tbuckley/cabot-search huggingface dataset:
A multicenter phase I study of cabazitaxel, mitoxantrone, and prednisone for chemotherapy-naïve patients with metastatic castration-resistant prostate cancer.
Authors: Mallika Sachdev Dhawan, Mina Lee, Alan H. Bryce, Vivian K. Weinberg, Charles J. Ryan, Christina Louise Derleth, Andrea Lynne Harzstark, Eric Jay Small, Rahul Raj Aggarwal
Journal: Journal of Clinical Oncology (2016)

202 Background: Cabazitaxel and prednisone (Cbz/pred) extend survival in mCRPC patients (pts) following docetaxel and first-line studies comparing Cbz to docetaxel are ongoing. Mito/pred also has anti-tumor activity in mCRPC and a non-overlapping mechanism of action and toxicity profile with Cbz. A multicenter phase 1 trial was initiated to establish the maximally tolerated dose (MTD) and recommended phase 2 dose (RP2D) of the combination of Cbz, Mito, and Pred(CAMP). Methods: Chemotherapy (chemo)-naive pts with mCRPC were enrolled in an accelerated titration design. The primary objective was to determine the MTD and RP2D of CAMP; secondary objectives included PSA response rate and duration of response. Cbz 20 and 25 mg/m 2 were evaluated in combination with escalating doses of Mito (starting dose 4 mg/m 2 ), both administered on day 1 of a 21-day cycle. Pred 5 mg BID and pegfilgrastim were given with each cycle. Results: 23 pts were enrolled. The median age was 66 (range 51-78) and the median baseline PSA was 62.5 (range 3-791.2). There were 2 DLTs (sepsis and febrile neutropenia) observed at the dose level of Cbz 25 mg/m 2 + Mito 10 mg/m 2 (n = 4). There was 1 DLT (febrile neutropenia) observed with Cbz 20 mg/m 2 (N = 12), establishing Cbz 20 mg/m 2 + Mito 12 mg/m 2 as the MTD and RP2D. The most common grade ³ 3 related adverse events were hematologic (neutropenia, n = 9; thrombocytopenia, n = 3; febrile neutropenia, n = 3). The median number of treatment cycles was 7.5 (range 2-16), and 2 pts remain on study. Greater than or equal to 50% maximal PSA declines from baseline were observed in 12 of 19 evaluable pts(63%). The median duration of response has not been reached (range 4.9-10.0+ months). Conclusions: The approved single-agent dose of Mito (12 mg/m 2 ) was safely combined with Cbz 20 mg/m 2 , a dose with demonstrated activity in mCRPC and potentially less hematologic toxicity than 25 mg/m 2 . Preliminary efficacy data are encouraging with durable control of disease observed in a subset of pts. Further study of the treatment combination is warranted. Clinical trial information: NCT01594918.
The relationship of B7H3 expression to androgen and prostate cancer outcomes in a large natural history cohort of men undergoing prostatectomy.
