The microRNA cluster C19MC is deregulated in parathyroid tumours

A subset of over-expressed microRNAs (miRNAs) identified in parathyroid carcinomas (Ca) compared to normal glands belongs to C19MC, a cluster on chromosome 19q13.4 involved in stem cell biology and tumourigenesis. In this study, the expression of C19MC-MIR371-3 clusters and the molecular mechanisms presiding their modulation were investigated in a series of six normal parathyroids, 24 adenomas (Ad), 15 Ca and five matched metastases. The general expression levels of C19MC or MIR371-3 clusters in Ad lesions did not differ from normal glands, while they distinguished Ad from Ca at unsupervised hierarchical cluster analysis (P=0.0008). MIR517C showed the most significant difference in expression between Ca and Ad (P=0.0003) and it positively correlated with serum calcium, parathormone and tumour weight. In regard to the molecular mechanism determining C19MC cluster activation, we could detect C19MC copy number (CN) gain in ten Ca (67%) extending distal to the MIR371-3 cluster in almost all samples. Conversely, only four Ad (16%) showed C19MC amplification, with one case presenting distal genomic aberration to MIR371-3. Globally, CN variations of 19q13.4 loci were significantly associated with MIR517C up-regulation (P=0.006). Opposite to normal glands where C19MC promoter was methylated, hypomethylation occurred in 15 out of 30 analysed tumours. Though the epigenetic status did not correlate with C19MC miRNA expression levels, loss of C19MC promoter methylation was significantly associated with Ca and metastatic disease (P=0.01). In conclusion, C19MC cluster aberrations are a characteristic of Ca with respect to Ad. Altogether, these evidences point towards a role for 19q13.4 miRNA clusters as oncogenes in parathyroid tumourigenesis.     

Post-load insulin resistance does not predict virological response to treatment of chronic hepatitis C patients without the metabolic syndrome

Background and aimThe role of insulin resistance in predicting virological response to therapy of chronic hepatitis C is debated. We assessed the association between basal (defined as homeostasis model assessment of insulin resistance (HOMA-IR) > 2) and post-load insulin resistance (as oral glucose insulin sensitivity index < 9.8 mg/kg/min) with the rapid and sustained virological responses in chronic hepatitis C.MethodsObservational prospective study of 124 treatment-naïve patients with chronic hepatitis C not fulfilling the metabolic syndrome criteria, adherent to a standard treatment with pegylated interferon alpha plus ribavirin.ResultsInsulin resistance was detected in 50% (by HOMA-IR) and 29% (by oral glucose insulin sensitivity index) of patients. Independent predictors of rapid virologic response were hepatitis C virus (HCV) genotype 2 (odds ratio 5.66; 95% confidence interval 1.88–17.01), HCV genotype 3 (odds ratio 5.23; 95% confidence interval 1.84–14.84) and lower basal ferritin levels (odds ratio 0.99; 95% confidence interval 0.993–0.998). Independent predictors of sustained virologic response were HCV genotype 2 (odds ratio 19.54; 95% confidence interval 2.29–166.41) and HCV genotype 3 (odds ratio 3.24; 95% confidence interval 1.10–9.58). Rapid virologic response was by itself predictive of sustained virologic response (odds ratio 40.90; 95% confidence interval 5.37–311.53).ConclusionsInsulin resistance, measured by both static and dynamic methods, does not predict rapid or sustained virologic response in chronic hepatitis C patients without the metabolic syndrome.     

