tbuckley/cabot-search huggingface dataset:
A dose-finding study of the SMAC mimetic Debio 1143 when given in combination with avelumab to patients with advanced solid malignancies.
Authors: Rosalyn A. Juergens, Quincy S. Chu, Daniel John Renouf, Scott Andrew Laurie, Daniela Purcea, Elaine McWhirter, Diane Arndt, Karen A. Gelmon, John Hilton, Bruno Gavillet, Peter Michael Ellis, Michael B. Sawyer, Christian K. Kollmannsberger, Natalie Andrews Wright, Elisabeth Rouits, Frank Brichory, Gregoire Vuagniaux, Sergio A. Szyldergemajn, Glenwood Goss
Journal: Journal of Clinical Oncology (2019)

2599 Background: Second mitochondria-derived activator of caspase (SMAC) mimetics regulate apoptosis and modulate NFκB signaling which drives the expression of genes involved in immune and inflammatory responses. In patient (pt) tumors, Debio 1143 increased PD-1/PD-L1 expression and tumor infiltrating lymphocytes. In pre-clinical models, it synergizes in vitro and in vivo with PD1/PD-L1 checkpoint inhibitors (CPIs). Methods: In a phase I study, using a mCRM model, avelumab (10 mg/kg i.v. on D1&amp;15 q4w) was combined with escalating doses of Debio 1143 (100 mg/d to 250 mg/d orally, D1-10 &amp; D15-24 q4w) to define the RP2D. Consenting adult pts with advanced solid tumors, normal organ function, and PS-ECOG = 0-1 were eligible provided none received prior CPI. Dose-limiting toxicities (DLTs), efficacy, safety, PK, PD and biomarkers were assessed. Results: As of DEC’18, 16 pts were treated; M/F: 8/8; ECOG = 0 in 6 (38%); median age = 58 (28-79); 5 pts had NSCLC, 2 MPM, 2 ovarian and 7 had other tumors (n = 1 each). Common AEs were: nausea (69%); fatigue (62%); vomiting (50%); cough, dyspnea, myalgia (44% each); diarrhea, anorexia (38% each); pruritus and constipation (31% each). These were generally grade 1-2, occasionally grade 3. One pt had a DLT at 250 mg/d dose: a grade 3 AST/ALT increase. No treatment-related AEs grade 4 or higher occurred. No dose-relationships for laboratory abnormalities were observed, except for ALT/AST increases, which at 200 mg/d were all grade 1 and asymptomatic. Maximal tolerated dose was not reached and there were no dose reductions. In 15 evaluable pts, 1 PR (NSCLC) and 5 SD (RECIST v1.1) were observed. Tumor shrinkage &gt; 15% was seen in 2 other NSCLC pts. PK showed high interpatient variability and dose-proportional increase. TNFα and IFNγ peaked in plasma following Debio 1143 dose on D1 after 8 hrs, and on D17/22, in a dose-proportional manner. Four pts developed anti-avelumab antibodies. Conclusions: Debio 1143 at 200 mg/d can be safely combined with avelumab. Toxicity was predictable and mild. Clinical activity was observed in NSCLC pts. PK was linear; no drug interaction was suspected. PD and biomarker analysis is ongoing. Expansion at this RP2D is ongoing in NSCLC. Clinical trial information: NCT03270176.
An endoscopist with a painful finger
Authors: Taj Tomouk, Meg Birks
Journal: BMJ (2019)

A middle aged gastroenterologist presented with a two day history of sudden onset and exquisitely painful erythematous swelling around the distal interphalangeal joint of her left ring finger. She had no history of acute trauma but described repetitive hand use while performing four endoscopy sessions weekly for around 25 years: the left hand had been used to manoeuvre the endoscope and the left ring finger to press the control buttons. She was otherwise fit and well, right handed, and a non-smoker.

