tbuckley/cabot-search huggingface dataset:
P05.21 T1-flair to T1-gadolinium MRI ratio as a predictive value of treatment response in non-small-cell lung cancer (NSCLC) patients affected by multiple brain metastases
Authors: M Alemany, M Domènech, N Vilariño, M Jové, I Brao, M Arellano, A Lucas, A Navarro, R Palmero, M Simó, R Velasco, E Nadal, J Bruna
Journal: Neuro-Oncology (2018)

Treatment strategies for multiple brain metastases (BM) are usually palliative, being whole brain radiation therapy (WBRT) the mainstay therapy so far. However, side effects such as cognitive decline, are not exempted. Systemic therapies as alternative treatment, although controversial, can be an alternative. To avoid WBRT adverse events and control both, extracranial and intracranial disease. Our purpose is to analyze the impact of peritumoral edema on the intracranial response to current systemic therapy. A retrospective study including 28 patients, stage IV nonsquamous NSCLC with multiple BM (>3) treated with chemotherapy (CT)based on carboplatin plus pemetrexed (group A, n=18) or CT plus WBRT (group B, n=10) during the period 2014–2016. Patients received upfront CT if neurologic symptoms were absent or minor (using or not steroids). Intracranial response by RANO-BM criteria was correlated with the degree of BM-associated edema estimated by measuring the maximum diameter ratio among T1-Flair and T1-gadolinium (F/G) per each BM at the baseline MRI. Median age was 55 (40–72) and most patients were men (71%), had smoking history (89%) and lung adenocarcinoma (89%). Only 1 patient harboured an EGFR mutation. Most patients had ECOG PS0-1 (96%) and 46% were off steroids. Median DS-GPA was 2 (1–4). The median follow-up was 11.6 months. No differences were observed in baseline characteristics among both groups, except for steroids doses that were higher in group B. Median OS was similar between group A and B (12.9 vs 10.9 months respectively, p=.317). Median F/G ratio was significantly higher in patients treated with WBRT compared with those treated with upfront CT (2.36 vs 1.58; p=.008). In patients treated with CT, F/G ratio was higher in those who developed intracranial progression to CT (2.60 ± 1.58) compared with those who achieved partial response or stable disease (1.32 ± 0.45 and 1.47 ± 0.45; p=.006). In patients treated with WBRT, F/G ratio was not predictive of response. Based on ROC analysis, a 2.1 cutoff on F/G ratio had a sensitivity of 71.4% and a specificity of 81.5% to identify the patients who benefited from upfront systemic treatment. Peritumoral edema measured by F/G ratio is associated with failure of systemic CT in NSCLC patients affected by multiple and asymptomatic BM at baseline. F/G ratio seems a promising tool to identify BM patients in whom WBRT can be delayed. A prospective validation is warranted.
Evaluating the impact of Via Pathways (VP) on the adoption of changing treatment paradigms in metastatic hormone-sensitive prostate cancer (mHSPC).
