tbuckley/cabot-search huggingface dataset:
Impact of treatment sequence on the outcomes of metastatic castration resistant prostate cancer patients (mCRPC) with germline BRCA2 mutations: A subanalysis of the PROREPAIR-B study.
Authors: Nuria Romero-Laorden, Elena Castro, Ana Medina, David Lorente, Enrique González-Billalabeitia, María José Méndez-Vidal, Aranzazu Gonzalez del Alba, Rebeca Lozano, Pablo Borrega, Eva Fernandez Parra, M Isabel Sáez, Iciar Garcia Carbonero, Alejo Rodriguez Vida, Rafael Morales Barrera, Angela del Pozo, Colin Pritchard, Pablo Lapunzina, Jose Maria Piulats Rodriguez, Javier Puente, David Olmos
Journal: Journal of Clinical Oncology (2018)

5071 Background: Germline mutations in BRCA2 have been identified in 3-5% of mCRPC patients. PROREPAIR-B (Castro et al ESMO 2017) is the first prospective study to report a worse survival from mCRPC associated to these mutations. Significant interactions between treatment-type (androgen signaling inhibitors:ASI/Taxane) and BRCA2 status for cause-specific survival (CSS) from 1st line (1L; p = 0.015) and 2nd line (2L; p = 0.006) were identified. In this exploratory subanalysis, we report mCRPC outcomes according to BRCA2 status and treatment sequence. Methods: PROREPAIR-B (NCT03075735) is a prospective multicentre observational cohort study. Patients who were taxane- and ASI-naïve at time of mCRPC, and who were treated or intended to treat with any of these two sequences: a) 1L ASI, 2L taxane; or b) 1L taxane; 2L ASI were elegible. Enpoints: assessment of the impact of BRCA2 on CSS, PFS from 1L initiation to clinical/radiological progression on 2L or death (PFS2). Analyses were stratified according to treatment sequence. Results: 348 out of 419 patients were eligible: 190 (7 BRCA2) for the ASI-taxane and 158 (7 BRCA2) for the taxane-ASI sequence. Patients in the taxane-ASI cohort were significantly younger (p < 0.001) and have worse ECOG (p = 0.002), higher PSA (p = 0.007), elevated LDH (p < 0.001) and elevated ALP (p = 0.01) compared to the ASI-taxane group, but there were not significant differences between BRCA2 patients in both groups. No significant differences in outcomes between BRCA2 carriers and non-carriers were observed with the ASI-Taxane sequence: CSS (median 24.0 vs 31.1 months, p = 0.9) and PFS2 (18.9 vs 21.1 months, p = 0.6). Conversely, in the taxane-ASI sequence BRCA2 status was associated to significantly worse CSS (10.7 vs 28.4 m, p < 0.001) and PFS2 (8.6 vs 17.1 m; p < 0.001). In the multivariable analyses BRCA2 remained an independent prognostic factor for CSS (HR 2.95; CI95% 1.21-7.15) and PFS2 (HR 5.50; CI95% 2.35-12.89). Conclusions: These results suggest that the outcomes of BRCA2 mutation carriers may differ according to treatment sequences. This contributes to explain the differences in outcomes reported by previous series. Clinical trial information: NCT03075735.
Down-regulation of neutral sphingomyelinase 1 to predict prognosis in hepatocellular carcinoma.
