tbuckley/cabot-search huggingface dataset:
Intercalating docetaxel between novel hormone therapies (NHT) abiraterone and enzalutamide in metastatic castration resistant prostate cancer (mCRPC): Does it resensitize patients to the second NHT agent?
Authors: Benjamin Louis Maughan, Karim Boudadi, Rosa Maria Nadal, Emmanuel S. Antonarakis
Journal: Journal of Clinical Oncology (2016)

e16550 Background: Prior studies with Enza and Abi have suggested decreased response rates and progression free survival when these agents are used sequentially. This suggests that there are mechanisms of resistance common to both Enza and Abi. Evidence also suggests that taxane chemotherapy may reverse/downregulate some of these resistance pathways, such as elimination of AR splice variants. Methods: A retrospective review of mCRPC pts at Johns Hopkins treated with sequential NHT (NHT1-NHT2) vs. pts who received intercalated docetaxel between NHT (NHT1-D-NHT2) was conducted. PSA-PFS and PSA50 responses to the second NHT were compared between the 2 cohorts. Within the NHT1-D-NHT2 group, outcomes of NHT2 vs. NHT1 were compared to determine if intercalated docetaxel improved responses to subsequent NHT. Kaplan-Meier curves and the Log-Rank test were used to compare PSA-PFS. A multivariate (MVA) analysis was also conducted using a Cox regression model. Results: 80 pts were identified: 54 in the NHT1-NHT2 group, and 26 in the NHT1-D-NHT2 group. Baseline characteristics in the 2 groups showed a difference in PSA level (mean 92 vs. 397, P < 0.001), but similar Gleason sums ≥ 8 (61% vs 68%, P = 0.88), and similar prevalence of visceral metastases (18.5% vs 30.8%, P = 0.26). NHT1-D-NHT2 had significantly worse clinical outcomes compared to NHT1-NHT2: median PSA-PFS to the second NHT was 4.4 vs 1.6 months (P = 0.01), and median clinical/radiographic PFS to the second NHT was 5.7 vs 2.2 months (P < 0.01), respectively. The MVA model confirmed inferior PSA-PFS for the NHT1-D-NHT2 group (P = 0.03). In the NHT1-D-NHT2 group, there was no significantly improved sensitivity to NHT2 vs. NHT1, with a median PFS of 1.5 vs 4.6 months (P = 0.009), respectively. Conclusions: This hypothesis-generating study suggests that the response to a second NHT is not preserved/improved with intercalated docetaxel treatment, despite biological evidence to suggest that resistance mechanisms to NHT may be downregulated by chemo. Prospective studies are required to determine if taxanes may sensitize pts to additional NHT.
<i>ALK</i> FISH positivity and crizotinib efficacy in patients (pts) with non-small cell lung cancer (NSCLC).
Authors: Jean-Charles Soria, Steffan N. Ho, Marileila Varella-Garcia, A. John Iafrate, Benjamin J. Solomon, Alice T. Shaw, Fiona Helen Blackhall, Tony Mok, Yi-Long Wu, Ekaterina Pestova, Fred W. Siebert, Keith D. Wilner, Anna Polli, Jolanda Paolini, Silvana Lanzalone, Stephanie J. Green, D. Ross Camidge
Journal: Journal of Clinical Oncology (2016)

9062 Background: Crizotinib trials provide a large dataset to evaluate the distribution of % ALK+ cells by FISH in ALK+ NSCLC and the association between degree of ALK positivity and clinical outcome. Methods: Data were pooled from 3 ongoing crizotinib trials in ALK+ NSCLC: a large single-arm trial in the ≥ 2nd-line (NCT00932451) and 2 phase 3 trials vs. chemotherapy in the 1st- (NCT01154140) and 2nd-line (NCT00932893) settings. Prospective screening was performed at central laboratories using Vysis ALK Break Apart FISH and a cutoff of ≥ 15% ALK+ cells to define ALK positivity. Association between % ALK+ cells by FISH and clinical outcome in ALK+ pts was assessed using logistic regression for objective response (OR) and proportional hazards regression for PFS. Results: Screening of tumor samples from 11,081 pts identified 1958 (18%) ALK+ and 7512 (68%) ALK− pts, with 1540 (14%) undetermined. The median % ALK+ cells was 58% in ALK+ pts and 2% in ALK− pts, with 11% of ALK+ pts and 2% of ALK− pts near the 15% ALK+ cell cutoff (15−24% and 10−14% ALK+ cells, respectively). 