Flexor sheath …
Radiotherapy with continued EGFR-TKIs for oligoprogressive disease in non-small cell lung cancer: A real-world study.
Authors: Fang Wu, Sixuan Wu, Chunhong Hu
Journal: Journal of Clinical Oncology (2019)

e20640 Background: Almost all epidermal growth factor recept (EGFR)-mutated non-small-cell lung cancer (NSCLC) will develop tyrosine kinase inhibitors (TKIs) resistance. The treatment of oligoprogression is debatable after TKIs resistance. We conducted a real-world retrospective study to evaluate the efficacy of radiotherapy and continuation of TKIs in advanced NSCLC patients with oligoprogressive disease after EGFR-TKIs. Methods: From January 2011 to January 2019, we retrospectively analyzed EGFR-mutated NSCLC patients with oligoprogression in our institution. 33 patients were treated by radiotherapy and continuation of TKIs after oligoprogression. We used Kaplan-Meier and Cox regression model to analyse the prognostic factors of median progression-free survival (PFS) and median overall survival (OS) from the time of oligoprogression. Variables we selected for analyses included gender, age, smoking status, performance status (PS) score, stage at initial diagnosis, initial resectable, radiotherapy dose, EGFR mutation type, number of metastasis, sites of radiation, T790M status and the time of oligometastasis to radiotherapy. Results: 33 patients develop resistance to EGFR-TKIs at a median time of 11.0 months. The mPFS and mOS were 6.5 (95%CI, 1.4-11.6) and 21.8 (95%CI, 14.8-28.8) months, respectively. T790M mutation was tested in nine patients, four of which were mutation negative and five were positive. The mPFS was 15.5 (95%CI, 7.4-23.6) months in T790M mutation positive patients and 6.0 (95%CI, 0-14.0) months in negative patients. The mPFS in patients who started radiotherapy within or beyond 1 month after oligometastasis was 10.8 months (95% CI, 4.9-16.7 months) and 5.3 months (95% CI, 2.4-8.2 months). Cox regression model showed no variables significantly correlated with PFS difference. Univariate analysis identified female patients have longer OS (P = 0.038). The results of Multivariate analysis indicated that there was no OS-related prognostic factors. Conclusions: Radiotherapy with continued TKIs is an efficacious treatment option in advanced NSCLC patients with oligoprogressive disease after EGFR-TKIs. T790M mutation is a common mutation in NSCLC patients with oligoprogression. Gender was prognostic factors for OS. Moreover, there was a better prognosis in patients with T790M mutation positive or radiotherapy within 1 month after oligometastasis. However, this was not statistically significant. Larger sample size studies are needed to validate these clinical results.
INFORM2 exploratory multinational phase I/II combination study of nivolumab and entinostat in children and adolescents with refractory high-risk malignancies: INFORM2 NivEnt.