Authors: Ashley Ross, Benjamin Benzon, Shuang Zhao, Mandeep Takhar, Michael Haffner, Nicholas Erho, Paula Hurley, Jeffrey J. Tosoian, Mohammed Alshalalfa, Stephanie Glavaris, Brian Simons, Phuoc T. Tran, Elai Davicioni, Jeffrey Karnes, Edward M. Schaeffer, Charles G. Drake, Felix Yi-Chung Feng
Journal: Journal of Clinical Oncology (2016)

256 Background: B7-H3 (CD276), part of the B7 superfamily, has been shown to play an immunomodulatory role, however its regulation, receptor and mechanism of action remain unclear. Protein levels of B7-H3 have been previously shown to relate to prostate cancer outcomes and currently, humanized monoclonal antibodies are being developed for clinical use (MGA271, Macrogenics). Here we use genomic expression data to examine the relationship of B7-H3 to prostate cancer outcomes and molecular subtypes. Methods: Prostatectomy tissue from 905 patients were profiled using the Affymetrix HuEx 1.0 ST microarray. Kruskal-Wallis tests were used to identify significant associations of B7-H3 expression with clinico-pathologic variables, and survival analysis were used to evaluate the prognostic value of B7-H3. Pearson’s correlation analyses were also performed to assess the relationship of B7-H3 expression with molecular subtypes and individual transcripts. Androgen receptor (AR) occupancy of promoter regions was derived in silico from chromosomal immune-precipitation (ChIP) data. Results: B7-H3 expression was positively associated with Gleason score (p &lt; 0.01) and tumor stage (p &lt; 0.01). High B7-H3 expression also correlated with the development of metastasis and prostate cancer specific mortality (HR of 3.4 and 2.4 respectively, p &lt; 0.05 for both), but this was not significant on multi-variable analysis. B7-H3 was positively associated with ERG+ disease (n = 670, r = 0.85, p &lt; 0.05) and AR expression (n = 670, r = 0.46, p &lt; 0.001). B7-H3 was found to be one of the most correlated genes with AR (95th percentile) and ChIP analysis revealed AR binding upstream of B7-H3, suggesting potential androgen dependent regulation. Conclusions: B7-H3 expression correlates with high Gleason grade and advanced prostate cancer stage with higher quartiles of expression portending poor oncologic outcomes in two independent prostatectomy cohorts. B7-H3 expression appears to relate to the androgen receptor.
First-in-Human Study Testing a New Radioenhancer Using Nanoparticles (NBTXR3) Activated by Radiation Therapy in Patients with Locally Advanced Soft Tissue Sarcomas
Authors: Sylvie Bonvalot, Cécile Le Pechoux, Thierry De Baere, Guy Kantor, Xavier Buy, Eberhard Stoeckle, Philippe Terrier, Paul Sargos, Jean Michel Coindre, Nathalie Lassau, Rafik Ait Sarkouh, Mikaela Dimitriu, Elsa Borghi, Laurent Levy, Eric Deutsch, Jean-Charles Soria
Journal: Clinical Cancer Research (2016)

Purpose: This phase I study aimed to determine the recommended dose (RD), safety profile, and feasibility of a procedure combining intratumoral injection of hafnium oxide nanoparticles (NBTXR3; a radioenhancer) and external beam radiotherapy (EBRT) for preoperative treatment of adults with locally advanced soft tissue sarcoma (STS).Experimental Design: Patients had a preoperative indication of EBRT for STS of the extremity or trunk. Baseline tumor volume (TV) was calculated by MRI. NBTXR3 was injected percutaneously into tumors at 53.3 g/L. Dose escalation was based on four levels equivalent to 2.5%, 5%, 10%, and 20% of baseline TV. NBTXR3 was visualized in the tumor 24 hours postinjection, and EBRT was initiated (50 Gy over 5 weeks). Surgery was performed 6 to 8 weeks after EBRT completion.Results: Twenty-two patients completed NBTXR3 injection, EBRT, and surgery and were followed for a median 22 months (range, 6-40). At NBTXR3 20% of TV, two dose-limiting toxicities occurred: injection-site pain and postoperative scar necrosis. The RD was defined as 10%. No leakage of NBTXR3 into surrounding tissues occurred; intratumor NBTXR3 levels were maintained during radiotherapy. At the RD, median tumor shrinkage was 40% (range 71% shrinkage, 22% increase); median percentage of residual viable tumor cells was 26% (range, 10%-90%). Patients receiving 20% of TV demonstrated pathologic complete responses. Seven grade 3 adverse events occurred, which were reversible.Conclusions: A single intratumoral injection of NBTXR3 at 10% of TV with preoperative EBRT was technically feasible with manageable toxicity; clinical activity was observed. Clin Cancer Res; 23(4); 908-17. ©2016 AACR.
