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Lynch syndrome (LS) is the most common inherited disorder responsible for an increased risk of developing cancers at different sites, most frequently in the gastrointestinal and genitourinary tracts, caused by a germline pathogenic variant affecting the DNA mismatch repair system. Surveillance and risk-reducing procedures are currently available and warranted for LS patients, depending on underlying germline mutation, and are focused on relevant targets for early cancer diagnosis or primary prevention. Although pharmacological approaches for preventing LS-associated cancer development were started many years ago, to date, aspirin remains the most studied drug intervention and the only one suggested by the main surveillance guidelines, despite the conflicting findings. Furthermore, we also note that remarkable advances in anticancer drug discovery have given a significant boost to the application of novel immunological strategies such as immunocheckpoint inhibitors and vaccines, not only for cancer treatment, but also in a preventive setting. In this review, we outline the clinical, biologic, genetic, and morphological features of LS as well as the recent three-pathways carcinogenesis model. Furthermore, we provide an update on the dedicated screening, surveillance, and risk-reducing strategies for LS patients and describe emerging opportunities of harnessing the immune system.

Background This study assesses the relationships between dynamic functional network connectivity (DFNC) and dementia risk. Methods DFNC of the default mode (DMN), salience (SN), and executive control networks was assessed in 127 cognitively unimpaired older adults. Stepwise regressions were performed with dementia risk and protective factors and biomarkers as predictors of DFNC. Results Associations were found between times spent in (i) a "weakly connected" state and lower self-reported engagement in early- and mid-life cognitive activity and higher LDL cholesterol; (ii) a "SN-negatively connected" state and higher blood pressure, higher depression score, and lower body mass index (BMI); (iii) a "strongly connected" state and higher self-reported engagement in early-life cognitive activity, Preclinical Alzheimer's cognitive composite-5 score, and BMI; and (iv) a "DMN-negatively connected" state and higher self-reported engagement in early- and mid-life stimulating activities and lower LDL cholesterol and blood pressure. The lower number of state transitions was associated with lower brain perfusion. Conclusion DFNC states are differentially associated with dementia risk and could underlie reserve.

Background New treatments are currently offering new opportunities and challenges in clinical management and research in the migraine field. There is the need of homogenous criteria to identify candidates for treatment escalation as well as of reliable criteria to identify refractoriness to treatment. To overcome those issues, the European Headache Federation (EHF) issued a Consensus document to propose criteria to approach difficult-to-treat migraine patients in a standardized way. The Consensus proposed well-defined criteria for resistant migraine (i.e., patients who do not respond to some treatment but who have residual therapeutic opportunities) and refractory migraine (i.e., patients who still have debilitating migraine despite maximal treatment efforts). The aim of this study was to better understand the perceived impact of resistant and refractory migraine and the attitude of physicians involved in migraine care toward those conditions. Methods We conducted a web-questionnaire-based cross-sectional international study involving physicians with interest in headache care. Results There were 277 questionnaires available for analysis. A relevant proportion of participants reported that patients with resistant and refractory migraine were frequently seen in their clinical practice (49.5% for resistant and 28.9% for refractory migraine); percentages were higher when considering only those working in specialized headache centers (75% and 46% respectively). However, many physicians reported low or moderate confidence in managing resistant (8.1% and 43.3%, respectively) and refractory (20.7% and 48.4%, respectively) migraine patients; confidence in treating resistant and refractory migraine patients was different according to the level of care and to the number of patients visited per week. Patients with resistant and refractory migraine were infrequently referred to more specialized centers (12% and 19%, respectively); also in this case, figures were different according to the level of care. Conclusions This report highlights the clinical relevance of difficult-to-treat migraine and the presence of unmet needs in this field. There is the need of more evidence regarding the management of those patients and clear guidance referring to the organization of care and available opportunities.

