tbuckley/cabot-search huggingface dataset:
Abstract B034: Time to treatment and overall survival among men with localized prostate cancer
Authors: Dudith Pierre-Victor, Paul Pinsky, Iman K. Martin, Worta McCaskill-Stevens
Journal: Cancer Research (2018)

Abstract Background: Prostate cancer is the second most common cancer diagnosed among men in the United States. Delays from the time of confirmed diagnosis to primary treatment are more common for prostate compared to other malignancies. The objective of this study was to investigate factors associated with time to treatment and the effect of time to treatment on overall survival among men with early-stage prostate cancer. Methods: From the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial, men diagnosed with localized prostate cancer who received treatment within a year of diagnosis were selected for analysis (N=6,349). Selected men had date of diagnosis, treatment date, and mortality status as of 2012. We investigated sociodemographic and clinical factors associated with time to treatment using Cox regression. We also used Cox regression to examine the effect of time to treatment on overall survival. Covariates included Gleason score, PSA level, age at diagnosis, employment status, education level, race, marital status, and comorbidity burden. Results: The median time to treatment was 73 (IQR: 44-120) days. Demographic factors associated with longer time to treatment included being Black (adjusted hazard ratio (aHR)= 0.85, 95%CI: 0.76-0.95), having some college education (aHR= 0.91, 95%CI: 0.85-0.97), and having a baccalaureate degree or a post-baccalaureate degree (aHR= 0.89, 95% CI: 0.84-0.95). Clinical factors associated with longer time to treatment were being diagnosed at an older age (aHR= 0.86, 95%CI:0.80-0.93 for age of 70-74 years and aHR= 0.80, 95%CI: 0.74-0.87 for 75 year and older) and having an elevated PSA level (HR=0.89, 95%CI: 0.81-0.94 for third PSA quartile (6.11-9.0) and HR=0.87, 95%CI: 0.81-0.94 for fourth PSA quartile (9.0 and above). Gleason score and comorbidity burden were not associated with time to treatment. Being married (aHR=1.11, 95%CI: 1.03-1.19) and being retired (aHR=1.09, 95%CI:1.034-1.16) were associated with shorter time to treatment. After adjusting for sociodemographic and clinical characteristics, time to treatment did not have a significant effect on overall survival. Conclusions: College education, being Black, older age at diagnosis, and higher PSA levels were associated with longer time to treatment. Being married and being retired were associated with shorter time to treatment. Longer time to treatment was not associated with overall mortality among PLCO men with localized prostate cancer. Citation Format: Dudith Pierre-Victor, Paul Pinsky, Iman K. Martin, Worta McCaskill-Stevens. Time to treatment and overall survival among men with localized prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Prostate Cancer: Advances in Basic, Translational, and Clinical Research; 2017 Dec 2-5; Orlando, Florida. Philadelphia (PA): AACR; Cancer Res 2018;78(16 Suppl):Abstract nr B034.
Nutritional status in cancer: Perspectives of healthcare professionals.
Authors: Niamh O'Donoghue, Suzanne Doyle, Declan Walsh, Seamus O'Reilly
Journal: Journal of Clinical Oncology (2018)

