tbuckley/cabot-search huggingface dataset:
DSM265 for Plasmodium falciparum chemoprophylaxis: a randomised, double blinded, phase 1 trial with controlled human malaria infection
Authors: Mihály Sulyok, Thomas Rückle, Alexandra Roth, Raymund E Mürbeth, Stephan Chalon, Nicola Kerr, Sonia Schnieper Samec, Nathalie Gobeau, Carlos Lamsfus Calle, Javier Ibáñez, Zita Sulyok, Jana Held, Tamirat Gebru, Patricia Granados, Sina Brückner, Christian Nguetse, Juliana Mengue, Albert Lalremruata, B Kim Lee Sim, Stephen L Hoffman, Jörg J Möhrle, Peter G Kremsner, Benjamin Mordmüller
Journal: The Lancet Infectious Diseases (2017)

A drug for causal (ie, pre-erythrocytic) prophylaxis of Plasmodium falciparum malaria with prolonged activity would substantially advance malaria control. DSM265 is an experimental antimalarial that selectively inhibits the parasite dihydroorotate dehydrogenase. DSM265 shows in vitro activity against liver and blood stages of P falciparum. We assessed the prophylactic activity of DSM265 against controlled human malaria infection (CHMI).
Identification of glucose transporter type 1 overexpression as a predictor of survival in patients with malignant pleural mesothelioma
Authors: D. A. Fennell, A. Klabatsa, M. T. Sheaff, J. P. C. Steele, M. T. Evans, J. C. Strefford, A. Pallaska, J. Shamash, R. M. Rudd
Journal: Journal of Clinical Oncology (2004)

7199 Background: Malignant pleural mesothelioma (MPM) is characterized by resistance to cytotoxic therapy dependent in part on apoptosis induction. Apoptosis and glycolysis are linked. The aim of this study was to determine the expression and prognostic significance of glucose transporter 1 (GLUT-1) in MPM. Methods: GLUT-1 was measured in 51 archival MPM specimens by immunohistochemistry. Placenta was used as a positive control with antibody diluent as a negative control. 36 MPM patients (pts) were previously treated in 3 consecutive phase II clinical trials at St Bartholomew's Hospital (vinorelbine1 14 pts, vinorelbine/oxaliplatin 7 pts, irinotecan cisplatin mitomycin C 15 pts). GLUT-1 intensity and extent were scored in duplicate and impact on response rate (RR), progression free survival (PFS) and overall survival (OS) studied. Comparison was made with the EORTC prognostic score (EPS)2. Results: GLUT-1 was expressed in 12 specimens (23%). HIF-1α expression was observed in 79%. No association with between GLUT-1 and RR was observed (χ2 test p > 0.05). Trend to shorter PFS was observed in GLUT-1 positive pts. PFS was 4.4 months (95% confidence limits (CI) 0–11) compared to 6.9 months (95% CI 4.8–9.0, log rank statistic (LR) 0.9, p > 0.05). OS was worse in GLUT-1 positive MPM, 9.4 months (95% CI 4.9–14.8), compared to 14.2 months (95% CI 11.0–17.4, LR 4.2, p = 0.04). The EPS showed a trend to worse survival for poor risk patients with an OS of 12.5 months (95% CI 8.0–17.0) compared to good risk patients with an OS of 14.0 months (95% CI 2.1–25.8, LR 3.3 p = 0.07). High resolution, genome-wide array comparative genomic hybridisation studies are in progress investigating links between DNA copy number changes and glycolytic protein expression and will be presented. Conclusions: GLUT-1 is overexpressed in some pts with MPM and predicts for poor clinical outcome at least as efficiently as the EORTC prognostic score 2. Identification of pts with GLUT-1 positive MPM at diagnosis should facilitate design and interpretation of clinical trials. References: 1. Steele JP et al J Clin Oncol 2000;18(23):3912–7 2. Curran D et al J Clin Oncol 1998;16(1):145–52 No significant financial relationships to disclose.
Clinical Characteristics and Treatment with Various Tyrosine Kinase Inhibitors in Patients with ETV6-ABL1 positive Eosinophilia-Associated Myeloproliferative Neoplasms
Authors: Andreas Reiter, Gunay Ahmadova, Mohamad Jawhar, Andres Virchis, Tim Somervaille, Mark Williams, Bernd Schönberger, Rebecca Frewin, Philipp J. Jost, Annett Maschke, Peter Keller, Torsten Haferlach, Nicole Naumann, Juliana Schwaab, Alice Fabarius, Wolf-Karsten Hofmann, Claudia Haferlach, Nicholas C.P. Cross, Georgia Metzgeroth
Journal: Blood (2016)
Dextran sulfate nanoparticles as a theranostic nanomedicine for rheumatoid arthritis
Authors: Roun Heo, Dong Gil You, Wooram Um, Ki Young Choi, Sangmin Jeon, Jong-Sung Park, Yuri Choi, Seunglee Kwon, Kwangmeyung Kim, Ick Chan Kwon, Dong-Gyu Jo, Young Mo Kang, Jae Hyung Park
Journal: Biomaterials (2017)
Doctors call for national rules on OTC prescribing
Authors: Gareth Iacobucci
Journal: BMJ (2017)