Lung cancer is the most frequent human malignancy and the principal cause of cancer-related death worldwide. Adenocarcinoma is now the main histologic type, accounting for almost half of all the cases. The 2015 World Health Organization has adopted the classification recently developed by the International Association for the Study of Lung Cancer, American Thoracic Society, and European Respiratory Society. This new adenocarcinoma classification has incorporated up-to-date advances in radiological, molecular and oncological knowledge, providing univocal diagnostic criteria and terminology. For resection specimens, new entities have been defined such as adenocarcinoma in situ and minimally invasive adenocarcinoma to designate adenocarcinomas, mostly nonmucinous and ≤ 3 cm in size, with either pure lepidic growth or predominant lepidic growth with ≤ 5 mm invasion, respectively. For invasive adenocarcinoma, the new classification has introduced histological subtyping according to the predominant pattern of growth of the neoplastic cells: lepidic (formerly non mucinous brochioloalveolar adenocarcinoma), acinar, papillary, micropapillary, and solid. Of note, micropapillary pattern is a brand new histologic subtype. In addition, four variants of invasive adenocarcinoma are recognized, namely invasive mucinous (formerly mucinous brochioloalveolar adenocarcinoma), colloid, fetal, and enteric. Importantly, three variants that were considered in the previous classification have been eliminated, specifically mucinous cystadenocarcinoma, signet ring cell, and clear cell adenocarcinoma. This review presents the changes introduced by the current histological classification of lung adenocarcinoma and its prognostic implications.

Five days fasting in 12 non-obese, healthy volunteers caused a reduced capacity to excrete a single water load and to form maximally hypotonic urine. The minimum value of osmolarity of urine after fasting was on average 113mOsm/l, while it was 63 mOsm/l under control conditions. This abnormality in the formation of hypotonic urine could not be explained as the consequence of reduced glomerular filtration or enhanced solute excretion. The reduced diluting capacity is associated with an inadequate reduction of tubular water reabsorption.

To seven healthy volunteers, 12 and 24 g i.v. fructose were administrated in the form of 20 % solution at a rate of 4 g/min. After both doses, during the 10th min after the completed intravenous administration, a statistically significant increase of serum ammonia and serum uric acid occurred. After 24 g, the rise of the uric acid level remains significant during the 40th min after administration, while ammonia values return to the basal level. Increments of ammonia and uric acid are higher after a larger fructose dose. Under the same set-up and at the same rate, 24 g fructose were administered to eight patients with compensated cirrhosis of the liver. The rise of uric acid was practically the same as in healthy subjects similar to the rise of the ammonia level during the 10th min after administration. 40 min after administration, however, the ammonia level in cirrhotic patients remained significantly raised, as compared with the initial level.

The course of turbidity curves in patients suffering from chronic neurosis in the stage of decompensation is marked, as compared with healthy controls and acute neurotic conditions, particularly by a higher level of turbidity and a delayed return of the turbidity to the initial level; occasionally the shape of the curve reminds of the so-called vegetative type of blood sugar curves. These changes are not influenced by an altered gastric evacuation nor by age. The mechanisms responsible for the development of the anomaly described are discussed and the authors draw attention to the significance of emotions.

