tbuckley/cabot-search huggingface dataset:
PAM50 HER2-enriched/ERBB2-high (HER2-E/ERBB2H) biomarker to predict response and survival following lapatinib (L) alone or in combination with trastuzumab (T) in HER2+ T-refractory metastatic breast cancer (BC): A correlative analysis of the EGF104900 phase III trial.
Authors: Tomás Pascual, Laia Pare, Patricia Galvan, Miguel A. Izquierdo, Vanessa Rodrik-Outmezguine, Barbara Adamo, Maria Vidal, Jamunarani Veeraraghavan, Rachel Schiff, C. Kent Osborne, Mothaffar F. Rimawi, Paolo Nuciforo, Aleix Prat
Journal: Journal of Clinical Oncology (2018)

1025 Background: In HER2+ BC, HER2-E subtype with high ERBB2 mRNA expression (HER2-E/ERBB2H) is better associated with response following neoadjuvant L and T without chemotherapy than either variable alone (ASCO2018 submitted). Here, we evaluated the ability of this combined biomarker to predict response and survival following anti-HER2 therapy alone in T-refractory HER2+ BC. Methods: EGF104900 randomized 296 women with HER2+ advanced BC who experienced progression on prior T-containing regimens to receive either L alone or L+T. The primary endpoint was progression-free survival (PFS). Secondary endpoints included overall survival (OS), overall response rate (ORR) and clinical benefit rate (CBR). The expression of 50 PAM50 genes was evaluated from FFPE tumors using an nCounter. A pre-defined HER2-E/ERBB2H definition was applied blinded from clinical data. Multivariable analyses were used to test the association of the HER2-E/ERBB2H variable with PFS, OS, ORR and CBR. Interaction tests between the biomarker and treatment were also evaluated. Results: 177 tumors (60%) were analyzed. Subtype distribution was 58.2% HER2-E, 15.3% Basal-like, 10.2% Luminal B, 2.3% Luminal A and 14.1% normal-like. The HER2-E/ERBB2H group represented 48% of all samples. The adjusted PFS hazard ratio (HR) of the HER2-E/ERBB2H group vs. others was 0.48 (95% CI 0.34-0.69, P < 0.001). Median PFS of the HER2-E/ERBB2H group was 3.5 months (2.6-54) compared to 1.2 months (1-1.7) in others. The ORR and CBR of the HER2-E/ERBB2H group were higher compared to others (ORR 16.25% vs. 3.66%; p = 0.017 and CBR 66.25% vs. 26.83%; P < 0.001). For OS, the adjusted HR for HER2-E/ERBB2H vs. others was 0.65 (0.44-0.96, P = 0.034). Median OS was higher in the HER2-E/ERBB2H group (14.4 months) compared to others (9.1 months). No significant interaction was observed between HER2-E/ERBB2H and treatment. Conclusions: HER2-E/ERBB2-high biomarker in HER2+ T-refractory advanced BC can identify patients who might be good candidates to receive anti-HER2 treatment alone without chemotherapy.
Indeed association does not equal prediction: the never-ending search for the perfect acute:chronic workload ratio
Authors: Billy T Hulin, Tim J Gabbett
Journal: British Journal of Sports Medicine (2018)

We recently demonstrated associations between workload and injury.1 2 Regrettably, in these manuscripts, we used the words ‘ predict ’ and ‘ predictive ’ within the titles. Although we clearly used more appropriate language throughout these manuscripts, the titles of our work have resulted in a misconception that we believe the acute:chronic workload ratio can predict injury with some certainty.3 4 Our purpose for investigating workload–injury relationships in these studies was to identify workloads that practitioners could use (along with other information) to make informed decisions in regards to when injury risk may be increased or decreased—it was not our intention to imply that one variable could predict injury with crystal ball-like accuracy. We discussed at length that other variables will undoubtedly also have associations with injury,1 2 and that good athlete monitoring involves consideration of factors in addition to workload.5 However, we feel that these views may have been dismissed and, consequently, our purpose here is to provide novel perspectives and some clarity and context on the practical applications of the acute:chronic workload ratio.