Cost cutting plans from clinical commissioning groups (CCGs) to limit GPs’ prescribing of over-the-counter (OTC) medicines have sparked debate among doctors and prompted calls for national guidance.

In a letter to local GPs on 13 March 2017 obtained by The BMJ , Lambeth CCG set out new plans to limit GP prescriptions of OTC medicines as part of a push to save money by promoting self care. This follows similar moves by a string of CCGs including Bristol,1 Lincolnshire,2 and Essex.3

Azeem Majeed, head of the department of primary care and public health at Imperial College London and a GP in Lambeth, said he was concerned that policies were being applied on an “ad hoc” basis by CCGs and called for them to be set by national policy makers. He warned that such policies could disproportionately affect poorer patients who are less able to buy medicines over the counter.

But Clare Gerada, former chair of the Royal College of General Practitioners and also a GP in Lambeth, said that she backed the policy because of the high cost …
Frequency of DNA repair gene mutations in localized and metastatic prostate cancer.
Authors: Marc Dall'Era, Allison Glass, Primo Lara, Ryan Hartmaier, Ralph deVere White, John McPherson
Journal: Journal of Clinical Oncology (2017)

10 Background: DNA repair gene mutations are important molecular alterations in prostate cancer pathogenesis. Germline mutations in DNA repair genes, particularly BRCA2, were recently recognized as associated with metastatic prostate cancer and may also be particularly sensitive to platinum based chemotherapy and PARP inhibitor therapy. We sought to characterize alterations in DNA repair pathway genes in both primary and metastatic prostate tumors. Methods: We studied the distribution of DNA repair gene mutations in 936 prostate cancers harvested from localized and metastatic tumors. Tumor DNA underwent hybrid capture for all coding exons of 395 cancer-related genes plus select introns from 19 or 31 genes frequently rearranged in cancer and sequenced to a median exon coverage depth of &gt;500x using Illumina sequencing and were analyzed for base substitutions/insertions, copy number alterations and rearrangements. We utilized two described lists of genes involved in DNA repair : our own in-house list of 74 (UCD) and a list of 20 DNA repair genes associated with cancer predisposition syndromes utilized in a recent publication by Pritchard et al. We further stratified the frequency of mutations by tissue site (prostate versus metastases). Results: We identified 228/936 unique samples with at least one likely functional mutation in a DNA repair gene (24.4%). Mutations were identified in 20.1% of prostate tumors (13% UCD, 18.4% Pritchard et al.) and in 18.8% of bone metastases. The highest rates of DNA repair mutations were found in visceral metastases including brain, pelvis and liver, higher than either prostate tissue or bone sites (p=&lt;0.01). The most commonly (≥1% of samples) mutated genes in the DNA repair pathways are: BRCA2 (11.43%), ATM (5.77%), MSH6 (2.46%), MSH2 (2.14%), ATR (1.60%), MLH1 (1.28%), and BRCA1(1.18%). Conclusions: DNA repair gene mutations are more common in metastatic than localized prostate tumors. Visceral metastases appear enriched for these mutations compared with localized tumors or bone metastases. Genomic profiling may identify prostate cancers potentially sensitive to platinum-based chemotherapy or PARP inhibition.
Necuparanib combined with nab-paclitaxel + gemcitabine in patients with metastatic pancreatic cancer: Phase 2 results.
Authors: Eileen Mary O'Reilly, Devalingam Mahalingam, James M. Roach, Paul Justin Miller, Molly E. Rosano, Silva Krause, William Avery, Tanios S. Bekaii-Saab, Spencer H. Shao, Donald A. Richards, Louis Vaickus, Julie Wolf, Keith Flaherty, David P. Ryan
Journal: Journal of Clinical Oncology (2017)

