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.     

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.     

Diagnostics of the neuromyelitis optica spectrum disorders (NMOSD)

This document presents the guidelines for anti-aquaporin-4 (AQP4) antibody testing that has been developed following a consensus process built on questionnaire-based surveys, internet contacts, and discussions at workshops of the sponsoring Italian Association of Neuroimmunology (AINI) congresses. Essential clinical information on neuromyelitis optica spectrum disorders, indications and limits of anti-AQP4 antibody testing, instructions for result interpretation, and an agreed laboratory protocol (Appendix) are reported for the communicative community of neurologists and clinical pathologists.     

Prevalence of Traumatic Findings on Routine MRI in a Large Cohort of Professional Fighters

BACKGROUND AND PURPOSE:Previous studies investigating MR imaging abnormalities among fighters have had small sample sizes. This investigation assessed a large number of fighters using the same conventional sequences on the same scanner.MATERIALS AND METHODS:Conventional 3T MR imaging was used to assess 499 fighters (boxers, mixed martial artists, and martial artists) and 62 controls for nonspecific WM changes, cerebral microhemorrhage, cavum septum pellucidum, and cavum vergae. The lengths of the cavum septum pellucidum and cavum vergae and the ratio of cavum septum pellucidum to the septum pellucidum lengths were assessed.RESULTS:The prevalence of nonspecific WM changes was similar between groups. Fighters had a prevalence of cerebral microhemorrhage (4.2% versus 0% for controls, P = .152). Fighters had a higher prevalence of cavum septum pellucidum versus controls (53.1% versus 17.7%, P < .001) and cavum vergae versus controls (14.4% versus 0%, P < .001). The lengths of the cavum septum pellucidum plus the cavum vergae (P < .001), cavum septum pellucidum (P = .025), and cavum septum pellucidum to the septum pellucidum length ratio (P = .009) were higher in fighters than in controls. The number of fights slightly correlated with cavum septum pellucidum plus cavum vergae length (R = 0.306, P < .001) and cavum septum pellucidum length (R = 0.278, P < .001). When fighters were subdivided into boxers, mixed martial artists, and martial artists, results were similar to those in the whole-group analysis.CONCLUSIONS:This study assessed MR imaging findings in a large cohort demonstrating a significantly increased prevalence of cavum septum pellucidum among fighters. Although cerebral microhemorrhages were higher in fighters than in controls, this finding was not statistically significant, possibly partially due to underpowering of the study.

Multiple sports such as boxing, mixed martial arts, football, and soccer involve repetitive head trauma in young people, and this trauma is accumulated over many years. Many studies have attempted to describe conventional MR imaging findings associated with repetitive head trauma in the hope that an early in vivo diagnosis may preclude further trauma and help guide possible treatment.^1–9 However, these studies have often involved a small number of athletes, leading to variable findings and a low significance of results.^10,11 In some studies, MR imaging results were normal for athletes with head trauma,^7,9 whereas other studies demonstrated a variably increased prevalence of cerebral microhemorrhage (CMH),^4,5 nonspecific WM changes (NSWMCs),¹¹ or cavum septum pellucidum (CSP)/cavum septum pellucidum and vergae (CSPV).^1,2,10Regarding professional fighting, previous studies have similarly demonstrated the occurrence of imaging abnormalities, with imaging findings ranging from smaller volumes in structures such as the thalamus, vermis, and hippocampus and microhemorrhages in the parenchyma to macrohemorrhages such as subdural hematomas and parenchymal contusions.^{4–6,8,12,13} However, these studies were also limited by small sample sizes and a relatively low prevalence of microhemorrhages, so the calculated increased prevalence was not found to be statistically significant.^4,5Other studies have demonstrated a higher incidence of CSP among fighters, with some research finding a trend toward significance in fighters versus controls.¹⁰ However, an early large study of fighters demonstrated increased CSP prevalence in controls rather than in fighters.³ More recent studies in retired professional American football players found that the prevalence and size of the CSP were increased in the athletes versus controls.^2,14 Comparing these studies is complicated by differences in patient populations (eg, different sports, various age groups, current athletes versus retired athletes).^2,4,5,14 Additionally, even though an increased prevalence of CSP has been demonstrated among fighters in previous research, neuroradiologists disagree over whether this is a manifestation of trauma or simply a normal variant.Other conventional MR imaging findings in patients with repetitive head trauma include the presence of NSWMCs.⁷ However, some research into repetitive head trauma has demonstrated normal imaging findings in these patients.¹¹ This finding is consistent with our anecdotal experience.In this study, we chose to focus on a sport with a known high incidence of repetitive head trauma (professional fighters), using a large sample size and ensuring that all fighters were scanned with the same protocol on the same 3T MR imaging scanner. We sought to assess the prevalence of NSWMCs, CMH, and CSP/CSPV among these fighters versus the prevalence of these imaging abnormalities among healthy controls.