Reciprocal inhibition in forearm muscles in patients with essential tremor

Reciprocal inhibition of the H-reflex in the forearm flexor muscles was studied in 11 patients with essential tremor and in 10 normal controls. Whereas patients and controls had a similar first, disynaptic phase of reciprocal inhibition, patients had a significantly reduced second phase. Patients with more severe functional impairment had more pronounced abnormalities of reciprocal inhibition. Abnormalities of reciprocal inhibition may play a role in the pathophysiology of essential tremor and probably arise from defective suprasegmental control. © 1998 John Wiley & Sons, Inc. Muscle Nerve 21:796–799, 1998.     

Multicenter randomized phase II trial of atezolizumab with or without cobimetinib in biliary tract cancers

BACKGROUNDMEK inhibitors have limited activity in biliary tract cancers (BTCs) as monotherapy but are hypothesized to enhance responses to programmed death ligand 1 (PD-L1) inhibition.METHODSThis open-label phase II study randomized patients with BTC to atezolizumab (anti–PD-L1) as monotherapy or in combination with cobimetinib (MEK inhibitor). Eligible patients had unresectable BTC with 1 to 2 lines of prior therapy in the metastatic setting, measurable disease, and Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1. The primary endpoint was progression-free survival (PFS).RESULTSSeventy-seven patients were randomized and received study therapy. The trial met its primary endpoint, with a median PFS of 3.65 months in the combination arm versus 1.87 months in the monotherapy arm (HR 0.58, 90% CI 0.35–0.93, 1-tail P = 0.027). One patient in the combination arm (3.3%) and 1 patient in the monotherapy arm (2.8%) had a partial response. Combination therapy was associated with more rash, gastrointestinal events, CPK elevations, and thrombocytopenia. Exploratory analysis of tumor biopsies revealed enhanced expression of antigen processing and presentation genes and an increase in CD8/FoxP3 ratios with combination treatment. Patients with higher baseline or lower fold changes in expression of certain inhibitory ligands (LAG3, BTLA, VISTA) on circulating T cells had evidence of greater clinical benefit from the combination.CONCLUSIONThe combination of atezolizumab plus cobimetinib prolonged PFS as compared with atezolizumab monotherapy, but the low response rate in both arms highlights the immune-resistant nature of BTCs.TRIAL REGISTRATIONClinicalTrials.gov {"type":"clinical-trial","attrs":{"text":"NCT03201458","term_id":"NCT03201458"}}NCT03201458.FUNDINGNational Cancer Institute (NCI) Experimental Therapeutics Clinical Trials Network (ETCTN); F. Hoffmann-La Roche, Ltd.; NCI, NIH (R01 CA228414-01 and UM1CA186691); NCI’s Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancers (P50 CA062924); NIH Center Core Grant (P30 CA006973); and the Passano Foundation.     

International trends in hepatocellular carcinoma incidence, 1978–2012

Primary liver cancer, the major histology of which is hepatocellular carcinoma (HCC), is the second leading cause of cancer death worldwide. We comprehensively examined recent international trends of primary liver cancer and HCC incidence using population-based cancer registry data. Incidence for all primary liver cancer and for HCC by calendar time and birth cohort was examined for selected countries between 1978 and 2012. For each successive 5-year period, age-standardized incidence rates were calculated from Volumes V to XI of the Cancer Incidence in Five Continents (CI5) series using the online electronic databases, CI5plus. Large variations persist in liver cancer incidence globally. Rates of liver cancer remain highest in Asian countries, specifically in the East and South-East, and Italy. However, rates in these high-risk countries have been decreasing in recent years. Rates in India and in most countries of Europe, the Americas and Oceania are rising. As the population seroprevalence of hepatitis B virus (HBV) continues to decline, we anticipate rates of HCC in many high-risk countries will continue to decrease. Treatment of hepatitis C virus (HCV) is likely to bring down rates further in some high-rate, as well as low-rate, countries with access to effective therapies. However, such gains in the control of liver cancer are at risk of being reversed by the growing obesity and diabetes epidemics, suggesting diabetes treatment and primary prevention of obesity will be key in reducing liver cancer in the longer-term.     

