tbuckley/cabot-search huggingface dataset:
Validation of the International Metastatic Renal-Cell Carcinoma Database Consortium prognostic model (IMRCC), in patients (pt) treated with pazopanib (Pz) as first line for metastatic renal carcinoma (mRC): First results of the SOGUG SPAZO study.
Authors: Begoña Perez-Valderrama, Jose Angel Arranz Arija, Pablo Borrega, Angel Rodriguez Sanchez, Alvaro Pinto, Daniel E. Castellano, María José Juan Fita, Gustavo Rubio, Constanza Maximiano Alonso, Isabel Chirivella, JosÃ© Carlos Villa Guzman, Javier L. Puertas, Rocio García Domínguez, Luis León Mateos, Raquel Luque, Martin Lázaro Quintela, Julio Jose Lambea- Sorrosal, Aranzazu Gonzalez del Alba, Edelmira Velez De Mendizabal, Jose-Luis Gonzalez-Larriba
Journal: Journal of Clinical Oncology (2015)

e15597 Background: The IMRCC prognostic model for mRCC treated with VEGF-targeted agents (Heng, JCO '09) has been externally validated (Heng, Lancet Oncol '13), however, pt treated with Pz were not included in these series. Methods: The SPAZO study was designed to analyze retrospectively the effectiveness of 1st-line Pz and subsequent targeted therapies in mRCC, in pt treated in daily clinical practice in Spain since Pz was approved. We present the results of 1st-line Pz, with the aim of validating the IMRCC model in this setting. Results: We included 254 pt treated in standard practice. There were 69% male, mean age 66 y (26–92), 82.1% ECOG 0-1, 74.8% nephrectomized and 93.7% of clear cell type. Metastatic sites were: lung 73.1%, lymph node 47.2%, bone 27.2%, soft tissue 16.3%, liver 14.5%, adrenal 8.3%, brain 7.5%, pleura/peritoneum 6.3%, pancreas 5.9%, kidney 3.1% and skin 2.5%. Pt were classified according to Heng’s number (n) of prognostic factors (Karnofsky <80%, <1 year from diagnosis to treatment, Hb <LLN, and corrected Ca, neutrophils and platelets >ULN), into favorable-risk (FR, n= 0, 48 pt, 18.9%), intermediate-risk (IR, n= 1-2, 146 pt, 57.5%), or poor-risk (PR, n>2, 60 pt, 23.6%). After a median follow-up of 21 mo, 139 pt have progressed and 120 have died. Pz was discontinued due to progression (55%), toxicity (12%), comorbidities (3%), or complete remission (2%). A 20.5% of pt received antiangiogenic TKI as 2nd-line, and 19.7% a mTOR inhibitor. Response rate (RR), median (months) of progression-free survival (PFS), and overall survival (OS) are showed in the table (95% CI). Conclusions: Our results validate the effectiveness of pazopanib as first-line for mRC in clinical practice, and the use of the IMRCC classification to predict prognosis. NCT02282579. Funded by a grant from GlaxoSmithKline. Clinical trial information: NCT02282579.. SPAZO HENG 2009 Overall FR IR PR Overall FR IR PR RR * 30.1% 51.1% 34,6% 17% PFS 11 (9 – 13) 22 (5 – 39) 11 (9 – 13) 4 (2 – 6) OS 22 (16 – 28) NR 22 (15 – 29) 6 (3 – 9) 22 (20 – 26) NR 27 8.8 2-y OS 47.4% (40 – 55) 81.1% (74 – 88) 49.7% (45 – 55) 13.8% (8 – 20%) 47% (42 – 52) 75% 53% 7% * N = 219 evaluable pt. NR: Not reached.
NEPA, a fixed-dose combination of netupitant and palonosetron, for prevention of chemotherapy-induced nausea and vomiting (CINV) following repeated chemotherapy cycles: Results of a phase III trial.