1357 ALK+ pts received crizotinib initially or on crossover from chemotherapy. Only small differences in mean/median % ALK+ cells were seen across best response categories (CR, PR, SD, PD). ORs were seen across the range of % ALK+ cells, including 7/19 (37%) at 15% ALK+ cells (ORR for all crizotinib-treated pts: 54%). Using % ALK+ cells as a continuous variable, higher percentages of ALK+ cells were associated with larger differences between crizotinib and chemotherapy in OR and PFS, but the treatment by % ALK+ interaction tests were not significant (OR: P = 0.07; PFS: P = 0.16). Conclusions: These results indicate that among ALK+ pts as defined by ≥ 15% ALK+ cells by FISH, differences in OR or PFS outcomes for crizotinib vs chemotherapy as a function of % ALK+ cells were not statistically significant. The non-significant trend to greater benefit at higher ALK+ cell percentages may reflect the greater impact of technical or biologic false-positive signals at lower ALK+ cell percentages. Given that borderline ALK− pts (10−14% ALK+ cells) comprised 2% of all ALK− pts and that ORs were observed even at 15% ALK+ cells, further diagnostic evaluation of borderline cases may be in order.
Hyperfractionated cyclophosphamide as urgent therapy: A single institution experience.
Authors: Danny Landau, Ahmad El-Far, Daniel Anscher, Michael Landis
Journal: Journal of Clinical Oncology (2017)

e19045 Background: Hematologic cancers can present with severe issues such as airway compromise, hypercalcemia, etc. Due to high drug costs and payment concerns, therapies that are inexpensive but effective are necessary. Within our institution, we utilize hyperfractionated cyclophosphamide (cyclophosphamide 300 mg/m 2 IV q 12 hours X 6) [HyperC] for these patients. We opted to see if this approach is justified. Methods: We reviewed data via our EMR of people who received HyperC. Data was limited to urgent therapy. Data was collected from 2015-2017. The cost of therapy was also looked at relative to other therapies with our pharmacy team. Categories are as per the charts below. Results: See Table. Conclusions: HyperC is cost effective and efficacious for patients who need urgent therapy. [Table: see text][Table: see text][Table: see text]
A case series of immune checkpoint inhibitor induced diabetes mellitus (ICI-DM).
Authors: Venessa H Tsang, Roderick J Clifton-Bligh, Georgina V. Long, Alexander David Guminski, Alexander M. Menzies
Journal: Journal of Clinical Oncology (2018)

e22080 Background: Immune checkpoint inhibitors have activity across oncology, with mostly mild and reversible toxicity. ICI-DM has been reported in only 13 (0.2%) patients (pts) in trials, with little known about this toxicity. Methods: Consecutive pts at a single centre who developed new onset insulin-requiring diabetes after commencing ICI were retrospectively examined. Blood samples at ICI start and ICI-DM diagnosis examined biochemistry and autoimmunity. Results: 9 pts presented with ICI-DM from Mar 2015 to Jan 2018; median age 65 y, 8 males, 8 metastatic melanoma. No pts had a history of diabetes. All received anti-PD-1/L1 antibodies, either alone (n = 4) or in combination with other ICI. The median time from ICI start to ICI-DM diagnosis was 24 weeks (IQR 12-36). Most patients had other iRAE (n = 8), including pancreatitis (n = 1) and pancreatic exocrine failure (n = 1). All pts until end 2016 (n = 5) presented with ketoacidosis and were hospitalised, while the later 4 pts were not acidotic and 3 were managed as outpts. Continuous glucose (GLU) monitoring revealed wide glycaemic variability including frequent recurrent hypoglycaemia distinct from early type 1 diabetes mellitus (T1DM) despite strict adherence to diet, GLU monitoring and insulin dosing. All patients had normal serum C-peptide at ICI start, which declined by ICI-DM diagnosis. At diagnosis, median HbA1c was 7.5% (IQR 6.8-7.9), median GLU 24.5mmol/L (IQR 21.5-36.7), and C-peptide concentration was low or inappropriately