Authors: Cornelis Martinus van Tilburg, Ruth Witt, Kristian W. Pajtler, Plass Christoph, Isabel Poschke, Michael Platten, Inga Harting, Oliver Sedlaczek, Angelika Freitag, David Meyrath, Lenka Taylor, Gnana Prakash Balasubramanian, Natalie Jäger, Elke Pfaff, Barbara Christine Worst, Till Milde, Stefan M. Pfister, David T. W. Jones, Annette Kopp-Schneider, Olaf Witt
Journal: Journal of Clinical Oncology (2019)

TPS10065 Background: Immune checkpoint inhibition in children has shown limited success rates until now. This is most likely due to the fact that the vast majority of pediatric cancers are so-called immunologic cold tumors, and that patients have been enrolled in an unselected manner in single agent trials. Recently, it has been shown that the class I selective HDAC inhibitor entinostat has significant immune enhancing activity in vitro and in vivo. This is mediated through multiple mechanisms including depletion of myeloid-derived suppressor cells, activation of neoantigen transcription and increase of MHC expression. Methods: INFORM2 NivEnt is an exploratory nonrandomized, open-label, multinational and multicenter seamless phase I/II basket trial of nivolumab and entinostat in children and adolescents with relapsed, refractory or progressive high-risk solid and CNS tumors. Patients aged 6-21 will be allocated to the following biomarker-defined groups: high mutational load ( &gt; 100 somatic SNVs/exome; group A), high PD-L1 mRNA expression (RPKM &gt; 3; group B), focal MYC(N) amplification (group C), low mutational load and low PD-L1 mRNA expression and no MYC(N) amplification (Biomarker low group D). Phase I determines the recommended phase 2 dose for the combination for the age groups 6-11 and 12-21 years. Patients will receive nivolumab 3mg/kg every 2 weeks. Entinostat has 2 dose levels: 2mg/m 2 and 4mg/m 2 once per week. Patients can seamlessly enter the phase II which investigates activity (defined as best response during the first 6 cycles) in the 4 biomarker groups A-D. The duration of treatment is 12 cycles, preceded by 1 entinostat priming week. Interim analyses for futility will be performed after every 10 patients in each group. The study will enroll a maximum of 128 patients in Germany, The Netherlands, Sweden, France, Australia and additional countries under discussion. A comprehensive accompanying biomarker program will investigate a series of immune and epigenetic pharmacodynamic biomarkers. Clinical trial information: NCT03838042.
A window of opportunity trial of atorvastatin in p53-mutant and p53 wild type malignancies.
Authors: Mohammad Telfah, Tomoo Iwakuma, Andres Bur, Lisa Shnayder, Terry Tsue, Mazin Mazin Al-Kasspooles, John Ashcraft, Benjamin Martin, Raed Moh'd Taiseer Al-Rajabi, Anup Kasi, Qamar J. Khan, Tara L. Lin, Anwaar Saeed, Stephen K. Williamson, Prabhakar Chalise, Andrew K. Godwin, Greg Reed, Sufi Thomas, Takefumi Komiya, Joaquina Celebre Baranda
Journal: Journal of Clinical Oncology (2019)

TPS3165 Background: Mutations in p53 contribute to tumor progression. A rational approach is to destabilize mutant (m) p53. The group at the University of Kansas Cancer Center screened compounds that suppress m p53 in a preclinical model. Luciferase-based reporter assay identified statins as suppressors of m p53 expression. In vitro validation assay demonstrated atorvastatin (A) suppressed m p53 level and cell growth selectively; and depletion of mevalonic acid lead to degradation of m p53. These effects were limited to mutations in the conformation of p53, while wild-type and DNA contact mutations were not as sensitive to statin-induced degradation of p53. M p53 xenograft model confirmed that A could suppress tumor growth at a concentration that can decrease LDL level. The primary objective of this trial is to determine if A decreases the level of conformational m p53. The secondary objective is to assess the effects of A on Ki-67 and caspase-3 in conformational m p53 tumors. Methods: This is an open-label, window of opportunity pilot trial to see if A given for 1 to 4 weeks at a dose of 80 mg/day is sufficient to reduce the levels of conformational m p53 in the tumor tissues. Subjects with new diagnosis of malignancy with a planned surgical therapy, and subjects with previously treated AML, in between treatment regimens, are eligible. Tissues from solid tumors, and bone marrow or peripheral blood samples from AML will be used to screen for m p53 by immunohistochemistry (IHC). Subjects will receive A at 80 mg/day po for 1 to 4 weeks. Pharmacokinetics at pre-dose and 1-hour post-dose on Day 1 and on the day of surgery will be done. Mutational analysis using exome sequencing technique will be done on m p53. Using IHC, the amount of p53 in pre-treatment and post-treatment samples will be measured and compared simultaneously. The levels of Ki67 and caspace-3 will be tested and compared between pre-treatment and post-treatment samples in subjects with conformational m p53, between conformational and non-conformational m p53, and in wild-type p53 tumors. The trial is actively enrolling subjects. The results of this trial will determine further investigations on the role of atorvastatin in tumors with p53 mutations in a placebo-controlled, randomized trial. Clinical trial information: NCT03560882.
