tbuckley/cabot-search huggingface dataset:
ARK5 regulates the growth of HTLV-1-infected T cells during glucose starvation
Authors: Mariko Tomita, Shuhei Taniguchi, Atsushi Suzuki, Tetsuro Nakazato, Chie Ishikawa, Taeko Okudaira, Hiroyasu Esumi, Naoki Mori
Journal: Cancer Research (2008)

599   A human retrovirus, HTLV-1 (human T-cell leukemia virus type 1) is the causative agent of ATL (adult T-cell leukemia), which is an aggressive and fatal T cell malignancy characterized by dysregulated proliferation of CD4-positive T cells. HTLV-1-infected T cells are resistant to apoptotic cell death induced by various stimuli. AMP-activated protein kinase-related kinase 5 (ARK5) suppresses cell death in AKT-dependent manner. It has been shown that ARK5 was transcriptionally regulated by large-Maf family proteins including c-Maf in multiple myeloma cells. However, the role of ARK5 on survival of HTLV-1-infected T cells is not elucidated. In this study, we found that ARK5 expression was induced by HTLV-1 transforming protein Tax and played an important role on survival of HTLV-1-infected T cells during glucose starvation. ARK5 and c-Maf mRNA was overexpressed in HTLV-1-infected T-cell lines but not in HTLV-1-uninfected T-cell lines. In vitro infection of T-cell line, TY8-3, with HTLV-1 induced the expression of ARK5 and c-Maf mRNA. Inducible expression of Tax in a T-cell line also up-regulated the expression of ARK5 and c-Maf mRNA. Analysis of the ARK5 promoter revealed that transcription of this gene was activated by Tax but not by c-Maf. Knockdown of c-Maf mRNA expression by using small interfering RNA (siRNA) did not affect ARK5 mRNA expression in HTLV-1-infected T cells. Tax mutant which defects of ability of activation of NF-κB signaling pathway could not increase transcriptional activity of ARK5 gene. Coexpression of IκBα, IkBβ, IKKβ, and IKKγ dominant-negative constructs with Tax inhibited activation of ARK5 gene transcription induced by Tax. Bay11-7082, an IκBα phosphorylation inhibitor, reduced the expression of ARK5 mRNA in HTLV-1-infected T cells. Introduction of NF-κB (p65) expression plasmid increased transcriptional activity of ARK5 gene. Previously, it has been shown that ARK5 suppresses the cell death induced by glucose starvation in human hepatoma cells. Therefore, the role of ARK5 on survival of HTLV-1-infected T-cell lines during glucose starvation was assessed. We found that the viability of non-ARK5-expressing HTLV-1-uninfected T cells was markedly reduced in glucose reduced media. In contrast, more than 70% of ARK5-expressing HTLV-1-infected T-cell lines were viable during glucose starvation, except AKT-inactive MT-4 cells. Knockdown of ARK5 expression by siRNA did not affect the viability of HTLV-1-infected T-cell lines in glucose-containing media, but reduced the viability of these cells in glucose-reduced media. Our results demonstrated that Tax induced the expression ARK5 gene by activating NF-κB signaling pathway and ARK5 contributed to survival of HTLV-1-infected T cells during glucose starvation in AKT-dependent manner. Our findings implicated that ARK5 plays important roles in the survival of ATL cells and is a good therapeutic target of ATL.
TCT-589 Clinical Outcomes of the Sentinel Cerebral Protection System in Patients Undergoing Transcatheter Aortic Valve Replacement: A Meta-Analysis
Authors: Paul Ndunda, Mohinder Vindhyal, Sachin Srinivasan, Tabitha Muutu, Sumaya Hammami, Zaher Fanari
Journal: Journal of the American College of Cardiology (2018)
Network meta-analysis comparing first-line therapies and maintenance regimens in EGFR mutated advanced non-small-cell lung cancer (NSCLC).