normal (median 0.35nmol/L, IQR 0.25-0.49). In 7 pts who underwent HLA typing, 5 had alleles consistent with increased risk T1DM, but autoantibodies seen in most T1DM were infrequent: GAD antibodies in 2pt IA-2 antibodies in 1pt, and all were negative for insulin- and ZnT8-antibodies. No pts developed T1DM antibodies on subsequent testing (range 1-32 months). All patients continued ICI, with 7 having a complete or partial response, and all patients required ongoing insulin. Conclusions: ICI-DM is an infrequent but permanent toxicity with ICI. It appears to be distinct from T1DM, occurring in older pts, without autoantibodies, and with difficult glycaemic control. Most pts present acutely with ketoacidosis, often many months after starting therapy.
Abstract 12577: Safety and Efficacy of Everolimus-Eluting Stent versus Zotarolimus-Eluting Stent: A Meta-Analysis of Randomized Controlled Clinical Trials and Observational Studies
Authors: Hongqiu Gu, Kun Hua, Yang Wang, Jingang Yang, Wei Li
Journal: Circulation (2014)

Background: The safety and efficacy of EES versus ZES are controversial both in randomized controlled clinical trials (RCTs) and observational studies. The aim of this study was to assess the safet...
Survival outcomes from CALGB 80803 (Alliance): A randomized phase II trial of PET scan-directed combined modality therapy for esophageal cancer.
Authors: Karyn A. Goodman, Nathan Hall, Tanios S. Bekaii-Saab, Fang-Shu Ou, Erin Twohy, Michael O. Meyers, Daniel J. Boffa, Kisha Mitchell, Kyle Perry, Wendy L Frankel, Alan P. Venook, Eileen Mary O'Reilly, David H. Ilson
Journal: Journal of Clinical Oncology (2018)

4012 Background: We evaluated use of early PET response after induction chemotherapy (CT) to direct changing to alternative CT during preoperative chemoradiation (CRT) among patients (pts) with resectable esophageal and gastroesophageal junction (GEJ) adenocarcinomas who are PET nonresponders. We previously reported the primary endpoint of improving pathologic complete response (pCR) in PET nonresponders; pre-specified efficacy criteria were met for improvement in pCR rates with changing CT during CRT. We now report survival outcomes by PET response status. Methods: 257 pts enrolled, underwent baseline PET and were randomized to 1 of 2 induction CT arms: modified FOLFOX-6 (oxaliplatin, leucovorin, 5-FU) days 1, 15, 29 or carboplatin/paclitaxel (CP) days 1, 8, 22, 29. Repeat PET was performed days 36-42; change in maximum standardized uptake value (SUV) from baseline was assessed. PET nonresponders ( < 35% decrease in SUV: PET-NR) crossed over to alternative CT regimen during CRT (50.4 Gy/28 fractions). PET responders (≥35% decrease in SUV: PET-R) continued on same CT during CRT. Pts underwent surgery at 6 weeks post-CRT. Overall survival (OS) was measured from randomization to death from any cause; 2-year (yr) OS rates were estimated using the Kaplan-Meier method. Results: 240 eligible pts received protocol treatment and 222 had an evaluable repeat PET. With median follow-up of 35.9 months (mo) (95% CI: 33.1-41.2), median OS was 34.4 mo (95%CI: 28.4-49.7) and 2-yr OS was 61.8% (95%CI: 55.7-68.5%). Median OS for PET-R was 40.2 mo (95% CI:31.0, not estimable [NE]) and for PET-NR was 27.4 mo (95% CI: 20.3, NE). Median and 2-yr OS by induction CT and PET response appear below. Clinical trial information: NCT01333033. Conclusions: PET response after induction CT is prognostic for outcome in pts with esophageal and GEJ adenocarcinomas. Outcomes for PET-R pts receiving induction and concurrent FOLFOX are encouraging. Support: U10CA180821, U10CA180882 Response Group Events/N Median OS (mo) 95% CI (mo) 2-yr OS (%) 95% CI (%) CP N = 111 PET-R 31/63 31.0 (20.4, NE) 57.4 (46.2, 71.3) PET-NR 28/48 26.4 (16.0, NE) 52.4 (39.8, 69.0) FOLFOX N = 111 PET-R 29/72 48.7 (33.1, NE) 73.3 (63.4, 84.7) PET-NR 20/39 30.9 (25.4, NE) 64.0 (50.0. 82.0)
<i>FGFR3</i> Driven Metastatic Urothelial Carcinoma of the Urinary Bladder (mUCB): A Comprehensive Genomic Profiling Study.