e18550 Background: Nutritional disorders are common in cancer. Consequences include increased treatment toxicity, reduced quality of life and decreased survival. Despite this, nutritional screening and assessment are not routine. This study aimed to understand healthcare professionals’ knowledge and practice in relation to nutrition in cancer. Methods: A semi-structured questionnaire (32 questions) assessed healthcare professionals’ knowledge and practice. Consultants and Specialist Registrars (SpRs) in Haematology, Oncology (Medical, Radiation, Surgical), Palliative Medicine, Oncology Liaison Nurses and Oncology Dietitians were invited to participate. Areas examined included professional demographics, nutritional screening and assessment, understanding of cancer cachexia and management of at risk patients. Results: 124 responses were received: Consultants/SpRs: 48% (n = 60); Oncology Dietitians: 29% (n = 36); Oncology Liaison Nurses: 8% (n = 10); Other: 15% (n = 18). Two thirds (n = 82) worked in a designated cancer centre. Of those with formal education in nutrition (non-dietitian), 87% (n = 20) found it helpful in their practice. 43% were unaware if a screening policy/tool was used in their workplace. Those with formal nutrition education felt more confident to give advice (p < 0.05). Understanding of cancer cachexia was variable; most (69%; n = 86) were not familiar/somewhat familiar with the definition proposed in the 2011 consensus paper. 56% (n = 70) were unable to identify a patient at nutritional risk. 37% (n = 46) only referred to a dietitian once cachectic. Most common perceived barriers to optimal nutrition care: lack of dietetic services (63%), time constraints (53%) and insufficient training on identification and treatment of cachexia (49%). Conclusions: Most respondents were unable to identify at risk patients. Awareness of cancer cachexia and its’ consequences was highly variable; many would wait until a patient was cachectic before referring to a dietitian. Formal nutritional education for non-dietetic healthcare professionals is limited. This may affect ability to promptly recognise and manage at risk patients. Addressing knowledge deficits may improve early recognition and support timely interventions.
Safety findings from FORWARD II: A Phase 1b study evaluating the folate receptor alpha (FRα)-targeting antibody-drug conjugate (ADC) mirvetuximab soravtansine (IMGN853) in combination with bevacizumab, carboplatin, pegylated liposomal doxorubicin (PLD), or pembrolizumab in patients (pts) with ovarian cancer.
Authors: David M. O'Malley, Kathleen N. Moore, Ignace Vergote, Lainie P. Martin, Lucy Gilbert, Antonio Gonzalez Martin, Dale L. Nepert, Rodrigo Ruiz-Soto, Michael J. Birrer, Ursula A. Matulonis
Journal: Journal of Clinical Oncology (2017)

5553 Background: FORWARD II is a phase 1b study of the FRα-targeting ADC, mirvetuximab soravtansine (IMGN853), in combination with bevacizumab (BEV), carboplatin, PLD, or pembrolizumab in adults with FRα-positive EOC, primary peritoneal, or fallopian tube tumors (NCT02606305). Methods: The escalation stage of this trial evaluated the safety and tolerability of IMGN853 as part of 4 combination regimens: IMGN853 + BEV; + carboplatin; + PLD; and + pembrolizumab. IMGN853 was administered in combination on Day 1 of a 21 (BEV or carboplatin) or 28-day cycle (PLD). Pembrolizumab escalation is continuing. The starting dose of IMGN853 was 5 mg/kg (adjusted ideal body weight, AIBW), one level lower than the recommended single agent phase 2 dose (RP2D; 6 mg/kg AIBW) defined in a first-in-human study (NCT01609556). Adverse events (AEs) were evaluated by CTCAE v4.0. Results: 46 pts enrolled in the first 3 cohorts. IMGN853 was escalated from 5 to 6 mg/kg. Carboplatin and PLD dosing were escalated from AUC4 to AUC5 and 30 to 40 mg/m 2 , respectively; BEV dosing remained constant at 15 mg/kg. Diarrhea, nausea, and fatigue were common across cohorts (all grades; 33-57%) and mostly low grade (i.e. ≤ 2), consistent with the IMGN853 safety profile from the earlier phase I monotherapy study. AEs of interest related to the combination agents were seen in each arm. For example, grade 1/2 proteinuria (36%) and grade 3 hypertension (21%) were only observed in the BEV combination. Thrombocytopenia (44%) and neutropenia (39%), grades 1-3, occurred most frequently in the carboplatin arm. Grade 3 anemia and vomiting (each 14%), as well as low grade (≤ 2) constipation (43%), were seen in the PLD cohort. Conclusions: The RP2D dose of IMGN853 was readily combined with the highest doses (as per protocol) of BEV, carboplatin, and PLD. The AE profiles for these combinations were manageable and as expected based on known profiles of each agent; importantly, no new safety signals were identified. Updated data from all 4 combination regimens will be presented. Clinical trial information: NCT02606305.
Government is urged to scrap visa cap for all foreign doctors after Brexit
Authors: Gareth Iacobucci, Matthew Limb
Journal: BMJ (2018)

Visa restrictions that prevent foreign doctors taking up their posts in the NHS should be abolished permanently after Brexit, the government’s Migration Advisory Committee has recommended.

Currently, doctors from the European Economic Area are allowed to work in the UK without any restrictions, but those from outside the EEA need a “tier 2” visa. A cap on the number of tier 2 visas issued to doctors and nurses from outside the EEA who had been offered posts in the NHS was lifted in July after pressure from, among others, The BMJ ’s Scrap the Cap campaign (bmj.com/scrap-the-cap).

