tbuckley/cabot-search huggingface dataset:
c15-149: A phase 1b study of the oral CDK4/6 inhibitor ribociclib in combination with docetaxel plus prednisone in metastatic castration resistant prostate cancer (mCRPC)—A prostate cancer clinical trials consortium study.
Authors: Catriona Lewis, David C. Smith, Benedito A. Carneiro, Charles J. Ryan, Tammy J. Rodvelt, Mina Lee, Terence W. Friedlander, Amy M. Lin, Won Kim, Brigid Miralda, Gregory Campbell, Rahul Raj Aggarwal
Journal: Journal of Clinical Oncology (2018)

e17028 Background: Ribociclib is a potent and selective cyclin-dependent kinase (CDK) 4/6 inhibitor with significant pre-clinical activity in enzalutamide-resistant prostate cancer cell lines. Prior pre-clinical studies have demonstrated synergy with taxane chemotherapy. We conducted a multi-institutional phase 1b study to evaluate the safety and preliminary efficacy of ribociclib in combination with docetaxel in patients (pts) with mCRPC. Methods: Pts with mCRPC with prior progression on abiraterone and/or enzalutamide, and no prior chemotherapy for mCRPC were eligible. Dose escalation utilized a 3+3 design with escalating doses of ribociclib starting at 200 mg daily in combination with docetaxel 75 mg/m2, with mandatory G-CSF prophylaxis. The primary objective was to determine the maximally tolerated and recommended phase 2 dose (RP2D). Secondary objectives included pharmacokinetics (PK), PSA50 response rate (≥ 50% decline from baseline in PSA), and objective response rate (ORR). Results: 14 pts were enrolled, with a median age of 68 (55-80) and baseline PSA of 206 (40-1714). 2 dose limiting toxicities (DLTs) (febrile neutropenia and grade 4 neutropenia) were observed at the starting dose/schedule. Using an alternative dosing schema with docetaxel 60 mg/m2 and ribociclib days 1-4 and 8-15, with G-CSF support on days 5-7, no further DLTs were observed. Most common grade ≥ 3 AEs included neutropenia (64%) and febrile neutropenia (14%). Reasons for treatment discontinuation included disease progression (N = 7), adverse event (N = 5), and study withdrawal (N = 1); one pt remains on treatment. PSA50 response rate was 29% among 14 evaluable pts. PK analyses demonstrated a modest and predictable impact of ribociclib on docetaxel clearance. The RP2D is ribociclib 400 mg daily in combination with docetaxel 60 mg/m2. Conclusions: With intermittent dosing and G-CSF support, combining ribociclib with docetaxel chemotherapy is feasible with neutropenia as the most commonly observed AE. A phase 2 study of the combination will further assess efficacy and safety. Clinical trial information: NCT02494921.
Updated results of the INTELLANCE 2/EORTC trial 1410 randomized phase II study on Depatux –M alone, Depatux-M in combination with temozolomide (TMZ) and either TMZ or lomustine (LOM) in recurrent EGFR amplified glioblastoma (NCT02343406).