Authors: Karin Jordan, Giorgia Rossi, Giada Rizzi, Marco Palmas, Richard J. Gralla
Journal: Journal of Clinical Oncology (2013)

e20716 Background: NEPA is a fixed-dose combination of netupitant (NETU), a highly selective NK 1 receptor antagonist and palonosetron (PALO), a pharmacologically and clinically distinct 5-HT 3 receptor antagonist. Recent clinical trials have been conducted to definitively establish the superiority of the combination, NEPA, over single agent PALO in the prevention of CINV following a single cycle of highly (HEC) and moderately (MEC) emetogenic CT. This study was designed to examine the tolerability and efficacy of NEPA over multiple cycles of HEC and MEC. Methods: Trial design: multinational, randomized, double-blind, parallel group, phase III study assessing the safety and efficacy of a single oral dose of NEPA (NETU 300 mg + PALO 0.50 mg) administered only on day 1 of each cycle, and given with concomitant oral dexamethasone on day 1 (with MEC) and days 1-4 (when given with HEC) prior to repeated cycles of HEC or MEC. A standard arm 3-day oral aprepitant + PALO + dexamethasone was included as a control group with an unbalanced 3:1 (NEPA : aprepitant) randomization ratio. There was no limit to the number of chemotherapy cycles allowed. Safety was the primary objective of the study as assessed by adverse events; secondary variables included ECGs, left ventricular ejection fraction, cardiac troponin levels and laboratory tests. Efficacy was assessed as the proportion of patients with complete response (no emesis, no rescue medication). Results: 413 patients were randomized in this study with the last patient visit occurring on 13 September, 2012. The analyses will be completed by March 2013 and will be fully available by ASCO 2013. Conclusions: Few large randomized trials have documented safety and efficacy of antiemetic control with multiple cycles of chemotherapy, and especially with HEC. The in depth safety profile will provide new information for all study arms over multiple cycles. NEPA is designed to provide maximal convenience while providing high degrees of antiemetic control throughout the patient’s full course of chemotherapy. Clinical trial information: NCT01376297.
Safety and clinical activity of nivolumab (anti-PD-1, BMS-936558, ONO-4538) in combination with ipilimumab in patients (pts) with advanced melanoma (MEL).
Authors: Jedd D. Wolchok, Harriet M. Kluger, Margaret K. Callahan, Michael Andrew Postow, Ruth Ann Gordon, Neil Howard Segal, Naiyer A. Rizvi, Alexander M. Lesokhin, Kathleen Reed, Matthew M. Burke, Anne Caldwell, Stephanie Anne Kronenberg, Blessing Agunwamba, William Feely, Quan Hong, Christine E. Horak, Alan J. Korman, Jon M. Wigginton, Ashok Kumar Gupta, Mario Sznol
Journal: Journal of Clinical Oncology (2013)

9012^ Background: CTLA-4 and PD-1 are critical immune checkpoint receptors. In MEL pts, ipilimumab (anti-CTLA-4) prolonged survival in two phase III trials, and nivolumab (anti-PD-1) produced an objective response rate (ORR) of 31% (n=106) in a phase I trial. PD-1 is induced by CTLA-4 blockade, and combined blockade of CTLA-4/PD-1 showed enhanced antitumor activity in murine models. Thus, we initiated the first phase 1 study to evaluate nivolumab/ipilimumab combination therapy. Methods: MEL pts with ≤3 prior therapies received IV nivolumab and ipilimumab concurrently, q3 wk × 4 doses, followed by nivolumab alone q3 wk × 4 (Table). At wk 24, combined treatment was continued q12 wk × 8 in pts with disease control and no DLT. In two sequenced-regimen cohorts, pts with prior standard ipilimumab therapy were treated with nivolumab (q2 wk × 48). Results: As of Dec. 6, 2012, 69 pts were treated. We report efficacy data on 37 pts with concurrent therapy in completed cohorts 1-3 (Table); ORR was 38% (95% CI: 23-55). In cohort 2 (MTD), ORR was 47% and 41% of pts had ≥80% tumor reduction at 12 wk (Table) with some pts showing rapid responses, prompt symptom resolution, and durable CRs. Related adverse events (rAEs) for concurrent therapy were similar in nature with some higher in frequency than those typically seen for the monotherapies and were generally manageable using immunosuppressants. Cohort 3 exceeded the MTD (DLT: gr 3-4 ↑ lipase). At the MTD, gr 3-4 rAEs occurred in 59% of pts and included uveitis/choroiditis, colitis, and reversible lab abnormalities. Conclusions: Nivolumab and ipilimumab can be combined with a manageable safety profile. Clinical activity for concurrent therapy appears to exceed that of published monotherapy data, with rapid and deep tumor responses (≥80% tumor reduction at 12 wk) in 30% (11/37) of pts. A phase III trial is planned to compare concurrent combination dosing with each monotherapy. Clinical trial information: NCT01024231. [Table: see text]