Authors: Minglin Lin, Weijia Liao, Junfei Jin
Journal: Journal of Clinical Oncology (2017)

e15647 Background:Neutral sphingomyelinase 1 (NSMase1) catalyzes sphingomyelin to generate ceramide and mediates tumor cell apoptosis; however, the roles of NSMase1 in hepatocellular carcinoma (HCC) remain unclear. This study aims to evaluate the clinical value and prognostic significance of NSMase1 in HCC. Methods:A total of 142 patients who underwent radical hepatectomy were involved in this study. The expression of NSMase1 in HCC tissues and adjacent nontumorous liver tissues (ANLTs) was detected by quantitative real-time polymerase chain reaction and immunohistochemistry, and the association between NSMase1 expression and clinicopathologic features as well as prognosis of HCC patients was analyzed. Univariate and multivariate analyses were applied to identify independent prognostic factors. Results: NSMase1, at both mRNA and protein levels, was significantly decreased in HCC tissues compared to ANLTs. Low NSMase1 expression was associated with tumor size ( P= 0.029), TNM stage ( P= 0.040) and recurrence ( P= 0.006). Statistically, both the overall survival (OS) and disease-free survival (DFS) of low NSMase1 expression group were significantly shorter compared with high NSMase1 expression group ( p= 0.001; p= 0.001; respectively). Remarkably, the multivariate analysis showed that the low NSMase1 expression was an independent prognostic factor for OS (hazard ratio = 1.840; 95% confidence interval, 1.178-2.875, P= 0.007) and DFS (hazard ratio = 1.706; 95% confidence interval, 1.096-2.655, P= 0.018) in all enrolled HCC patients. Conclusions: NSMase1 down-regulation might actually serve as an independent prognostic factor for HCC patients. However, the roles of “NSMase1-ceramide” metabolic network in HCC deserve further studies.
TCT-286 Novel Approach for Treatment of Aortic Stent Graft Endoleak: a Preclinical Feasibility Study of Catheter-Delivered Expandable Foam
Authors: Gilberto Melnick, Marco Ferrone, Nicolas Isaza, Genghua Yi, Yanping Cheng, Jeffrey Carpenter, Duncan Maitland, Todd Landsman, Juan Granada, Grzegorz Kaluza
Journal: Journal of the American College of Cardiology (2018)
Acalabrutinib alone or in combination with rituximab (R) in follicular lymphoma (FL).
Authors: Nathan Hale Fowler, Morton Coleman, Don A. Stevens, Sonali M. Smith, Parameswaran Venugopal, Peter Martin, Tycel Jovelle Phillips, Richy Agajanian, Deborah Marie Stephens, Raquel Izumi, Jean Cheung, J. Greg Slatter, Ming Yin, Minoti Hiremath, Naomi N. H. Hunder, Beth Christian
Journal: Journal of Clinical Oncology (2018)

7549 Background: Bruton tyrosine kinase (BTK) inhibition has shown clinical benefit in FL. Acalabrutinib is a highly selective, potent, covalent inhibitor of BTK. We evaluated acalabrutinib ± R in a Phase 1b study of patients (pts) with treatment-naive (TN) or relapsed/refractory (R/R) FL. Methods: Pts with R/R FL (≥1 prior treatment) were randomized to acalabrutinib (mono) or acalabrutinib + R (combo); TN pts received the combo. In 28-day cycles, R (375 mg/m2 IV) was given weekly in Cycle 1 and on Day 1 of Cycles 2-6; acalabrutinib (100 mg PO bid [2 pts received 200 mg qd]) was given until progressive disease (PD) or intolerance. The primary endpoint was safety. Secondary endpoints included overall response rate (ORR), duration of response (DOR), pharmacokinetics (PK) and pharmacodynamics. Results: Thirteen TN and 27 R/R pts were treated. In all pts, the median age was 66 years (range 32-83), 98% of pts had ECOG PS ≤1, and 88% had stage III/IV disease. R/R pts received a median of 2 prior therapies (range 1-5). At a median follow-up of 22 and 7.6 months, 62% of TN and 26% of R/R pts, respectively, were still on treatment. Discontinuations were primarily due to PD (TN 15%; R/R 56%) and adverse events (AEs; TN 8%; R/R 11%). BTK occupancy and PK parameters were consistent with previous acalabrutinib studies. In all pts, common AEs (any grade) were fatigue (48%), headache (43%), diarrhea (40%), nausea (30%) and sinusitis (25%). Common Gr 3/4 AEs were hypertension (8%), increased alanine aminotransferase, increased aspartate aminotransferase, and cellulitis (all 5%), with no Gr 5 events. There were no cases of atrial fibrillation or Gr ≥3 hemorrhage. Efficacy outcomes are reported in the table. Conclusions: Acalabrutinib, alone and combined with R, was well-tolerated and yielded promising response rates in FL. These results support further evaluation of acalabrutinib in FL. Clinical trial information: NCT02180711. TN combo (n = 13) R/R combo (n = 13) R/R mono (n = 12)a ORRb (≥ partial response), n (%) 12 (92) 5 (39) 4 (33) 95% CI 64, 100 14, 68 10, 65 Complete response 4 (31) 1 (8) 1 (8) Median DOR, mo NR NR NR Rangec 12.1 to 20.5+ 10.8+ to 20.5+ 0.03+ to 18.7+ NR: not reached. a Pts dosed at 200 mg qd not included (1 SD, 1 PD). b Investigator assessed using Cheson 2014 criteria. c “+” indicates ongoing response.