Authors: Martin J. Van Den Bent, Pim French, Marica Eoli, Juan M. Sepúlveda, Anna Maria Elisabeth Walenkamp, Jean-Sebastien Frenel, Enrico Franceschi, Paul M. Clement, Michael Weller, Iris de Heer, Jim Looman, Jyotirmoy Dey, Scott Krause, Hao Xiong, Peter J Ansell, Sarah Nuyens, Maarten Spruyt, Joana Brilhante, Thierry Gorlia, Vassilis Golfinopoulos
Journal: Journal of Clinical Oncology (2018)

2023 Background: Depatux-M is a tumor-specific antibody-drug-conjugate consisting of an antibody (ABT-806) bound to the toxin monomethylauristatin-F. In the primary analysis on EORTC 1410 we reported a trend (p = 0.06) towards improved overall survival (OS) in patients with EGFR-amplified (amp) recurrent glioblastoma treated with Depatux-M in combination with TMZ. Methods: Eligible were patients with centrally confirmed EGFRamp glioblastoma at 1st recurrence after TMZ chemo-irradiation, occurring ≥3 months after radiotherapy. Patients were randomized to either a) Depatux-M 1.0 mg/kg every 2 weeks intravenously, or b) the same treatment combined with TMZ 150-200 mg/m2 day 1-5 every 4 weeks, or c) either LOM or TMZ (TMZ/LOM) depending on the time of relapse. Primary endpoint was OS. Pharmacokinetic (PK) sampling was done on day (d) 1 before and after dosing, d 4-7, d 1 course 2 before and after dosing, d 5-7 course 4, d 1 course 3, and then every 2 cycles. All available PK samples were used to calculate the Depatux-M average concentration during course 1 (CavgC1). The level of EGFRamp was determined using both qPCR, next generation sequencing and FISH. Results: An updated OS comparison of Depatux-M in combination with TMZ versus TMZ/LOM with longer follow-up, performed after 220 observed deaths using log-rank test and cox models stratified by stratification factors at randomization showed a HR of 0.68 (95%CI [0.48, 0.95]; p = 0.024) and 1-year OS rates of 40% versus 28%. In multivariate analysis including performance status, MGMT, surgery for the recurrence, time from last TMZ to relapse and lesion diameter, CavgC1 was a significant predictor for OS (HR 0.96, 95% CI [0.93, 0.98], p = 0.0013). In Depatux-M treated patients, EGFR status (high vs low level amplification) did not correlate with OS. Conclusions: This updated OS analysis of Depatux-M in combination with TMZ confirmed the OS improvement in EGFRamp recurrent glioblastoma. In Depatux-M treated patients, higher drug levels during course 1 were associated with improved OS but high levels of EGFR amplification at first diagnosis were not. Clinical trial information: NCT02343406.
T-cell biological aging in melanoma: Impact on immunotherapeutic discontinuation.
Authors: Christin Elizabeth Burd, Andrea M Holderbaum, Suohui Zhang, Lianbo Yu, Janice K Kiecolt-Glaser, William Edgar Carson, Kari Lynn Kendra
Journal: Journal of Clinical Oncology (2018)

e21578 Background: Senescence is an irreversible cell cycle arrest associated with sustained p16INK4a (p16) expression and biological aging. The inability of senescent cells to proliferate suggests that biological aging may impair T-cell responses during cancer immunotherapy. This study reports the impact of a melanoma diagnosis on T-cell senescence and explores the relationship between pre-treatment T-cell p16 expression and immunotherapeutic discontinuation. Methods: Peripheral blood T-lymphocytes (PBTLs) were isolated from control donors (n = 61) and patients due to receive immunotherapy. Patients were diagnosed with unressectable disease (MM; n = 32) or were to receive adjuvant therapy (AM; n = 10). RNA isolated from each sample was subjected to a custom Nanostring assay that measures p16 and markers of T-cell subtype, cytokine production and exhaustion. Age-corrected p16 levels were compared between controls and MM or AM patients by ANOVA (Bonferroni correction). Therapeutic modality and treatment duration was obtained via retrospective chart review. MM patients received: pembrolizumab (21), ipilumumab (IPI)/nivolumumab (NIVO) (8), IPI (2) or NIVO (1). Median follow-up: 69.6 wks. Patients were divided into p16-high and -low groups based upon age-corrected values at baseline. The hazard ratio for therapeutic discontinuation between groups was assessed via Cox regression. A pilot analysis to assess the feasibility of on-therapy, longitudinal p16 measurements was initiated in a small subset of patients (n = 4). Results: Age-corrected PBTL p16 levels were 4.2 ± 1.0 times higher in pre-treatment AM and MM patients in comparison to controls (p < 0.001). Pre-treatment MM patients in the p16 high group were more likely to discontinue therapy than those in the p16 low group (HR = 3.1, p = 0.05). Early analyses revealed changes in PBTL p16 levels following each round of immunotherapy. Conclusions: Melanoma is associated with accelerated PBTL aging and therefore, patient chronological and immunological age are not equivalent. Elevated PBTL p16 levels prior to the initiation of immunotherapy are associated with decreased therapeutic duration in MM.