Authors: David Friedland, Amanda Barry, Peter G. Ellis, Christopher Sweeney, Stephanie McCutcheon, Kathleen Lokay, Hans Benson, Melinda Krebs
Journal: Journal of Clinical Oncology (2016)

e16510 Background: Dissemination of new oncology data and tracking implementation has major challenges. Results from the co-operative group trial CHAARTED demonstrated an improvement in OS with the addition of a generic drug, docetaxel, to medical/surgical castration for the initial treatment of mHSPC. This data was first presented at the 2014 ASCO Annual Meeting and subsequently reviewed by the Via Pathways Prostate Committee. This Committee updates VP recommendations quarterly after evaluating newly published literature. Based on the CHAARTED results, the Committee agreed to recommend docetaxel + medical/surgical castration for high volume disease (visceral metastases or ≥ 4 bone lesions with ≥ 1 beyond the vertebral bodies and pelvis) and medical/surgical castration alone for low volume disease. This analysis examines the impact of these changes. Methods: On 7/10/14, these changes were available to VP users through a web-based portal. Decisions made by physicians navigating VP are captured in the VP database. Initial decisions for mHSPC from 7/7/09-10/25/15 were included. Results: 1248 treatment decisions met the eligibility criteria. Prior to the VP update on 7/10/14, 94.6% of 884 decisions were medical/surgical castration alone. After the update, 66.2% of 133 decisions for high volume disease were for docetaxel + medical/surgical castration and 90.9% of 231 decisions for low volume disease were for medical/surgical castration alone. Decisions are summarized in the table. Conclusions: Institutions utilizing VP demonstrated rapid adoption of the recommendation for initial docetaxel use with medical/surgical castration for high volume mHSPC. Evidence-based, physician-driven VP can improve quality of care by disseminating evidence quickly and enabling practices to evaluate adherence to changing treatment paradigms. Medical/Surgical Castration (n) Docetaxel + Medical/ Surgical Castration (n) Trial (n) Hospice or Observation (n) Other (n) Before VP Change 94.6% (836) 0.1% (1) 1.0% (9) 1.4% (12) 2.9% (26) After VP Change Low Volume 90.9% (210) 0.9% (2) 0.0% (0) 3.9% (9) 4.3% (10) High Volume 18.8% (25) 66.2% (88) 8.3% (11) 0.0% (0) 6.8% (9)
Biological and clinical insights from genetics of insomnia symptoms
Authors: Jacqueline M. Lane, Samuel E. Jones, Hassan S. Dashti, Andrew R. Wood, Krishna G. Aragam, Vincent T. van Hees, Linn B. Strand, Bendik S. Winsvold, Heming Wang, Jack Bowden, Yanwei Song, Krunal Patel, Simon G. Anderson, Robin N. Beaumont, David A. Bechtold, Brian E. Cade, Mary Haas, Sekar Kathiresan, Max A. Little, Annemarie I. Luik, Andrew S. Loudon, Shaun Purcell, Rebecca C. Richmond, Frank A. J. L. Scheer, Barbara Schormair, Jessica Tyrrell, John W. Winkelman, Juliane Winkelmann, Kristian Hveem, Chen Zhao, Jonas B. Nielsen, Cristen J. Willer, Susan Redline, Kai Spiegelhalder, Simon D. Kyle, David W. Ray, John-Anker Zwart, Ben Brumpton, Timothy M. Frayling, Deborah A. Lawlor, Martin K. Rutter, Michael N. Weedon, Richa Saxena
Journal: Nature Genetics (2019)
Altered immune environment in Lynch syndrome-related endometrial cancer: Implications for immunotherapy?
Authors: Janelle B. Pakish, Gary B. Chisholm, Qian Zhang, Joseph Celestino, Samuel C Mok, Melinda S Yates, Karen H. Lu
Journal: Journal of Clinical Oncology (2016)