Authors: Gilberto Lopes, Pui San Tan, Sanchalika Acharyya, Marcel Bilger, Benjamin Haaland
Journal: Journal of Clinical Oncology (2016)

e20570 Background: More evidence is needed to select the best treatment strategy for patients harboring EGFR mutations and its subtypes Methods: We performed a systematic search and included studies reporting OS and/or PFS efficacy estimates by EGFR mutation status or subtypes (Del19/L858R). Hazard ratios of competing treatments were pooled using a Bayesian hierarchical model incorporating both within and between study heterogeneities. Treatment benefits were evaluated using posterior hazard ratios with 95% credible intervals (CrI) and ranked by surface under the cumulative ranking curve (SUCRA) for OS benefit Results: 4,177 records were screened and 20 trials were meta-analyzed. Statistically significant OS and PFS benefits were seen with (i) first-line intercalated chemotherapy+erlotinib in EGFR mutation positive, and (ii) first-line afatinib in Deletion 19. In L858R, no OS benefit was seen although treatments showed PFS benefits Conclusions: Among all available strategies, first-line intercalated chemotherapy+erlotinib in EGFR mutation positive and afatinib in Del 19 are the only strategies showing both OS and PFS benefits First-line treatment Maintenance treatment OS PFS HR (95% CrI) SUCRA HR (95% CrI) EGFR mutation positive Intercalated chemotherapy+erlotinib Erlotiniba 91.5% 0.48 (0.26-0.88) 0.25 (0.15-0.43) Erlotinib+bevacizumab Erlotinib+bevacizumab 89.1% 0.40 (0.11-1.52) 0.18 (0.11-0.30) Afatinib Afatinib 65.0% 0.90 (0.74-1.10) 0.38 (0.29-0.49) Chemotherapy+bevacizumab Bevacizumab 54.8% 0.90 (0.38-2.14) 0.23 (0.12-0.45) Chemotherapy No maintenance 48.7% 1.00 1.00 Chemotherapy+erlotinib Erlotinib 48.5% 1.00 (0.66-1.50) 0.49 (0.18-1.31) Erlotinib Erlotinib 43.3% 1.03 (0.83-1.30) 0.32 (0.24-0.42) Gefitinib Gefitinib 43.0% 1.03 (0.86-1.23) 0.45 (0.37-0.56) EGFR mutation Deletion 19 Afatinib Afatinib 96.3% 0.59 (0.43-0.80) 0.24 (0.18-0.32) Gefitinib Gefitinib 69.3% 0.80 (0.58-1.11) 0.33 (0.26-0.43) Chemotherapy No maintenance 37.5% 1.00 1.00 Erlotinib Erlotinib 34.1% 1.03 (0.75-1.42) 0.20 (0.14-0.29) Chemotherapy Gefitinib 12.8% 1.89 (0.47-7.56) - Erlotinib+bevacizumab Erlotinib+bevacizumab - - 0.08 (0.04-0.17)
Integration of somatic molecular profiling for rare epithelial gynaecologic cancer patients.
Authors: Victor Rodriguez Freixinos, Stephanie Lheureux, Victoria Mandilaras, Blaise Clarke, Neesha Dhani, Helen Mackay, Marcus Butler, Lisa Wang, Lillian L. Siu, Suzanne Kamel-Reid, Tracy Stockley, Phillipe Bedard, Amit M. Oza
Journal: Journal of Clinical Oncology (2016)

5509 Background: Rare gynaecologic cancers (R-GYN) represent over 50% of all gynaecologic malignancies. Conducting clinical trials in R-GYN is challenging due to the limited number of patients (pts) and differences in biologic behavior. Somatic molecular profiling (SMP) may increase biologic understanding of R-GYN and identify pts for target specific therapies. Methods: A cohort of epithelial R-GYN pts was analyzed for somatic variants (SV) through an institutional SMP screening (NCT01505400) using a customized Sequenom SNP genotyping panel or targeted sequencing (NGS) using the Illumina MiSeq TruSeq Amplicon Cancer Panel or the Ion Proton Ampliseq Cancer Hotspot Panel version 2, in a CLIA certified laboratory. Outcomes of genotype-matched (GM) versus genotype-unmatched (GUnM) trials were compared. Results: 721 GYN pts underwent SMP and 189 were classified as R-GYN (26%), with a median of 1.5 prior systemic treatments [0-4]. 