Multimodality treatment of 132 consecutive patients with locally advanced pancreatic cancer.
Authors: Jantien A. Vogel, Thijs de Rooij, Krijn P van Lienden, Johanna W Wilmink, Hanneke W van Laarhoven, Jeanin E van Hooft, Otto M van Delden, Marcel G Dijkgraaf, Robert C. G. Martin, Olivier R.C. Busch, Marc G Besselink
Journal: Journal of Clinical Oncology (2016)

e15738 Background: FOLFIRINOX and irreversible electroporation(IRE) show promising results for locally advanced pancreatic cancer(LAPC). However, most studies only include patients with stable disease under chemotherapy. Our aim was to describe outcomes of multimodality treatment with FOLFIRINOX-chemotherapy, surgical exploration and IRE in a complete LAPC-cohort. Methods: Prospective single-center cohort (09.2013-03.2015), including all consecutive histologically proven LAPC-patients ( > 90°arterial or > 270°venous involvement). Preferred chemotherapy consisted of FOLFIRINOX, or, if unfeasible, gemcitabine. Radiotherapy was only used for local pain control. After three months, restaging was performed to assess RECIST1.1-response, radiological resectability and IRE-eligibility (tumor ≤ 5cm). All patients with non-progressive disease (RECIST) and IRE-eligible tumors underwent explorative laparotomy. Results: Of 132 patients with LAPC, 70% (n = 93) received chemotherapy (63% (n = 59) FOLFIRINOX). After 3 months, 45% (n = 59/132) had non-progressive disease. Of all 132 patients, 27% (n = 36) underwent surgical exploration with a resection in 11% (n = 14/132, R0 8/14) and IRE in 11% (n = 15/132). After surgical exploration, the Clavien-Dindo grade ≥ 3 complication rate was 39% (6/14 resection, 7/15 IRE, 1/7 other) and 90-day mortality 11% (1/14 resection, 2/15 IRE, 1/7 other). Median overall survival (mOS) and 1-year cumulative survival from diagnosis were 11 months and 43% respectively for all patients, 19 months and 71% for patients with non-progressive disease, 23 months and 82% in resected patients, and 16 months and 71% in IRE patients, with a median follow up of 10 months. Conclusions: A multimodality approach to LAPC is feasible with acceptable outcomes, especially in patients receiving FOLFIRINOX. This study highlights the importance of reporting on the outcomes of consecutive rather than selected cohorts of LAPC. Final survival data will have to be awaited before the added value of IRE can be evaluated. Clinical trial information: NTR4230.
Prevalence of high-risk human papillomaviruses and abnormal PAP smears among women visiting gynaecological outpatient units in Kazakhstan: A cross sectional study.
