tbuckley/cabot-search huggingface dataset:
Efficacy and prognostic factors for y-90 radioembolization (Y-90) in metastatic neuroendocrine tumors with liver metastases.
Authors: Erica S Tsang, Jonathan M. Loree, Janine Marie Davies, Sharlene Gill, David Liu, Stephen Ho, Hagen F. Kennecke
Journal: Journal of Clinical Oncology (2018)

e16180 Background: Y-90 can be an effective liver-directed therapy for patients with metastatic neuroendocrine neoplasms (NETs), but population-based data is limited regarding use and efficacy. We characterized the use of Y-90 in NET patients and identified factors associated with response. Methods: Sequential patients with metastatic liver-dominant NETs across 6 treatment centres received Y-90 between June 2011 and January 2017 in British Columbia, Canada. Baseline characteristics, radiographic response (RECIST 1.1), and outcomes were summarized. Results: 47 patients received Y-90, with a median age of 56.0 y (range 21-78). 47% were male, and) and 96% had ECOG 0-1. NET primary location included pancreas (32%), small bowel (38%), large bowel (6%), unknown primary (15%), and other (9%). 70% had liver metastases alone, and tumors were graded as G1 (62%), G2 (23%), G3 (2%), and unknown (13%). Prior therapies included surgical resection of primary (66%), other local therapy (26%), somatostatin analogue (SSA; 68%), and systemic therapy (36%). Median Y-90 dose was 2.2 GBq (range 0.8-3.6), delivered as Sirspheres (68%) and Theraspheres (30%). Median time to Y-90 from diagnosis of metastases measured 1.6y. Most patients received segmental Y-90 (92%), with 1 (66%), 2 (32%), and 3 (2%) treatments. Y-90 therapy resulted in partial response (53%), stable (34%), and progressive disease (13%). Y-90 was well tolerated, with infrequent grade 3-4 biochemical toxicities (2%) and grade 3 abdominal pain (6%). On multivariate logistic regression (backwards elimination), older age and extrahepatic metastases were associated with response (Table). Tumor grade, hepatic tumor burden and number of Y-90 treatments did not affect response. Median overall survival from Y-90 was 27.6 months (95% CI 8.4-46.8). Conclusions: In our population-based cohort, Y-90 was well tolerated in patients with metastatic liver-dominant NETs. Extrahepatic metastases and age were associated with radiographic response. OR (95% CI) P value Age (≥ 70 vs. < 70 years) 14.8 (1.2-182.3) 0.04 Extrahepatic metastases 8.9 (1.2-63.3) 0.03 Baseline CgA (≥ vs. < ULN) 0.2 (0.02-1.2) 0.16 Previous systemic therapy (not SSA) 6.0 (0.98-36.1) 0.05
A randomized, double-blind, placebo-controlled, phase II study to assess the efficacy and safety of farletuzumab (MORAb-003) in combination with carboplatin plus either paclitaxel or pegylated liposomal doxorubicin (PLD) in subjects with low CA125 platinum-sensitive ovarian cancer.
Authors: Thomas J. Herzog, Sharad A. Ghamande, Hani Gabra, Deborah Kay Armstrong, Keiichi Fujiwara, Bradley J. Monk, Sandro Pignata, Antonio Gonzalez-Martin, Jalid Sehouli, Charles Schweizer, Susan Weil, Kimberly Hoffman, Luigi Grasso, Robert L. Coleman, Ignace Vergote
Journal: Journal of Clinical Oncology (2016)

