action of such combinations remains incomplete. RANKL and its receptor, RANK, are frequently expressed in NSCLC (tumor and immune cells). Denosumab demonstrated survival advantage over bisphosphonate in metastatic NSCLC (mNSCLC) to bone; a recent retrospective case series suggests a relationship between concurrent ICB and denosumab duration and survival in mNSCLC. Neoadjuvant nivolumab recently showed encouraging pathologic response rates in resectable NSCLC; neoadjuvant trials lend themselves to translational research. Methods: POPCORN is a multicenter phase 1b/2 study to determine the mechanism of action, activity and safety of neoadjuvant nivolumab plus denosumab versus nivolumab alone. 30 patients with resectable stage 1A (tumor &gt; 2cm) – 3A NSCLC will be randomized 1:1 to two arms (Table). Exclusion criteria include uncontrolled autoimmune disease, steroid contraindications, and unhealed dental disease. Tumor tissue at baseline, surgery and relapse, and peripheral blood at various timepoints (including on-therapy) will be collected. The primary endpoint is to define pharmacodynamic correlates of the two arms through investigations including T-cell receptor clonality, RNA/transcription profile changes (tumor and peripheral blood), and expression of tumor/immune markers of interest via multiplex immunohistochemistry, compared between groups. Secondary endpoints include pathologic response rates, toxicity, R0 resection, and PFS/OS (exploratory). Statistical analysis will be primarily descriptive on the intention-to-treat population. The trial is sponsored by Metro North Hospital and Health Service (Queensland, Australia) with funding from AMGEN, Inc. Clinical trial information: ACTRN12618001121257. [Table: see text]
Limiting Opioid Prescribing—Reply
Authors: Kao-Ping Chua, Chad M. Brummett, Jennifer F. Waljee
Journal: JAMA (2019)

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Efficacy of frontline treatment regimens in follicular lymphoma: A network meta-analysis of phase III randomized controlled trials.
Authors: Yucai Wang, Shouhao Zhou, Fang Yang, Grzegorz S. Nowakowski, Thomas Matthew Habermann, Michael Wang, Thomas E. Witzig
Journal: Journal of Clinical Oncology (2019)

7556 Background: The frontline treatment for advanced follicular lymphoma has evolved with the introduction of maintenance therapy, bendamustine (Benda), obinutuzumab (G), and lenalidomide (Len). We conducted a network meta-analysis of phase 3 randomized controlled trials (RCTs) to identify the regimens with superior efficacy. Methods: Data were extracted from 7 RCTs (FOLL05, StiL NHL1, BRIGHT, PRIMA, GALLIUM, StiL NHL7, and RELEVANCE). Progression-free survival (PFS) was compared between 11 regimens with different immunochemotherapy and maintenance strategies. To incorporate direct and indirect comparisons, random-effects Bayesian network meta-analyses were conducted after adjusting for study-wise variation. The posterior inference was derived based on Markov chain Monte Carlo methods and implemented using JAGS v4.3.0. Pairwise comparison of hazard ratios (HRs) and 95% credible intervals (CIs) were calculated. Results: PFS HRs of other regimens compared to the reference regimen are summarized in the Table. Compared to Rituximab(R)-Benda, R-CHOP had inferior PFS, R-CHOP-R, G-CHOP-G, and R-Len-R had similar PFS, while R-Benda-R, R-Benda-R4 and G-Benda-G had better PFS. Compared to R-CHOP-R, G-CHOP-G and R-Len-R had similar PFS, while R-Benda-R, R-Benda-R4 and G-Benda-G had better PFS. In addition, the PFS for G-Benda-G was similar to R-Benda-R4 (HR 0.94, 95% CI 0.78-1.09) but better than R-Benda-R (HR 0.82, 95% CI 0.75-0.97). Conclusions: Compared with the commonly used R-Benda and R-CHOP-R regimens, G-CHOP-G, R-Benda-R and R-Benda-R4 had better PFS, while the chemotherapy-free regimen R-Len-R had similar PFS. [Table: see text]
Vaccination for Pancreatic Ductal Adenocarcinoma: A Hard Nut to Crack
Authors: Diego Salas-Benito, Ignacio Melero, Mariano Ponz-Sarvise
Journal: Clinical Cancer Research (2019)

No immunotherapy strategy is yet offering consistent results against pancreatic ductal adenocarcinoma. A randomized clinical trial testing repeated immunization with a Listeria monocytogenes-based vaccine encoding for mesothelin in combination with a GM-CSF-transfected allogeneic pancreatic cell vaccine reports no survival benefit for the vaccinated patients.See related article by Le et al., p. 5493.
Safety and activity of ivosidenib in patients with IDH1-mutant advanced cholangiocarcinoma: a phase 1 study
Authors: Maeve A Lowery, Howard A Burris, Filip Janku, Rachna T Shroff, James M Cleary, Nilofer S Azad, Lipika Goyal, Elizabeth A Maher, Lia Gore, Antoine Hollebecque, Muralidhar Beeram, Jonathan C Trent, Liewen Jiang, Bin Fan, Elia Aguado-Fraile, Sung Choe, Bin Wu, Camelia Gliser, Samuel V Agresta, Shuchi S Pandya, Andrew X Zhu, Ghassan K Abou-Alfa
Journal: The Lancet. Gastroenterology & hepatology (2019)
Microbiota-gut-brain research: A plea for an interdisciplinary approach and standardization
Authors: Mattia Andreoletti, Maria Rescigno
Journal: Behavioral and Brain Sciences (2019)

Abstract Hooks et al. note that microbiota-gut-brain research suffers from serious methodological flaws and interpretative issues. We suggest two corrective measures: first, taking more seriously the need of interdisciplinary work; second, interpreting some of the methodological issues as ordinary challenges of standardization, typical of emerging disciplines.
Healthcare provider awareness and integration of immunotherapy for stage III NSCLC.
Authors: Rachael Andrie, Timothy A. Quill, Angelique Vinther, Tina B. Stacy, Kevin Obholz
Journal: Journal of Clinical Oncology (2019)

123 Background: In February 2018, immunotherapy was approved for patients with unresectable stage III NSCLC without progression after concurrent chemoradiotherapy (cCRT). The anti–PD-L1 inhibitor durvalumab is now considered by most experts to be the standard of care (SoC) in this setting based on improved survival outcomes. Methods: We conducted a series of 5 CME-certified symposia to provide healthcare providers (HCPs) with education that included expert and guideline recommendations on the optimal use of durvalumab therapy for patients with unresectable stage III NSCLC. These symposia were conducted at 3 major oncology conferences (NCCN Annual, AACR, ASCO Annual) and 2 managed care pharmacy (MCP) conferences (AMCP Annual, AMCP Nexus) over an 8-month period after durvalumab was approved (Table). Polling questions designed to assess key aspects of HCP knowledge and practice patterns were repeated at each symposium and responses were collected through an audience response system. Results: Across the 5 symposia, on average fewer than 45% of responding HCPs recommended durvalumab consolidation therapy for an ideal patient candidate with stage III NSCLC after cCRT (Table). Among responding HCPs across 4 symposia, on average fewer than 30% identified the optimal recommended duration of 1 year of durvalumab therapy based on current clinical evidence. Physicians did identify the optimal management of immune-related pulmonary toxicity associated with durvalumab treatment more often than other HCPs (Table). Conclusions: These pre-education data suggest that a large percentage of HCPs are not fully aware of the available clinical evidence and are delayed in the implementation of immunotherapy for unresectable stage III NSCLC. [Table: see text]