5582 Background: Microsatellite instable (MSI) colon tumors associated with germline defects in mismatch repair genes (Lynch syndrome) have shown increased tumor immunogenicity and improved survival. Tumor immunogenicity in Lynch-related endometrial cancer (EC) is not yet clear; however, this subgroup may benefit from immunotherapy. Methods: 20 Lynch-related ECs were identified from a patient registry study. Cases were matched 1:2 to microsatellite stable (MSS) ECs based on age, BMI, stage, grade, and histology. Formalin fixed, paraffin embedded tumors were stained by a fluorescent multiplexing immunohistochemistry method. Automated multispectral imaging and analysis software were used to visualize and quantify staining in both tumor epithelial and stromal compartments. Nonparametric Mann-Whitney test was used to determine statistical significance of positive cell counts for CD8, CD68, granzyme B, and PD-L1 between the groups with a P value of < 0.05 indicating statistical significance Results: Tissue staining for 15 Lynch cases was evaluable. Of those cases, primary germline mutations were as follows: 2 (13.3%) in MLH1, 10 (66.7%) in MSH2, and 3 (20.0%) in MSH6. Lynch cases were found to have significantly higher CD8+ cells (82.8 vs 28.7 cells/mm2; p = 0.01) and granzyme B+ cells (139.8 vs 54.8 cells/mm2; p = 0.03) in tumor associated stroma compared to MSS matched cases. CD8+ cells were also increased within the tumor epithelial compartment in Lynch cases (12.8 vs 4.3 cells/mm2; p = 0.04). Lynch cases had fewer CD68+ cells in the stromal (14.3 vs 33.7 cells/mm2; p = 0.017) and tumor epithelial (0.7 vs 3.3 cells/mm2; p < 0.001) compartments. There was no significant difference in PD-L1 expression in the two groups within the stromal (Lynch 54.4% vs MSS 56.8%; p = 0.94) or epithelial (Lynch 2.7% vs MSS 5.2%; p = 0.14) compartments. Conclusions: Lynch related EC has increased tumor immunogenicity as demonstrated by elevated CD8+ and granzyme B+ cells in tumor associated stroma. This suggests that Lynch related EC patients are likely to respond favorably to immunotherapy. Additionally, although there was no difference in PD-L1 staining, we caution its use as the sole predictor of response to immunotherapy.
Prognostic and predictive inflammation-based markers for advanced colorectal cancer of the elderly patients.
Authors: Guifang Guo
Journal: Journal of Clinical Oncology (2016)

e15069 Background: Many studies found positive relationship of inflammation-based markers and cancers prognosis. However, this relationship was hardly clarified in geriatric cancers. This study aimed to distinguish some inflammation plasma factors which might become prognostic and predictive markers in the elderly patients with metastatic colorectal cancer(MCRC). Methods: Patients of age > 65 with MCRC, given palliative chemotherapy and targeted therapy at our institution from January 1st 2004 to October 1st 2015, were identified. The impact of some inflammation plasma factors on patients’ survival and chemotherapy efficacy were analyzed, including carcino embryonie antigen(CEA), carbohydrate antigen 19-9(CA 19-9), lactate dehydrogenase(LDH), C reactive protein(CRP) and the neutrophil-to-lymphocyte ratio(NLR). Other important clinicopathologic factors for prognosis, such as clinical stage, pathological grade, primary tumor sites, metastasis sites and different chemotherapy were contained in multivariate analysis. Results: The total of 270 patients with 2053 cycles of chemotherapy (mean cycles of 7.6), were followed up from five to 119.5 months(median 22.6 months). Median progression-free survival(PFS) for first-line chemotherapy was 8.4 months(95%CI 6.7-10.2 months) and median overall survival(OS) 32.62 months. (95%CI 25.6-35.8 months). OS significantly reduced in the groups of CEA ≥ 23ng/mL(P= 0.042), LDH ≥ 400U/L(P= 0.015), CA199 ≥ 37U/ml (P< 0.001), CRP ≥ 8.2mg/L(P= 0.003) and NLR ≥ 2.1(P= 0.022). Even when many important clinicopathologic factors were included in multivariate analysis, both CA199(RR 1.539, 95%CI 1.029-2.462, P= 0.036) and CRP(RR 1.631, 95% 1.081-2.462, P= 0.020) were still independent prognostic factors for OS. CEA ≥ 23ng/ml group had remarkable short PFS(P= 0.02), which(RR 2.552, 95%CI 1.283-5.078, P= 0.008) was also an independent prognostic factor in multivariate analysis. There was no relation found between ORR or DCR and any inflammation factor. Conclusions: In the elderly patients with MCRC, our study suggested abnormal increase in CA19-9 and CRP were independent prognostic factors for OS, and CEA was an independent predictive factor of PFS.