Seizure protein 6 and its homolog seizure 6-like protein are physiological substrates of BACE1 in neurons
Authors: Martina Pigoni, Johanna Wanngren, Peer-Hendrik Kuhn, Kathryn M. Munro, Jenny M. Gunnersen, Hiroshi Takeshima, Regina Feederle, Iryna Voytyuk, Bart De Strooper, Mikail D. Levasseur, Brian J. Hrupka, Stephan A. Müller, Stefan F. Lichtenthaler
Journal: Molecular Neurodegeneration (2016)

The protease BACE1 (beta-site APP cleaving enzyme) is a major drug target in Alzheimer's disease. However, BACE1 therapeutic inhibition may cause unwanted adverse effects due to its additional functions in the nervous system, such as in myelination and neuronal connectivity. Additionally, recent proteomic studies investigating BACE1 inhibition in cell lines and cultured murine neurons identified a wider range of neuronal membrane proteins as potential BACE1 substrates, including seizure protein 6 (SEZ6) and its homolog SEZ6L. We generated antibodies against SEZ6 and SEZ6L and validated these proteins as BACE1 substrates in vitro and in vivo. Levels of the soluble, BACE1-cleaved ectodomain of both proteins (sSEZ6, sSEZ6L) were strongly reduced upon BACE1 inhibition in primary neurons and also in vivo in brains of BACE1-deficient mice. BACE1 inhibition increased neuronal surface levels of SEZ6 and SEZ6L as shown by cell surface biotinylation, demonstrating that BACE1 controls surface expression of both proteins. Moreover, mass spectrometric analysis revealed that the BACE1 cleavage site in SEZ6 is located in close proximity to the membrane, similar to the corresponding cleavage site in SEZ6L. Finally, an improved method was developed for the proteomic analysis of murine cerebrospinal fluid (CSF) and was applied to CSF from BACE-deficient mice. Hereby, SEZ6 and SEZ6L were validated as BACE1 substrates in vivo by strongly reduced levels in the CSF of BACE1-deficient mice. This study demonstrates that SEZ6 and SEZ6L are physiological BACE1 substrates in the murine brain and suggests that sSEZ6 and sSEZ6L levels in CSF are suitable markers to monitor BACE1 inhibition in mice.
<i>JAMA Neurology</i> at the Forefront, 1997-2016
Authors: Roger N. Rosenberg
Journal: JAMA Neurology (2016)

Our website uses cookies to enhance your experience. By continuing to use our site, or clicking "Continue," you are agreeing to our Cookie Policy | Continue JAMA Neurology HomeNew OnlineCurrent IssueFor Authors Podcast Publications JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry (1919-1959) JN Learning / CMESubscribeJobsInstitutions / LibrariansReprints & Permissions Terms of Use | Privacy Policy | Accessibility Statement 2023 American Medical Association. All Rights Reserved Search All JAMA JAMA Network Open JAMA Cardiology JAMA Dermatology JAMA Forum Archive JAMA Health Forum JAMA Internal Medicine JAMA Neurology JAMA Oncology JAMA Ophthalmology JAMA Otolaryngology–Head & Neck Surgery JAMA Pediatrics JAMA Psychiatry JAMA Surgery Archives of Neurology & Psychiatry Input Search Term Sign In Individual Sign In Sign inCreate an Account Access through your institution Sign In Purchase Options: Buy this article Rent this article Subscribe to the JAMA Neurology journal
Oral chemotherapy: Improved medication outcomes in private practice.