Biomarker analysis of PALLET: A neoadjuvant trial of letrozole (L) ± palbociclib (P).
Authors: Vera Martins, Lucy Kilburn, Andrew Dodson, Arjun Modi, Katherine L. Pogue-Geile, Mothaffar F. Rimawi, Shannon Leigh Huggins-Puhalla, Cynthia Huang Bartlett, Sophie Perry, Leona Batten, C. Kent Osborne, Samuel A. Jacobs, Stephen R. D. Johnston, Judith Bliss, Mitchell Dowsett
Journal: Journal of Clinical Oncology (2019)

570 Background: PALLET randomized 307 postmenopausal women with ER+ primary breast cancer to one of 4 treatment groups (3:2:2:2 ratio): A: L for 14wks; B: L for 2wks then L+P to 14wks; C: P for 2wks then L+P to 14wks; D: L+P for 14wks. This allowed a randomized 1:2 comparison of L (Group A) vs L+P (Groups B+C+D) at 14wks. P was given 125mg/d PO (21 days on, 7 days off). Adding P to L markedly enhanced Ki67 suppression and Complete Cell Cycle Arrest (CCCA, Ki67 &lt; 2.7%) by 14wks but did not substantially increase clinical response. We now report exploratory analysis of the association of baseline expression of 6 pre-specified biomarkers involved in estrogen and CDK4/6 signaling with CCCA at 14wks and changes in their expression during therapy. Methods: Estrogen receptor (ER), progesterone receptor (PgR), RB and CCNE1 were measured by IHC and CCND1 by IHC and FISH (CCND1/CEP11 ratio≥2.0 amplified). Baseline biomarker values were available with 14wk Ki67 values in up to 64 patients for L alone and up to 124 patients for L+P. Of these 59% and 90%, respectively, achieved CCCA. Results: With L alone CCCA was significantly less frequent (indicating relative resistance) with low baseline PgR (odds ratio [OR] 0.22, 95%CI 0.05-0.96, p = 0.04) or high CCNE1 levels (OR 10.39, 95%CI 1.19-90.48, p = 0.03). With L+P CCCA was also significantly less frequent with high CCNE1 (OR 50.34 95%CI 5.12-495.34, p = 0.001) or with low baseline ER (OR 0.21 95%CI 0.08-0.60, p = 0.004). CCCA was not significantly different with either treatment according to CCND1 amplification status or expression overall. However, CCCA showed a tendency to being less frequent in non-amplified cases with low baseline cyclin-D1 expression when treated with L+P (p = 0.10). There were no significant changes in ER levels or CCND1 amplification over 14wks. By 14 wks PgR, RB, CCND1 and CCNE1 levels were significantly suppressed by L or L+P (geomeans PgR: -96.4% vs -94.9%; CCND1: -79.9% vs -70.7%; CCNE1: -68.2% vs -74.7%; RB: -23.5% vs 26.1%, respectively) and there was no significant difference between the treatments. Conclusions: These data support low ER, possibly indicating limited luminal status, and high CCNE1 as markers of poor Ki67 response to L+P in primary disease and are consistent with findings in studies in advanced disease. Clinical trial information: NCT02296801.