Abstract 16: Genomewide Association Study of Isoproterenol-Induced Heart Failure in a Large Mouse Panel
Authors: Christoph D Rau, Jessica J Wang, Shuxun Ren, Yibin Wang, Aldons J Lusis
Journal: Circulation Research (2012)

Heart failure is highly heterogeneous and association studies in humans have yielded few insights into its genetic basis. We have developed a resource, the Hybrid Mouse Diversity Panel, to efficiently perform association studies on complex diseases in a mouse model. Each strain within the panel has been densely genotyped and the panel displays significant baseline inter-strain variation. We used the panel to explore isoproterenol (a β-adrenergic agonist) induced heart failure. Eight week old females from 105 unique inbred strains (average N = 6.7) were divided into control (average N = 2.5) and treated (average N = 4.1) cohorts. Treated mice received 20 μg/g/day of drug through an abdominally implanted Alzet micropump. All mice underwent echocardiography to assess left ventricular function both before and at weekly timepoints after treatment. At three weeks, all mice were sacrificed. Hearts (sectioned by chamber) lungs, liver and adrenal glands were weighed before storage for further analysis. Phenotypes were analyzed using the Efficient Mixed-Model Association (EMMA) algorithm to correct for population substructure. Promising gene candidates were tested on zebrafish morpholino models to assess any phenotypic effects. Here we report initial findings from the panel. Chronic β-adrenergic stimulation results in marked variations in both weight and echocardiographic measurements. EMMA analysis of the data revealed several dozen putative peaks, including several repeated peaks in correlated phenotypes as well as replication of previously reported loci in both human and mouse studies. Further analysis of these peaks will shed light on the genetics underlying heart failure.
Screening for carcinoma in situ (CIS) testis and occurrence of metachronous germ cell cancer (mGCC).
Authors: Maria Gry Gundgaard, Kristian Almstrup, Birgitte Groenkaer Toft, Ewa Rajpert-De Meyts, Mikael Roerth, Hans von der Maase, Mette Sakso Mortensen, Jakob Lauritsen, Klaus Kaae Andersen, Mads Agerbaek, Niels Vilstrup Holm, Susanne Oksbjerg Dalton, Christoffer Johansen, Gedske Daugaard
Journal: Journal of Clinical Oncology (2014)

4554 Background: CIS is present in the contralateral testicle in 5-6% of untreated patients with unilateral germ cell cancer (GCC). A Danish screening program for contralateral CIS was initiated in order to prevent mGCC. Methods: In total, 4,180 GCC patients diagnosed from 1984 through 2007 were offered a contralateral single-site biopsy in relation to orchiectomy (intention to screen, ITS). A non-screened group included 450 patients. Recommended treatment for CIS was radiotherapy (RT) in doses of 14 to 20 Gy, also in chemotherapy treated (CT) patients. CIS-negative (CISneg) patients who developed mGCC had the biopsy revised according to today’s standard including immunohistochemical staining. Data was merged with national administrative registries, and information on second GCC and vital status was obtained for all patients up to December 2012. Results: Median observation time was 14.1 years (range 0.1-28.9). Contralateral CIS was found in 193 patients (4.6%). Seven CIS-positive (CISpos) patients developed mGCC (n=3 after 14 Gy and n=4 after CT without local RT). Out of 3,987 CISneg patients, 55 developed mGCC. Revision of 46 biopsies available showed CISpos in 17 and confirmed CISneg biopsies in 29 patients. Older age at diagnosis and treatment with CT were significantly correlated with decreased risk of mGCC (HR 0.93 per year, p<0.0001 and HR 0.34, p=0.006, respectively). Conclusions: The risk of mGCC in a screened population was significantly lower than in a non-screened group after re-evaluation of false-negative biopsies. Further efforts should concentrate on the improvement of screening to eliminate false-negative biopsies and on the definition of risk factors to avoid taking biopsies in low-risk groups. Cumulative incidence of mGCC (% [95% CI]). Time point years ITS, n=4,180 ITS with CISpos patients removed, n=3,970 Nonscreened group, n=450 15 1.7 (1.3-2.2)* 1.2 (0.8-1.6)** 2.8 (1.2-4.3) 20 2.1 (1.5-2.7)* 1.3 (0.9-1.7)** 3.3 (1.6-5.0) *p=0.12, **p=0.003; compared to non-screened group.