The acute:chronic workload ratio should never be viewed in isolation. The size of an athlete’s chronic workload is …
Small‐molecule inhibitors of multidrug resistance‐associated protein 1 and related processes: A historic approach and recent advances
Authors: Sven Marcel Stefan, Michael Wiese
Journal: Medicinal Research Reviews (2018)

Abstract Multidrug resistance‐associated protein 1 (MRP1, ABCC1) is an ATP‐binding cassette (ABC) transport protein. This efflux pump uses the energy of ATP hydrolysis to export structurally diverse antineoplastic agents in human cancers. The upregulation of MRP1 (either inherent or acquired) is one major reason for the occurrence of the phenomenon called multidrug resistance (MDR). MDR is characterized by a reduced outcome of chemotherapy due to the active intracellular clearance of cytostatic drugs below the necessary effect concentration. Much effort has been made to overcome MDR, which implied high‐throughput screenings of already known pharmacological and natural compounds, modification of intrinsic substrates, as well as design and synthesis of new inhibitors. This review is meant not only to summarize the most recent results over the past 10 years, but also to highlight major achievements regarding reversal of MRP1‐mediated MDR, from the time of its discovery until today. The focus lies on small‐molecule compounds that feature either direct MRP1 inhibition/transport blockage, toxicity against MRP1‐overexpressing cells, inhibition/modification of intracellular processes necessary for MRP1 function, or modification of MRP1‐related metabolic and genomic mechanisms. Considering all aspects, this review might be useful to (re)consider possible strategies to overcome MRP1‐mediated MDR. Furthermore, it may be the basis for developing new, even better, highly potent, less toxic, and selective (as well as broad‐spectrum) MRP1 inhibitors that will enter clinical evaluations in different malignancies and finally conduce to overcome MDR in general.
Biocompatible PEGylated Gold nanorods function As cytokinesis inhibitors to suppress angiogenesis
Authors: Hongyuan Song, Ting Guo, Zichang Zhao, Youheng Wei, Haoyang Luo, Weizong Weng, Rui Zhang, Ming Zhong, Chunying Chen, Jiacan Su, Wei Shen
Journal: Biomaterials (2018)
Pain, psychiatric comorbidities, and psychosocial stressors associated with Klippel-Trenaunay syndrome
Authors: Jamison A. Harvey, Henry Nguyen, Katelyn R. Anderson, Jennifer J. Schoch, Emily C. Bendel, David J. Driscoll, Brian A. Palmer, Megha M. Tollefson
Journal: Journal of the American Academy of Dermatology (2018)
Everolimus (EVE) + exemestane (EXE) vs EVE alone or capecitabine (CAP) for estrogen receptor-positive (ER+), human epidermal growth factor receptor 2-negative (HER2-) advanced breast cancer (ABC): BOLERO-6, an open-label phase 2 study.
Authors: Guy Heinrich Maria Jerusalem, Elena Kovalenko, Denise A. Yardley, Richard H. De Boer, Sara A. Hurvitz, Bent Ejlertsen, Sibel Blau, Mustafa Ozguroglu, Laszlo Landherr, Marianne Ewertz, Tanya Taran, Jenna Fan, Florence Noel-Baron, Anne-Laure Louveau, Howard A. Burris
Journal: Journal of Clinical Oncology (2018)