TPS5608 Background: Farletuzumab (FAR) is a humanized monoclonal antibody that binds to folate receptor-alpha which is highly expressed in epithelial ovarian cancer (EOC) and largely absent from normal tissue. FAR potentially has anti-tumor activity via antibody dependent cell cytotoxicity (ADCC) and complement-dependent cytotoxicity. A completed Phase 3 trial studied 1100 EOC subjects treated with carboplatin plus paclitaxel or docetaxel randomized in combination equally to three arms to placebo, FAR 1.25 or 2.5 mg/kg. Neither FAR dose met the study's primary PFS endpoint. Prespecified subgroup analyses demonstrated that subjects with CA-125 ≤ 3×ULN and subjects with higher FAR exposure showed superior PFS and OS compared to placebo (JCO 2016, in press). CA125 is also implicated in the inhibition of target cell killing via ADCC by suppressing natural killer cell function, therefore higher CA125 levels may disrupt a potential FAR-mediated immune response. Based on the Phase 3 study results, a follow-on Phase 2 study in low CA125 EOC subjects using a modified FAR dosing regimen has been initiated. Methods: This global, randomized, placebo-controlled, phase 2 study (MORAb-003-011 / ENGOT-ov27 / BGOG-ov18; Clinical Trial Registry NCT02289950) will enroll approximately 210 subjects with high-grade serous EOC in platinum-sensitive first relapse. Eligible subjects must have evaluable disease and CA125 ≤ 3x ULN confirmed by central lab. Subjects will be treated at investigator discretion in a targeted 1:1 ratio to either carboplatin/paclitaxel or carboplatin/ PLD, and randomized in a 2:1 ratio to receive weekly FAR (10 mg/kg first 2 weeks followed by 5 mg/kg) or placebo. Upon completion of 6 cycles, subjects may continue on single test article maintenance until progression. Primary end point is PFS by RECIST (target HR of 0.667; 85% power; 1-sided type I error 0.10), with OS a key secondary. Thirty-four subjects are enrolled. Clinical trial information: NCT 022899950.
Endoscopic ablation for esophageal early squamous cell neoplasia – can we predict success and recurrence?
Authors: Rehan Haidry
Journal: Endoscopy (2018)

See also: Lessons from pathological analysis of recurrent early esophageal squamous cell neoplasia after complete endoscopic radiofrequency ablationEndoscopy eFirstDOI: 10.1055/s-0044-101352
Phase II trial of modified FOLIRI plus Panitumumab as first-line treatment in elderly patients with RAS wild-type metastatic colorectal cancer.
Authors: Athanasios Karampeazis, Lampros Vamvakas, Nikolaos K. Kentepozidis, Athanasios Kotsakis, Kostas Kalbakis, Spyros Xynogalos, Ioannis Sougklakos, Christos E. Emmanouilides, Alexandra Voutsina, Dora Hatzidaki, Vassilis Georgoulias
Journal: Journal of Clinical Oncology (2017)

e15053 Background:The role of combination chemotherapy plus anti-EGFR treatment in older patients with metastatic colorectal cancer (mCRC) is unclear. We conducted an open label phase II trial in order to evaluate the safety and efficacy of modified FOLFIRI plus panitumumab as first-line treatment in elderly patients with RAS wild-type mCRC. Methods: Patients ≥70 years old with unresectable all-RAS wild-type mCRC were treated with Panitumumab 6mg/kg as 60min iv infusion followed by Irinotecan 130mg/m 2 as 90min iv infusion, Leucovorin 400mg/m 2 as 2h iv infusion and 5-Fluorouracil 400mg/m 2 as bolus iv infusion on day 1 and 5-Fluorouracil 1.200 mg/m 2 as continuous iv infusion for 46h, every 2 weeks. Sample size calculation was based on the minimax Simon two-step design: The null hypothesis was that the overall response rate (ORR) is ≤ 30% versus the alternative hypothesis of ORR ≥ 50% (α = 0.05, power 80%). Results: Forty-six patients were enrolled in the study. Two patients did not receive treatment because they were RAS mutant. Median age for the 44 treated patients was 76 years (range 70-88). Males were 32 and the PS was 0, 1 and 2 in 25%, 70.5% and 4.5% of patients, respectively. Rectal cancer accounted for 25% while 15.9% of patients had the primary tumour in situ. Twenty-one partial responses were observed for an ORR of 47.7% (95%CI: 32.9%-62.5%) while seven patients (15.9%) had stable disease. After a median follow-up of 36.0 months, the median progression-free survival was 6.1 months (95%CI: 3.6-8.7) and the median overall survival was 20.9 months (95%CI: 11.7-30.1). Grade 3-4 neutropenia was recorded in 4 (9%) and grade 3-4 diarrhea in 9 (20.4%) patients while one patient had a grade 4 bowel perforation. One patient experienced grade 3 mucositis, two patients grade 3 skin toxicity and two patients grade 3 fatigue. There were no toxic deaths while one patient died due to bowel obstruction and one due to postoperative complications after removal of the primary tumor. Conclusions: The modified FOLFIRI plus panitumumab combination presented significant efficacy with manageable toxicity in elderly patients with mCRC.
Pomalidomide (POM) + low-dose dexamethasone (LoDEX) + daratumumab (DARA) in relapsed and/or refractory multiple myeloma (RRMM) after lenalidomide (LEN)-based treatment (Tx) failure.
Authors: David Samuel DiCapua Siegel, Gary J. Schiller, Christy Joy Samaras, Michael Sebag, Jesus G. Berdeja, Siddhartha Ganguly, Jeffrey Matous, Kevin W. Song, Christopher Seet, Giampaolo Talamo, Shanthi Srinivas, Mirelis Acosta-Rivera, Michael Bar, Donald Quick, Bertrand Marquess Anz, Gustavo Fonseca, Donna Ellen Reece, Faiza Zafar, Weiyuan Chung, Nizar J. Bahlis
Journal: Journal of Clinical Oncology (2018)