370 Background: The Phase 1 portion of a Phase 1/2 trial of Necuparanib (“Necu”) combined with nab-paclitaxel (nabP) + gemcitabine (gem) in patients with metastatic pancreatic cancer (ClinicalTrials.gov Identifier NCT01621243) showed acceptable safety and tolerability and encouraging signals of activity and established a dose for the randomized, placebo (PBO)-controlled Phase 2 portion. Methods: In Phase 2, patients received daily s.c. injections of either 5 mg/kg Necu daily or PBO, combined with i.v. 125 mg/m 2 nabP and 1000 mg/m 2 gem (Days 1, 8, 15 of each 28-day cycle). The primary endpoint was overall survival (OS); other endpoints included progression-free survival (PFS), response rates, safety, and CA19.9 levels. An interim futility analysis was conducted in July 2016 once 57 deaths (50% of the target number of 114 events required for trial completion) had occurred. Results: The analysis was conducted on data from 120 randomized patients (62 Necu, 58 PBO). The Z-score for futility was -0.42 (prespecified boundary of -0.148 was crossed as actual score was lower). Median OS was Necu = 10.71 and PBO = 9.99 months; hazard ratio (HR) = 1.12 (favoring PBO); OS curves were intertwined. PFS was Necu = 5.52 and PBO = 6.93 months; HR = 0.97. RECIST response rates were comparable between arms: complete response, Necu = 0%, PBO = 3%; partial response, Necu = 26%, PBO = 26%; stable disease, Necu = 31%, PBO = 34%; disease control rate, Necu = 56%, PBO = 64%. The most common Grade 3+ adverse events (AEs) were neutropenia (Necu = 33%, PBO = 33%), thrombocytopenia (Necu = 27%, PBO = 5%), and anemia (Necu = 22%, PBO = 11%). There were lower rate of serious AEs with Necu (48%) vs. PBO (60%). Modest increases in APTT, AST, and ALT were noted following Necu relative to PBO. 23% of Necu and 5% of PBO patients were IgG positive with an anti-heparin/PF4 antibody titer of ≥ 0.4 at any time. There were no treatment differences for decreases in CA19.9. Conclusions: No new safety signals were observed and the toxicity profile was considered manageable; however, Necu in combination with nabP and gem did not show a sufficient level of efficacy in metastatic pancreatic cancer to warrant continued enrollment. Clinical trial information: NCT01621243.
A combination of oxaliplatin and UFT-l,-leucovorin as first line treatment in advanced colorectal cancer. An ONCOPAZ phase II study
Authors: J. De Castro, J. Vicent, C. García-Girón, M. Constela, E. Fonseca, J. Montalar, M. Lomas, L. Antón-Aparicio, F. Dorta, M. González-Barón
Journal: Journal of Clinical Oncology (2004)

