tbuckley/cabot-search huggingface dataset:
CRAN-40. A NATIONAL UK GUIDELINE FOR MANAGING PITUITARY ADENOMAS IN CHILDREN AND YOUNG PEOPLE UNDER 19 YEARS DEVELOPED ACCORDING TO THE AGREE II FRAMEWORK
Authors: Jo Blair, Márta Korbonits, Amy Ronaldson, Mary Dang, Helen Spoudeas
Journal: Neuro-Oncology (2018)

Pituitary adenomas are usually benign tumours arising from the hormone-secreting cells of the anterior pituitary gland, resulting in excess hormone secretion and the development of characteristic syndromes, such as Cushing’s disease, acromegaly and hyperprolactinaemia, and/or mass effects on surrounding vital structures causing for example visual disturbances and pituitary hormone deficiencies. In children and young people under 19 years (CYP), the management of pituitary adenomas is particularly challenging given their extreme rarity, more aggressive phenotype and likely genetic predisposition, as well as the lack of age- and pituitary-specific multidisciplinary teams in current decision-making and service provision. Hence, the UK sought to create national, high-quality, multi-professional guidance using AGREE II methodology under the auspices of the UK paediatric endocrine (BSPED), paediatric oncology (CCLG) and paediatric (RCPCH) societies. Twenty geographically diverse experts in adult and paediatric endocrinology, neuroradiology, clinical oncology, neurosurgery, paediatric neuropathology, and neuro-ophthalmology constituted the guideline development group and formulated 155 clinical questions. Following a systematic literature review of 409 identified papers dating from 1990 to 2016, the group made 56 evidence-based recommendations for biochemical, radiological, cytological, genetic, and ophthalmic assessment of suspected pituitary adenomas as well as surgical and oncological treatment, and follow-up. A further 55 recommendations were made based on group expert opinion and were reviewed by two rounds of an international Delphi expert consensus process. This guideline should facilitate improved clinical care and outcomes in CYP with pituitary adenomas.
Prognostic factors for early recurrences following cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) for colorectal and appendiceal peritoneal metastases
Authors: N. Chandran, G. Tan, C. Chia, M. Teo
Journal: Annals of Oncology (2018)

Introduction: The introduction of cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) has improved the prognosis of selected patients with peritoneal metastases (PM) of colorectal and appendiceal primaries. However, despite careful patient selection and complete macroscopic resection, early recurrences (ER) still occur. This study aims to identify risk factors for ER. Methods: Patients with appendiceal and colorectal PM treated with CRS and HIPEC between January 2001 and June 2016 at the National Cancer Centre Singapore were analyzed. Comparison between patients who developed ER (< 12 months) and those with late recurrence (>12 months) or no recurrence was performed using univariate and multivariate analyses. Results: In the appendiceal group, 9 out of 58 patients (16%) developed ER. The median disease-free interval (DFI) of patients with ER was 10 months and in patients with no ER was 26 months. Univariate analysis identified male gender, elevated preoperative CEA levels, preoperative CA 19-9 levels and high PCI score as factors associated with ER. There were no significant factors for ER on multivariate analysis. For the colorectal cohort, 30 out of 83 patients (36%) developed ER. The median DFI of patients with ER was 11.5 months and in patients without ER it was 21 months. Univariate analysis identified that increased age, elevated CA-125 levels, high PCI score, intraoperative complications and longer length of hospital stay after CRS and HIPEC was associated with ER. Multivariate analysis identified elevated preoperative CA-125 levels as significantly associated with ER. Conclusion: ER is a considerable consequence in patients with peritoneal metastases of appendiceal and colorectal primaries. By identifying factors associated with ER, patients at risk may benefit from an alternative treatment strategy and follow up.
Heart specific PGC-1α deletion identifies metabolome of cardiac restricted metabolic heart failure
Authors: Olli Kärkkäinen, Tomi Tuomainen, Maija Mutikainen, Marko Lehtonen, Jorge L Ruas, Kati Hanhineva, Pasi Tavi
Journal: Cardiovascular Research (2018)