Authors: Jeffrey S. Ross, Laurie M. Gay, Elizabeth Kate Ferry, Joseph Jacob, Oleg Shapiro, Jean H. Hoffman-Censits, Sherri Z. Millis, Julia Andrea Elvin, Jon Chung, Jo-Anne Vergilio, James Suh, Shakti H. Ramkissoon, Eric Allan Severson, Sugganth Daniel, Jonathan Keith Killian, Siraj Mahamed Ali, Alexa Betzig Schrock, Vincent A. Miller, Gennady Bratslavsky
Journal: Journal of Clinical Oncology (2018)

4531 Background: Using comprehensive genomic profiling (CGP), we queried whether FGFR3-driven mUCB could be further defined by additional genomic alterations (GA) and biomarkers of response to immunotherapies. Methods: DNA from FFPE tissues of 1,576 mUCB underwent hybrid-capture based CGP to evaluate all classes of genomic alterations. Tumor mutational burden (TMB) was determined on 1.1 Mbp of sequenced DNA and microsatellite instability (MSI) was determined by principal components analysis of optimal homopolymer loci. Results: 385 (24%) of the 1,576 UCB featured GA affecting FGFR1-4. Of the FGFR3 GA identified in mUBC (FGFR3mut), 77% were SV, 2% were amplifications, 18% were fusions/rearrangements, and 4% had more than 1 GA type. When compared with a cohort of 1,275 FGFR3 WT mUCB, the GA/tumor and frequency of TERT GA were similar. GA in TP53 and RB1 were more common in FGFR3 WT than FGFRmut, whereas cell cycle GA (e.g., CDKN2A) were more common in FGFR3mut tumors. Genes associated with DNA repair were altered in both groups, with ARID1A GA more frequent in FGFR3 WT, KDM6A GA more frequent in FGFR3mut, and BRCA1/2 GA less frequent overall and similar in both groups. Targetable ERBB2 GA were significantly more common in FGFR3 WT cases. Targets in the MTOR pathway, including GA in PIK3CA and TSC1, were also more common in FGFR3mut mUBC. MSI-High status was extremely rare in both groups. The median TMB was higher in FGFR3 WT, and samples more often had TMB of ≥10 mut/Mb or ≥20 mut/Mb. Conclusions: CGP reveals both similarities and differences in the genomic landscapes of FGFR3mut and FGFR3 WT mUBC. In the 2% of mUBC with FGFR3 driver GA, other targetable GA affecting kinases or the MTOR pathway are present. As evidenced by TMB, the opportunity for immunotherapies remains significant. FGFR3 WT FGFR3mut Significance Cases 1,275 301 Median age (years) 67 67 NS Male/Female 75/25 72/28 NS GA/tumor 7.3 8.3 NS TERT 67% 73% NS TP53 64% 27% P < 0.0001 CDKN2A 30% 60% P < 0.0001 RB1 24% 3% P < 0.0001 ARID1A 24% 17% P = 0.001 KDM6A 20% 37% P < 0.0001 BRCA1 3% 1% NS BRCA2 3% 3% NS PIK3CA 20% 27% P = 0.001 ERBB2 18% 6% P < 0.0001 TSC1 6% 17% P < 0.0001 MSI < 1% 1% NS Median/Mean TMB (mut/Mb) 7.2/10.7 6.3/9.3 NS TMB > 10 mut/Mb 38% 28% P = 0.0008 TMB > 20 mut/Mb 13% 9% NS