52 low grade serous, 2 transitional and 1 squamous OC, 10 cervical adenosquamous/adenocarcinomas, 23 serous endometrial, 2 vaginal, 12 vulvar, 37 clear cell, 17 mucinous, 1 small cell and 32 carcinosarcomas. Pathology review confirmed diagnosis in 95%. A total of 134 pts (71%) had ≥ 1 SV (range 1-4), being the most common: 37% TP53; 39% KRAS; 37% PIK3CA. Upon SMP, 75 pts were not treated further, 64% due to progressive disease (PD). 91/189 pts were referred for clinical trials and 39/189 (21%) participated in 45 studies. 19/189 pts (10%), with a median of 0.5 prior systemic treatments [0-1], participated in GM trials (1 pt with vaginal cancer participated in two consecutive GM trials). Main reasons for non-enrollment were not fulfilling eligibility criteria (49%) and PD (29%). RECIST 1.1 response among evaluable pts showed: 3 PR (7%) (2 in GM trials) and 18 pts had SD ≥ 4 months(m) [9/18 pts (50%) in GM vs. 9/26 pts (35%) in GUnM]. Of 9/18 pts who had received prior systemic therapy for recurrent disease, the median time to progression of GM was 5.3 m (0.9-22) compared with 2.8 m (1.7-25.1) for the immediate prior line of therapy (p = 0.17). Conclusions: SMP screening of R-GYN identified actionable SV in 71% of pts, expanding the spectrum of therapeutic approaches in a population with limited standard options.
ACRIN 6698 trial: Quantitative diffusion-weighted MRI to predict pathologic response in neoadjuvant chemotherapy treatment of breast cancer.
Authors: Savannah C. Partridge, Zheng Zhang, David C Newitt, Jessica E Gibbs, Thomas L Chenevert, Mark Alan Rosen, Patrick J Bolan, Helga Marques, Laura Esserman, Nola M Hylton
Journal: Journal of Clinical Oncology (2017)

11520 Background: Diffusion-weighted (DW) MRI is a non-contrast technique that can reflect treatment-induced alterations in tumor microstructure and cellularity. ACRIN 6698 was performed as a sub-study of the I-SPY 2 TRIAL to evaluate quantitative DW MRI for early assessment of breast cancer response to neoadjuvant chemotherapy (NAC) in a multisite, multiplatform trial. Methods: The IRB-approved trial was performed at ten institutions. Of 406 enrolled breast cancer patients, 272 were randomized to treatment (12 weekly cycles paclitaxel+/-experimental agent, followed by AC) and underwent breast DW MRI at four time points: pre-NAC (T1), early-NAC after 3 cycles paclitaxel (T2), mid-NAC between paclitaxel and AC (T3) and post-NAC (T4). Tumor apparent diffusion coefficient (ADC) was measured at each time point and compared for patients with and without complete pathologic response (pCR) by Wilcoxon signed rank test. Exploratory analyses were performed across subtypes defined by hormone receptor (HR) and HER2 expression. Performance for predicting pCR was assessed by calculating the area under the ROC curve (AUC). Results: Of 272 treated patients, 227 comprised the final cohort (14 were excluded for missing MRI exams, 31 for poor image quality). Median patient age was 48 (range, 25-77) years, and 71/227 (31.3%) achieved pCR. Subtype groups were HR+/HER2+ (n = 38), HR+/HER2- (n = 95), HR-/HER2+ (n = 20), and HR-/HER2- (n = 74). For the full cohort (all subtypes and treatments), both ADC and change in ADC from T1 were significantly predictive of pCR at T3 (AUC = 0.63, 95% CI 0.55-0.71; AUC = 0.62, 95% CI 0.53-0.70, respectively), and also at T4. ADC measures were not predictive of pCR at either T1or T2. Stratifying by subtype showed change in ADC at T3 was more predictive in HR-/HER2+ (AUC = 0.86) and HR+/HER2- (AUC = 0.75) tumors than HR-/HER2- and HR+/HER2+ tumors (AUC = 0.59 and 0.56, respectively). Conclusions: DW MRI reflects cytotoxic effects of chemotherapy, and mid-treatment ADC was a predictive marker of pCR. The predictive value of ADC varied across biologic subtypes. Further work is needed to determine the comparative predictive value of ADC to other imaging metrics. Clinical trial information: NCT01564368.