In its final report to the government on immigration from the EEA and how the UK’s post-Brexit work immigration system should work, the committee said that after Brexit the cap should be …
Survival and delayed effects of risk-stratified hepatoblastoma patients treated in the JPLT-2 trial.
Authors: Eiso Hiyama, Sho Kurihara, Yuka Ueda, Tomoro Hishiki, Kohmei Ida, Kenichiro Watanabe, Michihiro Yano, Yukichi Tanaka, Ken Hoshino, Keiko Hiyama
Journal: Journal of Clinical Oncology (2018)

10524 Background: The Japanese Study Group for Pediatric Liver Tumor (JPLT) -2 trial (2000-2012) has been conducting to evaluate the efficacy of the CITA regimen, consisting of cisplatin/pirarubicin, in patients with hepatoblastoma (HB) stratified by risk according to the PRETEXT staging system. Methods: In JPLT-2, PRETEXT I/II tumors were initially resected or underwent two courses of low-dose CITA before resection and an additional four courses of CITA after resection. Of the PRETEXT III/IV or metastatic tumors, those that responded to two courses of CITA underwent four more courses of CITA, and the non-responsive tumors received four courses of a second-line regimen consisting of ifosfamide, pirarubicin, etoposide, and carboplatin. Highly metastatic or refractory tumors were treated with high-dose chemotherapy and stem cell transplantation. Results: Among the 360 patients who were eligible in the JPLT-2 trial, 5-year event-free/overall survival rates of patients with PRETEXT I/II/III HB were 94/82%, while those of patients with PRETEXT IV and metastatic HB were 65.4/74.6% and 44.3/60.9%, respectively (Table). Except for 40 patients who underwent primary resection, complete resection of the primary tumor after CITA was achieved in 86%, 66%, and 56% of patients with PRETEXT II/III, PRETEXT IV, and metastatic tumors, respectively. The outcomes of the patients who received high-dose chemotherapy did not improve. Of those patients who survived, 68 experienced late-phase complications with otoxicity, 12 cardiotoxicity, 5 maldevelopment, and 12 second malignancies. Conclusions: Compared with other multicenter cooperative protocols, treatment with the CITA regimen achieved similar rates of survival and resectability. However, the rates of otoxicity and a second malignancy were higher and that of cardiotoxicity lower compared with other studies. Reduction of the chemotherapy dose should be considered in low-risk patients, while more promising strategies such as novel targeted drugs should be developed for intermediate- and high-risk patients with HB. Clinical trial information: UMIN000001116.Summary of JPLT-2. PRETEXT (n) 5y- EFS (%) 5y-OS (%) I M- 22 75.2 95.5 II M- 108 83.5 90.5 III M- 113 80.0 91.5 IV M- 56 65.4 74.6 M 61 44.3 60.9 M: metastasis
The real life outcomes of modified docetaxel and cisplatin plus fluorourasil regimen in patients with metastatic gastric cancer.
Authors: Tulay Eren, Nuriye Ozdemir Yildirim, Ozan Yazici, Goksen Inanc Imamoglu, Dogan Yazilitas, Suheyla Aytac, Nurullah Zengin
Journal: Journal of Clinical Oncology (2016)