PIKHER2: A phase Ib/II study evaluating safety and efficacy of oral BKM120 in combination with lapatinib in HER2-positive, PI3K-activated, trastuzumab-resistant advanced breast cancer.
Authors: Anthony Goncalves, Nicolas Isambert, Mario Campone, Veronique Dieras, Jean Marie Boher, Agnes Boyer-Chamard, Benjamin Esterni, Magali Provansal, Jean-Marc Extra, Patrice Viens
Journal: Journal of Clinical Oncology (2013)

TPS663 Background: Phosphatidylinositol-3-kinase (PI3K)/AKT/mammalian target of rapamycin (mTOR)-pathway is frequently activated in HER2-positive breast cancer and may play a major role in resistance to trastuzumab. BKM120 is an oral pan-class I PI3K inhibitor with potent and selective activity against wild-type and mutant PI3K p110α. PIKHER2 study will evaluate safety and efficacy of oral, daily lapatinib-BKM120 combination in HER2-positive, trastuzumab-resistant advanced breast cancer (ABC) with activated PI3K/AKT/mTOR pathway. Methods: This open label, single arm, multi-center study includes a phase Ib dose-escalation part and a phase II expansion part at the recommended dose (RP2D). Primary objectives include determination of the maximum-tolerated dose (MTD) of BKM120 in combination with lapatinib in trastumuzab-resistant HER2-positive ABC (phase Ib part) and evaluation of the activity of BKM120-lapatinib combination at RP2D as measured by objective response rate (ORR) in patients with activated PI3K/AKT/mTOR pathway, as defined by PTEN-negative by IHC and/or somatic mutations (exons 9 and 20) of PIK3CA and/or overexpression of phospho-AKT by IHC (phase II part). Secondary objectives include safety and tolerability of the combination, clinical benefit and progression-free survival, pharmacokinetic profiles, biological and pharmacodynamic correlates. Main eligibility criteria are PS ≤ 1, HER2-positive ABC resistant to trastuzumab, documented activated PI3K/AKT/mTOR pathway (phase II part only). A modified CRM using an adaptive Bayesian model guides the dose escalation of both agents with a maximum of 24 patients planned to be enrolled in phase Ib part. Efficacy will be tested according to a standard 2-stage Simon design under the following unacceptable and desirable hypotheses: H0, ORR &lt;= 10% (unacceptable rate) vs. H1, ORR &gt;=30% (desirable rate). A maximum of 35 patients with activated PI3K/AKT/mTOR pathway is planned to be enrolled in phase II part with an interim look after 18 evaluable patients will have been recruited. Clinical trial information: NCT01589861.
Conference of the International Federation of Psychotherapy: The Universal and the Cultural in Psychotherapy
Journal: Psychotherapy and Psychosomatics (2017)

The International Federation for Psychotherapy (IFP) proposes the International Conference in Marrakesh, Morocco, on April 20-22, 2017.The conference aims at highlighting the role of the universal and the cultural in psychotherapy.Delegates will have an enriching and rewarding experience attending keynote presentations and plenary lectures, participating in debates and scientific symposia on selected topics, and presenting oral communications.We are very committed to ensure that the Marrakesh Congress will contribute to an improvement in the field of psychotherapy.We also hope that you will enjoy the reports on a broad spectrum of scientific and clinical approaches and the communication with old and new friends in an energetic city.Welcome to the beautiful city of Marrakesh and to the 2017
Human papillomavirus type 16 (HPV16) E6/E7-specific cytotoxic T lymphocytes (CTL) for immunotherapy of HPV-associated cancer (Ca).