Mechanisms of Cell-to-Cell Transmission of Pathological Tau
Authors: Garrett S. Gibbons, Virginia M. Y. Lee, John Q. Trojanowski
Journal: JAMA Neurology (2018)

<h3>Importance</h3> Intracellular tau protein aggregates are a pathological hallmark of neurodegenerative tauopathies, including Alzheimer disease (AD), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), and Pick disease. Emerging evidence supports a model of cell-to-cell transmission of proteinaceous pathological tau seeds, which leads to recruitment and templated fibrillization of endogenous cellular tau followed by the spread of abnormal tau throughout the brain. These findings lead to the strain hypothesis, which predicts that distinct conformational strains or polymorphs of tau may underlie the clinical and neuropathological heterogeneity and cell-type specificity of tauopathies. In this review, we describe the evidence for propagation of distinct tau strains in cell culture and animal models of AD and mechanistic insights into cell-to-cell transmission of pathological tau. <h3>Observations</h3> Intracranial injections of synthetic tau-preformed fibrils and human brain-derived pathological tau into nontransgenic wild-type mice and transgenic mouse models of AD expressing β-amyloid and tau-amyloid deposits yield widespread pathological tau aggregates observed in neuroanatomically connected brain regions distant from the site of injection. Furthermore, when human brain–derived pathological tau obtained from distinct tauopathies (ie, brains with AD, PSP, and CBD) were injected into the brains of wild-type mice, they seeded tau pathology and faithfully recapitulated cell-type specific tau inclusions characteristic of each tauopathy in a time-dependent, dose-dependent, and injection site–dependent spread reflective of the connectome of the injection site. <h3>Conclusions and Relevance</h3> These findings provide compelling evidence that misfolded or pathological conformers of tau undergo cell-to-cell spread in a tauopathy strain-specific manner. Importantly, evidence to date supports that pathological tau strains do not behave like infectious agents, despite growing evidence that these tau strains undergo templated propagation and spread linked to the neuroanatomical connectome of the injection site.
Outbreak of human leptospirosis linked to contaminated water bodies in Northern Israel, June to August 2018
Authors: Yuval Dadon, Eric J. Haas, Ehud Kaliner, Emilia Anis, Shepherd Roee Singer, Yafit Atiya-Nasagi, Michal Cohen-Dar, Eva Avramovich, Roni King, Oded Sued, Tamir Goshen, Sharon Amit, Ian Miskin, Efrat Gino, Ruth Yishai, Rivka Sheffer, Itamar Grotto, Jacob Moran-Gilad
Journal: Eurosurveillance (2018)

We report preliminary findings of a large outbreak of human leptospirosis with 36 confirmed/probable and 583 suspected cases from June-August 2018, linked to contaminated water bodies in Northern Israel. There was a travel-associated case in Germany; additional cases are being investigated in other countries. The presumed chain of transmission, implicating wild boar and cattle, raises multiple challenges for risk assessment, risk management and risk communication currently being addressed by a public health response team.