Bone marrow examination (BMex) in staging of SCLC after implementation of PET/CT scan.
Authors: Karin Holmskov Hansen, Mette Boes Eriksen, Tine Schytte, Olfred Hansen
Journal: Journal of Clinical Oncology (2017)

e20014 Background: Correct staging of small cell lung cancer (SCLC) in limited disease (LD) or extensive disease (ED) is crucial as it has an impact on the therapeutic decision-making. The staging procedures in SCLC in the late 1990s included chest X-ray, blood samples, abdominal ultrasonography (UL), and iliac crest BMex. The aim of this study was to evaluate the continued eligibility of performing BMex in patients (ptt) with SCLC as a routine staging procedure, and to see how often therapeutic decisions were influenced by a positive BM before and after the PET/CT scan era. Methods: All diagnostic and staging procedures were registered in ptt with SCLC referred to our department from 1995 to 1999 in cohort 1 (C1). Cohort 2 (C2) included SCLC patients referred from 2009 to 2013. In C2 results of PET/CT in terms of bone metastases were related to results of BMex. Results: In C1 194 ptt was referred with 136 (70%) having ED. BMex was omitted in 32 (17%) fragile ptt having known ED while all LD ptt underwent BMex. BM involvement was seen in 37 (23%) of all 162 BMex and 36% of the 104 ED ptt examined. When BM was negative the staging of ED was due to other imaging. The BM had an impact on therapeutic decision-making in 5 (4%) of 136 having ED and 5 (3%) of 162 BMex. In C2 211 ptt of 292 (72%) had ED and 203 (70%) of all ptt underwent BMex. BM biopsy was done in 137 (65 %) ED and in 66 (69 %) LD. Of 137 ED ptt BM involvement was found in 31 (23 %) cases. A PET/CT scan was performed in 13 (42 %) of these ptt of which bone metastases was found in 12 (92 %). One patient (8%) had a PET/CT without bone lesions. Bone metastases were seen at PET/CT scan in 61 ptt in C2, of these 22 (36%) had negative BM, whereas 12 (20%) had BM involvement and in 3 ptt (5%) BMex were inconclusive. No BMex was performed in 24 ptt (39%). BMex had an impact on therapeutic decision-making in 3 (1.4%) of 211 having ED and 5 (2.5%) of 203 BMex. Conclusions: Due to staging by PET/CT and CT scan in SCLC ptt the impact of BMex in the therapeutic decision-making has decreased and fewer ptt are undergoing BMex. Though a negative PET/CT cannot exclude BM involvement BMex may be considered omitted.
TCT-128 Contrast-Induced Acute Kidney Injury after Percutaneous Coronary Intervention: Comparison of Five Contrast Media
Authors: Lorenzo Azzalini, Luz Maria Vilca, Francesca Lombardo, Enrico Poletti, Alessandra Laricchia, Davide Maccagni, Ozan Demir, Massimo Slavich, Francesco Giannini, Mauro Carlino, Alberto Margonato, Alberto Cappelletti, Antonio Colombo
Journal: Journal of the American College of Cardiology (2018)
Comparative effectiveness of lung cancer screening by computed tomography (CT) vs. chest x-ray (CXR) vs. no screening.