Predictors of New-Onset Diabetes in Patients Treated With Atorvastatin
Authors: David D. Waters, Jennifer E. Ho, David A. DeMicco, Andrei Breazna, Benoit J. Arsenault, Chuan-Chuan Wun, John J. Kastelein, Helen Colhoun, Philip Barter
Journal: Journal of the American College of Cardiology (2011)

We sought to examine the incidence and clinical predictors of new-onset type 2 diabetes mellitus (T2DM) within 3 large randomized trials with atorvastatin. Statin therapy might modestly increase the risk of new-onset T2DM. We used a standard definition of diabetes and excluded patients with prevalent diabetes at baseline. We identified baseline predictors of new-onset T2DM and compared the event rates in patients with and without new-onset T2DM. In the TNT (Treating to New Targets) trial, 351 of 3,798 patients randomized to 80 mg of atorvastatin and 308 of 3,797 randomized to 10 mg developed new-onset T2DM (9.24% vs. 8.11%, adjusted hazard ratio [HR]: 1.10, 95% confidence interval [CI]: 0.94 to 1.29, p = 0.226). In the IDEAL (Incremental Decrease in End Points Through Aggressive Lipid Lowering) trial, 239 of 3,737 patients randomized to atorvastatin 80 mg/day and 208 of 3,724 patients randomized to simvastatin 20 mg/day developed new-onset T2DM (6.40% vs. 5.59%, adjusted HR: 1.19, 95% CI: 0.98 to 1.43, p = 0.072). In the SPARCL (Stroke Prevention by Aggressive Reduction in Cholesterol Levels) trial, new-onset T2DM developed in 166 of 1,905 patients randomized to atorvastatin 80 mg/day and in 115 of 1,898 patients in the placebo group (8.71% vs. 6.06%, adjusted HR: 1.37, 95% CI: 1.08 to 1.75, p = 0.011). In each of the 3 trials, baseline fasting blood glucose, body mass index, hypertension, and fasting triglycerides were independent predictors of new-onset T2DM. Across the 3 trials, major cardiovascular events occurred in 11.3% of patients with and 10.8% of patients without new-onset T2DM (adjusted HR: 1.02, 95% CI: 0.77 to 1.35, p = 0.69). High-dose atorvastatin treatment compared with placebo in the SPARCL trial is associated with a slightly increased risk of new-onset T2DM. Baseline fasting glucose level and features of the metabolic syndrome are predictive of new-onset T2DM across the 3 trials.
Malignant Glioma Therapy by Vaccination with Irradiated C6 Cell-Derived Microvesicles Promotes an Antitumoral Immune Response
Authors: Benjamín Pineda, Francisco Javier Sánchez García, Nora Karen Olascoaga, Verónica Pérez de la Cruz, Alelí Salazar, Sergio Moreno-Jiménez, Norma Hernández Pedro, Adrián Márquez-Navarro, Alma Ortiz Plata, Julio Sotelo
Journal: Molecular Therapy (2019)

Glioblastoma is the most common and malignant tumor of the CNS, with a mean survival of 14 months after diagnosis. Its unfavorable prognosis reveals the need for novel therapies. It is known that radiation can induce a systemic antitumor effect. Tumor cells produce and release microvesicles in response to cell damage such as radiation. Microvesicles contain a plethora of bioactive molecules, including antigens involved in modulation of the immune response. In this study, we characterized and evaluated irradiated C6 cell-derived microvesicles as a therapeutic vaccination in C6 malignant glioma. Cultured C6 glioma cells were irradiated with a single dose of 50 Gy to obtain the microvesicles. Subcutaneous implantation of C6 cells was performed when the tumor reached 2 cm in diameter, and non-irradiated and irradiated C6 cell-derived microvesicles were administered subcutaneously. Tumor growth, apoptosis, and immunophenotypes were determined. Reduction of tumor volume (more than 50%) was observed in the group treated with irradiated C6 cell-derived microvesicles compared with the control (p = 0.03). The percentages of infiltrative helper, cytotoxic, and regulatory T lymphocytes as well as apoptotic cells were increased in tumors from immunized rats compared with controls. These findings make microvesicle-based vaccination a promising immunotherapeutic approach against glioblastoma. Glioblastoma is the most common and malignant tumor of the CNS, with a mean survival of 14 months after diagnosis. Its unfavorable prognosis reveals the need for novel therapies. It is known that radiation can induce a systemic antitumor effect. Tumor cells produce and release microvesicles in response to cell damage such as radiation. Microvesicles contain a plethora of bioactive molecules, including antigens involved in modulation of the immune response. In this study, we characterized and evaluated irradiated C6 cell-derived microvesicles as a therapeutic vaccination in C6 malignant glioma. Cultured C6 glioma cells were irradiated with a single dose of 50 Gy to obtain the microvesicles. Subcutaneous implantation of C6 cells was performed when the tumor reached 2 cm in diameter, and non-irradiated and irradiated C6 cell-derived microvesicles were administered subcutaneously. Tumor growth, apoptosis, and immunophenotypes were determined. Reduction of tumor volume (more than 50%) was observed in the group treated with irradiated C6 cell-derived microvesicles compared with the control (p = 0.03). The percentages of infiltrative helper, cytotoxic, and regulatory T lymphocytes as well as apoptotic cells were increased in tumors from immunized rats compared with controls. These findings make microvesicle-based vaccination a promising immunotherapeutic approach against glioblastoma.