Curcumin changes the polarity of tumor‐associated microglia and eliminates glioblastoma

Glioblastoma (GBM) is one of the most pernicious forms of cancer and currently chances of survival from this malady are extremely low. We have used the noninvasive strategy of intranasal (IN) delivery of a glioblastoma‐directed adduct of curcumin (CC), CC‐CD68Ab, into the brain of mouse GBM GL261‐implanted mice to study the effect of CC on tumor remission and on the phenotype of the tumor‐associated microglial cells (TAMs). The treatment caused tumor remission in 50% of GL261‐implanted GBM mice. A similar rescue rate was also achieved through intraperitoneal infusion of a lipid‐encapsulated formulation of CC, Curcumin Phytosome, into the GL261‐implanted GBM mice. Most strikingly, both forms of CC elicited a dramatic change in the tumor‐associated Iba1+ TAMs, suppressing the tumor‐promoting Arginase1^high, iNOS^low M2‐type TAM population while inducing the Arginase1^low, iNOS^high M1‐type tumoricidal microglia. Concomitantly, we observed a marked induction and activation of microglial NF‐kB and STAT1, which are known to function in coordination to cause induction of iNOS. Therefore, our novel findings indicate that appropriately delivered CC can directly kill GBM cells and also repolarize the TAMs to the tumoricidal M1 state.     

The Influence of Sociodemographic Factors,Lifestyle, and Risk Perception on Dietary Patterns in Pregnant Women Living in Highly Contaminated Areas: Data from the NEHO Birth Cohort

During pregnancy, maternal nutrition and lifestyle play a critical role in influencing fetal development and newborn health outcomes. The aim of this study is to investigate the factors influencing the adherence to dietary patterns in pregnant women living in highly contaminated areas, and whether women with higher environmental risk perception manifest different nutritional behaviors during pregnancy. Food consumption data on 816 pregnant women from the Neonatal Environment and Health Outcomes (NEHO) residential birth cohort were analyzed. Dietary patterns were computed by principal component analysis. A multinomial logistic regression was also applied to identify sociodemographic, lifestyle, and pregnancy-related determinants of adherence to dietary patterns during pregnancy. Three patterns of food consumption—explaining 24.9% of the total variance—were identified as “prudent”, “high energy”, and “vegetarian” patterns. Results suggest that food choices during pregnancy follow a social gradient and align with other health behaviors during pregnancy: older, better educated, and physically active women with higher risk perception are more likely to follow healthier dietary patterns. Knowledge about what is eaten can contribute to dietary choices. Interventions to improve the prenatal nutrition knowledge of pregnant women are needed, especially concerning younger mothers and those with lower educational levels.     

Intracranial circulation: pulse-sequence considerations in three- dimensional (volume) MR angiography

The technique and feasibility of magnetic resonance (MR) angiography of intracranial vessels were studied in 35 healthy volunteers. Variations in image orientation, repetition time (TR), and flip angle were evaluated to determine their effects on flow-related enhancement. Gradient modifications--including echo time (TE), motion compensation, bandwidth, and field of view--were also studied in an effort to reduce motion-induced phase shifts. Results indicated that a FISP (fast imaging with steady precession) sequence with a TR of 50 msec, TE of 15 msec, velocity compensation in the read and section-select directions, acceleration compensation in the read direction, anisotropic volume, and a 1.25-mm partition thickness produced three-dimensional angiographic MR images that were accurate and reproducible in the depiction of the major intracranial vessels. Difficulties with field of view, persistent signal void secondary to higher-order motion, and spatial resolution remain major problems requiring additional study.     