Authors: Dilyara Kaidarova, Murat Kairbayev, Hong Kim, Byoung-Don Han, Ismailov Sanzhar, Azat Shibanova, Yerlan Kukubassov, Rash Shalbayeva, Zhanar Yeleubayeva, Raikhan Bolatbekova, Han Jeong Park, Hye Jeong Kim
Journal: Journal of Clinical Oncology (2018)

e13596 Background: Cervical cancer is the second most common type of gynecological cancer worldwide. Nearly all cases are associated with high-risk human papillomaviruses (hrHPV). Data on the epidemiology of HPV in Kazakhstan and Central Asia are limited. Our study was carried out to determine the prevalence of hrHPV and abnormal pap results associated with HPV positivity in women attending gynecological outpatient units. Methods: We prospectively recruited 1,800 women at gynecology outpatient units in four large regions of Kazakhstan in 2015. Study participants did not have a known history of HPV infection. Co-testing for pap smear and a short survey obtained in all cases. Final analyses included 1,730 cases. 70 cases were excluded due to missing data. The HPV test samples were screened in South Korea with DNA Chip test with hrHPV genotyping in all positive cases. Pap smears reviewed at cytology laboratory at the Institute of Oncology, Kazakhstan. Results: The mean age of the study group was 40.0±9.8 years (range 18-65 years. Prevalence of HPV was 27.8% (481 cases) and cytology abnormalities were present in 40.5% (702 cases). HPV infection found more often in young women under the age of 25 (46.4%, p < 0.01). ASCUS was also more commonly reported in this age group (p = 0.029). HrHPV prevalence in women aged 25 to 35 yeas and higher varied between 25.7% to 28.3% and had no statistical difference. The pap-test results were in opposite to HPV prevalence whereas severity of abnormalities increased with age. LSIL in the age group of 46-55 years was more common than in 56 years and older population and represented 7.8% and 8.3% respectively (p < 0.05). The HSIL diagnosed more often in women above 56 years and accounted for 2.5%.. One case of cervical cancer was found in all study population. Conclusions: For our best knowledge this is the largest study focusing on hrHPV prevalence and abnormal cytology in Kazakhstani women. Our results are in accordance with other related data from similar studies. Data suggest benefit of targeting cytology based screening for women under 30 years of age and HPV based screening for older women population instead of “one size fits all” approach.
Phase 2 study of pembrolizumab in advanced small-cell lung cancer (SCLC): KEYNOTE-158.
Authors: Hyun Cheol Chung, Jose A. Lopez-Martin, Stephen Chuan-Hao Kao, Wilson H. Miller, Willeke Ros, Bo Gao, Aurelien Marabelle, Maya Gottfried, Alona Zer, Jean-Pierre Delord, Nicolas Penel, Shadia Ibrahim Jalal, Lei Xu, Susan Zeigenfuss, Scott K. Pruitt, Sarina Anne Piha-Paul
Journal: Journal of Clinical Oncology (2018)

8506 Background: The antitumor activity of pembrolizumab, an IgG4 anti-PD-1 monoclonal antibody, was evaluated in patients (pts) with SCLC in KEYNOTE-158 (NCT02628067), a phase 2 basket study of 11 cancer types. Methods: Enrolled pts were aged ≥18 y with advanced SCLC; had measurable disease per RECIST v1.1; ECOG PS ≤1; incurable disease with prior failure of, progression on, or intolerance to standard therapy; and evaluable tumor samples for PD-L1 (PD-L1 IHC 22C3 pharmDx assay [Agilent Technologies]) and other biomarkers. Pembrolizumab 200 mg Q3W was administered for 2 y or until disease progression or intolerable toxicity. The primary endpoint was ORR. DOR, PFS, and OS were secondary endpoints and were estimated by the Kaplan-Meier method. Tumor imaging was performed every 9 wks for the first year, then every 12 wks. Response was assessed per RECIST v1.1 by independent central radiologic review. PD-L1–positive was defined as PD-L1 combined positive score ≥1. Results: Among 107 SCLC pts, median age was 63 y (range, 24–84) and 85 (79%) had 1–2 prior therapies. At the data cutoff date (Aug 23, 2017), 36 pts (34%) were continuing on-study; median follow-up was 10.1 mo (range, 0.5–17.5). Tumors were PD-L1–positive in 42 pts (39%) and PD-L1–negative in 50 (47%); 0 had microsatellite instability-high (MSI-H) tumors and 83 (78%) had microsatellite-stable (MSS) tumors. ORR was 18.7% (20/107; 95% CI, 11.8–27.4) overall, 35.7% (15/42; 95% CI, 21.6–52.0) in pts with PD-L1–positive tumors, and 6.0% (3/50; 95% CI, 1.3–16.5) in pts with PD-L1–negative tumors. Overall, median DOR had not been reached (range, 2.1+ to 13.2+ mo); 12 pts (77%) had DOR ≥9 mo. Median PFS was 2.0 mo (95% CI, 1.9–2.1) in all pts, 2.1 mo (95% CI, 2.0–9.9) in pts with PD-L1–positive tumors, and 1.9 mo (95% CI, 1.6–2.0) in pts with PD-L1–negative tumors. Median OS was 9.1 mo (95% CI, 5.7–14.6) overall, 14.6 mo (5.6–not estimable) in pts with PD-L1–positive tumors, and 7.7 mo (95% CI, 3.9–10.4) in pts with PD-L1–negative tumors. Treatment-related AEs occurred in 63 pts (59%) and led to 4 discontinuations and 1 death (pneumonia). Conclusions: Pembrolizumab has shown promising antitumor activity and durable responses in advanced SCLC, especially in pts with PD-L1–positive tumors. Clinical trial information: NCT02628067.
