tbuckley/cabot-search huggingface dataset:
P03.20 Comparison of histopathology profiles in surgically resected cerebral radiation necrosis with recurrent irradiated brain tumor
Authors: L. Rogers, C. Tatsuoka
Journal: Neuro-Oncology (2017)

Introduction: A conundrum exists in establishing the diagnosis of cerebral radiation necrosis (RTN), a dysregulated repair process following brain radiation therapy (RT), by tissue examination because specific histologic characteristics have not been defined and distinguished from those of recurrent brain tumor (RBT) after RT. The distinction of these two entities is critical in patient management. We compared the type and grade of histologic characteristics identified in surgically-derived tissue specimens obtained at imaging recurrence in brain tumor patients treated with RT and in whom the specimen contained predominantly or totally RTN versus predominantly or totally RBT. Materials and Methods: Subjects in this retrospective IRB-approved study had diagnosis of RTN or RBT identified by a review of brain pathology reports at UHCMC from 2004--2013. RTN was defined by > 80% features of RTN; RBT was defined by >80% active tumor. All other cases (“mixed RTN and RBT”) were excluded. Clinical, imaging and treatment data were reviewed. Histologic profiling included vascular changes (telangiectasia, hyalinization, wall thickening and necrosis, thrombosis, endothelial hypertrophy, circumferential endothelial hyperplasia [CEN]), necrosis (coagulative [CN], pseudopalisading, zonal geographic [ZGN]), tumor features (perinuclear halos, mitosis, tumor satellitosis, epithelial differentiation), tissue reaction (granulation tissue, collagen scar, demyelination, “RT astrocytes” [RTA]), microcysts, dystrophic calcification [DC], blood products, and inflammatory infiltrates. Each characteristic was graded 0, <25%, 26—50%, 51—75%, 76–100% by a board-certified neuropathologist (MC). Profiles were compared with pretreatment tumor when available. Results: 66 patients treated with EBRT and/or SRS were identified, 40 with RBT (glioma 25, metastasis 15) and 26 with RTN (metastasis 14, glioma 12). Using Fisher’s exact and Chi-square tests we identified significant (p <.05) differences in the frequency and severity of ZGN, RTA and DC in glioma and metastasis RTN as compared with RBT. Vascular hyalinization, hemosiderin, collagen scar and granulation tissue were increased in glioma RTN as compared with RBT. Glioma RBT was associated with more CN, mitosis, and CEH than RTN. Metastatic RBT was associated with more epithelial differentiation than RTN. Conclusions: The quantitative histologic profiles we identified in RTN as compared with RBT may assist neuropathologists in the interpretation of surgically resected tissue specimens following RT for a brain tumor. Grant support CTSC UL1TR000439
P16.23 Surgical resection of melanoma brain metastases, a highly effective modality for local control in the era of prolonged survival from stage IV melanoma
Authors: B. Shivalingam, R. Manoharan
Journal: Neuro-Oncology (2017)

Introduction: Novel systemic therapies targeting the MAP kinase pathway (BRAF inhibitors) or immune checkpoints have significantly improved the overall survival of patients with metastatic melanoma, with a 2 year overall survival now above 50%. The importance of achieving durable local control of brain metastases is therefore reinforced. We sought to determine the local control rate after complete surgical resection of individual brain metastases in patients with stage IV melanoma. Secondary outcome measures were morbidity and mortality associated with these surgeries, frequency of distant recurrence of brain metastases, and overall survival. Additionally, we sought to define patterns of treatment in relation to radiation options and systemic therapies. METHODS: Clinicopathological data was retrospectively collected from 104 consecutive patients recorded in a prospective database who underwent surgical resection of 1 – 4 melanoma brain metastases between May 2008 and December 2014 at Melanoma Institute Australia and Royal Prince Alfred Hospital, Sydney Australia. Group 1 comprised all those treated between May 2008 and May 2011 (before the routine use of effective drug therapies). Group 2 comprised all those treated between June 2011 and December 2014. Given the marked heterogeneity between the treatment the two groups have received, we felt that statistical analyses for direct comparisons would be inappropriate. Results: Group 1 had 46 patients with a total of 78 cerebral melanoma metastatic lesions resected and Group 2 had 58 patients with a total of 106 lesions resected. The local control rate at 24 months was 91% in both Group 1 and Group 2. The median overall survival was higher in Group 2 than Group 1, as reflected by 13.5 months and 11.5 months respectively. The use of whole brain radiation therapy, systemic therapy, stereotactic ­radiosurgery (SRS) to cavity varied between the two groups, with 72%, 35%, 0% in Group 1 and 57%, 34%, 10% in Group 2, respectively. The rates of SRS failure varied between the two groups, with 4% in Group 1 and 34% in Group 2. Peri-operative complications rates and death rate of 4% and 1% respectively was detected in Group 1, and 6% and 2% respectively in Group 2. CONCLUSION: Surgical resection of melanoma brain metastases is a highly effective and safe means of local control for stage IV melanoma patients who now see prolonged survival when treated in a multimodal way by a cohesive multidisciplinary group.
Abstract 129: Suppressor of Cytokine Signaling 1 in Dendritic Cells Inhibits Myocardial Inflammation in Experimental Autoimmune Myocarditis
Authors: Kazuko Tajiri, Kyoko Imanaka-Yoshida, Michiaki Hiroe, Nobutake Shimojo, Satoshi Sakai, Kazutaka Aonuma, Yasuhiro Yasutomi
Journal: Circulation Research (2012)