P01.043 Is surgical resection useful in elderly newly diagnosed glioblastoma patients? Outcome evaluation and prognostic factors assesment
Authors: F Pessina, P Navarria, M Conti Nibali, M Riva, G Carta, E Clerici, M Simonelli, R Rudà, M Scorsetti, L Bello
Journal: Neuro-Oncology (2018)

The incidence of glioblastoma among elderly patients is constantly increasing. The value of radiation therapy and concurrent/adjuvant chemotherapy has been widely assessed. So far, the role of surgery has not been thoroughly investigated. The study aimed to evaluate safety and impact of several entities of surgical resection on outcome of elderly patients with newly diagnosed glioblastoma treated by a multimodal approach. Patients ≥65 years, underwent surgery were included. The extent of surgical resection (EOR) was defined as complete resection (CR=100%), gross total resection (GTR=90%-99%), sub-total resection (STR=78%-90%), partial resection (PR=30%-78%), and biopsy. After surgery, all patients received adjuvant radiotherapy (60Gy/2Gy fraction) with concomitant/adjuvant temozolomide chemotherapy. From March 2004 to December 2015, 178 elderly with a median age of 71 years (range 65–83 years) were treated. CR was obtained in 8 (4.5%), GTR in 63 (35.4%), STR in 46 (25.8%), PR in 16 (9.0%), and biopsy in 45 (25.3%). RT was started in all patients, concurrent/adjuvant CHT in 149 (83.7%) and 132 (74.2%). The median follow up time was 12.2 months (range 0.4–50.4 months). The median,1,2-year progression free survival were 8.9 months (95%CI 7.8–100. months), 32.0 ± 3.5%, and 12.9 ± 2.6%. The median,1,2-year overall survival were 12.2 (95%CI 11.3–13.1 months), 51.1 ± 3.7%, and 16.3 ± 2.9%. Tumor location, extent of resection and neurological status after surgery statistically affected survival (p<<0.01). Maximal surgical resection is safe and feasible also in elderly patients with influence on survival. A preoperative evaluation have to be carried out.
TIPZy (Testosterone Increase Post Zytiga): Increase in serum levels of testosterone (T) after treatment of patients with abiraterone acetate (A) and prednisone (P).
Authors: Cy Aaron Stein, Tanya B. Dorff, Daniela Castanotto
Journal: Journal of Clinical Oncology (2018)

e17025 Background: A is a high-affinity ligand of the enzyme CYP17. The binding of A to this enzyme produces a block in its activity, and lowers the concentration of precursor molecules of T, thus decreasing serum and intratumoral levels T. The extent of CYP17 inhibition must have inter-patient variability. Methods: Observational. Results: We found 10 patients in whom serum T levels, instead of decreasing after treatment with A, increase with time. All patients exhibiting TIPZy had been treated with ADT (Lupron or Zoladex) and 9/10 had PSAs <50 ng/dL before starting treatment with A+P at disease progression. Levels of T began to rise within several weeks after initiation of treatment with A, and reached >100 ng/dL within six months in some patients, plateauing. The highest level of TIPZy achieved was 180 mg/dL, seen in one patient, though increases in T to 100 ng/dL were not uncommon in this limited number of patients. However, there was no relationship between the rise in T and PSA: Patients with rising Ts and falling PSAs were observed, in addition to patients whose Ts and PSAs rose simultaneously. The clinical significance of TIPZy is not apparent because of the small number of patients. In patients experiencing TIPZy, withdrawal of A+P caused a rapid fall in serum T to the typical castrate levels induced by ADT. Conclusions: We hypothesize that the cause of TIPZy is due to leakage of small amounts of testosterone precursors through A-induced block of CYP17 activity, and reversal of catabolism of T (which produces androstanediols and other catabolites) by the so-called “back door” pathway. This should lead to a slow accumulation of T in some patients treated with A+P. It remains surprising that TIPZy was not noted previously but demographic differences may be important. Clinical and genomic studies are planned to validate our hypothesis.
Chemotherapy for lung cancer in patients on renal replacement therapy: The Mayo Clinic experience.