Apatinib affects the proliferation, migration and apoptosis of esophageal cancer cells both in vitro and in xenografts by regulating Ras/Raf/MEK/ERK and JAK2/STAT3 signaling pathways.
Authors: Jingping Yu
Journal: Journal of Clinical Oncology (2019)

e15501 Background: To investigate the effects of apatinib on esophageal cancer cells in vitro and xenograft models, and discuss the mechanisms of its actions. Methods: Used various assays to measure the different biological processes of esophageal cancer cells: used MTT assay to measure the proliferation rate; used transwell assay to determine the migration capacity and used colony formation assay to assess the clone formation rate. The effect of apatinib on cell cycle and apoptosis was analyzed by flow cytometry. The expression levels of VEGF and VEGFR2 were measured by qRT-PCR. The concentration of VEGF in the supernatant of cancer cell was assessed by ELISA. The expression levels of MEK, ERK, p-MEK, p-ERK, STAT3, p-STAT3, CHK2 and CDC2 after VEGF stimulation were detected by western blot. We also established human esophageal squamous carcinoma xenograft model in nude mice. The mice were randomly divided into healthy control group, low dose group (250mg) and high dose group (500mg), with 6 mice in each group. The tumor growth rate of each group was calculated, and the expression levels of VEGF and VEGFR2 in tumor tissues were detected by immunohistochemistry. Results: Apatinib inhibited the proliferation of esophageal cancer cell in a time-dependent (P &lt; 0.05) and concentration-dependent (P &lt; 0.05) manner; it also inhibited the cell migration capacity (P &lt; 0.05) and colony formation rate (P &lt; 0. 05). In addition, apatinib induced apoptosis in esophageal cancer cells and increased the proportion of cells in G2 / M phase (P &lt; 0.05). The mRNA levels of VEGF (P &lt; 0.05) and VEGFR2 (P &lt; 0.05) and the protein levels of VEGF (P &lt; 0.05) were also suppressed by apatinib. Western blot showed that apatinib could down-regulate the expression of p-MEK, p-ERK, STAT3, p-STAT3, CHK2 and CDC2 (P &lt; 0.05). The inhibition rates of apatinib in esophageal carcinoma xenograft model was 29.25% and 19.96% for 250mg and 500mg drug treatment groups. Compared with healthy control group, the VEGF levels in drug treatment groups were not significantly different (P &gt; 0.05), but the VEGFR2 levels were significantly decreased (P &lt; 0.05). Conclusions: Apatinib can induce apoptosis of esophageal cancer cell KYSE-150 and ECA-109, and inhibit the cell proliferation, migration and colony formation. Moreover, apatinib can inhibit the tumor growth in esophageal carcinoma xenograft models. This inhibitory action of apatinib is related to the alterations in VEGF-related pathways such as Ras / Raf / MEK / ERK and JAK2 / STAT3 pathways.