Authors: Carlos Almeida Ramos, Neeharika Narala, Ann M. Leen, Ulrike Gerdemann, Erich M. Sturgis, Matthew L. Anderson, Barbara Savoldo, Helen E. Heslop, Malcolm K. Brenner, Cliona M. Rooney
Journal: Journal of Clinical Oncology (2012)

2558 Background: Vaccines prevent HPV-associated Ca, but their benefits in established Ca are disappointing: although these tumors express viral E6 and E7 antigens (Ags) immune responses are limited even after vaccination, likely due to negative environmental cues that block tumor recognition and T cell (TC) activation in vivo. We postulated that ex vivo stimulation of TCs in an immunologically favorable milieu would allow us to reactivate tumor-directed CTLs from Ca patients and benefit the recipients on reinfusion. Methods: We studied 68 patients with HPV+ Ca. To detect HPV16 E6/E7-specific TCs (HPV-TCs) in blood, we measured the IFNγ ELISpot responses of TCs stimulated by monocyte-derived dendritic cells (DCs) loaded with pepmixes (peptide libraries of 15-mers overlapping by 11 aa) spanning E6/E7. Because HPV-TCs from these patients may be anergized by their tumors, potent Ag presenting strategies might be required for reactivation, and thus we stimulated these cells in the presence of IL-6, -7, -12 and -15, as we have shown that these can induce responses to poorly immunogenic Ags. Results: We successfully reactivated HPV-TCs from 8/16 cervical and 33/52 oropharyngeal Ca patients. We could expand these HPV-TCs to clinically useful numbers by using patient B-cell blasts (BBs) as APCs. Stimulation of DC-stimulated HPV-TCs by E6/E7 pepmix-loaded BBs further expanded (3.8 ± 1.5×/round) HPV-TC lines, which phenotypically are almost exclusively composed of TCs (98 ± 3% CD3+), with a variable proportion of mostly effector memory (CD45RA–, CD45RO+, CD62L– and CCR7–) CD4+ and CD8+ cells (37 ± 28% and 49 ± 27%, respectively). The viral/tumor associated epitopes recognized mapped to E6 aa 49-71, 77-91 and 125-143, and E7 aa 1-19 and 73-87. The expanded cells from patients killed E6/E7+ targets (specific lysis up to 45-61% vs. 0-8% in controls, 40:1 E:T ratio). Conclusions: We have developed a system that allows the robust generation of HPV-directed CTLs from patients with HPV16+ Ca, which recognize specific epitopes in tumor-associated Ags. Our lines have the potential to be used for adoptive cellular immunotherapy of HPV+ Ca.
Active surveillance in phenotypically heterogeneous early-stage prostate cancer.
Authors: John W. Davis, Mary F. Achim, John Francis Ward, Curtis Alvin Pettaway, Brian Francis Chapin, Xuemei Wang, Deborah A. Kuban, Steven J. Frank, Andrew Lee, Louis L. Pisters, Surena F. Matin, Jay Bakul Shah, Jose A. Karam, John N. Papadopoulos, Karen Elizabeth Hoffman, Thomas J. Pugh, Seungtaek Choi, Christopher Logothetis, Patricia Troncoso, Jeri Kim
Journal: Journal of Clinical Oncology (2014)

5083 Background: Active surveillance (AS) in prostate cancer (PC) is predicated on slow, stepwise disease (Dz) progression. Patient (Pt) selection, although not standardized in prospective AS trials, is based on clinical stage, prostate-specific antigen (PSA), and phenotypic characteristics of tumors on biopsy (BX). Changes on repeat BXs often trigger intervention. In a single-institution prospective cohort study, pts with early stage PC were stratified to AS group (GR) I (favorable risk), II (pt’s choice), or III (competing comorbidities prevent local therapy [TX]). We describe early results for GR II, use of confirmatory and subsequent BX, and reclassification and TX rates. Methods: Enrolled 2006-2012 were 191 men into GR I, 369 into GR II, and 14 into GR III. GR I required a single core of Gleason score (GS) 3+3 < 3mm, or 3+4 < 2mm, and a PSA < 4 ng/mL. Pts with a life expectancy >10 years (yr) selecting AS were considered GR II. Pts had mandatory confirmatory BX at registration or within 6 months (mo) of diagnostic BX, and then repeat BXs every 1-2 yr. PSA and digital rectal examination were done every 6 mo. Dz was reclassified based on increases in tumor volume (TV) or grade. Results: In 369 GR II pts, clinical stage cT1c was found in 86%; median PSA was 4.4 ng/mL; and GS was 3+2 in 0.3%, 3+3 in 77.2%, 3+4 in 19.2%, and 4+3 in 3.3%. After a median 3 yr follow-up, 119 (32%) had been treated with curative modalities—surgery (43%), radiation (53%), and cryotherapy (3%). One pt (PSADT, <2 yrs; GS, 6 to 7) had an anterior tumor and a positive pelvic lymph node at 1.5 yrs. One pt with pT3b N0 at surgery at 9 mo had persistently elevated PSA. Time on study pre-TX was <6 mo in 53%, 6-<12 mo in 8%, 12-<24 mo in 24%, 24-<36 mo in 9%, and 36->48 mo in 5%. Dz was reclassified on BX that triggered TX in 106 pts based on increased BX TV and/or GS upgrading in 74 (70%) (6 to >7 in 61 [82%], 3+4 to 4+3 in 7 [10%], and Gleason 7 to >7 in 6 [8%]). Conclusions: In a prospective AS cohort with phenotypically heterogeneous tumors, one third were eventually treated for cure—mostly in the first yr, owing to BX variability. Biologically concerning TX triggers (GS 6/7 to 8/9) occurred in 12% of treated. Despite limitations of selection criteria and monitoring tools, AS is an important initial option in localized PC.
Nicotinamide Phosphoribosyltransferase in Smooth Muscle Cells Maintains Genome Integrity, Resists Aortic Medial Degeneration, and Is Suppressed in Human Thoracic Aortic Aneurysm Disease
Authors: Alanna Watson, Zengxuan Nong, Hao Yin, Caroline O’Neil, Stephanie Fox, Brittany Balint, Linrui Guo, Oberdan Leo, Michael W.A. Chu, Robert Gros, J. Geoffrey Pickering
Journal: Circulation Research (2017)

The thoracic aortic wall can degenerate over time with catastrophic consequences. Vascular smooth muscle cells (SMCs) can resist and repair artery damage, but their capacities decline with age and stress. Recently, cellular production of nicotinamide adenine dinucleotide (NAD+) via nicotinamide phosphoribosyltransferase (Nampt) has emerged as a mediator of cell vitality. However, a role for Nampt in aortic SMCs in vivo is unknown.To determine whether a Nampt-NAD+ control system exists within the aortic media and is required for aortic health.Ascending aortas from patients with dilated aortopathy were immunostained for NAMPT, revealing an inverse relationship between SMC NAMPT content and aortic diameter. To determine whether a Nampt-NAD+ control system in SMCs impacts aortic integrity, mice with Nampt-deficient SMCs were generated. SMC-Nampt knockout mice were viable but with mildly dilated aortas that had a 43% reduction in NAD+ in the media. Infusion of angiotensin II led to aortic medial hemorrhage and dissection. SMCs were not apoptotic but displayed senescence associated-ß-galactosidase activity and upregulated p16, indicating premature senescence. Furthermore, there was evidence for oxidized DNA lesions, double-strand DNA strand breaks, and pronounced susceptibility to single-strand breakage. This was linked to suppressed poly(ADP-ribose) polymerase-1 activity and was reversible on resupplying NAD+ with nicotinamide riboside. Remarkably, we discovered unrepaired DNA strand breaks in SMCs within the human ascending aorta, which were specifically enriched in SMCs with low NAMPT. NAMPT promoter analysis revealed CpG hypermethylation within the dilated human thoracic aorta and in SMCs cultured from these tissues, which inversely correlated with NAMPT expression.The aortic media depends on an intrinsic NAD+ fueling system to protect against DNA damage and premature SMC senescence, with relevance to human thoracic aortopathy.