Introduction: Autoimmunity is considered to play an important role in the development of myocarditis and dilated cardiomyopathy. Recent reports have indicated that a subgroup of myocarditis patients may benefit from immune-targeted therapies. Suppressor of cytokine signaling1 (SOCS1) is an intracellular, cytokine-inducible protein that regulates the responses of immune cells to cytokines. We therefore hypothesized that overexpression of SOCS1 may inhibit the inflammation of myocarditis and cardiomyopathy. Methods and Results: Myocarditis was induced by subcutaneous immunization with cardiac specific peptides derived from α-myosin heavy chain in BALB/c mice on days 0 and 7. Plasmid DNA encoding SOCS1 (pSOCS1) was injected intraperitoneally into mice on days 0, 5 and 10. pSOCS1 treatment significantly decreased heart-to-body weight ratios and the number of infiltrating cells in the heart. Echocardiography showed preserved contractile function in pSOCS1-treated mice. Although autoimmune myocarditis is a CD4+ T cell-mediated disease, pSOCS1 treatment does not have a direct suppressive effect on autoreactive T-cell activation. The introduced pSOCS1 suppressed proinflammatory cytokine production and STAT1 phosphorylation in dendritic cells (DCs). In addition, the proliferative responses of autoreactive CD4+ T cells co-cultured with DCs from pSOCS1-treated mice were much weaker than those of cells cultured with DCs from control plasmid-injected mice. These results suggested that the inoculated pSOCS1 may have been transfected into DCs and impaired DC function in vivo. Conclusion: The administration of pSOCS1 protected mice from the development of experimental autoimmune myocarditis, which was mediated by the inhibition of DC function that in turn reduced the activation of autoreactive CD4+ T cells.
Nuclear HSET as a negative prognostic indicator and racial disparity biomarker in breast cancer patients.
Authors: Angela Ogden, Padmashree C.G. Rida, Sergey Klimov, Vaishali Pannu, Yuan Liu, Michelle D. Reid, Xiaoxian Li, Guilherme Henrique Cantuaria, Ritu Aneja
Journal: Journal of Clinical Oncology (2015)

1078 Background: The kinesin HSET (human spleen, embryo, and testes) is a negative prognostic indicator in cancer. Specifically, increased expression levels are associated with brain metastases in lung cancer, and increased nuclear levels are associated with worse overall and progression-free survival in breast cancer. HSET is overexpressed in triple-negative breast cancer, which is associated with African American (AA) race; however, a definitive role for HSET in health disparity has not been established. Methods: To probe associations between HSET levels, race, and prognosis, formalin-fixed paraffin-embedded breast tumor biopsies from 149 AA and 109 European American (EA) patients were immunostained for HSET. Staining intensity (0-3) and extent (0-100%) in nuclei and cytoplasms were determined by blinded pathologists. Weighted indices were calculated as the products of the staining intensity and extent and were stratified into low, moderate, and high groups. Associations of these groups with negative prognostic indicators and overall and progression-free survival were determined using Cox proportional hazards and Kaplan-Meier analyses. Results: High nuclear HSET was associated with more advanced grade and a higher percentage of Ki67-positive cells than low nuclear HSET regardless of race (P < 0.05 for all). However, high nuclear HSET was only associated with triple-negative receptor status (P < 0.001) and worse overall survival (P = 0.02) in AAs. In multivariate analysis, AA breast cancer patients with high nuclear HSET had a 5.05-fold increased risk of worse overall survival after adjusting for grade, stage, and triple-negative receptor status (95% CI = 1.77-14.40). They also had a 2.72-fold increased risk of worse progression-free survival in multivariate analysis (95% CI = 1.00-7.39). Cytoplasmic HSET was not significantly associated with survival in either race. Conclusions: These data suggest that nuclear HSET is a valuable negative prognostic biomarker in AA breast cancer patients. Determination of nuclear HSET levels may help to risk-stratify AAs with breast cancer, who suffer disproportionate disease-specific morbidity and mortality relative to their EA counterparts.
Adoption of Sorafenib for the Treatment of Advanced-Stage Hepatocellular Carcinoma in Oncology Practices in the United States
Authors: Helen M. Parsons, Quyen Chu, Jordan J. Karlitz, Jennifer L. Stevens, Linda C. Harlan
Journal: Liver Cancer (2017)