1005 Background: BOLERO-6 (NCT01783444) was designed to estimate the clinical benefit of EVE + EXE vs EVE alone or CAP for ER+ HER2– ABC that progressed on nonsteroidal aromatase inhibitors. Methods: Patients were randomized 1:1:1 to EVE 10 mg/day + EXE 25 mg/day, EVE alone or CAP 1250 mg/m2 twice-daily. The primary objective was to estimate the hazard ratio (HR) of progression-free survival (PFS) for EVE + EXE vs EVE. The key secondary objective was to estimate the HR of PFS for EVE + EXE vs CAP. Other secondary objectives were overall survival (OS) and safety. This was not a confirmatory study and no statistical comparisons were planned Results: 309 patients received EVE + EXE (n=104), EVE (n=103) or CAP (n=102). Baseline characteristics were generally consistent; however vs the EVE + EXE arm, patients in the CAP arm were younger (68% vs 63% were aged <65 years), more had bone-only lesions (24% vs 13%), were Caucasian (89% vs 75%) or fully active (56% vs 52%) and fewer had visceral disease (62% vs 66%) or ≥3 metastatic sites (44% vs 50%). Median follow-up from randomization to data cut-off (June 1, 2017) was 37.6 months. The estimated HR of PFS for EVE + EXE vs EVE was 0.74 (90% CI 0.57–0.97). The estimated HR of PFS for EVE + EXE vs CAP was 1.26 (90% CI 0.96–1.66) but a stratified multivariate Cox regression model adjusted on prognostic factors and baseline covariates with imbalances between arms gave a HR closer to 1 (HR 1.15; 90% CI 0.86–1.52). More patients in the CAP arm were censored for initiating new antineoplastic therapies (20% vs 9% with EVE + EXE). Median OS was 23.1 months with EVE + EXE vs 29.3 months with EVE (HR 1.27; 90% CI 0.95–1.70) and 25.6 months with CAP (HR 1.33; 90% CI 0.99–1.79). Grade 3/4 adverse events (AEs) were most common with CAP. Serious AEs were most common with EVE + EXE. Conclusions: The estimated HR of PFS for EVE + EXE vs EVE (0.74) is indicative of a treatment benefit. While the estimated HR of PFS for EVE + EXE vs CAP was 1.26, the CAP arm may have been favored by baseline imbalances and potential informative censoring. The safety profile of EVE + EXE was consistent with the known profile of this combination. Clinical trial information: NCT01783444.
Adaptive phase II randomized trial of nivolumab after induction treatment in triple negative breast cancer (TONIC trial): Final response data stage I and first translational data.
Authors: Marleen Kok, Leonie Voorwerk, Hugo Horlings, Karolina Sikorska, Koen van der Vijver, Maarten Slagter, Sarah Warren, SuFey Ong, Terry Wiersma, Nicola Russell, Ferry Lalezari, Michiel de Maaker, Inge Kemper, Ingrid A. Mandjes, Myriam Chalabi, Gabe S. Sonke, Roberto Salgado, Sabine C. Linn, Ton Schumacher, Christian U. Blank
Journal: Journal of Clinical Oncology (2018)

1012 Background: Anti-PD(L)1 can result in durable responses in patients with metastatic triple negative breast cancer (TNBC). However, only a subgroup of TNBC patients benefits from anti-PD(L)1 with response rates of 5-10% in unselected cohorts. Strategies to render the tumor micro-environment (TME) more susceptible to anti-PD(L)1 might include stimulation of anti-cancer immune responses by induction treatment with irradiation or low dose chemotherapy. Methods: In stage I (non-comparative Simon's two stage design) patients with metastatic TNBC who received ≤ 3 lines of palliative chemotherapy were randomly allocated to one of five 2-week induction treatments consisting of 1) 3x8 Gy irradiation of one metastatic lesion 2) 2x doxorubicin 15mg weekly flat dose3) cyclophosphamide 50mg daily orally 4) 2x cisplatin 40mg/m2 weekly 5) no induction treatment. After this induction period, all patients received nivolumab until iRECIST progression. After at least 5x10 evaluable patients with paired biopsies (stage I) arms will be closed according to a 'pick the winner' concept taking into account safety, clinical responses and immunological correlates. Results: Stage I has been closed with 66 patients available for response evaluation. Previous treatments for metastatic disease were 0, 1 or 2+ lines in 23%, 45% and 32%, respectively. For the total group the ORR is 20% with 2 CRs and 11 PRs. In addition, two patients had SD for > 24 weeks (3%), resulting in a clinical benefit rate of 23%. ORR on nivolumab after induction with irradiation, doxorubicin, cyclophosphamide and cisplatin were 8% (1/12), 35% (6/17), 8% (1/12) and 23% (3/13), respectively. In the nivolumab-only cohort the ORR was 17% (2/12). Analyses of changes in the TME, gene expression and TCR sequencing induced by irradiation, low dose chemotherapy and nivolumab will be presented at the meeting as well as the design of stage II according to the 'pick the winner' strategy. Conclusions: This basket trial shows that short term induction with irradiation or low dose chemotherapy before nivolumab is feasible. Final clinical and translational results of stage I will be presented at ASCO 2018. Clinical trial information: NCT02499367.
Lack of evidence to favor specific preventive interventions in psychosis: a network meta‐analysis
Authors: Cathy Davies, Andrea Cipriani, John P.A. Ioannidis, Joaquim Radua, Daniel Stahl, Umberto Provenzani, Philip McGuire, Paolo Fusar‐Poli
Journal: World Psychiatry (2018)