8027 Background: POM + LoDEX + DARA in RRMM was approved in the US based on a phase 1b trial in heavily pretreated patients (pts; ≥ 2 prior lines [median, 4]; ORR, 60%). Data on the use of this regimen in earlier lines of Tx and immediately after LEN-based Tx are limited. Thus, MM-014 (NCT01946477) cohort B was initiated in pts with first- or second-line LEN-based Tx failures immediately before study entry to assess outcomes with POM + LoDEX + DARA sequenced earlier in Tx. Methods: Pts with RRMM after 1 or 2 prior lines who received a LEN-based Tx immediately before study and had progressive disease (PD) were eligible. In 28-d cycles (c), pts received POM 4 mg/d on d 1-21 + LoDEX 40 mg/d (20 mg/d if aged > 75 yrs) on d 1, 8, 15, and 22, and DARA 16 mg/kg IV on DEX dosing days of c 1 and 2, then d 1 and 15 of c 3-6, then d 1 of c 7+. Thromboprophylaxis was mandatory. The primary objective was ORR by modified IMWG criteria. Results: A total of 46 pts were in the ITT population (median follow-up, 7.8 mos). 13 pts discontinued Tx (PD, 7; AEs, 2; other reasons, 4). Pts were refractory to (n = 36; 78%) or had relapsed after (n = 10; 22%) LEN-based Tx. Median duration of prior LEN-based Tx was 23.6 mos; 20 pts (43%) received LEN 25 mg/d in their last LEN-based Tx. ORR was 76.7% in efficacy-evaluable pts (n = 43), 72.2% in LEN-refractory pts, and 75.0% in pts who received LEN 25 mg/d in their last LEN-based Tx. Efficacy and safety are shown in the Table. At baseline, 10 pts (21.7%) had grade ≥ 2 neutropenia. There was 1 each of grade 3/4 pulmonary embolism and peripheral neuropathy. Any-grade infusion-related reactions occurred in 13 pts. Neutropenia (POM and DARA) and infusion-related reactions (DARA only) were primary reasons for dose interruptions. Conclusions: These results underscore the importance of POM-based Tx in RRMM after LEN. POM + LoDEX + DARA was safe, with promising activity when sequenced in earlier lines immediately after LEN-based Tx failure. Clinical trial information: NCT01946477.Efficacy and safety. Outcomes, % N = 46 ORR 71.7 CR 4.3 VGPR 21.7 PR 45.7 Minimal response 6.5 Clinical benefit 78.3 SD 8.7 PD 6.5 1-year PFS 76.9 Grade 3/4 TEAEs (occurring in ≥ 10%) Neutropenia 71.7 Thrombocytopenia 23.9 Anemia 17.4 Infection 28.3
Targeted next-generation DNA sequencing of paired tumor and normal DNA to reveal frequent actionable germline alterations.
Authors: Wolfgang Michael Korn, Iwei Yey, Jessica Van Ziffle, James P Grenert, Nancy Joseph, David A. Solomon, Megan Laurance, Eric Talevich, Courtney Onodera, Gregor Krings, Bradley A. Stohr, Amie Blanco, Boris C. Bastian
Journal: Journal of Clinical Oncology (2017)