Authors: Tallat Mahmood, Elaine McNamara, Lindsey Redoutey, Jane Alcyne Severson
Journal: Journal of Clinical Oncology (2015)

e20691 Background: Despite the perception that oral chemotherapy is less toxic than intravenous therapy, they pose their own unique challenges in terms of acquisition, education, side effect management and adherence. We sought to evaluate the impact of incorporating Michigan Oncology Quality Consortium’s (MOQC) defined oral oncolytic processes had on improving medication outcomes. Methods: A retrospective chart audit was conducted of patients who were prescribed oral chemotherapy between May 2011 and July 2013 including: date prescribed, the actual patient start date and any reported problems with their medications. Subsequently, our practice joined the MOQC initiative, which included four major components: implementation of care manager, self-management focused education, the Edmonton Symptom Assessment System and an adherence monitoring tool. A repeat audit was conducted from August 2013 to March 2014, following incorporation of workflow changes. A T test was performed. Results: 25 patients were in the first cohort and 24 in the second- post intervention cohort. In the first cohort, 13/25 patients had a documented start date, and of these 13, 10 had ≥ 4 weeks delay to actually starting their oral chemotherapy, 3/13 had a 2-4 week delay to start treatment. 12 /25 patients discontinued their drug within the first month due to side effects without consulting their physician. In the second-post intervention cohort, 24/24 patients had the start date documented; 24/24 started therapy 1 week after the prescription was written. Post intervention, there were no self-discontinuations of the drug and four physician-directed dose reductions. Differences between start date documentation compliance and, self-discontinuation of medication pre and post intervention are statistically significant with p-value < 0.001. Conclusions: A multi-disciplinary approach involving the introduction of a care manager, self-management education, and enhanced symptom and adherence monitoring lead to earlier recognition of symptoms and intervention. This lead to greater adherence to oral chemotherapy regimens for our patients. Pre Post p-value Start Date Documented 13/25 24/24 < 0.001 Self-Discontinuation of Drug (without MD evaluation) 12/25 0/24 < 0.001
Abnormal B-cell maturation in the bone marrow of patients with germline mutations in PIK3CD
Authors: Alina E. Dulau Florea, Raul C. Braylan, Kristian T. Schafernak, Kelli W. Williams, Janine Daub, Rakesh K. Goyal, Jennifer M. Puck, V. Koneti Rao, Stefania Pittaluga, Steven M. Holland, Gulbu Uzel, Katherine R. Calvo
Journal: Journal of Allergy and Clinical Immunology (2016)
OP53INHIBITION OF LACTATE DEHYDROGENASE A (LDHA) USING SODIUM OXAMATE LEADS TO METABOLIC CHANGES, DECREASED GROWTH AND MIGRATION IN MEDULLOBLASTOMA CELL LINES
Authors: Cara Valvona, Laura Donovan, Helen L. Fillmore, Geoffrey J. Pilkington
Journal: Neuro-Oncology (2015)

Integrated genomic data has identified four distinct Medulloblastoma (MB) sub-groups differing in clinical outcomes, of which group 3 is the most frequently metastatic and characteristically over-expresses cMyc. Lactate dehydrogenase A (LDHA), known for its key role in metabolic functions, is a downstream target of cMyc and HIF1α. We hypothesised LDHA inhibition would influence a change from a glycolytic to an oxidative phosphorylation phenotype, thus leading to decreased MB viability and migration. LDHA protein was examined in MB cell lines (Res256 and UW402) using IHC, Flow cytometry and Western blot. Lactate and pyruvate concentrations, viability, and proliferation were evaluated in the presence or absence of sodium oxamate under normoxic and hypoxic conditions. MB migration (gap-closure) and distance travelled (cell-tracking) was measured using live cell imaging. LDHA expression was elevated under hypoxic conditions in MB cells. LDHA activity was inhibited by sodium oxamate causing a concentration and time dependent decrease in lactate concentration. Significance varied depending on normoxic versus hypoxic conditions (p < 0.05-p < 0.001). Under hypoxic conditions, pyruvate levels also decreased with LDHA inhibition (p < 0.05). Sodium oxamate significantly reduced proliferation and increased the percentage of MB cells in G2/M cell cycle phase. Sodium oxamate treatment also caused a significant decrease in MB migration in a concentration/time dependent manner that was not dependent on reduced proliferation. Inhibition of LDHA activity by sodium oxamate significantly decreased lactate concentrations and significantly inhibited MB migration and proliferation. Targeting MB metabolism through LDHA is a promising approach, which could prevent the use of harsh therapy regimens, and warrants further investigation.