3726 Background: To assess the efficacy and safety of the oxaliplatin-UFT-l,LV combination as first-line treatment in patients with advanced CRC. Methods:Between 04/99 and 01/00, 81 patients with recurrent or metastatic CRC were included. Mean age was 63 years (40–77), male/female ratio 46/35, ECOG 0/1/2 39/36/6. The study regimen consisted of Oxaliplatin 85 mg/m2 in 120-minute intravenous infusion on days 1 and 15; intravenous l,LV 250 mg/m2 given in two hours on day 1, followed by oral UFT 390 mg/m2 on days 1 to 14, and oral l,LV 7.5 mg/12 hours on days 2 to 14. Pills were taken before meals to favour absorption (for instance, at 8 a.m. and 8 p.m.). Cycles were repeated every 28 days. Results:A total of 470 cycles of chemotherapy were delivered with a median of six cycles per patient (range 1–12). A pre-scheduled preliminary analysis was performed after inclusion of 16 patients. High gastro-intestinal toxicity was observed: G 3–4 diarrhoea 9/16 (56%), G 3–4 nausea-vomiting 3/16 (18%). This lead to reduction of the UFT dose to 300 mg/m2. With this new dosage G 3–4 diarrhoea and G 3–4 nausea/vomiting were present only in 24 and 14% respectively. Other grade 3–4 toxicities were stomatitis in 1 (1%), anemia in 3 (5%), neutropenia in 2 (3%), thrombocytopenia in 1(1%), fatigue in 7 (11%). Oxaliplatin-associated peripheral sensory neuropathy was observed in 84% of patients, with grade 3 neurotoxicity occurring in 10 (16%) patients. Grade 3–4 laryngopharyngeal dysestesia was observed in two patients (3%). All patients were evaluable for response:one patient achieved complete response, 27 had partial response, ORR 35% (95% CI 24–46%) with 44% stable disease and 20% PD. The median time to progression was 7.3 months and the median overall survival was 16.8 months. Conclusions: Oxaliplatin and UFT-1,LV is an active combination in advanced colorectal cancer and demonstrate response rate and survival similar intravenous regimens. The toxicity is moderate at 300 mg/m2 dose of UFT. No significant financial relationships to disclose.
Phase II, randomized, double blind, placebo-controlled study comparing siltuximab plus bortezomib versus bortezomib alone in pts with relapsed/refractory multiple myeloma.
Authors: Robert Z. Orlowski, Liana Gercheva, Cathy Williams, Heather J Sutherland, Tadeusz Robak, Tamás Masszi, Vesselina Goranova-Marinova, Meletios A. Dimopoulos, James D. Cavenagh, Ivan Spicka, Angelo Maiolino, Alexander Suvorov, Joan Blade, Olga S Samoilova, Helgi Van De Velde, Rajesh Bandekar, Britte Kranenburg, Hong Xie, Jean-Francois Rossi
Journal: Journal of Clinical Oncology (2012)

8018^ Background: Preclinical studies of siltuximab (S), a chimeric anti-IL-6 mAb, in combination with bortezomib (B) indicate an additive to synergistic effect in multiple myeloma (MM) cell lines. This randomized study evaluated the safety and efficacy of S+B compared with placebo (plc)+B in pts with relapsed/refractory MM after 1−3 prior tx lines, measurable disease but no prior B exposure. Methods: 286 pts were randomized 1:1 to S+B: B+plc. S 6 mg/kg or plc was given IV q2w. B 1.3 mg/m 2 was given IV on d 1, 4, 8, 11, 22, 25, 29, 32 for a max of 4 of 42-d cycles and then reduced to q1w for 35-d cycles. B was stopped for pts with PD/intolerability, and high dose oral dexamethasone (dex) 40 mg could then be started qd on d 1−4, 9−12, 17−20 for a max of 4 of 28-d cycles and on d 1−4 of subsequent cycles until PD, while S/plc continued. Primary endpoint was PFS by EBMT criteria censored at the start of dex/subsequent tx. Secondary endpoints included overall response rate (ORR), OS, and safety before dex. Results: 142 and 144 pts received S+B and B+plc, respectively. Baseline demographics and disease characteristics were well balanced across S+B and B+plc, except for age (median 64 vs. 61 yrs) and myeloma type (IgG 65 vs. 71%, IgA 27 vs. 20%). Median tx duration was 5.1 mo in both grps. Median PFS was 8.1 mo in S+B and 7.6 mo in B+plc (HR 0.869, p = 0.345). ORR (CR+PR) was 55% in pts on S+B and 47% on B+plc (p = 0.213); CR rates were 11 and 7% (p = 0.342), respectively. With 24.5 mo median follow up, median OS was 30.8 mo for S+B and 36.9 mo for B+plc (HR 1.353 for S+B, p = 0.103). Fewer pts on S+B than B+plc moved to dex (23 vs. 31%) and had subsequent SCT (5 vs. 11%). Gr ≥3 AEs occurred in 91% on S+B and 74% on B+plc. Common gr ≥3 AEs in S+B were neutropenia (49%), thrombocytopenia (48%), leukopenia (14%). SAEs occurred in 29% on S+B and 24% on B+plc. Death occurred within 30 d of last study agent administration pre-dex in 8% on S+B and 5% on B+plc. Conclusions: The combination of S+B had higher response rates but did not prolong survival compared with B+plc. A negative survival trend heavily influenced by differences in dex and SCT rescue was noted. S+B appears to be generally well tolerated but had a higher incidence of hematologic AEs.
Prognostic value of MAGE-A3 and PRAME gene expression in non-small-cell lung cancer (NSCLC).
Authors: Albert Linder, Henry Budihardjo-Welim, Wiorika Velehorschi, Thierry Coche, Olivier Gruselle, Diego D'Agostino, Jamila Louahed, Frederic Lehmann, Vincent G. Brichard
Journal: Journal of Clinical Oncology (2012)