11575 Background: Targeted next-generation DNA sequencing of paired tumor and normal DNA samples allows for detection of biologically relevant variants in the tumor with significantly greater accuracy than tumor-only sequencing. In addition, this approach presents with the opportunity of unveiling previously unknown cancer predisposition traits in a patient’s germline DNA. Methods: We sought to determine the rate of pathogenic germline alterations in 546 consecutive pediatric and adult patients who underwent molecular profiling using the UCSF 500 assay, a hybrid capture-based DNA sequencing assay targeting the coding regions of ~500 cancer-related genes, TERT promoter, select introns from 40 genes (for detection of gene fusions and other structural variants), and intergenic regions at regular intervals along each chromosome (for chromosomal copy number and LOH assessment). Results: Pathogenic germline alterations were found in 89/546 patients (16.3%), including 25 pediatric and 64 adult cases. Germline variants were identified in 37 genes with MUTYH (n = 15, 17%), CHEK2 (n = 10, 11%), BRCA2 (n = 9, 10%), BRCA1 (n = 5, 6%), TP53 (n = 5, 5%), and APC (n = 4, 5%) being altered most frequently. Loss of heterozygosity of genes affected in the germline was seen in tumor DNA 37 (42%) cases, highlighting their likely role as drivers of tumorigenesis. Clinically relevant germline findings not associated with increased cancer risk were identified in 6 (7%) of the cases, for example a COL1A1 mutation associated with Ehlers-Danlos Syndrome. In In 73 (82%) of the cases, pathogenic germline alterations were new findings and genetic counseling was recommended. A possible, previously unknown, role of germline mutations was found in some instances, including a TSC2 germline mutation in a patient with hybrid oncocytoma/chromophobe tumor (HOCT) with loss of the normal TSC2 allele in the tumor. Conclusions: Our data suggest that paired tumor/normal DNA analysis uncovers actionable heritable traits in a substantial fraction of patients and represents the preferred approach to analyzing malignancies in children and adults.
Malignant pleural mesothelioma (MPM): Outcome of 352 patients (pts) treated by a dedicated multidisciplinary team (MT) in the highly asbestos polluted area of Casale Monferrato, Piedmont (Italy).
Authors: Federica Grosso, Annalisa Roveta, Giulia Gallizzi, Alberto Muzio, Giacomo Taverna, Fausto Pernazza, Antonietta Aurelio, Silvia Zai, Roberta Libener, Stefano Barbero, Massimo D'angelo, Gabriele Ferretti, Paola Franzone, Margherita Girino, Maurizio Mancuso, Narciso Mariani, Gianmauro Numico, Massimo Pastormerlo, Ezio Piccolini, Daniela Degiovanni
Journal: Journal of Clinical Oncology (2016)