Authors: Konstantinos Leventakos, Insara J Jaffer Sathick, Heidi Diann Finnes, Aaron Scott Mansfield, Brian Addis Costello, Julian R. Molina, Nelson Leung
Journal: Journal of Clinical Oncology (2016)

e20569 Background: The administration of chemotherapy for lung cancer in patients on renal replacement therapy (RRT) is a controversial topic. Most of the available data come from case reports and small series. Herein we present our experience treating these patients. Methods: We retrospectively identified between January 1995 and June 2015 patients who were on RRT at the time of their lung cancer diagnosis. We describe the chemotherapy regimens, dose modifications and timing of hemodialysis, side effects and outcome of these patients. Results: We identified 6 patients on RRT with lung cancer who received targeted therapy or chemotherapy. All were male and the mean age was 63 (range 40-78) years. Treatment regimens, dose modifications and timing of hemodialysis are shown in Table 1. Among 5 patients who received chemotherapy only 1 tolerated all cycles and 2 required treatment delays due to Grade 3-4 adverse reactions. The median overall survival of these patients was 4.2 (range 3-6) months. Conclusions: We present the largest single institution cohort of patients with ESRD and lung cancer treated with chemotherapy. Our experience confirms a grave prognosis and suggests that administration of systemic chemotherapy in these patients is feasible with close monitoring for adverse events, proper dosing of chemotherapy and timing with hemodialysis. The decision to treat must be balanced with toxicity risk. Chemotherapy regimens used at Mayo Clinic in patients with lung cancer. Age, Histology/stage Chemotherapy Dose/Duration 78, SCLC / limited Carboplatin# 225 mg/m2 D1 and Etoposide* 75 mg/ m2 D1 & D3 / 1 cycle 72, Mixed adenocarci noma / IV Paclitaxel* 150 mg/m2 D1 and carboplatin# (AUC of 5) D1 / 5 cycles 51, SCLC / extensive Cyclophosphamide^ 675 mg/m2 D1, vincristine* 1 mg D1 and doxorubicin& 22 mg/m2 D1 / 2 cycles followed by oral etoposide* 50mg twice daily x 1 month 67, Adenocarcinoma / IIIB Paclitaxel* 200 mg/m2 D1, Carboplatin# 150mg/m2 D1/ 2 cycles 40,SCLC / extensive Carboplatin# 150 mg/m2 D1 etoposide* 50 mg/m2 D1-D3 / 6 cycles 67,adenocarcinoma / IIIB Erlotinib* 150mg every 48 hour # start HD 2 hours post dose, * before or after HD, ^ start HD 6-12 hours post dose, $ before HD or on non-HD day, HD : hemodialysis
Preference for risk reducing surgery among <i>BRCA1/2</i> mutation carriers in an Asian tertiary cancer center.
Authors: Samuel Guan Wei Ow, Sai Meng Tham, Pei-Yi Ong, Soo-Chin Lee
Journal: Journal of Clinical Oncology (2018)

e13535 Background: Prophylactic Mastectomy (PM) and Bilateral Salpingo-Oophrectomy (BSO) reduces Breast Cancer (BC) and Ovarian Cancer (OC) risk in BRCA1/2 Mutation Carriers (MC), with uptake rates of 46-86% reported in the Western population. However, preferences for Risk Reducing Surgery (RRS) among MC in Asia are not well understood. Methods: 129 BRCA1/2 MC were diagnosed in our Cancer (CA) Genetics Clinic from 2001-2017, for which 112 had available case records for review. Clinical characteristics were analyzed. Results: Of 112 MC, 92.0% were female, 54.2% Chinese, 57.1% BRCA1 carriers, and median age at gene test 47y (18-77). 87/112 (78.6%) had CA diagnosed prior to testing at median age of 43y (25-72) that were predominantly BC (64.4%; 42.3% triple negative) and OC (31.0%; 93.8% high grade serous). 