7056 Background: We investigated the expression of some cancer–testis genes and their association with disease prognosis. Here we report our results for the expression, in resected NSCLC samples, of two tumor-specific antigens (Ags): MAGE‑A3 and PRAME, both under evaluation in clinical trials. Methods: We conducted a single-center, uncontrolled, retrospective study of tissue from resected stage I–III NSCLC patients (pts): 650 were in stage I, 215 in stage II and 395 in stage III. 1260 FFPE tumor tissue samples from the tumor tissue bank of the Department of Pathology, Lungenklinik Hemer (Germany), were tested for MAGE‑A3 and PRAME expression by specific qRT-PCR assays. The prognostic value of these Ags was determined by estimating the median overall survival (OS), disease-free interval (DFI) and disease-free survival (DFS). Results: Expression rates were 36% for MAGE‑A3 and 66% for PRAME. The co‑expression rate was 30%. Almost all tumors expressing MAGE‑A3 also expressed PRAME. We observed no difference overall in Ag expression according to stage, tumor size and pts’ age. Squamous tumors expressed MAGE‑A3 and PRAME more frequently than did adenocarcinomas (43 vs. 27 % and 80 vs. 44% respectively), and PRAME expression rates were higher in males than in females (70 vs. 53%). In the overall population, which included stages IA–IIIB, no prognostic value was detected for the expression of either Ag. In subset analyses, we found in 83 stage IIIB pts a trend to worse OS linked to MAGE‑A3 expression (HR=1.977, p=0.0312). In 395 stage IB pts, PRAME expression was associated with worse OS (HR=1.483, p=0.0344) and DFS (HR=1.492, p=0.0167). Conclusions: The MAGE‑A3 expression rate found is consistent with the results observed in the phase III MAGRIT trial (J‑H Kim et al., 2011). No prognostic value for either PRAME or MAGE‑A3 was observed in the overall population, in contrast to previous reports with smaller sample sizes (Gure et al., 2005, Boli et al., 2002) and in other tumors (Vourch’jourdain et al., 2009, Epping et al., 2008). We observed a trend toward poor prognostic value of MAGE‑A3 in stage IIIB pts and of PRAME in stage IB pts.
Retrospective study of patients (pts) who were managed with Watch and Wait strategy (W&amp;W) after neoadjuvant chemoradiation (NCRT) for Locally Advanced Rectal Cancer (LARC).
Authors: Sina Vatandoust, Yick Ho Lam, Amitesh Chandra Roy, David Wattchow, Paul Hollington, Christos Stelios Karapetis
Journal: Journal of Clinical Oncology (2015)