e15548 Background: Gastric cancer is usually diagnosed at locally advanced or metastatic stage. The superiority of combined systemic treatment to single agent and palliative treatment has been shown. The basis of first line treatment of metastatic gastric cancer is still fluorouracil based regimes. Docetaxel-cisplatin-5-fluorourasil (DCF) protocol is one of the standard regimes at present however it is difficult to administer owing to high toxicity rates. The aim of the present study was to modify the dose of DCF regime in order to render it more tolerable and to evaluate the efficacy and tolerability of modified DCF (mDCF) protocol as real life data. Methods: Overall 267 patients followed in Ankara Numune Research and Education Hospital were included in the study. All patients were administered mDCF regime as metastatic first line treatment. Patients were evaluated in terms of response rates, time to progression, overall survival and treatment toxicities. Doses in mDCF arm was as follows: docetaxel 60 mg/m2 1. Day, cisplatin 60 mg/m2 1.Day and 5-fluorouracil (5-FU) 600 mg/m2/day (1-5 days) every three weeks. Patients did not undergo any primary growth factor prophylaxis. Results: In the study, files of overall 267 patients who did not previously receive treatment were evaluated retrospectively. All patients were administered mDCF treatment median number of cycles in all patients was 6 (range 2-10). Median age of patients was 55 (range 22-76). ECOG performance status was between 0-2. Response rates were as follows: complete response 5 (1,9%) patients, partial response 74 (27,7%) patients and stable disease 95 (35,6%) patient. Median progression free survival (PFS) was 6.0 (95%CI, 5,3-6,6) months, and median overall survival (OS) 10.0 (95% CI, 8,8-11,1) months. In the our study, grade 3-4 neutropenia was found at the rate of 28,1%, anemia 11,6%, thrombocytopenia 4,1% and Febrile neutropenia 4,9%. Conclusions: Although mDCF regime seems to be as effective as original DCF regime, grade 3-4 toxicity rates were found to be lower. Modified DCF may be preferred as a tolerable and effective regime in ECOG 0-2 metastatic gastric cancers.
OS1.6 Characterizing the Over-expression of Yki/YAP/TAZ Transcription Factors in Gliomagenesis and Results of a Phase 0 Clinical Trial for a Proposed Novel Treatment of Glioblastomas
Authors: K Vigneswaran, S Oh, S Lallani, R Read, J Olson
Journal: Neuro-Oncology (2018)

Glioblastomas (GBMs) harbor frequent genetic lesions that include amplification, mutation, and/or over expression of receptor tyrosine kinases (RTKs). Using a novel kinome wide RNAi screen we identified the Hippo kinase pathway and it downstream targets, Yki-YAP/TAZ transcription factors, as tumor enhancers in gliomagenesis. YAP/TAZ promote the initiation and progression of other tumor types and several published studies show that pharmacologic inhibition of YAP and TAZ with the drug verteporfin (VP) blocks tumor cell growth. Thus, we hypothesize that, because of RTK mutations, YAP/TAZ become overexpressed and activated to constitutively drive a TEAD-dependent gene expression program that provokes an uncontrolled expansion of RTK-PI3K mutant neural stem/progenitor cells to create malignant glial tumors. We tested VP in vitro on genotyped neurosphere cultures which were assessed for self-renewal, proliferation, and survival using neurosphere formation and WST-1 assays. To confirm that VP inhibits expression of YAP/TAZ-TEAD transcriptional targets, we performed experiments and harvested RNA for RNAseq, qPCR, and completed western blots and ChIP analysis. In-vivo experiments were carried out in murine xenografts bearing YAP/TAZ-expressing GBM that were used to make organotypic slice cultures which were treated with VP and assayed for tumor growth and cell survival. A Phase 0 clinical trial was designed to determine VP bioavailability. Because VP has virtually the same excitation and emission spectra as protoporphyrin IX, we administered VP to patients prior to surgery and used fluorescence-assisted microscopy to determine if VP is visible in tumors. On encountering tumor intraoperatively, the operative microscopy system was used to illuminate the tumor bed with blue light (400–410 nm), and photographs were taken through the microscope using a camera adapted for imaging in the red (620–700 nm) emissions spectrum. Resected tumor tissue remaining after satisfying clinical goals was sent for ex vivo research analysis. Our data reveal that YAP and TAZ become overexpressed in tumor cells with RTK mutations, and that YAP/TAZ drive brain tumor cell growth and progression by up-regulation of novel RTK genes including EGFR. VP treatment knocks down target gene transcription, protein levels, leads to cell death and halts tumor progression. VP extraction from tumor tissue and fluoroscopic examination show successful drug uptake from all patients in a Phase 0 clinical trial. We believe that as a consequence of RTK mutations, YAP/TAZ becomes over-expressed in gliomas and constitutively drive a TEAD-dependent gene expression program that provokes an uncontrolled expansion of RTK -PI3K mutant neural stem/progenitor cells to create malignant glial tumors that can be treated with VP which shows bioavailability in glioblastomas.
P04.30 Methadone does not increase toxicity of temozolomide in glioblastoma cells
Authors: P Latzer, T Kessler, F Sahm, P Rübmann, T Hielscher, M Platten
Journal: Neuro-Oncology (2018)