e20078 Background: MPM has dismal prognosis with median overall survival (OS) of 12 months. Pts treated in referral centres perform better. Since 2009 in the highly asbestos polluted area of Casale Monferrato, a MT has been created between the Community Hospital and the General Hospital in Alessandria. Consecutive unselected pts data was prospectively registered in a data base (DBmeso). We here describe the series of pts treated by the MT and report on their outcomes. Methods: Data was retrieved by DBmeso and analyzed with MedCalc Statistical Software version 16.1. Results: Since 2009/1 to 2015/11, 352 pts (114 female, 238 male), median age 70 (IQR 63-77) have been treated by the MT. Pts characteristics were: asbestos exposure professional in 141 (40%), domestic in 14 (4%), environmental in 197 (56%); PS 0 in 281 (80%), 1 in 53 (15%) and ³ 2 in 18 (5%); epithelioid histology in 260 pts (74%), biphasic in 47 (13%) and sarcomatoid in 44 (13%), stage I-II in 142 pts (40%) and III-IV in 202 (60%). Due to advanced age and/or comorbidities, 70 pts (20%) received supportive care only. Pemetrexed + platinum derivatives (PP) was administered to 240 pts (68%), pemetrexed (Pem) alone to 29 (8%), other chemotherapies to 13 (4%). Overall 105 pts (30%) participated to clinical trials. Surgery was performed in 43 pts (12%): P/D in 31 and EPP in 12 pts. Palliative RT was delivered to 55 pts (16%). Second and third line chemotherapy were performed in 140 (77%) and 76 (27%) pts, respectively. With a median follow up of 29.5 months, OS for the entire population was 15.2 (CI95% 13.4-17.5) months, 18.4 (CI95% 15.8-20.2) for pts receiving PP, 9.3 (CI95% 5.8-13) for Pem and 8.5 (range 6.8-12) for those receiving BSC only. Conclusions: The outcomes of this large MPM series compares very favourably with literature confirming that dedicated MT in experienced referral centres is crucial in dealing with hard-to-treat, rare cancers. This deserves to be considered when defining public health programs.
Pilot trial of intratumoral (IT) G100, a toll-like receptor-4 (TLR4) agonist, in patients (pts) with Merkel cell carcinoma (MCC): Final clinical results and immunologic effects on the tumor microenvironment (TME).
Authors: Shailender Bhatia, Natalie Miller, Hailing Lu, Dafina Ibrani, Michi Shinohara, David R. Byrd, Upendra Parvathaneni, Natalie Vandeven, Rima Kulikauskas, Jan Ter Meulen, Frank J. Hsu, David M Koelle, Paul Ngheim
Journal: Journal of Clinical Oncology (2016)

3021 Background: MCC is an aggressive skin cancer with suboptimal therapies. Despite persistent expression of Merkel cell polyomavirus in ~80% of pts, MCC tumors are able to evade host immunity. G100 consists of glucopyranosyl lipid-A (GLA), a TLR-4 agonist, administered IT. In preclinical models, G100 activates dendritic cells, T cells and other effector immune cells, and triggers local and systemic (abscopal) anti-tumor responses. G100 may overcome immune suppression in the MCC TME and lead to effective systemic anti-tumor responses. Methods: 10 MCC pts were enrolled to receive IT G100. Pts with loco-regional MCC (Cohort A) received G100 5 µg IT on days 1, 8 followed by surgery & radiation (RT) starting in week 4. Pts with metastatic disease (Cohort B) received G100 5 µg IT on days 1, 8 and 22 of a 6-week long cycle 1. For cycles 2-4, pts could receive 8 Gy RT to the injectable tumor on day 0 followed by G100 on days 1, 8, 15, 22, 29, and 35. Pre- and post-treatment tumor biopsies and blood were collected for immune monitoring. Results: All 10 pts (3 cohort A; 7 cohort B) completed 1 or more cycles of IT G100. Treatment-related AEs were mostly grade 1/2 (injection site reactions). 2/3 Cohort A pts with stage IIIB MCC are recurrence-free at 23+ and 19+ months (mo); one of these pts had pathologic CR after 2 G100 injections. Of 7 pts with stage IV MCC in Cohort B, 2 pts had PRs and are progression-free at 14+ and 13+ mo and 5 pts had PD. Multispectral immunohistochemistry of tumor biopsies from responders demonstrate increased inflammation with infiltration of CD8 and CD4 T cells following IT G100; T-cell receptor sequencing supports infiltration of new clonotypes rather than enrichment of existing ones. RNA expression analyses exhibit global activation of immune-related genes within the TME, including pro-inflammatory chemokines, cytokines, and PD-L1. Conclusions: In this pilot human trial in MCC pts, IT G100 had acceptable safety and encouraging clinical efficacy. Treatment induced inflammatory changes in the TME. The inflamed TME with PD-L1 expression after IT G100 suggest potential for synergy with inhibitors of the PD-1/PD-L1 axis. Clinical trial information: NCT02035657.
International Union of Basic and Clinical Pharmacology. CVI: GABA<sub>A</sub>Receptor Subtype- and Function-selective Ligands: Key Issues in Translation to Humans
Authors: Werner Sieghart, Miroslav M. Savić
Journal: Pharmacological Reviews (2018)