Preventing psychosis in patients at clinical high risk may be a promising avenue for pre‐emptively ameliorating outcomes of the most severe psychiatric disorder. However, information on how each preventive intervention fares against other currently available treatment options remains unavailable. The aim of the current study was to quantify the consistency and magnitude of effects of specific preventive interventions for psychosis, comparing different treatments in a network meta‐analysis. PsycINFO, Web of Science, Cochrane Central Register of Controlled Trials, and unpublished/grey literature were searched up to July 18, 2017, to identify randomized controlled trials conducted in individuals at clinical high risk for psychosis, comparing different types of intervention and reporting transition to psychosis. Two reviewers independently extracted data. Data were synthesized using network meta‐analyses. The primary outcome was transition to psychosis at different time points and the secondary outcome was treatment acceptability (dropout due to any cause). Effect sizes were reported as odds ratios and 95% confidence intervals (CIs). Sixteen studies (2,035 patients, 57% male, mean age 20.1 years) reported on risk of transition. The treatments tested were needs‐based interventions (NBI); omega‐3 + NBI; ziprasidone + NBI; olanzapine + NBI; aripiprazole + NBI; integrated psychological interventions; family therapy + NBI; D‐serine + NBI; cognitive behavioural therapy, French &amp; Morrison protocol (CBT‐F) + NBI; CBT‐F + risperidone + NBI; and cognitive behavioural therapy, van der Gaag protocol (CBT‐V) + CBT‐F + NBI. The network meta‐analysis showed no evidence of significantly superior efficacy of any one intervention over the others at 6 and 12 months (insufficient data were available after 12 months). Similarly, there was no evidence for intervention differences in acceptability at either time point. Tests for inconsistency were non‐significant and sensitivity analyses controlling for different clustering of interventions and biases did not materially affect the interpretation of the results. In summary, this study indicates that, to date, there is no evidence that any specific intervention is particularly effective over the others in preventing transition to psychosis. Further experimental research is needed.
Patient(Pt)-reported toxicities by chemotherapy regimen for early breast cancer (BC) (LCCC1334/1440).
Authors: Kirsten A. Nyrop, Allison Mary Deal, Shlomit S. Shachar, Ethan M. Basch, Bryce B. Reeve, Jordan T Lee, Seul Ki Choi, William Allen Wood, Carey K. Anders, Lisa A. Carey, Elizabeth Claire Dees, Trevor Augustus Jolly, Katherine Elizabeth Reeder-Hayes, Gretchen Genevieve Kimmick, Meghan Sri Karuturi, Raquel E. Reinbolt, Joellen C. Speca, Hyman B. Muss
Journal: Journal of Clinical Oncology (2018)

