Summary Background Metachromatic leukodystrophy (a deficiency of arylsulfatase A ARSA) is a fatal demyelinating lysosomal disease with no approved treatment. We aimed to assess the long-term outcomes ...in a cohort of patients with early-onset metachromatic leukodystrophy who underwent haemopoietic stem-cell gene therapy (HSC-GT). Methods This is an ad-hoc analysis of data from an ongoing, non-randomised, open-label, single-arm phase 1/2 trial, in which we enrolled patients with a molecular and biochemical diagnosis of metachromatic leukodystrophy (presymptomatic late-infantile or early-juvenile disease or early-symptomatic early-juvenile disease) at the Paediatric Clinical Research Unit, Ospedale San Raffaele, in Milan. Trial participants received HSC-GT, which consisted of the infusion of autologous HSCs transduced with a lentiviral vector encoding ARSA cDNA, after exposure-targeted busulfan conditioning. The primary endpoints of the trial are safety (toxicity, absence of engraftment failure or delayed haematological reconstitution, and safety of lentiviral vector-tranduced cell infusion) and efficacy (improvement in Gross Motor Function Measure GMFM score relative to untreated historical controls, and ARSA activity, 24 months post-treatment) of HSC-GT. For this ad-hoc analysis, we assessed safety and efficacy outcomes in all patients who had received treatment and been followed up for at least 18 months post-treatment on June 1, 2015. This trial is registered with ClinicalTrials.gov , number NCT01560182. Findings Between April, 2010, and February, 2013, we had enrolled nine children with a diagnosis of early-onset disease (six had late-infantile disease, two had early-juvenile disease, and one had early-onset disease that could not be definitively classified). At the time of analysis all children had survived, with a median follow-up of 36 months (range 18–54). The most commonly reported adverse events were cytopenia (reported in all patients) and mucositis of different grades of severity (in five of nine patients grade 3 in four of five patients). No serious adverse events related to the medicinal product were reported. Stable, sustained engraftment of gene-corrected HSCs was observed (a median of 60·4% range 14·0–95·6 lentiviral vector-positive colony-forming cells across follow-up) and the engraftment level was stable during follow-up; engraftment determinants included the duration of absolute neutropenia and the vector copy number of the medicinal product. A progressive reconstitution of ARSA activity in circulating haemopoietic cells and in the cerebrospinal fluid was documented in all patients in association with a reduction of the storage material in peripheral nerve samples in six of seven patients. Eight patients, seven of whom received treatment when presymptomatic, had prevention of disease onset or halted disease progression as per clinical and instrumental assessment, compared with historical untreated control patients with early-onset disease. GMFM scores for six patients up to the last follow-up showed that gross motor performance was similar to that of normally developing children. The extent of benefit appeared to be influenced by the interval between HSC-GT and the expected time of disease onset. Treatment resulted in protection from CNS demyelination in eight patients and, in at least three patients, amelioration of peripheral nervous system abnormalities, with signs of remyelination at both sites. Interpretation Our ad-hoc findings provide preliminary evidence of safety and therapeutic benefit of HSC-GT in patients with early-onset metachromatic leukodystrophy who received treatment in the presymptomatic or very early-symptomatic stage. The results of this trial will be reported when all 20 patients have achieved 3 years of follow-up. Funding Italian Telethon Foundation and GlaxoSmithKline.
To assess the efficacy of high-frequency (20 Hz) brain stimulation on lower limb motor function in subjects with chronic (> 6 mo) subcortical stroke.
Double-blind, placebo-controlled crossover study.
...University hospital.
Right-handed subjects (N=10) affected by a first-ever subcortical stroke in the territory of the middle cerebral artery were included in this study.
Repetitive transcranial magnetic stimulation (rTMS) was delivered with the H-coil, specifically designed to target deeper and larger brains regions. Each subject received both real and sham rTMS in a random sequence. The 2 rTMS cycles (real or sham) were composed of 11 sessions each, administered over 3 weeks and separated by a 4-week washout period.
Lower limb functions were assessed by the lower limb Fugl-Meyer scale, the 10-m walk test, and the 6-minute walk test before and 1 day after the end of each treatment period, as well as at a 4-week follow-up.
Real rTMS treatment was associated with a significant improvement in lower limb motor function. This effect persisted over time (follow-up) and was significantly greater than that observed with sham stimulation. A significant increase in walking speed was also found after real rTMS, but this effect did not reach statistical significance in comparison with the sham stimulation.
These data demonstrated that 3 weeks of high-frequency deep rTMS could induce long-term improvements in lower limb functions in the chronic poststroke period, lasting at least 1 month after the end of the treatment.
Double occurrence of TTF1 and ΔNp63/p40 (henceforth, p40) within the same individual cells is exceedingly rare in lung cancer. Little is known on their biological and clinical implications.
Two index ...cases immunoreactive for both p40 and TTF1 and nine tumors selected from The Cancer Genome Atlas (TCGA) according to the mRNA levels of the two relevant genes entered the study.