Preclinical in vitro and in vivo evaluation of antitumor activity of UD-017, a novel selective and orally available CDK7 inhibitor, in colorectal cancer.
Authors: Sayaka Ogi, Yasuhiro Aga, Kazuhiro Onuma, Hidetoshi Sunamoto, Takashi Matsushita, Ayumi Ogawa, Tohru Hasegawa, Shigeyuki Kono, Noriaki Iwase, Yasunori Tokunaga, Shigeru Ushiyama
Journal: Journal of Clinical Oncology (2017)

e14085 Background: Cyclin dependent kinase 7 (CDK7) is an attractive target for cancer drugs due to its dual roles, cell cycle regulation and gene transcription/RNA procession. We synthesized UD-017, a small molecule, highly selective CDK7 inhibitor with a novel chemotype. In this study, we characterize antitumor activity of UD-017 in vitro and in vivo, and try to elucidate underlying mechanisms by which CDK7 inhibition contributes to the antitumor efficacy in colorectal cancer cells. Methods: We examined CDK7 selectivity of UD-017 against the other CDKs and kinases. We evaluated the antitumor activity in a variety of human cancer cell lines including colorectal cancer cells. We investigated the mechanism of antitumor activity of UD-017 using a human colorectal cancer cell line, HCT-116. In vivo antitumor efficacy of UD-017 was assessed in HCT-116 xenograft models and patient derived xenograft (PDX) model. Results:UD-017 inhibited CDK7 enzyme (IC 50 = 16 nM), which is at least 300-fold more selective against other CDKs. In a panel of 313 kinases assay, UD-017 inhibited CDK7 almost mono-specifically. UD-017 potently inhibited the growth of human cancer cells including the patient-derived colorectal cancer cells.In the mechanism study, UD-017 inhibited phosphorylation of CDK1, 2 and retinoblastoma, which was followed by cell-cycle arrest. Inhibition of both RNA polymerase II phosphorylation and c-Myc expression was observed followed by apoptosis induction. HCT-116 xenograft model and PDX model demonstrated the potent antitumor activity of UD-017 with dose-dependence by daily oral administration for 2 weeks. Furthermore, UD-017 showed the combination effect with 5-FU without further affecting the side effects of the chemotherapy. Conclusions:UD-017 is a potent and highly selective CDK7 inhibitor, and significantly inhibits the growth of human cancer cell lines with cell-cycle arrest and apoptosis induction. UD-017 showed potent and dose-dependent antitumor response in the HCT-116 xenograft model and PDX model. Further investigation towards clinical development is warranted.
Clinical predictors of second-line chemotherapy (ChT) benefit in pancreatic cancer (PC).