&lt;b&gt;&lt;i&gt;Background:&lt;/i&gt;&lt;/b&gt; The adoption of sorafenib into oncology practice as a first-line systemic treatment for advanced hepatocellular carcinoma (HCC) is not well understood. We examined sorafenib use since Food and Drug Administration (FDA) approval in 2007 and associated survival for individuals diagnosed with advanced HCC, conducting a population-based evaluation of treatment patterns and outcomes for this newly approved drug in the US over time. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; We identified individuals diagnosed with Barcelona Clinic Liver Cancer Stage C from the 2007 and 2012 National Cancer Institute Patterns of Care study. We examined trends in use as well as patient and clinical factors associated with receiving sorafenib using multivariate logistic regression analysis. We then evaluated the association between sorafenib use and overall hazard of death using multivariate Cox proportional hazards regression. &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; Among 550 individuals diagnosed with advanced HCC, we found no significant increase in the proportion of patients treated with sorafenib from 2007 to 2012 (26.3 vs. 30.4%). After adjusting for patient and clinical characteristics, non-Hispanic Blacks (compared to non-Hispanic Whites) and those with a lower Child-Pugh score remained more likely to receive sorafenib. Individuals receiving systemic chemotherapy only, radiation therapy only, or no treatment at all experienced a higher risk of death than those treated with sorafenib, while those receiving a transplant experienced a lower risk of death. &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; Sorafenib has not been widely adopted into oncology practice since FDA approval for advanced HCC. Few factors apart from Child-Pugh score and race/ethnicity predict sorafenib use in clinical practice, although sorafenib treatment is associated with a lower risk of death.
Gastrointestinal Surgery for Severe Obesity
Journal: Annals of Internal Medicine (1991)

Surgeons, gastroenterologists, endocrinologists, psychiatrists, nutritionists, and other health care professionals, as well as members of the public convened to address nonsurgical treatments for severe obesity, surgical treatments for severe obesity, and criteria for selection, the efficacy, and risks of surgical treatments for severe obesity, and the need for future research on and epidemiologic evaluation of these therapies. The National Institutes of Health Consensus Development Panel recommended that patients seeking therapy for severe obesity for the first time should be considered for treatment in a nonsurgical program that integrates a dietary regimen, appropriate exercise, behavior modification, and psychological support; that gastric restrictive or bypass procedures could be considered for well-informed and motivated patients in whom the operative risks were acceptable; that patients who are candidates for surgical procedures should be selected carefully after evaluation by a multidisciplinary team with medical, surgical, psychiatric, and nutritional expertise; that surgery be done by a surgeon who has substantial experience in the particular procedure and who works in a clinical setting with adequate support for all aspects of management and assessment; and that patients undergo lifelong medical surveillance after surgery.
P03.12 Peritumoral atrophy and neuronal deformation of meningioma
Authors: T. Kuroiwa, J. Ohki
Journal: Neuro-Oncology (2017)