Methadone is a well-known analgesic used in substitution therapy. In addition, methadone has been recently linked to cancer as it increases apoptosis and caspases activation in glioma cell lines treated with doxorubicin and it inhibits tumor growth in vivo. Although its effect on cancer is still under debate, since pro- and anti-tumoral effects have been observed and data supporting efficacy beyond casuistic reports are missing, methadone is widely used by glioblastoma patients under the assumption that it enhances the efficacy of alkylating chemotherapy. Therefore, the aim of our study is to evaluate the specific effect of methadone on glioblastoma. Glioma cell lines (LN-229, A172, U87 and LN-308) as well as glioblastoma initiating cells (GIC; S24, T325, T1, L2 and T269) were treated with methadone (D/L and L; 1 μg/ml), temozolomide (TMZ) (10–300 μM) and methadone (D/L and L) + TMZ. Anti-tumor effects were investigated based on apoptosis and cell death, cell cycle arrest, proliferation and clonogenicity. Methylation of the MGMT promoter was checked with the Illumina Infinium HumanMethylation450 (450k) array. In addition, the expression of the μ-opioid receptor was analyzed by single cell analysis and immunohistochemistry on human and mouse material along with a functional assay on glioma cells. The expression of the μ-opioid receptor has been faintly detected on human slices and in vitro. However, only few cells in glioblastoma patients expressed the receptor. In addition, most of the cell lines and GIC express a methylated MGMT promoter. Moreover, while there was a moderate G2 arrest of LN-229 after 6 days of treatment, 1 μg/ml methadone significantly enhanced the proliferation of T325. Furhtermore, there were no synergistic effects when combining methadone + TMZ in comparison to TMZ alone for all feature investigated in vitro. Methadone alone has a poor effect on glioma cells at extremely high concentration. The addition of methadone to TMZ does not provide further anti-tumoral effect compared to TMZ alone and the effect on GIC may even be adverse. Receptor expression on patient tissue is a rare exemption. The present data contrast earlier observation in A172 cells and do not support the use of methadone as a chemotherapy-enhancing agent in glioblastoma patients outside controlled clinical trials.
A randomized phase II trial of systemic chemotherapy with or without trastuzumab followed by surgery in HER2 positive advanced gastric or esophagogastric junction adenocarcinoma with extensive lymph node metastasis: Japan Clinical Oncology Group study JCOG1301C (Trigger study).
Authors: Masanori Tokunaga, Nozomu Machida, Junki Mizusawa, Hiroshi Katayama, Hiroya Taniguchi, Kohei Shitara, Toshihiko Tomita, Takaki Yoshikawa, Narikazu Boku, Takeshi Sano, Mitsuru Sasako, Masanori Terashima
Journal: Journal of Clinical Oncology (2016)

TPS4143 Background: The efficacy of trastuzumab for HER2-positive advanced gastric cancer was shown in ToGA trial, associated with a higher response rate. However, it is unclear if addition of trastuzumab to preoperative chemotherapy is effective for HER2-positive resectable gastric cancer. In Japan, preoperative chemotherapy with S-1 plus cisplatin (SP) is considered to be a promising treatment option for gastric cancer patients with extensive lymph node metastases because its efficacy was shown in single arm phase II trial (JCOG0405). Addition of trastuzumab to preoperative SP may enhance the anti-tumor activity and improve overall survival of patients with apparent para-aortic or regional lymph node metastasis. Methods: This study is designed as a randomized screening phase II study to compare preoperative SP plus trastuzumab and SP for HER2-positive gastric cancer with apparent para-aortic lymph nodes ( ≥ 1.0 cm in long axis) and/or regional lymph nodes ( ≥ 1.5 cm in short axis) metastasis (UMIN000016920). In both arms, an infusion of cisplatin (60 mg/m2/day, day 1) and oral S-1 (80 mg/m2/day, days 1–14) repeated every 3 weeks are given for 3 courses, and an additional infusion of trastuzumab (first course, 8 mg/kg; second course onward, 6 mg/kg, day 1, every 3 weeks) are also given in SP plus trastuzumab arm. After R0 resection, adjuvant chemotherapy with S-1 is performed for 1 year after surgery. The planned sample size was 130 patients in total with a 1-sided alpha of 0.2, a power of 0.75, and a 10% increase in the 3-year OS (70% vs 80%), and the patients will be accrued from 58 Japanese institutions over 3 years. The primary endpoint is overall survival. Because Japanese medical insurance does not reimburse the perioperative use of trastuzumab, this study is conducted under Advanced Medical Care B, a governmental program to allow an off-label use. As of January 2016, no patients have been enrolled yet. Clinical trial information: UMIN000016920.