18/87 (20.7%) had > 1 CA, 37.9% young-onset CA (≤40y), 8.0% BC & OC, 6.3% bilateral BC and 3.4% male BC. 77/112 (68.8%) were assessed to potentially benefit from RRS and counseled on this option, with 34/77 (44.2%) undergoing RRS. 23/70 (32.9%) patients eligible for PM did so at median age 42y (30-57) and at median of 5 months (1-62) from gene test. 28/63 (44.4%) patients eligible for BSO did so at median age of 43y (31-57) and at median of 5 months (1-160) from gene test. 18/77 (23.4%) underwent both PM and BSO. PM was more common among MC with prior BC (48.8% vs 10.3%, p < 0.01), while BSO was more common among MC age > 35y (51.0% vs 16.7%, p = 0.03) or with prior BC (53.5% vs 25.0%, p = 0.03). Among 19 female CA-free MC (median age 35, range 18-58), one-third underwent RRS (1 PM, 3 BSO and 2 both) with no new CA detected. New-onset BC was detected in 2/45 (4.3%) MC who chose surveillance and 0/23 (0%) who underwent PM (p = NS). Of 63 BSO-eligible MC, new-onset CA was diagnosed in 1/35 (1 OC, 2.9%) MC who chose surveillance and 2/28 (1 BC & 1 primary peritoneal CA, 7.1%) MC who underwent BSO (p = NS). Conclusions: Less than half of BRCA1/2 MC chose RRS in this predominantly Asian cohort, with PM and BSO more commonly taken up by those with prior BC. Further studies into knowledge, attitudes and preferences are warranted to understand and personalize their cancer prevention strategy.
Randomized phase II trial of S-1 plus cisplatin or docetaxel plus cisplatin with concurrent thoracic radiotherapy for inoperable stage III non-small cell lung cancer (TORG1018).
Authors: Kaoru Kubota, Tsuneo Shimokawa, Kazuhiko Yamada, Hiroshi Tanaka, Kazuma Kishi, Haruhiro Saito, Yuichi Takiguchi, Yukio Hosomi, Terufumi Kato, Naoyuki Nogami, Takeharu Yamanaka, Noriyuki Masuda, Koshiro Watanabe
Journal: Journal of Clinical Oncology (2017)

8534 Background: Concurrent chemoradiotherapy (CCRT) is standard of care in patients with inoperable stage III non-small cell lung cancer (NSCLC), however the best chemotherapy regimen has not been identified. The study was conducted to evaluate cisplatin plus S-1 (SP) or cisplatin plus docetaxel (DP) both with concurrent thoracic radiotherapy in patients with inoperable stage III NSCLC. Methods: Patients with inoperable stage III NSCLC were randomized to SP (S-1 40 mg/m 2 twice a day on days 1-14 and 29-42 plus cisplatin 60 mg/m 2 on days 1 and 29) or DP (docetaxel 50 mg/m 2 and cisplatin 80 mg/m 2 on days 1 and 29), stratified by institution, gender, histology, and stage. In both arms, concurrent radiotherapy began on day 1 (60 Gy/30 fr). After CCRT, patients in each group received two additional cycles of the consolidation chemotherapy. Primary endpoint was 2-year overall survival (OS), and secondary endpoints were OS, progression-free survival (PFS), toxicity profile, dose intensity and objective response rate (ORR). Results: From May 2011 to August 2014, 110 patients were enrolled from 19 institutions. Four patients (one in SP and 3 in DP) were ineligible, and 106 patients (53 in each arm) were evaluable for efficacy and safety. Patient characteristics were: male/female 83/23; median age 65 (range 42-74); performance status 0/1 59/47; IIIA/IIIB 59/47. With a median follow-up of 39.3 months, 2-year survival and median OS were 79% (95% CI: 66-88%) and 55.2 months in the SP arm and 69% (95% CI: 55-80%) and 50.8 months in the DP arm, respectively. ORR and median PFS in SP arm were 71.7% and 11.6 months, and ones in the DP arm were 67.9% and 19.9 months. Grade 3/4 leukopenia (62.3/34.0%) and neutropenia (56.6/28.3%) were significantly more frequent in DP arm than SP arm. Incidences of non-hematological toxicities including febrile neutropenia, anorexia, nausea, diarrhea, radiation pneumonitis and esophagitis tended to be higher in DP arm. No treatment-related death occurred. Conclusions: The 2-year OS favored for SP arm with less toxicity. We choose SP with concurrent thoracic radiotherapy as a future reference regimen. Clinical trial information: UMIN000005993.