Abstract Aims Heart failure (HF) is associated with drastic changes in metabolism leading to a cardiac energy deficiency well as maladaptive changes in multiple other tissues. It is still unclear which of these changes originates from cardiomyocyte metabolic remodelling or whether they are induced secondarily by systemic factors. Our aim here was to induce cardiac restricted metabolic changes mimicking those seen in HF and to characterize the associated metabolite changes in the heart, circulation, and peripheral tissues. Methods and results We generated a cardiac specific PGC-1α knockout mice (KO) to specifically induce metabolic dysregulation typically accompanied by HF and performed a non-targeted LC-MS metabolite profiling analysis of heart, plasma, liver, and skeletal muscle to identify metabolites associated with cardiac specific metabolic remodelling. The KO animals developed a progressive cardiomyopathy with cardiac dilatation leading to fatal HF. At 17 weeks of age, when significant remodelling had occurred but before the onset of HF, isolated PGC-1α deficient cardiomyocytes had suppressed glucose and fatty acid oxidation as well as blunted anaerobic metabolism. KO hearts displayed a distinctive metabolite profile with 92 significantly altered molecular features including metabolite changes in energy metabolism, phospholipid metabolism, amino acids, and oxidative stress signalling. Some of the metabolite changes correlated with the specific parameters of cardiac function. We did not observe any significant alterations in the metabolomes of the other measured tissues or in plasma. Conclusions Heart specific PGC-1α KO induces metabolic, functional, and structural abnormalities leading to dilating cardiomyopathy and HF. The metabolic changes were limited to the cardiac tissue indicating that cardiomyocyte metabolic remodelling is not sufficient to evoke the body wide metabolic alterations usually associated with HF.
NFM-13. LONG TERM FOLLOW-UP OF OPTIC PATHWAY GLIOMAS IN CHILDREN WITH NEUROFIBROMATOSIS TYPE 1 – AN ONCOLOGY HOSPITAL EXPERIENCE
Authors: Mariana Fernandes, João Passos, Daniela Garcez, Manuela Mafra, Maria Fátima Campos, Sofia Nunes, Duarte Salgado
Journal: Neuro-Oncology (2018)

Optic Pathway Gliomas (OPGs) are the most prevalent intracranial tumours in children with Neurofibromatosis type 1 (NF1). Although commonly indolent, OPGs may have an aggressive clinical course and their approach is often challenging. The aim of this study was to evaluate the outcome of OPGs diagnosed in patients with NF1 during childhood, followed up to 22 years. Retrospective review of demographics, neurological and ophthalmological evaluations, neuroimaging and treatments applied to all children with OPGs and NF1 presenting to an oncology hospital, 1991-2017. Of 62 children (31 males, 31 females, median age at diagnosis 4,0 years), 27(44%) were treated (based on clinical or imagiological progression), in 4 off which the initial decision had been watchful surveillance. Of the treated patients, all were submitted to chemotherapy, 4 underwent surgery, 1 radiotherapy. Visual acuity improved in 9, stabilized in 12 and worsened in 3. Complete response was obtained in 1 patient, partial response in 19 and disease stability in 6. One patient died. One patient is currently under treatment, the remaining 25 have stable disease. Patients who didn’t undergo treatment remain neuro-ophthalmologically stable, 2 had spontaneous tumour regression. Mean follow up time is 7,9 years. Despite the complex management of patients with NF1 and OPGs, inherent to their variable natural history and difficulties in clearly defining neuro-ophthalmological progression and response to treatment in the pediatric population, our results suggest that careful surveillance is acceptable in most patients and that a majority of patients who undergo treatment benefit from it.
Prognostic models in advanced gastric cancer in first and second line chemotherapy treatment in Spanish population.
Authors: Jorge Hernando-Cubero, Natalia Alvarez-Garcia, Roberto A. Pazo Cid, Javier Martinez Trufero, Maria Alvarez, Juan Lao Romera, Esther Millastre, Isabel Pajares Bernad, Julia Madani, Joaquin Gimeno, Ana Nuno-Alves, Eduardo Polo Marques, Vicente Alonso, Antonio Anton
Journal: Journal of Clinical Oncology (2017)