P03.01 Nursing Intervention of coping with life changes for family caregiver of primary malignant brain tumor patient
Authors: H SATO, Y NARITA, Y MIYAKITA
Journal: Neuro-Oncology (2018)

Primary malignant brain tumor (PMBT)is one of the most difficult disease to treat, which often get to a terminal disease in a short time. Therefore, family caregiver of patient who developed PMBT (referred to as family) became the main physical caregiver of patients’. And as a result, they have been suffering from specific stress and/or distress caused by the influence, such as resignation of their jobs and bearing a great burden of housework in their home. Nursing intervention (referred to as intervention) is needed to alleviate such stress and/or distress. However, there have been no studies about intervention that have focused on life changes of burdens. Therefore, we developed a nursing support model (referred to as a model) to coping with life changes for “family”. The purpose of this study is to evaluate the feasibility of intervention by applying intervention of model to cases. When family experiences a big life change, it occurs to patient relapse or have strong symptoms, so the model covered the period before and after relapse. At this time,the model provides intervention to coping with life changes, by understanding their experience from eleven items such as mental and physical situation and fulfilling their needs from five aspects i) communication with health care providers, ii) flexible correspondence at the time of deterioration, iii) consideration to family, iv) information provision, v) specialized advice, education and explanation. We used a longitudinal case study design as research design. The content of intervention were interviews with a nurse at least once a month. The contents of the intervention performed in the interview and the reaction to the intervention were tape recorded, and it was taken as the data for subsequent analysis. Evaluation of interventions were conducted with an interview within one month after the end of intervention for each participant. Intervention was provided to 6 family caregivers. The patients’ diagnosis were glioblastomas, anaplastic astrocytoma, diffuse astrocytoma. The intervention period was a maximum of 112 days, a minimum of 64 days. All participants responded fulfillment of needs, promotion of coping and adaptation to life in interviews. Moreover, in the interview, the additional need ‘Empathy / listening to feelings’ was appeared. Since all 6 participants evaluated that intervention based on model was acceptable, it is considered that this model can be applied in the clinical setting. Promotion of coping and adaptation to life were shown during the 2–4 month, but three of them wished to continue more. So it is necessary to extend of the duration. Since the aspect of ‘Empathy / listening to feelings’ additionally emerged as the need,this add the model, finally six aspects of needs were including the model.
Effect of Early Metoprolol During ST-Segment Elevation Myocardial Infarction on Left Ventricular Strain
Authors: Tomaž Podlesnikar, Gonzalo Pizarro, Rodrigo Fernández-Jiménez, Jose M. Montero-Cabezas, Javier Sánchez-González, Chiara Bucciarelli-Ducci, Nina Ajmone Marsan, Zlatko Fras, Jeroen J. Bax, Valentin Fuster, Borja Ibáñez, Victoria Delgado
Journal: JACC. Cardiovascular imaging (2018)
Reduced CD160 Expression Contributes to Impaired NK-cell Function and Poor Clinical Outcomes in Patients with HCC
Authors: Haoyu Sun, Jing Xu, Qiang Huang, Mei Huang, Kun Li, Kun Qu, Hao Wen, Renyong Lin, Meijuan Zheng, Haiming Wei, Weihua Xiao, Rui Sun, Zhigang Tian, Cheng Sun
Journal: Cancer Research (2018)

Abstract We previously reported that deficiencies in natural killer (NK)–cell number and function play an important role in the progression of hepatocellular carcinoma (HCC). However, the mechanisms underlying this phenomenon remain obscure. In this study, we analyzed the expression of CD160 on intrahepatic NK cells by evaluating peritumoral and intratumoral tissues of 279 patients with HCC and 20 healthy livers. We observed reduced expression of CD160 on intratumoral NK cells, and patients with lower CD160 cell densities within tumors exhibited worse disease and a higher recurrence rate. High-resolution microarray and gene set enrichment analysis of flow cytometry–sorted primary intrahepatic CD160+ and CD160− NK cells of healthy livers indicated that human CD160+ NK cells exhibited functional activation, high IFNγ production, and NK-mediated immunity. In addition, global transcriptomic analysis of sorted peritumoral and intratumoral CD160+ NK cells revealed that intratumoral CD160+ NK cells are more exhausted than peritumoral CD160+ NK cells and produce less IFNγ. High levels of TGFβ1 interfered with production of IFNγ by CD160+ NK cells, blocking of which specifically restored IFNγ production in CD160+ NK cells to normal levels. These findings indicate that reduced numbers of CD160+ NK cells, together with the functional impairment of CD160+ NK cells by TGFβ1, contribute to tumor immune escape. In addition, restoring the expression of CD160 and blocking TGFβ1 appear a promising therapeutic strategy against liver cancer. Significance: These findings show that reduced number and function of CD160+ NK cells in the tumor microenvironment contributes to immune escape of HCC; blocking TGFβ1 restores IFNγ production of CD160+ NK cells.