Nuclear factor-κB predicts outcome in locally advanced rectal cancer patients receiving neoadjuvant radio-chemotherapy

BackgroundNF-κB expression has been shown to be responsible for resistance to antineoplastic agents.AimsThe aim of our study was to investigate the importance of NF-κB expression as prognostic factor in locally advanced rectal cancer patients receiving neoadjuvant radiochemotherapy.MethodsWe retrospectively analysed the immunoreactivity for NF-κB in patients with locally advanced rectal cancer who underwent neoadjuvant treatment (chemotherapy and/or radiotherapy) in our Institution between March 2003 and June 2006.ResultsSeventy-four consecutive patients were enrolled into this study. Immunohistochemistry analysis for NF-κB was performed both in biopsies and in primary tumour samples. NF-κB was considered positive when at least 1% of the tumour cells showed nuclear positivity. A significant correlation between a positive NF-κB nuclear expression, both in biopsies and in tumour samples, and a worse overall survival was observed.Moreover, median time to progression was significantly shorter in the NF-κB-positive subgroup of patients.ConclusionGlobally, our findings seem to suggest that NF-κB could represent an important parameter able to predict the outcome in patients receiving neoadjuvant treatment for rectal cancer. It also could be useful in order to select patients to receive adjuvant chemotherapy, intensifying the adjuvant therapy and, in the next future, obviating the use of drugs involving NF-κB system in their mechanism of action in NF-κB-positive patients.     

Level of HER2/neu amplification in primary tumours and metastases in HER2-positive breast cancer and survival after trastuzumab therapy

BackgroundThe level of HER2/neu amplification may vary widely in breast cancers with HER2/neu alteration. The clinical significance of this phenomenon is still unclear. This study was aimed to explore the level of HER2/neu amplification in primary tumours and metastases in HER2-positive metastatic breast cancer (MBC) and its potential impact on survival after a trastuzumab-containing therapy.MethodsWe retrospectively identified MBC patients treated with a trastuzumab-containing therapy and performed dual-colour FISH on tumour samples from either primary tumour and/or metastasis in a central laboratory.ResultsWe retrieved 110 tumour samples from 91 patients and included 79 tumour samples (primary = 56; metastasis = 23) from 63 patients in the final analysis. We found higher level of HER2/neu amplification in the metastases than in the primary tumours (median HER2/CEP17 ratio: 10.5 vs 7.0, respectively). In 69% of patients (n = 16) with two tumour samples, the level of HER2/neu amplification was higher in the metastasis than in the paired primary tumour (median HER2/CEP17 ratio: 10.9 vs 8.3, respectively, p = 0.004). The incremental gain in level of HER2/neu amplification was associated with significantly shorter OS after trastuzumab-containing therapy (p = 0.023, HR 1.014, CI95%: 1.002–1.025).ConclusionsThe level of HER2/neu amplification tends to increase from the primary tumour to the paired metastases in a significant proportion of patients with HER2-positive MBC. This phenomenon, although still not completely understood, could lead to a shorter OS after trastuzumab therapy.     

Outcome of patients with splanchnic venous thrombosis presenting without overt MPN: A role for the JAK2 V617F mutation re-evaluation

Introduction

Although investigation for JAK2 V617F mutation is recommended in patients presenting with splanchnic venous thrombosis (SVT), no specific clinical advice is given to SVT patients presenting without myeloproliferative neoplasms (MPN) and JAK2 V617F mutation. In MPN-free SVT patients, to investigate the clinical outcome, the clinical impact of re-evaluation for the JAK2 V617F mutation, and relationships with the occurrence and time to diagnosis of MPN.

Materials and Methods

A cohort of non-cirrhotic SVT patients, enrolled at a single centre and prospectively analyzed.

Results

In 121 SVT patients prospectively followed from 1994 to 2012, a MPN was present in 28 (23.1%). Additional 13 patients (10.7%) showed only the JAK2 V617F mutation. During the follow-up, the JAK2 V617F mutation and/or MPN were identified in 8 patients (median time of development: 21 months, range 6-120), whereas 72 remained (MPN and JAK2 V617F)-free until the end of the observation.The mortality rate was higher among patients presenting with MPN and/or the JAK2 V617F mutation than in patients who developed later or remained disease-free (p = 0.032). The thrombosis-free survival was lower in patients with (p = 0.04) or developing later MPN and the JAK2 V617F mutation (p = 0.005) than in patients (MPN and JAK2 V617F)-free. The incidence of bleeding was similar among groups.