Authors: John Paul Flores, Alejandro Moreno-Koehler, Matthew Finkelman, Jaime Caro, Gary M. Strauss
Journal: Journal of Clinical Oncology (2016)

e18246 Background: We sought to compare effectiveness of lung cancer screening by CXR vs. CT vs. no screening to facilitate a cost-effectiveness analysis. PLCO and NLST compared CXR vs. no screening, and CT vs. CXR respectively. If efficacious, CXR may be a cost-effective alternative to CT as it is associated with a lower false-positive rate and potentially lower costs. Methods: PLCO and NLST trial data were obtained from NCI. Lung cancer incidence was compared by Fisher’s exact test. Overall survival (OS) of those diagnosed with lung cancer was calculated in an intent-to-screen analysis using the Kaplan-Meier method and compared by log-rank test. To compare to NLST, analysis of PLCO was limited to lung cancers diagnosed up to 7 years after randomization. This also accounts for sojourn time as follow-up in PLCO was prolonged (12 years) compared to screening (3 years). As only NLST enrolled based on smoking history, the NLST-eligible subset of PLCO was analyzed. Results: In NLST (N = 52,234), 1089 and 969 lung cancers were detected in CT and CXR groups respectively (RR = 1.12; 95%CI 1.03-1.22; p = 0.007). 5-year OS was superior with CT, 49% vs. 33% (p < 0.001). In PLCO (N = 150,835), 1072 and 1022 lung cancers were detected within 7 yrs of randomization in CXR and control groups, (RR = 1.05; CI 0.96-1.14; p = 0.27). 5-year OS was 27% vs. 18% (p < 0.001). In the NLST-eligible subset of PLCO (N = 30,321), within 7 years of randomization, 676 and 656 lung cancers were detected in the CXR and control groups (RR = 1.03; 95% CI 0.92-1.14; p = 0.61). 5-year OS was superior with CXR, 25% vs.18% (p < 0.001). Conclusions: CT screening is superior to CXR, while CXR screening is superior to no screening. Incidence is not significantly increased with CXR compared to no screening arguing against overdiagnosis, though incidence is increased with CT. CXR survival in NLST is better than PLCO, possibly reflecting the effect of adjuvant chemotherapy. These survival differences are the basis of an ongoing cost-effectiveness analysis. While CT is superior to CXR screening, CXR is a widely accessible, inexpensive screening tool that can substantially reduce the global burden of lung cancer mortality, particularly where the costs of CT are prohibitive.
Peritoneum metastasis (PM) as a prognostic factor in metastatic gastric cancer (MGC) treated with anti-PD-1/PD-L1 monotherapy.
Authors: Yukiya Narita, Keiji Sugiyama, Seiichiro Mitani, Kazunori Honda, Toshiki Masuishi, Hiroya Taniguchi, Shigenori Kadowaki, Takashi Ura, Masashi Ando, Masahiro Tajika, Kei Muro
Journal: Journal of Clinical Oncology (2017)

3051 Background: Anti-PD-1 monotherapy has proven effective for the patients (pts) with MGC. However, the identification of biomarkers for predicting clinical outcomes remain as critical needs. We aimed to identify baseline characteristics associated with time to treatment failure (TTF) or overall survival (OS) for anti-PD-1/PD-L1 monotherapy as second- or later-line therapy in MGC. Methods: Routine blood count parameters and clinical characteristics at baseline were retrospectively investigated in 31 pts with MGC in Aichi Cancer Center Hospital. Endpoints were TTF and OS following anti-PD-1/PD-L1 monotherapy. Kaplan-Meiyer and Cox regression analysis were applied for survival analyses. Results: Patient characteristics were as follows: median age (range), 68 (47–83); ECOG performance status (PS) 0/1, 21/10; PM +ve/-ve, 12/19; No. of metastatic sites 1–2/≥3, 18/13; No. of prior chemotherapy regimens 1–2/≥3, 11/20; and absolute eosinophil count (AEC) &lt;150/≥150 /μl, 14/17. Objective response rate and disease control rate (RECIST ver. 1.1) were 26% vs. 0% (odds ratio [OR], 3.76; P = 0.12) and 79% vs. 50% (OR, 3.58; P = 0.12) in the PM -ve group (Cohort A) and the PM +ve group (Cohort B), respectively. On univariate analysis, the pts with poor PS, PM +ve, and high AEC were significantly poor TTF; and poor PS and PM +ve were significantly identified as prognostic factors of poor OS. On multivariate analysis, only PM +ve was independent negative impact not only for TTF but also for OS. Median TTF and OS were 5.4 vs. 1.3 months (M) (adjusted hazard ratio [HR], 4.29; 95%CI, 1.60–11.5; P &lt; 0.01) and 28.2 vs. 7.5 M (adjusted HR, 3.68; 95%CI, 1.25–10.8; P = 0.02) in Cohort A and Cohort B. Six-months TTF probabilities of 42% vs. 0% ( P = 0.03) and one-year OS probabilities of 58% vs. 8% ( P&lt; 0.01) were observed in Cohort A compared to in Cohort B. Conclusions: PM -ve in the pts treated with anti-PD-1/PD-L1 monotherapy was associated with better efficacy. In the pts with PM -ve, anti-PD-1/PD-L1 monotherapy could be adapted in first-line therapy. [Table: see text]
Will research preprints improve healthcare for patients?