Psychological interventions to reduce positive symptoms in schizophrenia: systematic review and network meta‐analysis
Authors: Irene Bighelli, Georgia Salanti, Maximilian Huhn, Johannes Schneider‐Thoma, Marc Krause, Cornelia Reitmeir, Sofia Wallis, Felicitas Schwermann, Gabi Pitschel‐Walz, Corrado Barbui, Toshi A. Furukawa, Stefan Leucht
Journal: World Psychiatry (2018)

Psychological treatments are increasingly regarded as useful interventions for schizophrenia. However, a comprehensive evaluation of the available evidence is lacking and the benefit of psychological interventions for patients with current positive symptoms is still debated. The present study aimed to evaluate the efficacy, acceptability and tolerability of psychological treatments for positive symptoms of schizophrenia by applying a network meta-analysis approach, that can integrate direct and indirect comparisons. We searched EMBASE, MEDLINE, PsycINFO, PubMed, BIOSIS, Cochrane Library, World Health Organization's International Clinical Trials Registry Platform and ClinicalTrials.gov for randomized controlled trials of psychological treatments for positive symptoms of schizophrenia, published up to January 10, 2018. We included studies on adults with a diagnosis of schizophrenia or a related disorder presenting positive symptoms. The primary outcome was change in positive symptoms measured with validated rating scales. We included 53 randomized controlled trials of seven psychological interventions, for a total of 4,068 participants receiving the psychological treatment as add-on to antipsychotics. On average, patients were moderately ill at baseline. The network meta-analysis showed that cognitive behavioural therapy (40 studies) reduced positive symptoms more than inactive control (standardized mean difference, SMD=-0.29; 95% CI: -0.55 to -0.03), treatment as usual (SMD=-0.30; 95% CI: -0.45 to -0.14) and supportive therapy (SMD=-0.47; 95% CI: -0.91 to -0.03). Cognitive behavioural therapy was associated with a higher dropout rate compared with treatment as usual (risk ratio, RR=0.74; 95% CI: 0.58 to 0.95). Confidence in the estimates ranged from moderate to very low. The other treatments contributed to the network with a lower number of studies. Results were overall consistent in sensitivity analyses controlling for several factors, including the role of researchers' allegiance and blinding of outcome assessor. Cognitive behavior therapy seems to be effective on positive symptoms in moderately ill patients with schizophrenia, with effect sizes in the lower to medium range, depending on the control condition.
Facile single cell profiling and clonotype analysis of NSCLC immune microenvironments.