e15603 Background: No globally accepted prognostic score has been developed in advanced gastric cancer (AGC). The purpose of this study is to explore baseline host or tumor related prognostic factors in spanish AGC patients in first and second line chemotherapy treatment. In addition we compare our scores with previously published scores in asian and european population. Methods: A total of 166 patients with AGC treated in our institution between 2012 and 2016 were screened. 119 received first line chemotherapy (CT) and 47 of them also received second line CT and were included in the analysis. Prognostic factors were evaluated using the Cox proportional hazard model. We use as comparators four first line and three second line scores published in literature. Results: The overal survival (OS) in first line and second line patients were 9 and 5 months. To construct first line CT score we selected four risk factors: ECOG≥2, Her2 negative, Irinotecan based CT and albumin &lt; 3,6mg/dl. OS were 23 months in low risk group, who had zero or one risk points, 15 months for patients in the moderate risk group, who had two or three risk points, and 5 months for patients in the high risk group, who had all four risk points. In the second line CT score we included four risk factors: ECOG ≥2, albumin &lt; 3.6mg/dl, Hb &lt; 11.5mg/dl and CA19.9 reduction less than 30% after 2 CT cycles. OS were 30 months in low risk group, who had zero or one risk points, 16 months for patients in the moderate risk group, who had two or three risk points, and 3 months for patients in the high risk group, who had all four risk points. Conclusions: In the present study, we propose two new prognostic scores for patients with AGC developed in the same cohort and including HER2 status. This prognostic model could help clinicians choose and applicable treatment based on the stimated prognosis. [Table: see text]
Nervous System Disease in Systemic Lupus Erythematosus: Current Status and Future Directions
Authors: John G. Hanly, Elizabeth Kozora, Steven D. Beyea, Julius Birnbaum
Journal: Arthritis & Rheumatology (2018)

The American College of Rheumatology's case definitions for 19 neuropsychiatric syndromes in systemic lupus erythematosus ( SLE ) constitute a comprehensive classification of nervous system events in this disease. However, additional strategies are needed to determine whether a neuropsychiatric syndrome is attributable to SLE versus a competing comorbidity. Cognitive function is a clinical surrogate of overall brain health, with applications in both diagnosis and determination of clinical outcomes. Ischemic and inflammatory mechanisms are both key components of the immunopathogenesis of neuropsychiatric SLE ( NPSLE ), including abnormalities of the blood–brain barrier and autoantibody‐mediated production of proinflammatory cytokines. Advances in neuroimaging provide a platform to assess novel disease mechanisms in a noninvasive way. The convergence of more rigorous clinical characterization, validation of biomarkers, and brain neuroimaging provides opportunities to determine the efficacy of novel targeted therapies in the treatment of NPSLE .
Anti-PCSK9 treatment: is ultra-low low-density lipoprotein cholesterol always good?
Authors: Davide Noto, Antonina Giammanco, Carlo M Barbagallo, Angelo B Cefalù, Maurizio R Averna
Journal: Cardiovascular Research (2018)

Anti-PCSK9 (proprotein convertase subtilisin kexin 9) monoclonal antibodies (Mab) are novel, potent lipid-lowering drugs. They demonstrated to improve the lipid profile in high cardiovascular risk patients. Anti-PCSK9 Mab inhibit the targeted low-density lipoprotein (LDL)-receptor degradation induced by PCSK9 protein and are able to reduce LDL cholesterol (LDL-C) levels on top of conventional lipid-lowering therapy. Though these drugs proved to be very safe in the short-term, little is known about the possible long-term effects, due to the short period of their marketing. The genetic low cholesterol syndromes (LCS) represent the natural models of the lipid-lowering anti-PCSK9 therapy, and a valuable opportunity to predict the long-term effects of these drugs. By looking at the clinical features of such models, we could be able to foresee possible drug-induced side effects. In the present review, the correspondences and discordances between the side effects of anti-PCSK9 therapy and the corresponding LCS models will be examined in the attempt to forecast possible long-term consequences of these novel lipid-lowering agents.
A gene therapeutic approach to inhibit calcium and integrin binding protein 1 ameliorates maladaptive remodelling in pressure overload
Authors: Andrea Grund, Malgorzata Szaroszyk, Janina K Döppner, Mona Malek Mohammadi, Badder Kattih, Mortimer Korf-Klingebiel, Anna Gigina, Michaela Scherr, George Kensah, Monica Jara-Avaca, Ina Gruh, Ulrich Martin, Kai C Wollert, Antje Gohla, Hugo A Katus, Oliver J Müller, Johann Bauersachs, Joerg Heineke
Journal: Cardiovascular Research (2018)