Authors: Harlan M Krumholz, Joseph S Ross, Catherine M Otto
Journal: BMJ (2018)

Early publication of research findings without peer review could speed up knowledge dissemination and changes to clinical practice, argue <b>Harlan M Krumholz</b> and <b>Joseph S Ross</b>. But <b>Catherine M Otto</b> worries that publication without that quality control has the potential to confuse and cause harm
In vitro functional analysis of HER2 variants in lung cancers to evaluate their oncogenic activity and predict clinical response to HER2 targeted therapies.
Authors: Michael Offin, Zachary T. Olah, Joshua K. Sabari, Nidhi Tandon, Daniel Feldman, Ghassan K. Abou-Alfa, Benjamin H. Lok, Nitza Burck, Gabi Tarcic, Ben Miron, Maria E. Arcila, Mark G. Kris, Charles M. Rudin, Bob T. Li
Journal: Journal of Clinical Oncology (2017)

e23150 Background: HER2 variants are implicated as oncogenic drivers in a variety of cancers. However, not all HER2 variants found on next-generation sequencing (NGS) have been studied, raising the question if these variants of unknown significance (VUS) are oncogenic. This study explores the use of an in-vitro functional assay on HER2 and other variants found on NGS in patients (pts) with lung cancer, and its predictive value for response to HER2 targeted therapy. Methods: Pts with lung cancer at Memorial Sloan Kettering identified to have a HER2 variant by NGS on MSK IMPACT are eligible. NGS data on HER2 variants and co-mutations were analyzed. Functional status was determined by the NovellusDx FACT platform. Mutations were synthesized and transfected into HeLa cells with a fluorescently tagged signaling pathway reporter (MAPK, NFKB, JAK-STAT). Fluorescent microscopy quantified the translocation of reporters to the nucleus, inferring gain of function. Afatinib was added and its effect on pathway activation analyzed. Functional information was correlated with clinical outcomes. Results: As of 2/1/17, 13 pts were included, 9 unique HER2 variants analyzed. Known activating HER2 mutations analyzed (exon 20 insertions (A775_G776insYVMA, G778_P780insGSP, G776delinsVC), point mutations (V659E, L755P, S301F)) showed in vitro gain of function. HER2 VUS analyzed included D277Y showed no gain of function; exon 16 splice variant c.1889 showed gain of function. Afatinib was added to 4 cell lines with gain of function variants (G778_P780insGSP, V659E, L755P, exon 16 splice variant c.1889) all had inhibited pathway activation suggesting in vitro sensitivity to afatinib. Clinically, no response was seen in 2 pts treated with afatinib but more pts are planned to be treated. Objective responses to ado-trastuzumab emtansine (NCT02675829) were seen in 5 pts, all of which had HER2 variants with gain of function. Conclusions: In vitro functional analysis of HER2 variants based on NGS reports is feasible, and has the potential to identify novel actionable oncogenic drivers from VUS. Its predictive value for clinical response to targeted therapy requires further study.
The activity of the HDAC inhibitor HBI-8000 (Chidamide) combined with eribulin on 4T1 spontaneous metastasis development.