3603 Background: The management of LARC involves NCRT followed by resection +/- adjuvant chemotherapy. Rectal resection has associated short and long-term morbidity and functional compromise. Complete Response (CR) is observed in ~ 20% of cases after NCRT and resection may be avoidable in these pts. We retrospectively report a cohort of pts who received NCRT and have been followed up with ‘W&W’. Methods: All patients with LARC who had CR to NCRT, and did not proceed to surgery but instead were managed by a surveillance strategy, were identified from clinical records. All pts had received long course NCRT as suggested by multidisciplinary team meeting. CR was defined as the absence of any residual viable cancer, proven through examination, colonoscopy (+ biopsy if indicated) and imaging (including MRI). Pts with metastatic rectal cancer were excluded. Data on demographics, management and outcomes were extracted from records. Follow up included regular 3 monthly physical examination, sigmoidoscopy/colonoscopy (+ biopsy if indicated) and MRI scans. Follow up times were calculated from date of diagnosis of rectal cancer. Results: 22 pts achieved a CR and were managed by ‘W&W’, without surgery. Median follow up 19 (9-49) months (mo), 50% (n = 11) male, median age 62 (34-78), Stage at diagnosis: T2N0 4.5% (n = 1), T2N1 27.3% (n = 6), T3N0 13.6% (n = 3), T3N1 22.7% (n = 5) and T3N2 31.8% (n = 7). 2 pts had other concurrent cancers (1 with metastatic small cell carcinoma and 1 with breast cancer). 2 pts (9.1 %) developed salvageable local recurrences: 1 had local recurrence 11 mo after primary diagnosis and underwent ultra-low anterior resection; the other had recurrence 8 mo after the primary diagnosis and underwent low anterior resection, both with clear margins. Both were detected on follow-up reviews (evident at sigmoidoscopy). Another pt developed metastatic disease 10 mo after the original diagnosis. All 22 pts are alive at the time of this report. Conclusions: In this cohort of pts with LARC who had achieved CR to NCRT, W&W did not lead to unsalvageable local recurrence. Prospective study design and longer follow up is needed to confirm the utility of this approach.
Combined KIT and CTLA-4 blockade in patients with refractory GIST and other advanced sarcomas.
Authors: Alexander Noor Shoushtari, Sandra P. D'Angelo, Mary Louise Keohan, Mark Andrew Dickson, Mrinal M. Gounder, Abdul Karim Abdullah, Joseph Patrick Erinjeri, Mark J. Bluth, Yelena Ustoyev, Mercedes M. Condy, Howard Streicher, Naoko Takebe, Ronald P. DeMatteo, Gary K. Schwartz, William D. Tap, Richard D. Carvajal
Journal: Journal of Clinical Oncology (2014)

10521 Background: Few effective treatments (tx) exist for patients (pts) with tyrosine kinase inhibitor (TKI)-resistant gastrointestinal stromal tumors (GIST) and other advanced soft tissue sarcomas (STS). In a murine GIST model, we showed that the efficacy of KIT inhibition is immune-mediated via decreases in indoleamine 2,3-dioxygenase (IDO), with improved anti-tumor effects using combined KIT and CTLA-4 blockade (Balachandran, Nat Med 2011). Methods: This Phase Ib trial used a standard 3+3 design of ipi 10 mg/kg (q3 week [wk] x4 induction + q12 wk maintenance) plus escalating doses of dasatinib (das; 70 mg QD, 100 mg QD, 70 mg BID). Pts with refractory GIST or advanced STS and ≥1 prior tx were eligible. Primary objective was to estimate the maximum tolerated dose (MTD). Secondary objectives included response assessed by RECIST1.1, Choi, and immune-related response criteria (irRC) at week 12 and q6 wks afterward. Results: 13 pts were treated: median (range) age 56 (40-72), 7 male, prior tx = 4 (1-8). Histologies: 8 GIST, 2 leiomyosarcomas, 3 other. All GIST pts progressed on imatinib and sunitinib; 7 had prior sorafenib. Potential immune-mediated toxicities included grade (G) 1/2 rash (n=6), diarrhea (n=4), pruritus (n=2). Other common G1/2 toxicities included fatigue (n=8), anemia (n=6), edema (n=5), nausea (n=5) and pleural effusion (n=3). At das 70 mg QD, one dose-limiting toxicity (DLT) was seen: G3 upper GI hemorrhage. Two DLTs were observed at das 100 mg QD: G3 ALT elevation and G3 upper GI hemorrhage. 3/8 GIST pts achieved a durable Choi response (24, 25, 59+ wk). No irRC or RECIST responses were observed. Durable irRC SD was achieved in 1 pt with GIST (59+ wk) after 4 prior TKIs and 1 pt with high-grade sarcoma (34+ wk) after 5 prior tx. 4/5 pts completing ipi induction had radiologic SD vs wk 12 scans (24, 24, 33+, 59+ wk). Median ALC increased from b/l to wk 7 (1100 to 1550, p=0.04) with no association with clinical benefit. Conclusions: In this completed Phase Ib trial, the recommended phase 2 dose is das 70 mg QD + ipi 10 mg/kg. Disease stability was seen post-ipi induction, suggesting an immune-mediated effect. Analysis of tumor IDO expression and other immune correlates from serial biopsies obtained from a follow-up GIST cohort is ongoing. Clinical trial information: NCT01643278.