Abstract Aims Chronic heart failure is becoming increasingly prevalent and is still associated with a high mortality rate. Myocardial hypertrophy and fibrosis drive cardiac remodelling and heart failure, but they are not sufficiently inhibited by current treatment strategies. Furthermore, despite increasing knowledge on cardiomyocyte intracellular signalling proteins inducing pathological hypertrophy, therapeutic approaches to target these molecules are currently unavailable. In this study, we aimed to establish and test a therapeutic tool to counteract the 22 kDa calcium and integrin binding protein (CIB) 1, which we have previously identified as nodal regulator of pathological cardiac hypertrophy and as activator of the maladaptive calcineurin/NFAT axis. Methods and results Among three different sequences, we selected a shRNA construct (shCIB1) to specifically down-regulate CIB1 by 50% upon adenoviral overexpression in neonatal rat cardiomyocytes (NRCM), and upon overexpression by an adeno-associated-virus (AAV) 9 vector in mouse hearts. Overexpression of shCIB1 in NRCM markedly reduced cellular growth, improved contractility of bioartificial cardiac tissue and reduced calcineurin/NFAT activation in response to hypertrophic stimulation. In mice, administration of AAV-shCIB1 strongly ameliorated eccentric cardiac hypertrophy and cardiac dysfunction during 2 weeks of pressure overload by transverse aortic constriction (TAC). Ultrastructural and molecular analyses revealed markedly reduced myocardial fibrosis, inhibition of hypertrophy associated gene expression and calcineurin/NFAT as well as ERK MAP kinase activation after TAC in AAV-shCIB1 vs. AAV-shControl treated mice. During long-term exposure to pressure overload for 10 weeks, AAV-shCIB1 treatment maintained its anti-hypertrophic and anti-fibrotic effects, but cardiac function was no longer improved vs. AAV-shControl treatment, most likely resulting from a reduction in myocardial angiogenesis upon downregulation of CIB1. Conclusions Inhibition of CIB1 by a shRNA-mediated gene therapy potently inhibits pathological cardiac hypertrophy and fibrosis during pressure overload. While cardiac function is initially improved by shCIB1, this cannot be kept up during persisting overload.
Circulating tumor DNA (ctDNA) as a predictor of treatment for locally advanced pancreatic cancer
Authors: G. Botiralieva
Journal: Annals of Oncology (2018)

Introduction: By today R0 – curative resection is possible following neoadjuvant treatment for LAPC, however still there is no method to determine patients beforehand who will have a favorable surgical outcome. The aim of this study was to evaluate the prediction possibilities of ctDNA during chemo-radiotherapy after surgical treatment of locally advanced pancreatic cancer. Methods: 42 patients were enrolled in this study who were treated in National Cancer Research Centre. Pts received neoadjuvant FOLFIRINOX followed by CRT: either short-course (n = 12, 25 Gy/5 fractions), or longcourse (n = 30, 50.4 Gy/28 fractions). Serum ctDNA was measured at baseline, every week during CRT, and preoperatively. After extracting DNA from plasma, a tumor mutation specific droplet digital PCR assay was used to detect the fraction of ctDNA molecules. Outcomes of treatment were based on: CA19-9, CEA, RECIST score, tumor grade, T stage, tumor regression grade (TRG), R-resection status, pathologically involved lymph nodes, LVI, and PNI. Results: The median age of patients was 64 years (range 39-82 years). Following CRT, 33 (78,5%) were operable. The overall R0-node negative (R0-NN) resection rate was 59% for the entire cohort. The rate of R0-NN resection higher among patients with an undetectable preoperative ctDNA (n = 16) compared to those with a detectable (n = 26) preoperative ctDNA (88% R0-NN vs 50% R0-NN, respectively). Only ctDNA status was significantly associated with R0-NN resection (p = 0.025), whereas preoperative RECIST score, CA19-9, and CEA were not associated. For patients who received surgery, the ctDNA was significantly correlated with TRG (Pearson R = 0.399, p = 0.024). Conclusion: Detection of ctDNA is associated with poorer surgical outcome in patients treated with neoadjuvant CRT for locally advance pancreatic cancer. At the same time absence of ctDNA in blood serum leads to a better surgical outcomes, this fact is one more evidence for implementing this technique into a daily routine for more appropriate selection of patients who will benefit from surgical treatment.
CRAN-35. CHILDHOOD CYSTIC CRANIOPHARYNGIOMA: 15 YEARS OF INTRA-TUMORAL CHEMOTHERAPY WITH INTERFERON-ALPHA AT IOP/GRAACC/UNIFESP
Authors: Patricia Dastoli, Jardel Nicácio, Marcos Costa, Andrea Cappellano, Nasjla Silva, Sergio Calvalheiro
Journal: Neuro-Oncology (2018)