Sequential treatment with Nab-paclitaxel plus Gemcitabine and Folfirinox in metastatic pancreatic adenocarcinoma: GABRINOX phase II results.
Authors: Eric Assenat, Christelle De La Fouchardiere, Caroline Mollevi, Emmanuelle Samalin, Fabienne Portales, Françoise Desseigne, Christophe Carenco, Marie Dupuy, Ernesto Lopez-Martinez, Catherine Fiess, Thibault Mazard, Marc Ychou
Journal: Journal of Clinical Oncology (2018)

4109 Background: Folfirinox (FFX) and Nab-paclitaxel/Gemcitabine (AG) showed significant efficacy improvement compared to Gemcitabine alone in metastatic pancreatic cancer (mPC). Alternating AG and FFX may overcome resistance and delay tumor progression. We designed a multicenter phase I-II trial to evaluate a sequential treatment with AG followed by FFX in 1st-line. Phase I established the recommended doses and confirmed the feasibility in a 12-patient expansion cohort (Assenat et al, ESMO 2016). Phase II assessed the efficacy of the recommended doses. Methods: During phase II, AG and FFX were administered sequentially, each AG cycle followed by 2 FFX cycles. All chemotherapeutic agents were administered according to standard practice. The primary endpoint was the objective response rate (ORR). Results: 58 patients were included in 3 centers, between 2014 and 2016. Patients were 50% male, median age 60 years (34-72), ECOG PS 0 (37.9%) or 1 (62.1%). A median of 4 (1-9) cycles were administered, during 34.2 weeks (2.1-79.4). Neurotoxicity rate was low (gr3: 5.2%). Main grade 3/4 toxicities were thrombosis (17.2%/0%), thombopenia (31%/1.7%), neutropenia (34.5%/22.4%), febrile neutropenia (1.7%/1.7%), nausea (17.2%/0%), diarrhea (25.9%/1.7%), weight loss (1.7%/0%) and asthenia (31%/0%). No toxic death was reported. Efficacy analysis included 57 patients. Response was complete in 3.5% patients; partial in 59.7%; disease was stable in 21% patients, progressive in 15.8%. The primary objective was met with an ORR of 63.2% (95% CI: 49.3-75.5). After a median follow-up of 18.6 months (95% CI: 14.5-25.6), the median progression-free and overall survival were 9.6 months (95% CI: 6.0-12.3) and 17.8 (95% CI: 11.7-21.3) months. Conclusions: This phase II study confirmed the phase I data with an acceptable toxicity and a high response rate for this alternating AG and FFX treatment. Survival results are promising and justify considering further randomized trials in these setting. Clinical trial information: NCT01964287.Time (months) PFS rate (%) 95% CI OS rate (%) 95% CI 9 51.6 [37.8-63.8] 70.3 [56.6-80.4] 12 41.2 [27.3-54.7] 61.5 [47.6-72.7] 15 (PFS) / 18 (OS) 29.2 [16.2-43.4] 47.9 [33.3-61.0] Survival analyses: n = 58
BRAF Dimerization: An Underlying Resistance Mechanism in Low-Grade Pediatric Gliomas
Authors: Gabriele Romano, Lawrence N. Kwong
Journal: Cancer Discovery (2018)

Abstract Summary: BRAF fusions and mutations are the most frequent genetic alterations in pediatric low-grade gliomas. The work from Wang and colleagues identifies an acquired secondary BRAF mutation that confers resistance to pharmacologic BRAF inhibition in a BRAFV600E glioma. The authors demonstrate that the mutation results in increased BRAF homodimerization, which in turn is targetable with second-generation BRAF inhibitors. Cancer Discov; 8(9); 1064–5. ©2018 AACR. See related article by Wang et al., p. 1130.