The two index cases were peripherally located, poorly differentiated, and behaviorally unfavorable carcinomas, which shared widespread p40 and TTF1 decoration within the same individual tumor cells. They also retained SMARCA2 and SMARCA4 expression, while variably stained for p53, cytokeratin 5, and programmed death-ligand 1. A subset of basal cells p40+/TTF1+ could be found in normal distal airways. Biphenotypic glandular and squamous differentiation was unveiled by electron microscopy, along with EGFR, RAD51B, CCND3, or NF1 mutations and IGF1R, MYC, CCND1, or CDK2 copy number variations on next-generation sequencing analysis. The nine tumors from TCGA (0.88% of 1018 tumors) shared the same poor prognosis, clinical presentation, and challenging histology and had activated pathways of enhanced angiogenesis and epithelial-mesenchymal transition. Mutation and copy number variation profiles did not differ from the other TCGA tumors.
Double p40+/TTF1+ lung carcinomas are aggressive and likely underrecognized non–small cell carcinomas, whose origin could reside in double-positive distal airway stem-like basal cells through either de novo-basal-like or differentiating cell mechanisms according to a model of epithelial renewal.
Abstract Flexible flatfoot is the most prevalent condition seen in pediatric orthopedic clinics. It is characterized by an absence of the medial arch and a valgus position of the calcaneus. The ...purpose of the present study was to report on the results obtained in children treated using the calcaneo-stop procedure. A total of 410 flatfeet in 242 consecutive patients were treated using the calcaneo-stop procedure from January 1999 to March 2010 (10 years, 3 months) and were followed up to February 2012. The mean age at surgery was 11 (range 7 to 14) years, and the mean follow-up duration was 88 (range 14 to 157) months. A clinical evaluation, podoscopic examination, and radiologic assessment were performed in the participating patients preoperatively and at 6 months postoperatively. Of the 242 patients, 168 (69.42%) underwent bilateral foot surgery and 74 (30.58%) unilateral intervention, involving 33 right (44.6%) and 41 left (55.4%) feet. At follow-up, the outcome was satisfactory in 397 feet (96.83%); heel valgus was observed in only 12 feet (2.92%), and the footprint was normalized in 328 feet (80%). The calcaneo-stop procedure is a simple, reliable, and minimally invasive procedure for the treatment of pediatric flexible flatfoot. It allows alignment of the talus and calcaneus, restoring a proper foot arch.
Lymphocytic hypophysitis is a rarely recognized disease that is characterized by inflammatory infiltration and destruction of the pituitary gland. The etiology of lymphocytic hypophysitis is still ...unclear, but an autoimmune pathogenesis has been advocated. In fact, histopathologic specimens reveal a diffuse infiltration of the hypophysis by CD3+ CD4+ T cells and CD20+ plasma cells, and antipituitary antibodies are usually found in sera of affected patients. Although previous cases were found to be correlated only to pregnancy and the postpartum period, recent reports in men and women (without association with pregnancy) suggest a possibly higher prevalence of disease. We present the case of a 55-year-old woman affected by an unusually aggressive form of lymphocytic hypophysitis that infiltrated both cavernous sinuses causing bilateral internal carotid artery occlusion and acute ischemic stroke. Diagnosis was achieved with both a biopsy specimen of the pituitary gland and the detection of antipituitary antibodies. The prompt administration of steroid therapy was effective to obtain regression and stabilization of the disease, but both carotid arteries remained permanently occluded. The natural history of lymphocytic hypophysitis is unpredictable. It usually has a benign evolution, but in exceptional cases the inflammatory process may extend beyond the pituitary gland and infiltrate the surrounding structures. These extremely serious consequences highlight the importance of early diagnosis and treatment of this otherwise curable disease.
The prevalence of intrahepatic delta antigen and/or anti-delta antibody was retrospectively investigated in 102 children with chronic HBsAg-positive hepatitis who were seen consecutively in three ...medical institutions between 1974 and 1982. Delta infection markers were found in 13 patients (12.7%) who exhibited high serum titers of anti-delta antibody; intrahepatic delta antigen was detected in ten. Eleven of the 13 children had severe progressive liver disease associated in all but one with absence of hepatitis B virus replication as evaluated by analysis of serum hepatitis B virus DNA. The factors which seem to increase the risk of delta infection in children who are hepatitis B virus carriers are geographic origin, a history of exposure to blood derivatives and age. A further 37 of 102 children had chronic active hepatitis (20 patients) or cirrhosis (17 patients) without evidence of delta infection. These results indicate that delta infection occurs in children with chronic hepatitis. This possibility should be considered in investigation of children with HBsAg-positive chronic liver disease. Although the delta agent is an important cause of progressive liver disease in children who are chronic HBsAg carriers, severe liver injury and especially cirrhosis can occur without evidence of delta infection.
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