Authors: Reid Paul Bissonnette, Alain Rolland, Bob Goodenow, Mireille Gillings
Journal: Journal of Clinical Oncology (2017)

e14055 Background: In preclinical studies eribulin has shown significant effects on epithelial-mesenchymal transition (EMT) in human breast cancer cells in vitro and in vivo, inducing a switch from mesenchymal to epithelial states, decreasing migration and invasiveness of human breast cancer cells in vitro, as well as experimental metastases in vivo. HBI-8000 is a novel, orally bioavailable Class I selective HDAC inhibitor (HDACi). In addition to its demonstrated positive effects on antitumor immunity, it also exerts significant effects on EMT pathway components, enhancing CDH1 (e-cadherin) expression and inhibiting TGF-β induced metastasis. Methods: The syngeneic, orthotopic 4T1 model is thought to be a close representation of the clinical situation; similar to human mammary carcinoma, the major cause of morbidity and mortality is development of spontaneous metastases. 4T1-implanted mice treated with combinations of eribulin and HBI-8000 were monitored for primary tumor growth inhibition (TGI), survival, and metastatic lung foci. Tumor samples were analyzed by Q-PCR for expression of genes involved in EMT or in the metastatic process. Results: Eribulin alone had no effect on primary TGI. Eribulin combined with HBI-8000 resulted in significant (P &lt; 0.05) reductions in median tumor volume, tumor volume distribution (TMD) and survival (P &lt; 0.005). Single agent HBI-8000 had a similar effect on TGI, TMD (P &lt; 0.05) and survival (P &lt; 0.005). Whereas single agent HBI-8000 or eribulin failed to significantly reduce metastases, the eribulin-HBI-8000 combination produced significant (P &lt; 0.01) and synergistic inhibition of metastases, decreasing the number of lung foci approximately 10-fold. Gene expression analyzed by Q-PCR revealed correlations between metastasis blockade and increases in E-Cadherin, Occludin and Claudin1. There was a strong correlation with inhibition of HMGA2 (High Mobility Group AT-Hook 2) gene expression. Conclusions: Eribulin combined with HBI-8000 inhibited primary tumor growth and inhibited metastasis development and increased survival. This effect was correlated and consistent with changes in genes relevant to EMT, tumor plasticity and stemness.
P04.53 Multiregional radiomics profiling from multiparametric MRI: identifying an imaging predictor of IDH1 mutation status in glioblastoma multiforme
Authors: Y Chen, Z Chen, Z Li, H Bai, C Liang
Journal: Neuro-Oncology (2018)

Glioblastoma Multiforme (GBM) patients with isocitrate dehydrogenase 1 (IDH1) mutations have significantly improved prognosis than those without such mutations. We aimed to preoperatively predict IDH1 mutation status in GBM using multiregional radiomics features from multiparametric magnetic resonance imaging (MRI). In total 225 patients were recruited in this retrospective multicenter study. 1614 quantitative features were extracted from multiple tumor subregions (including enhancement area, non-enhancement area, necrosis and edema) in multiparametric MRI. After intensitynormalization, tumor subregion segmentation, resampling-based data balancing and relevant feature selection, a multiregional radiomics model was built using a machine-learning method for prediction of IDH1 mutation from a primary cohort (118 patients) and tested on an independent validation cohort (107 patients). Four single-region radiomics models with features from each tumor subregion, and a model combining multiregional features with clinical factors (age, sex, and Karnofsky performance status) were also built and tested. Among four single-region radiomics models, the model built from edema region achieved the best accuracy of 96% and the best F1-score of 0.75 in the independent validation cohort. The 8-feature multiregional radiomics model achieved an improved overall performance of an accuracy 96%, an AUC 0.90 and an F1-score 0.78 in the validation cohort, which significantly outperformed the single-region models. Among all predictive models, the model combining multiregional imaging features with patient age achieved the best performance of an accuracy 97%, an AUC 0.96 and an F1-score 0.84 in the validation cohort. The radiomics-based model built with a minimal set of multiregional features from multiparametric MRI has the potential to preoperatively detect the IDH1 mutation status in GBM patients. The proposed predictor may serve as a potential noninvasive biomarker to guide preoperative GBM patient care.