544 Background: Pt-reported outcomes reflect toxicity of anticancer drugs, and can be measured using “moderate, severe or very severe” ratings (MSVS) that mirror physician-assessed CTCAE grades 2-4. Methods: We prospectively collected pt-reported MSVS in pts with stage I-III BC at each cycle of conventional (neo)adjuvant chemotherapy. Results: In 135 patients, mean age was 52, 26% non-white, 32% ≤high school education. Fatigue, arthralgia, constipation, diarrhea, nausea, myalgia, and peripheral neuropathy toxicities varied significantly by chemotherapy regimen (p < 0.05). Pts who received anthracycline-based chemotherapy reported significantly more MSVS toxicities compared those who did not (mean 5.3 vs 3.5, p < 0.001). Conclusions: Modern (neo)adjuvant chemotherapy has substantial toxicity that varies by regimen; anthracycline-based regimens appear particularly difficult. These findings support efforts to tailor therapy and minimize overtreatment. Clinical trial information: NCT02328313.Patient-reported MSVS toxicities, by chemotherapy regimen. Toxicities All Regimens N = 135 Doxorubicin + cyclophosphamide à paciltaxel + carboplatin N = 18 Doxorubicin + cyclophosphamide à paclitaxel N = 49 Docetaxel + carboplatin* N = 22 Docetaxel + cyclophosphamide** N = 46 p value Moderate Severe/ Very Severe Combined Moderate/Severe/ Very Severe (MSVS) Fatigue 59 (44%) 30 (22%) 14 (78%) 40 (82%) 14 (64%) 21 (46%) .002 Insomnia 50 (37%) 27 (20%) 12 (67%) 32 (65%) 9 (41%) 25 (52%) .20 Anxiety 46 (34%) 15 (11%) 10 (56%) 22 (45%) 8 (36%) 21 (46%) .68 Arthralgia 42 (31%) 15 (11%) 9 (50%) 27 (55%) 5 (23%) 16 (35%) .04 Constipation 34 (25%) 19 (14%) 12 (67%) 22 (45%) 6 (27%) 13 (28%) .02 Myalgia 40 (30%) 11 (10%) 11 (61%) 24 (49%) 4 (18%) 12 (26%) .005 Diarrhea 34 (25%) 15 (11%) 3 (17%) 14 (27%) 15 (68%) 17 (37%) .004 Nausea 31 (23%) 16 (12%) 12 (67%) 19 (39%) 8 (36%) 8 (17%) .002 Peripheral neuropathy 31 (23%) 8 (6%) 9 (50%) 21 (43%) 5 (23%) 4 (9%) .0002 Depression 30 (22%) 9 (7%) 7 (39%) 16 (33%) 6 (27%) 10 (22%) .47 Dyspnea 15 (11%) 7 (6%) 3 (17%) 10 (20%) 3 (14%) 6 (13%) .80 Vomiting 6 (4%) 6 (4%) 2 (11%) 4 (8%) 4 (18%) 2 (4%) .25 *Two patients anti-HER2 therapy; **four patients anti-HER2 therapy
The Aspirin Regimens in Essential Thrombocythemia (ARES) phase II randomized trial design: Implementation of the serum thromboxane B2 assay as an evaluation tool of different aspirin dosing regimens in the clinical setting
Authors: Valerio De Stefano, Bianca Rocca, Alberto Tosetto, Denise Soldati, Giovanna Petrucci, Eloise Beggiato, Irene Bertozzi, Silvia Betti, Giuseppe Carli, Monica Carpenedo, Daniele Cattaneo, Viviana Cavalca, Alfredo Dragani, Elena Elli, Guido Finazzi, Alessandra Iurlo, Giuseppe Lanzarone, Laura Lissandrini, Francesca Palandri, Chiara Paoli, Alessandro Rambaldi, Paola Ranalli, Maria Luigia Randi, Alessandra Ricco, Elena Rossi, Marco Ruggeri, Giorgina Specchia, Andrea Timillero, Linda Turnu, Nicola Vianelli, Alessandro M Vannucchi, Francesco Rodeghiero, Carlo Patrono
Journal: Blood Cancer Journal (2018)