The combination of the two cardiac support mechanisms of intra-aortic balloon pumping (IABP) and non-pulsatile circulatory extracorporeal membrane oxygenation (ECMO) has been confirmed to improve efficacy of the cardiac support as a whole. However, reports on benefits of diastolic augmentation on coronary vascular bed and graft flowmetry during concomitant use of IABP and ECMO are lacking. The aim of this study was to evaluate the acute impact of IABP support on coronary vascular resistance (CVR) and coronary bypass flows (CBF) in high-risk patients with peripheral ECMO following coronary artery bypass grafting (CABG).In eight emergency CABG patients (mean age=67.8±1.9 years; gender: six male and two female; EF=25.5±2.4%) requiring mechanical circulatory support with ECMO hemodynamic parameters, CVR, CBF, diastolic filling index (DFI), graft flow reserve (GFR), and pulsatility index (PI) were analyzed with and without diastolic augmentation using a transit time flowmeter.The addition of IABP to ECMO decreased CVR significantly by 6.5%±1.9% compared to baseline with ECMO alone (1.62±0.2 versus 1.78±0.2; P0.0045). Accordingly, significant higher mean CBF were found during IABP assist, resulting in a 21.6%±2.6% increase (60.7±8.7 mL/min with versus 51.3±7.4 mL/min without IABP; P0.0001). IABP also significantly increased DFI by 9.8±0.9% (73.2%±1.4% with versus 66.7%±1.3% without IABP; P0.0001). GFR was recruited during IABP in all grafts (GFR1). There were no statistically significant differences in PI with and without IABP assistance (2.6±0.1 versus 2.5±0.2).IABP-induced pulsatility significantly improves diastolic filling index and mean coronary bypass graft flows by lowering coronary vascular resistance during non-pulsatile peripheral ECMO. The combination of ECMO with IABP may provide more optimal myocardial oxygen conditions resulting in an improved efficacy of the cardiac support as a whole in critical ill patients with postcardiotomy myocardial dysfunction following CABG.

AMONG the basic factors which have a bearing on iron metabolism and its serum level certain attention has been paid during the past two decades to the influence of biological rhythms1 and various stressing stimuli2. In conjunction with this we decided to make use of an experimental set-up which involves the prolonged and complete upset of the basic biological rhythm of the alternation of wakefulness and sleep—that is, sleep deprivation. This work was stimulated in particular by the finding of an extreme drop of plasma iron (revealed in preliminary experiments) during the 120th hour of vigilance in four experimental subjects3.

Der Einflus von Desferrioxamin B auf den Glucosestoffwechsel wurde bei 8 gesunden Versuchspersonen untersucht. Bei intravenoser Glucosebelastung bewirkte Desferrioxamin (500 mg i.m. 1 Std vorher und 500 mg i.v. unmittelbar vorher) eine signifikante Beschleunigung der Glucoseelimination aus der Blutbahn.

Angiosarcoma and anaplastic carcinoma are the most lethal neoplasms of the thyroid worldwide and share some similarities, which have led to a longstanding controversy on their etiopathological relationship. Thyroid angiosarcomas are characterized by vessel formation and an immunophenotype common to endothelial cells, while anaplastic carcinomas are partially or wholly composed of mesenchymal-like cells that have lost the morphologic and functional features of normal thyroid follicular cells. To investigate whether angiosarcomas represent the endothelial extreme of the differentiation spectrum of carcinomas or they are bona fide vascular neoplasms, we studied the clinico-morphologic and genetic characteristics of a series of 10 angiosarcomas and 22 anaplastic carcinomas. Immunohistochemically, among the endothelial markers, CD31 and ERG were the most consistently expressed in angiosarcomas. Among the markers of thyroid origin, PAX8 was the most reliable in anaplastic carcinomas, while TTF-1 reactivity was found in only 5% of anaplastic carcinomas and thyroglobulin was always negative. Pankeratin reacted with most angiosarcomas and anaplastic carcinomas and is therefore not useful in the differential diagnosis. Interestingly a mutated pattern of p53 immunostaining prompted a diagnosis of anaplastic carcinoma. To compare the genetic profile, we used the NGS approach to sequence hotspot regions within a panel of 57 genes. As a result, only a few mutations were found in angiosarcomas and all of them were single events (no TP53 or TERT mutation). On the other hand, anaplastic carcinomas were characterized by a higher number of mutations, and TP53 and TERT promoter mutations were the most frequent genetic alterations. The lack in angiosarcomas of the common mutations identified in anaplastic carcinomas supports a different genetic origin and strongly suggests that, in spite of a shared sarcomatous morphology and a similar clinical aggressiveness, angiosarcomas and anaplastic carcinomas rely on a completely different set of genetic alterations during their evolution.