Authors: Ilya Pokataev, Igor Bazin, Mikhail Fedyanin, Alexey Tryakin, Anna Popova, Alexey Rumyantsev, Olga Sekhina, Yury Patutko, Igor Fainstein, Sergei Tjulandin
Journal: Journal of Clinical Oncology (2017)

e15733 Background: Second line ChT is shown to improve outcome in selected patients with PC; however there are no approved models predicting its benefit. This retrospective study was aimed to evaluate prognostic factors in patients with PC who had disease progression following 1st line ChT and their value in prediction of 2nd line ChT benefit. Methods: Records of PC patients treated in N.N. Blokhin Russian Cancer Research Center since 2000 to 2015 were analyzed. Inclusion criteria for this retrospective analysis were: morphologically confirmed PC, disease progression after 1st line ChT or adjuvant / induction ChT with ChT-free interval &lt;6 months. The most common clinical factors were evaluated for prognostic significance in the Cox proportional hazards model with overall survival (OS) as the end-point. OS was calculated from the date of progression following previous ChT. Cutoff values for quantitative variables were determined using ROC curve analyses. Results: Records of 172 patients matched the inclusion criteria. Second line ChT was administered in 110 (64%) patients (47% of them received gemcitabine- and/or platinum-based doublets). The Cox multivariate analysis identified two independent prognostic factors: Karnofsky performance status (KPS) ≤70% and neutrophil-to-lymphocyte ratio (NLR) &gt;5 at the time of disease progression after 1st line ChT (Table). Administration of 2nd line ChT improved outcome of patients with favorable prognosis (score ≤1): median OS increased from 1.7 to 5.5 months in groups without (n=23) and with (n=90) ChT, respectively (p=0.02). In patients with poor prognosis (score&gt;1) there were no benefit by administration of 2nd line ChT: medians OS were 2.3 and 1.7 months in groups with (n=20) and without (n=39) ChT, respectively (p=0.23). Conclusions: This novel prognostic model can potentially predict 2nd line ChT benefit in patients with PC, however it needs to be validated in further trials. [Table: see text]
Multifocality and Hashimoto’s thyroiditis as independent predictors of structural recurrence in a cohort of low risk intrathyroidal papillary thyroid cancer.
Authors: Luciano Pezzullo, Vincenzo Marotta, Maria Grazia Chiofalo, Claudio Gambardella, Claudio Bellevicine, Marica Grasso, Giovanni Conzo, Giovanni Docimo, Giancarlo Troncone, Concetta Sciammarella, Annamaria Colao, Antongiulio Faggiano
Journal: Journal of Clinical Oncology (2017)

e17577 Background: Increasing incidence of thyroid malignancies is almost totally attributable to papillary thyroid cancer (PTC). Although all disease stages are involved, PTCs confined to the thyroid were those with the higher trend. The absence of dedicated randomized controlled trials makes challenging the management of these low risk PTC at different steps of the therapeutic process (extent of surgery, prophylactic central node dissection, and radio-iodine treatment). Thus, it is mandatory to set a prognostic system suitable for this clinical setting. We analyzed prognostic factors of structural recurrence in a large cohort of consecutive low-risk intra-thyroidal PTC. Methods: Multicenter retrospective study including pT1/2 PTC without any evidence of extra-thyroidal disease. The following parameters were considered: gender, age at diagnosis, histology, tumour size, multifocality, pathologically-proven Hashimoto’s thyroiditis (HT), and radiometabolic treatment (RAI). The parameters significantly associated with structural recurrence at the univariate analysis ( p &lt; 0.05) were included in the multivariate analysis. Results: We included 284 patients (mean follow-up 6.3 yrs). At univariate analysis, parameters achieving significance were: age at diagnosis ≥ 45 yrs (p = 0.001, OR 0.04, 95% CI 0-0.72), microcarcinoma (p &lt; 0.001, OR 0.02, 95% CI 0-0.39), multifocality (p &lt; 0.001, OR 4.3, 95% CI 1.88-9.84), HT (p = 0.018, OR 0.33, 95% CI 0.13-0.86), and RAI (p = 0.002, OR 19.43, 95% CI 1.16-323.3). At multivariate analysis, only multifocality (p = 0.042, OR 2.52, 95% CI 1.03-6.16) and HT (p = 0.036, OR 0.34, 95% CI 0.12-0.93) revealed as independent prognosticators. Conclusions: Our data show that multifocality and HT should be considered as the main parameters for the decision-making of low risk PTC. Further studies are required. Note: We acknowledge Umberto Veronesi Foundation for granting Vincenzo Marotta with Post-doctoral Fellowship year-2017 Award.