GABAA receptors are the major inhibitory transmitter receptors in the brain. They are ligand-gated chloride channels and the site of action of benzodiazepines, barbiturates, neuroactive steroids, anesthetics, and convulsants. GABAA receptors are composed of five subunits that can belong to different subunit classes. The existence of 19 homologous subunits and their distinct regional, cellular, and subcellular distribution gives rise to a large number of GABAA receptor subtypes with distinct pharmacology, which modulate different functions of the brain. A variety of compounds have been identified that were claimed to modulate selectively individual GABAA receptor subtypes. However, many of these compounds have only incompletely been investigated or, in addition to a preferential modulation of a receptor subtype, also modulate other subtypes at similar concentrations. Although their differential efficacy at distinct receptor subtypes reduced side effects in behavioral experiments in rodents, the exact receptor subtypes mediating their behavioral effects cannot be unequivocally delineated. In addition, the discrepant in vivo effects of some of these compounds in rodents and man raised doubts on the applicability of the concept of receptor subtype selectivity as a guide for the development of clinically useful drugs. Here, we provide an up-to-date review on the currently available GABAA receptor subtype-selective ligands. We present data on their actual activity at GABAA receptor subtypes, discuss the translational aspect of subtype-selective drugs, and make proposals for the future development of ligands with better anxioselectivity in humans. Finally, we discuss possible ways to strengthen the conclusions of behavioral studies with the currently available drugs.
2018 International Consensus Statement on Golf and Health to guide action by people, policymakers and the golf industry
Authors: Andrew D Murray, Daryll Archibald, Iain Robert Murray, Roger A Hawkes, Charlie Foster, Kevin Barker, Paul Kelly, Liz Grant, Nanette Mutrie
Journal: British Journal of Sports Medicine (2018)

Scientific and public interest relating to golf and health has increased recently. Players, potential players, the golf industry and facilities, and decision makers will benefit from a better understanding of how to realise potential health benefits and minimise health issues related to golf. We outline an International Consensus on Golf and Health. A systematic literature review informed the development of a survey. Utilising modified Delphi methods, an expert panel of 25 persons including public health and golf industry leaders, took part in serial surveys providing feedback on suggested items, and proposing new items. Predefined criteria for agreement determined whether each item was included within each survey round and in the final consensus. The working group identiﬁed 79 scientifically supportable statement items from literature review and discussions. Twenty-five experts (100%) completed all three rounds of surveys, rating each item, and suggesting modifications and/or new items for inclusion in subsequent surveys. After three rounds, 83 items achieved consensus with each with >75% agreement and <10% disagreement. These items are included in the final International Consensus on Golf and Health. The final consensus presented here can inform scientific knowledge, and action plans for (1) golfers and potential golfers, (2) golf facilities and the golf industry, and (3) policy and decision makers external to golf. These outputs, if widely adopted, will contribute to an improved understanding of golf and health, and aid these groups in making evidence-informed decisions to improve health and well-being.
Abstract 13479: Screening Abdominal Aortic Aneurysm (AAA) During Transthoracic Echocardiography (TTE): First Multicenter Study
Authors: Victor Aboyans, Serge Kownator, Vincent Bataille
Journal: Circulation (2012)

Background - The screening of abdominal aortic aneurysm (AAA) is associated with reduced AAA-related mortality, but population screening is poorly implemented. Opportunistic screening during imaging for other indications might be efficient. Single-center series report AAA rates from 0.8% to 6.5% in patients undergoing transthoracic echocardiography (TTE), with disparities plausibly explained by selection bias. In this first multicenter study, we assessed the feasibility of AAA screening in patients undergoing TTE. Methods - Seventy-nine centers participated in a nationwide survey during one week, in May 2011. All patients ≥65 yrs requiring TTE for any indication were included. Those with operated abdominal aorta were excluded. Time required for aorta imaging was recorded, along with participants’ demographic and clinical data. We defined AAA by an antero-posterior diameter of the infra-renal aorta ≥30 mm. Results - Among 1382 consecutive patients, imaging of abdominal aorta was feasible in 96.8% of cases ...