Management of patients with craniopharyngioma is still controversial. Currently, quality of life is the goal for all treatment modalities. To analyze the several treatment strategies and outcomes of craniopharyngioma patients in 15 years of experience in a single institution. The authors retrospectively evaluated 110 craniopharyngeoma patients treated between 2002 and 2017, at IOP/GRAACC/UNIFESP. Data regarding initial clinical presentation, body mass index (BMI), endocrinological complications, treatment modalities and outcomes were collected. From 110 patients, 95 patients were eligible for evaluation. Fifty-five were boys and 40 girls. The mean age at treatment was 10,5 years. Fifty-six percent of children presented with signs and symptoms of intracranial hypertension, 24% with visual impairment and 38,5% with endocrinological disturbances. At the time of diagnosis, the mean BMI was 20,48kg/m2. Thirty-eight children with cystic tumors were treated with intralesional interferon-alpha, 13 progressed to conventional treatment. Among the remaining 57 patients, 9 were treated with microsurgery, 29 with microsurgery + radiotherapy, 12 with endoscopic transesphenoidal surgery + radiotherapy and 7 recurrent patients with intracystic interferon-alpha. The mean BMI of patients treated exclusively with interferon-alpha was 22,88kg/m2 (ideal weight) and with microsurgery + radiotherapy was 29,65kg/m2 (overweight). After treatment, 61 cases (65%) progressed to panhypopituitarism. The mean follow up was 7,13 years. Eleven deaths occurred. Currently 41 patients are out of treatment. The interferon-alpha intracystic therapy has been shown to be effective in the control of predominantly cystic tumors, decreasing or delaying the morbidity from conventional treatment.
Response to Comment on Redondo et al. Racial/Ethnic Minority Youth With Recent-Onset Type 1 Diabetes Have Poor Prognostic Factors. Diabetes Care 2018;41:1017–1024
Authors: Maria Jose Redondo, Ingrid Libman, Peiyao Cheng, Craig Kollman, Mustafa Tosur, Robin L. Gal, Fida Bacha, Georgeanna J. Klingensmith, Mark Clements
Journal: Diabetes Care (2018)

We thank Dr. Nwosu for his thoughtful comments (1). We agree that insulin resistance influences insulin dose–adjusted hemoglobin A1c (IDAA1c). Nagl et al. (2) observed that the partial remission period was less frequent and shorter in girls than boys, but, without C-peptide measurements, the authors could only speculate that higher insulin resistance or lower insulin secretion might explain their findings. However, we found that, adjusting for BMI, age, and sex, insulin doses were still different between African Americans (AAs) and non-Hispanic whites (NHWs) ( P < 0.001) (3), suggesting that after controlling for factors that increase insulin resistance there was still a difference in insulin dose, and thus in IDAA1c. Other measures of partial remission period, e.g., insulin dose, are also affected by insulin resistance. Furthermore, although defining partial remission period based on …
TBIO-10. PEDIATRIC TARGETED THERAPY 2.0: DEVELOPMENT OF PERSONALIZED PEDIATRIC ONCOLOGY
Authors: Jonas Ecker, Florian Selt, Felix Sahm, David Capper, Andrey Korshunov, Kerstin Grund, Nicola Dikow, Christian Sutter, Cornelis van Tilburg, Hendrik Witt, Andreas von Deimling, David T W Jones, Stefan M Pfister, Olaf Witt, Till Milde
Journal: Neuro-Oncology (2018)

Precise diagnosis and robust detection of actionable alterations is required for individualized treatments. The Pediatric Targeted Therapy (PTT) 2.0 program aims at improvement of diagnostic accuracy and detection of targetable alterations by extended molecular diagnostics. The impact of these analyses on clinical management is being evaluated. Pediatric patients with relapsed or progressive tumors after treatment according to standard protocols are included, independent of the histological diagnosis. Formalin fixed paraffin embedded material and a blood sample for germline correction are requested. The methods employed are DNA methylation array, customized targeted gene panel sequencing (130 genes), RNA and Sanger sequencing in selected cases, and immunohistochemistry (IHC) of selected markers. A questionnaire-based follow-up is used to determine the clinical impact of the analysis. We have included n=111 cases from 22.02.2017.-31.12.2017, analysis was completed for n=83 cases (75%) at the time of abstract submission. The most common entities were brain tumors (n=56/83, 67%). DNA methylation array alone allowed diagnostic classification in n=45/83 cases (54.2%) and n=34/56 brain tumor cases (60,7%), respectively. Actionable targets as detected by copy number calculation, gene panel sequencing, RNA sequencing and IHC were found in n=47/83 cases (56.6%). Pathogenic germline alterations with clinical relevance were identified in n=7/83 cases (8.4%) and were confirmed by Sanger sequencing. Follow-up analyses are ongoing. In conclusion, combination of next-generation diagnostics such as methylation arrays and targeted sequencing in addition to selected IHC markers added robust information concerning diagnosis and targetable alterations. The impact on clinical decision-making and on outcome is currently being evaluated.