Loss and Gain of Human Acidic Mammalian Chitinase Activity by Nonsynonymous SNPs
Authors: Kazuaki Okawa, Misa Ohno, Akinori Kashimura, Masahiro Kimura, Yuki Kobayashi, Masayoshi Sakaguchi, Yasusato Sugahara, Minori Kamaya, Yoshihiro Kino, Peter O. Bauer, Fumitaka Oyama
Journal: Molecular Biology and Evolution (2016)

Acidic mammalian chitinase (AMCase) is implicated in asthma, allergic inflammation, and food processing. Little is known about genetic and evolutional regulation of chitinolytic activity of AMCase. Here, we relate human AMCase polymorphisms to the mouse AMCase, and show that the highly active variants encoded by nonsynonymous single-nucleotide polymorphisms (nsSNPs) are consistent with the mouse AMCase sequence. The chitinolytic activity of the recombinant human AMCase was significantly lower than that of the mouse counterpart. By creating mouse-human chimeric AMCase protein we found that the presence of the N-terminal region of human AMCase containing conserved active site residues reduced the enzymatic activity of the molecule. We were able to significantly increase the activity of human AMCase by amino acid substitutions encoded by nsSNPs (N45, D47, and R61) with those conserved in the mouse homologue (D45, N47, and M61). For abolition of the mouse AMCase activity, introduction of M61R mutation was sufficient. M61 is conserved in most of primates other than human and orangutan as well as in other mammals. Orangutan has I61 substitution, which also markedly reduced the activity of the mouse AMCase, indicating that the M61 is a crucial residue for the chitinolytic activity. Altogether, our data suggest that human AMCase has lost its chitinolytic activity by integration of nsSNPs during evolution and that the enzyme can be reactivated by introducing amino acids conserved in the mouse counterpart.
BILCAP: A randomized clinical trial evaluating adjuvant chemotherapy with capecitabine compared to expectant treatment alone following curative surgery for biliary tract cancer.
Authors: J. A. Bridgewater, C. Stubbs, J. N. Primrose
Journal: Journal of Clinical Oncology (2011)

4125 Background: Biliary tract tumours are relatively rare, accounting for 0.7% of malignant tumours in adults, with approximately 1200 new cases registered each year in England and Wales. The 1-year and 5-year survival is poor at 22% and 9% respectively. Approximately 15-20% of cases are suitable for surgical resection but the outlook remains poor with survival at 5 years approximately 15%. Most tumours are advanced at presentation and are unsuitable for surgical resection. Methods: BILCAP is a multi-centre prospective, randomised phase III trial investigating the role of adjuvant chemotherapy with oral fluoropyrimidine (capecitabine) in patients following potentially curative surgical resection of a biliary tract cancer. Patients who have undergone macroscopically complete surgical resection will be randomised to receive either adjuvant chemotherapy with capecitabine or observation. The study is supervised by the National Cancer Research Institute (UK) Upper Gastrointestinal Studies Group and funded by Cancer Research UK. Results: The primary endpoint is progression free survival (DFS) at 2 years. The intention is to increase 2 year DFS from 15 to 28%. This will require 360 patients enabling a 2-sided significance level of 5% and 80% power. Secondary endpoints are 5-year survival, toxicity, quality of life and health economics. Toxicity has been acceptable. Conclusions: 202 of 360 patients have been successfully recruited to date. With approximately 200 resections for biliary tract cancer per year in the UK, BILCAP has recruited more than 25% of all resected patients in the UK for the last 3 years (51pts in 2008, 53 pts in 2009 and 73 patients in 2010) and 36% in 2010. As such it is the most successful adjuvant study in biliary tract cancer and will complete accrual in Q1 2012. The results of BILCAP will define the international standard of care for patients with resected biliary tract cancer. Further detail on recruitment and toxicity will be presented. ISRCTN Number: ISRCTN72785446, EudraCT Number: 2005-003318-13. Publisher's Note The abstract by Bridgewater et al entitled, "BILCAP: A randomized clinical trial evaluating adjuvant chemotherapy with capecitabine compared to expectant treatment alone following curative surgery for biliary tract cancer," published in the 2011 Journal of Clinical Oncology 29, no. 15 suppl (May 20 2011) 4125–4125, contained errors. The authors discovered the Results section of the abstract contains errors that apply to both the definition of the primary outcome measure and the parameters of the sample size calculation. The primary outcome of the BILCAP trial was incorrectly defined as progression free survival, rather than overall survival. In addition, the stated detectable difference was incorrectly identified as 15% to 28%. This article was retracted on 17-07-2019.