Authors: Ameen Abdulla Salahudeen, Junjie Zhu, Jihang Ju, Valeria Giangarra, Luz Montesclaros, Jerald Sapida, Osman Sharifi, Josephine Lee, Dhananjay Wagh, John Coller, Joel W. Neal, Sukhmani Kaur Padda, Heather A. Wakelee, Chiara Sabatti, Calvin Jay Kuo
Journal: Journal of Clinical Oncology (2018)

12014 Background: Immunotherapies acting upon tumor infiltrating lymphocytes (TILs) generate deep and durable responses in NSCLC patients. However, the clonality, cell phenotype, and signaling states of TILs remain poorly defined in clinical specimens. In addition, current in vitro model systems do not typically preserve both the tumor epithelium and microenvironment as an intact syngeneic unit thus hindering conceptual and therapeutic advances. Methods: We developed 3-dimensional organoid cultures of surgically resected NSCLC specimens that intrinsically retained diverse tumor microenvironmental cellular components without requiring reconstitution. We then profiled TIL clonotypes and gene expression phenotypes in varying histologies of NSCLC with a 5’ based scRNA-seq platform capable of pairing alpha beta T cell receptor (TCR) sequence identity with 5’ based transcriptomes. Results: Fresh clinical samples were viably dissociated into single cell suspensions and droplet based scRNA-seq was carried out in a rapid and reliable manner. Correct, full length, and paired TCRA/TCRB clonotypes were detected at expected ratios and demonstrated a detection sensitivity of clonal expansion with a sensitivity of 1% for 1000 cells observed. In addition, paired transcriptome analysis facilitated phenotypic categorization of each unique clonotype, including cytotoxic and helper T, B, Treg, as well as TIL exhaustion. Furthermore, examination of NSCLC tumor microenvironments with varying patient smoking history and tumor histology exhibited differences suggesting a potential link between immune microenvironments and cancer etiology. Conclusions: Organoid cultures faithfully recapitulate tumor microenvironment diversity within NSCLC histologic types, and scRNA-seq profiling of clonotype TIL dynamics may elucidate underlying immune microenvironment dynamics in NSCLC patients. Further studies in this human preclinical model coupled with scRNA-seq may advance our understanding of tumor immunology within NSCLC subtypes as well as facilitate the discovery of novel immunotherapies.
SPIRE: A phase Ib/randomised IIa open label clinical trial combining guadecitabine (SGI-110) with cisplatin and gemcitabine chemotherapy for solid malignancies including bladder cancer.
Authors: Simon J. Crabb, Sarah Danson, James Catto, Cathy McDowell, Denise Dunkley, Robert A Huddart, Gareth Griffiths
Journal: Journal of Clinical Oncology (2018)

TPS4594 Background: Cisplatin based chemotherapy is a standard of care therapy for urothelial bladder cancer for palliative first line treatment of advanced/metastatic disease or radical neoadjuvant treatment of localized muscle invasive disease. However, cisplatin resistance, associated with disease progression or relapse, is common and remains a critical barrier to therapeutic advance. Pre-clinical data suggest cisplatin resistance in bladder cancer, and other cancers, might be avoided by co-administration of a DNA hypomethylating agent. Methods: SPIRE is a phase Ib/IIa trial evaluating whether the DNA methyltransferase inhibitor SGI-110 (guadecitabine), in combination with gemcitabine and cisplatin chemotherapy (GC), is safe and biologically effective. It incorporates a dose escalation phase in advanced/metastatic solid tumors, including bladder cancer, followed by a randomized dose expansion phase as neoadjuvant treatment prior to cystectomy for bladder cancer (T2-4a N0 M0). The primary objective is to determine a recommended phase II dose (RP2D) of SGI-110 in combination with GC, using pre-defined dose limiting toxicity criteria assessed by CTCAE v4.03, and a biologically effective dose based on serum DNA LINE-1 methylation and hemoglobin F re-expression status. Dose Escalation Phase: Treatment comprises GC (G 1000 mg/m2, IVI, days 8 and 15; C 70 mg/m2, IVI, day 8), and SGI-110 (SC, days 1-5), for up to 6 cycles of 21 days. Up to 6 patients are enrolled in each of up to 4 SGI-110 dose level cohorts utilizing a ‘rolling 6’ design. Dose Expansion Phase: 20 patients will be randomized 1:1 to GC, or GC + SGI-110 at the established RP2D, to expand safety and pharmacodynamic endpoint data. SPIRE is coordinated by the CRUK Southampton Clinical Trials Unit and is currently recruiting to a 3rd dose escalation cohort through the UK Experimental Cancer Medicine Centre (ECMC) network. It was developed through the CRUK Combinations Alliance. Funding: Cancer Research UK (C9317/A19903) and Astex Pharmaceuticals. Sponsor: University Hospital Southampton NHS Foundation Trust. Clinical trial information: ISRCTN16332228.