Abstract Once-daily (od), low-dose aspirin (75–100 mg) is recommended to reduce the thrombotic risk of patients with essential thrombocytemia (ET). This practice is based on data extrapolated from other high-risk patients and an aspirin trial in polycythemia vera, with the assumption of similar aspirin pharmacodynamics in the two settings. However, the pharmacodynamics of low-dose aspirin is impaired in ET, reflecting accelerated renewal of platelet cyclooxygenase (COX)-1. ARES is a parallel-arm, placebo-controlled, randomized, dose-finding, phase II trial enrolling 300 ET patients to address two main questions. First, whether twice or three times 100 mg aspirin daily dosing is superior to the standard od regimen in inhibiting platelet thromboxane (TX)A 2 production, without inhibiting vascular prostacyclin biosynthesis. Second, whether long-term persistence of superior biochemical efficacy can be safely maintained with multiple vs. single dosing aspirin regimen. Considering that the primary study end point is serum TXB 2 , a surrogate biomarker of clinical efficacy, a preliminary exercise of reproducibility and validation of this biomarker across all the 11 participating centers was implemented. The results of this preliminary phase demonstrate the importance of controlling reproducibility of biomarkers in multicenter trials and the feasibility of using serum TXB 2 as a reliable end point for dose-finding studies of novel aspirin regimens.
Abstract 17293: Human Leukocyte Antigen-G Polymorphisms Association to Post Heart Transplant Donor Specific Antibodies
Authors: Julieta Lazarte, Livia Goldraich, Cedric Manlhiot, Hiroyuki Kawajiri, Liza Grosman-Rimon, Arash Ghashghai, Vivek Rao, Diego Delgado
Journal: Circulation (2015)

Introduction: Human Leukocyte Antigen (HLA)-G is a natural immune regulator that inhibits T cells, NK cells and B cell activity. In the context of transplantation, less rejection and better graft outcomes are associated with higher serum levels of HLA-G. The association between HLA-G polymorphisms in the recipient and donor and post-transplant donor specific antibodies (DSA) has never been explored. DSA can lead to antibody-mediated rejection and are associated with worse outcomes. Objective: to determine the association between HLA-G single nucleotide polymorphisms (SNPs) in the recipient and donor and DSA. Methods: 251 adult heart recipients and 196 matching donors were evaluated for various HLA-G SNPs. Serum from patient and donor were tested for positive presence of HLA Class I antibodies. DNA was genotyped for 14bp INDEL, G*01:01, G*01:04 and G*0:05N. The analysis was performed first in univariable regression models and then in multivariable regression model using a backward selection approach of potential risk factors with a univariable associations with p-value &lt;0.10. The model automatically included time since transplantation as an obligatory covariate. Results: General characteristics: recipient age 48.2±12.1 years, 69% males and donor age 35.5±14.3 years. Of those, 19 (8%) had at least one positive DSA diagnosis. In a multivariable analysis adjusted for time since transplant, documented non-compliance and blood group A, the presence of donor G*01:04 allele was identified with a protective role for the development of DSA (0.079, CI 0.02-0.39, p= 0.002). Patient allele G*01:05N was associated with increased risk for DSA (12.95, CI 2.36-71.00, p= 0.003). Lastly, donor SNP 14bp (DEL vs INDEL/INS) was independently associated as a risk factor for DSA (5.75, CI 1.70-19.36, p= 0.005). Conclusions: Three SNPs from the donor and recipient were identified to influence the development of donor specific antibodies. This is the first study to investigate the association of HLA-G to the development of donor specific antibodies and to demonstrate both detrimental and beneficial roles for HLA-G polymorphisms.
Cytoreductive Nephrectomy — Patient Selection Is Key
Authors: Robert J. Motzer, Paul Russo
Journal: New England Journal of Medicine (2018)

Metastatic renal-cell carcinoma has diverse clinical presentations ranging from incidental detection to a highly symptomatic systemic illness. Patients with metastatic renal-cell carcinoma are assigned a risk category — favorable, intermediate, or poor — on the basis of two published models containing five or six pretreatment selection factors, including presence of anemia, elevated serum calcium concentration, and degree of disability from cancer-related symptoms (performance status).1 This stratification provides important prognostic insight about whether patients should be treated with cytoreductive radical nephrectomy, systemic therapies, or both.1 Nephrectomy for stage IV disease removes the primary kidney tumor and its potential for bleeding and . . .