In Vitro Propagation of Mesenchymal Stromal Cells From Marrow Aspirates of Patients with Chronic Lymphocytic Leukemia Is Dependent Upon Physiologic Oxygen Tension
Authors: Jessie-Farah Fecteau, Davorka Messmer, Suping Zhang, Bing Cui, Liguang Chen, Thomas J. Kipps
Journal: Blood (2011)
Proposal of a new population pharmacokinetics (PK) model of sorafenib and rationale for a three-daily schedule.
Authors: P. Boudou-Rouquette, B. Blanchet, O. Mir, B. Billemont, S. Ropert, S. Barete, R. Coriat, N. Franck, M. Tod, F. Goldwasser
Journal: Journal of Clinical Oncology (2010)

3044 Background: We created a population pharmacokinetics (PK) model for sorafenib (SOR)-treated patients (pts) and attempted to identify early PK parameters susceptible to predict toxicity. Methods: The population PK of SOR was defined from 71 pts and 363 samples. Plasma concentrations were assessed by HPLC with UV detection method. Nonlinear mixed-effects modelling estimated population PK parameters. Toxicity was prospectively recorded every 2 wks in a cohort of 63 pts with solid tumors, and tentatively related to steady-state area under the plasma concentration-time curve (AUC) after 15 (AUC15) and 28 (AUC28) days of treatment. Results: SOR PK was better described using a one-compartment model with saturated absorption and linear elimination. The AUC infraproportionally increased with dose [60.3 (56.3-64.4), and 75.9 (45.5-100.9) mg/L.h for 400 and 800 mg/day, respectively]. For dose >800 mg/d, fractionation schedule in 3 or 4 daily doses would increase AUC versus twice daily dosing regimen (101.7 vs 81.6 mg/l.h for 400 mg tid and 600 mg bid respectively, p<0.0001; 131.6 vs. 91.5 mg/L.h for 400 mg four times daily and 800 mg bid respectively, p<0.0001). In a cohort of 63 pts [median age: 66 years (34-92), Primary: melanoma (21), hepatocellular carcinoma (19), thyroid cancer (11), renal cancer (9), others (3)], median AUC was 60.8 mg/L.h (range : 18.1-238.1) on day 15 and 56.4 mg/L.h (23.0-179.1) on day 28. No correlation was found between AUC and early hand-foot syndrome. In pts with grade ≥ 2 diarrhea, AUC was significantly lower (p = 0.03) during the following 2 weeks, probably due to decreased SOR absorption. pts with AUC above the third interquartile (97.4-238.1 mg/l.h) on day 15 experienced significantly more diastolic blood pressure elevations (> 90 mm Hg, p < 0.01) and grade 2 alopecia (p = 0.005). Conclusions: The population PK model recommends a thrice daily dosing regimen especially over 800 mg per day. Early monitoring of SOR concentrations may help identify pts experiencing delayed toxicities or underexposed at standard dose. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Amgen, Bayer, Novartis, Pfizer Amgen, Bayer, Novartis, Pfizer