BACKGROUD: In the intracranial meningioma, we often observe peritumoral cortical atrophy. The atrophy is known to cause various neurological deficits. We analyzed neuropathological changes of the peritumoral cortical atrophy in the clinical cases. Materials and Methods: We analyzed 2 intracranial meningioma cases and 1 control case (2 females and 1 male, age = 72.0 ± 1.7, mean±SEM, 2 autopsy cases and 1 biopsy case). In the coronal sections of autopsied brains, we measured the size of meningioma, peritumoral gray matter and peritumoral white matter. In the histological section, we measured cortical thickness of peritumoral area, and also we measured nuclear height /width ratio of neuron, astrocyte and oligodendrocyte of the peritumoral area. Results: The thickness of peritumoral gray matter was 0.33 ± 0.12 of the control. The area size was 0.62 ± 0.07 of the control area. Nuclear size of neuron, astrocyte or oligodendrocyte in the peritumoral was not significantly different with those of the control. However, nuclear height/width ratio of neuron was significantly reduced in the peritumoral area to 0.46 ± 0.016 of the control (p<0.001). The nuclear height/width ratio of astrocyte and oligodendrocyte were also reduced to 0.73 ± 0.065 (p=0.03) and 0.89 ± 0.06 (p=0.12) of the control, respectively. The decrease observed in the neuron was significantly greater than those of astrocyte and oligodendrocyte (p=0.003). The reduction of nuclear height/width ratio was in parallel with the reduction of gray matter thickness (r=0.99). CONCLUSION: In the intracranial meningioma, peritumoral brain tissue shows atrophy and nuclear deformation of the surviving neuron. Not only the cortical atrophy but also the nuclear deformation might be responsible for neurological deficits.
SIRT1/HSF1/HSP pathway is essential for exenatide‐alleviated, lipid‐induced hepatic endoplasmic reticulum stress
Authors: Xiaobin Zheng, Fen Xu, Hua Liang, Huanyi Cao, Mengyin Cai, Wen Xu, Jianping Weng
Journal: Hepatology (2017)

Recent studies have indicated that lipid-induced endoplasmic reticulum (ER) stress is a major contributor to the progression of hepatic steatosis. Exenatide (exendin-4), a glucagon-like peptide-1 receptor agonist, is known to improve hepatic steatosis, with accumulating evidence. In this study, we investigated whether exenatide could alleviate lipid-induced hepatic ER stress through mammal sirtuin 1 (SIRT1) and illustrated the detailed mechanisms. Male C57BL/6J mice challenged with a high-fat diet (HFD) were treated with exenatide or normal saline by intraperitoneal injection for 4 weeks. We observed that HFD feeding induced hepatic ER stress as indicated by increased expression of glucose-regulated protein 78, phosphorylated protein kinase-like ER kinase, and phosphorylated eukaryotic initiation factor 2α, while these increases were significantly inhibited by exenatide. Exenatide notably decreased the liver weight and hepatic steatosis induced by HFD challenge. Consistently, in human HepG2 cells and primary murine hepatocytes, exendin-4 also significantly alleviated the ER stress and lipid accumulation induced by palmitate. Importantly, further studies showed that exendin-4 enhanced the binding of heat shock factor 1 to the promoter of heat shock protein (HSP) genes through SIRT1-mediated deacetylation, which then increased the expression of molecular chaperones HSP70 and HSP40 to alleviate hepatic ER stress. Finally, inhibition of SIRT1 by genetic whole-body heterozygous knockout or by lentiviral short hairpin RNA knockdown greatly diminished the effect of exenatide on deacetylating heat shock factor 1, increasing HSP expression and alleviating ER stress and hepatic steatosis in HFD-fed mice.The SIRT1/heat shock factor 1/HSP pathway is essential for exenatide-alleviated, lipid-induced ER stress and hepatic steatosis, which provides evidence for a molecular mechanism to support exenatide and incretin mimetics as promising therapeutics for obesity-induced hepatic steatosis. (Hepatology 2017;66:809-824).
Intensity of Statin Treatment and Mortality
Authors: José Pedro L. Nunes
Journal: JAMA Cardiology (2017)

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P16.13 Surgical Results of Growth Hormone-Secreting Pituitary Adenoma
Authors: O. Kim
Journal: Neuro-Oncology (2017)