Conclusions

MPN with or without circulating positive clones for JAK2 V617F mutation can occur long after a SVT, identifying at risk patients for new thrombotic events. If confirmed in other studies, re-evaluation for JAK2 V617F mutation may be of help in early MPN detection and clinical management of SVT patients.     

Ultrasound diagnosis of bony nerve entrapment: Case series and literature review

Introduction: Nerve entrapment due to osseous callus formation is a rare complication after bone fracture. Electrodiagnostic studies and routine radiographic imaging often fail to demonstrate the pathology. The diagnosis is difficult and is often made incidentally upon surgical exploration. Nerve ultrasonography has not been used routinely to assess such lesions. Methods: We report 5 cases of nerve entrapment in osseous callus after fractures that occurred in 2011 and 2012. The diagnosis was made by ultrasound (US). We then performed a review of the relevant literature. Conclusions: US is becoming an invaluable tool for diagnosing peripheral nerve entrapments. The current cases suggest that nerve US should be strongly considered as an adjunctive diagnostic tool for nerve palsies developing after trauma. Muscle Nerve 48 : 445–450, 2013     

Neurogenesis in temporal lobe epilepsy: Relationship between histological findings and changes in dentate gyrus proliferative properties

Objective

The relationship between hippocampal histopathological abnormalities, epileptogenesis and neurogenesis remains rather unclear.

Methods

Tissue samples including the subgranular zone of dentate gyrus (DG) were freshly collected for tissue culture for neurospheres generation in 16 patients who underwent surgery for drug-resistant temporal lobe epilepsy. Remaining tissues were histologically examined to assess the presence of mesial temporal sclerosis (MTS) and focal cortical dysplasia.

Results

MTS was detected in 8 cases. Neurospheres were formed in 10/16 cases. Only three out of these 10 cases exhibited MTS; on the contrary 5/6 cases lacking neurosphere proliferation presented MTS. There was a significant correlation between presence of MTS and absence of proliferation (p = 0.0389). We also observed a correlation between history of febrile seizures (FS) and presence of MTS (p = 0.0004) and among the 6 cases lacking neurosphere proliferation, 4 cases (66.6%) had experienced prolonged FS. Among “proliferating” cases the percentage of granular cells pathology (GCP) was lower (20% vs 50%) compared to “non proliferating” cases.

Conclusion

A decreased potential to generate neurosphere from the SGZ is related to MTS and to alterations of dentate gyrus granule cells, especially in MTS type 1b and GCP type 1. These histological findings may have different prognostic implications, regarding seizure and neuropsychological outcome, compared to patients with other epileptogenic lesions (such as FCD, glioneuronal tumours, vascular lesions).     

Pisa syndrome in Parkinson’s disease: an electrophysiological and imaging study

The pathophysiology of postural abnormalities in patients with Parkinson’s disease is poorly understood. In the present study, 13 patients with Pisa syndrome (PS) underwent EMG study of paraspinal lumbar (L2–L4) and thoracic (T8–T10) muscles, and of non-paraspinal muscles. Patients also underwent a whole spine X-ray and an MRI assessment of paraspinal muscles (L1–S1). The EMG evaluation disclosed two main patterns: patients with pattern I (n = 6, hyperactivity of lumbar paraspinals ipsilateral to the trunk leaning side) or pattern II (n = 7: hyperactivity of lumbar paraspinals contralateral to the trunk leaning side. In pattern I, half the patients also had ipsilateral hyperactivity of the thoracic paraspinals, the other half had contralateral thoracic hyperactivity; in pattern II, thoracic paraspinal hyperactivity was contralateral in all patients (like the lumbar paraspinal hyperactivity). Non-paraspinal muscles were hyperactive ipsilaterally in four of six patients with pattern I and in all patients with pattern II. The MRI showed mild muscular atrophy with fatty degeneration in patients with pattern I, whereas in pattern II patients this was greater and prevalent on paraspinal lumbar muscles ipsilateral to the leaning side. The present data support the hypothesis that two main patterns of muscular activation are associated with PS. In both patterns, hyperactivity of contralateral paraspinal muscles is probably compensatory for the trunk leaning.