In vitro efficacy of ARQ 092, an allosteric AKT inhibitor,on primary fibroblast cells derived from patients with PIK3CA-related overgrowth spectrum (PROS)

Postzygotic mutations of the PIK3CA [phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha] gene constitutively activate the PI3K/AKT/mTOR pathway in PIK3CA-related overgrowth spectrum (PROS) patients, causing congenital mosaic tissue overgrowth that even multiple surgeries cannot solve. mTOR inhibitors are empirically tested and given for compassionate use in these patients. PROS patients could be ideal candidates for enrolment in trials with PI3K/AKT pathway inhibitors, considering the “clean” cellular setting in which a unique driver, a PIK3CA mutation, is present. We aimed to assess the effects of blocking the upstream pathway of mTOR on PROS patient-derived cells by using ARQ 092, a potent, selective, allosteric, and experimental orally bioavailable and highly selective AKT-inhibitor with activity and long-term tolerability, currently under clinical development for treatment of cancer and Proteus syndrome. Cell samples (i.e., primary fibroblasts) were derived from cultured tissues obtained from six PROS patients [3 boys, 3 girls; aged 2 to 17 years] whose spectrum of PIK3A-related overgrowth included HHML [hemihyperplasia multiple lipomatosis; n?=?1], CLOVES [congenital lipomatosis, overgrowth, vascular malformations, epidermal nevi, spinal/skeletal anomalies, scoliosis; n?=?1], and MCAP [megalencephaly capillary malformation syndrome; n?=?4]. We performed the following: (a) a deep sequencing assay of PI3K/AKT pathway genes in the six PROS patients’ derived cells to identify the causative mutations and (b) a pathway analysis to assess the phosphorylation status of AKT [Ser473 and Thr308] and its downstream targets [pAKTS1 (Thr246), pRPS6 (Ser235/236), and pRPS6Kβ1 (Ser371)]. The anti-proliferative effect of ARQ 092 was tested and compared to other PI3K/AKT/mTOR inhibitors [i.e., wortmannin, LY249002, and rapamycin] in the six PROS patient-derived cells. Using ARQ 092 to target AKT, a critical node connecting PI3K and mTOR pathways, we observed the following: (1) strong anti-proliferative activity [ARQ 092 at 0.5, 1, and 2.5 μM blunted phosphorylation of AKT and its downstream targets (in the presence or absence of serum) and inhibited proliferation after 72 h; rapamycin at 100 nM did not decrease AKT phosphorylation] and (2) less cytotoxicity as compared to rapamycin and wortmannin. We demonstrated the following: (a) that PROS cells are dependent on AKT; (b) the advantage of inhibiting the pathway immediately downstream of PI3K to circumventing problems depending on multiple classes a PI3K kinases; and (c) that PROS patients benefit from inhibition of AKT rather than mTOR. Clinical development of ARQ 092 in PROS patients is on going in these patients.     

Italian intersociety consensus on prevention,diagnosis, and treatment of delirium in hospitalized older persons

Delirium is a severe neuropsychiatric syndrome characterized by inattention and global cognitive dysfunction in the setting of an acute medical illness, medical complication, drug intoxication, or drug withdrawal. The most important risk factors are advanced age and dementia, whereas pain, dehydration, infections, stroke, metabolic disturbances, and surgery are the most common triggering factors. Although delirium is a common clinical syndrome in different settings of care (acute care hospitals, inpatient rehabilitation facilities, nursing homes, and hospices), it often remains under-recognized, poorly understood, and inadequately managed. There exists a clear need for improved understanding to overcome cultural stereotypes, and for the development and dissemination of a comprehensive model of implementation of general good practice points. A network of Italian national scientific societies was thus convened (1) to develop a collaborative multidisciplinary initiative report on delirium in elderly hospitalized patients, (2) to focus the attention of health care personnel on prevention, diagnosis, and therapy of patients suffering from delirium, and (3) to make the health services research community and policy-makers more aware of the potential risks of this condition providing a reference for training activities and data collection.     

Versatility of endoaortic balloon occlusion device for less invasive management of complex and reoperative cardiac cases

Heart Teams are increasingly confronted with decision‐making in anatomically and clinically complex surgical candidates. Herein, we discuss the versatility of the endoaortic occlusion device (Intraclude; Edwards Lifesciences Inc) for the management of a various array of complex primary and reoperative cardiac cases. Three clinical scenarios are illustrated (ascending aortic pseudoaneurysm, mitral valve surgery after previous CABG, extensive thoracic aortic surgery with continuous visceral perfusion), suggesting the effectiveness of the patient‐specific strategy to minimize operative morbidity. Evolution of surgical techniques needs to be considered in decision‐making among alternative treatment strategies.