Objective: We retrospectively analyzed the surgical outcomes of 42 patients with growth hormone (GH)-secreting pituitary adenoma to evaluate the clinical manifestations and to determine which preoperative factors significantly influence remission. Methods: Forty-two patients with GH-secreting pituitary adenoma underwent transsphenoidal surgery (TSS) between 1995 and 2007. The patient group included 23 women and 19 men, with a mean age of 40.2 (range 13-61) years, and a mean follow-up duration of 49.4 (range 3-178) months after the operation. For comparable radiological criteria, we classified parasellar growth into five grades according to the Knosp classification. We analyzed the surgical results of the patients according to the most recent stringent criteria for cure. Results: The overall rate of endocrinological remission in the group of 42 patients undergoing primary TSS was 64% (26 of 42). The remission rate was 67% (8 of 12) for microadenoma and 60% (18 of 30) for macroadenoma. The remission rate was 30% (3 of 10) for the group with cavernous sinus invasion and 72% (23 of 32) for the group with intact cavernous sinus. Cavernous sinus invasion in Knosp grade III and IV was significantly correlated with the remission rate. There was a significant relationship between preoperative mean GH concentration and early postoperative outcome, with most patients in remission having a lower preoperative GH concentration. Conclusion: TSS is thought to be an effective primary treatment for GH-secreting pituitary adenomas according to the most recent criteria of cure. Because the remission rate in cases with cavernous sinus invasion is very low, early detection of the tumor before it extends into the cavernous sinus and a long-term endocrinological and radiological follow-up are necessary in order to improve the remission rate of acromegaly.
Zinc Oral Supplementation Induces a Significant Rise of TRECs and T CD4+ NaϊVe and Prevents the Increase of Ttv Viral Load after Stem Cell Transplantation: The Zenith Study
Authors: Lorenzo Iovino, Enrico Orciuolo, Gabriele Buda, Giovanni Carulli, Fabrizio Maggi, Daniele Focosi, Riccardo Morganti, Francesca Guerrini, Sara Galimberti, Mario Petrini
Journal: Blood (2016)
Heart Rate and Rhythm and the Benefit of Beta-Blockers in Patients With Heart Failure
Authors: Dipak Kotecha, Marcus D. Flather, Douglas G. Altman, Jane Holmes, Giuseppe Rosano, John Wikstrand, Milton Packer, Andrew J.S. Coats, Luis Manzano, Michael Böhm, Dirk J. van Veldhuisen, Bert Andersson, Hans Wedel, Thomas G. von Lueder, Alan S. Rigby, Åke Hjalmarson, John Kjekshus, John G.F. Cleland
Journal: Journal of the American College of Cardiology (2017)
Biomarker Accessible and Chemically Addressable Mechanistic Subtypes of BRAF Melanoma
Authors: Banu Eskiocak, Elizabeth A. McMillan, Saurabh Mendiratta, Rahul K. Kollipara, Hailei Zhang, Caroline G. Humphries, Changguang Wang, Jose Garcia-Rodriguez, Ming Ding, Aubhishek Zaman, Tracy I. Rosales, Ugur Eskiocak, Michael P. Smith, Jessica Sudderth, Kakajan Komurov, Ralph J. Deberardinis, Claudia Wellbrock, Michael A. Davies, Jennifer A. Wargo, Yonghao Yu, Jef K. De Brabander, Noelle S. Williams, Lynda Chin, Helen Rizos, Georgina V. Long, Ralf Kittler, Michael A. White
Journal: Cancer Discovery (2017)

Abstract Genomic diversity among melanoma tumors limits durable control with conventional and targeted therapies. Nevertheless, pathologic activation of the ERK1/2 pathway is a linchpin tumorigenic mechanism associated with the majority of primary and recurrent disease. Therefore, we sought to identify therapeutic targets that are selectively required for tumorigenicity in the presence of pathologic ERK1/2 signaling. By integration of multigenome chemical and genetic screens, recurrent architectural variants in melanoma tumor genomes, and patient outcome data, we identified two mechanistic subtypes of BRAFV600 melanoma that inform new cancer cell biology and offer new therapeutic opportunities. Subtype membership defines sensitivity to clinical MEK inhibitors versus TBK1/IKBKϵ inhibitors. Importantly, subtype membership can be predicted using a robust quantitative five-feature genetic biomarker. This biomarker, and the mechanistic relationships linked to it, can identify a cohort of best responders to clinical MEK inhibitors and identify a cohort of TBK1/IKBKϵ inhibitor–sensitive disease among nonresponders to current targeted therapy. Significance: This study identified two mechanistic subtypes of melanoma: (1) the best responders to clinical BRAF/MEK inhibitors (25%) and (2) nonresponders due to primary resistance mechanisms (9.9%). We identified robust biomarkers that can detect these subtypes in patient samples and predict clinical outcome. TBK1/IKBKϵ inhibitors were selectively toxic to drug-resistant melanoma. Cancer Discov; 7(8); 832–51. ©2017 AACR. See related commentary by Jenkins and Barbie, p. 799. This article is highlighted in the In This Issue feature, p. 783