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Background and aims: In patients with hepatocellular carcinoma (HCC), macrovascular invasion (MaVI) limits treatment options and decreases survival. Detailed data on the relationship between MaVI extension and patients' characteristics, and its impact on patients' outcome are limited. We evaluated the prevalence and extension of MaVI in a large cohort of consecutive HCC patients, analysing its association with liver disease and tumour characteristics, as well as with treatments performed and patients' survival. Methods: We analysed data of 4774 patients diagnosed with HCC recorded in the Italian Liver Cancer (ITA.LI.CA) database (2008-2018). Recursive partition analysis (RPA) was performed to evaluate interactions between MaVI, clinical variables and treatment, exploring the inter-relationship determining overall survival. Results: MaVI prevalence was 11.1%, and median survival of these patients was 6.0months (95% CI, 5.1-7.1). MaVI was associated with younger age at diagnosis, presence of symptoms, worse Performance Status (PS) and liver function, high alphafetoprotein levels and large HCCs. MaVI extension was associated with worse PS, ascites and greater impairment in liver function. RPA identified patients' categories with different treatment indications and survival, ranging from 2.4months in those with PS>1 and ascites, regardless of MaVI extension (receiving best supportive care in 90.3% of cases), to 14.1months in patients with PS 0-1, no ascites and Vp1-Vp2 MaVI (treated with surgery in 19.1% of cases). Conclusions: MaVI presence and extension, together with PS and ascites, significantly affect patients' survival and treatment selection. The decision tree based on these parameters may help assess patients' prognosis and inform therapeutic decisions.

In neuromuscular disorders (NMDs), nocturnal non-invasive ventilation (NIV) via a nasal mask is offered when hypercapnic respiratory failure occurs. With disease progression, nocturnal NIV needs to be extended into the daytime. Mouthpiece ventilation (MPV) is an option for daytime NIV. MPV represents a difficult task for home ventilators due to rapidly changing load conditions resulting from intermittent connections and disconnections from MPV circuit. The 252nd ENMC International Expert Workshop, held March 6th to 8th 2020 in Amsterdam, reported general guidelines for management of daytime MPV in NMDs. This report could not present all the detail regarding the technical issues important for clinical success of MPV. Based on the expert workshop discussions and the evidence from existing studies, the current narrative review aims to identify the technical issues of MPV and offers guidance via a decisional algorithm and educational figures providing relevant information that is important for successful implementation of MPV.

The aim of this retrospective study was to establish the range of functional changes at 12 and 24-month in 267 type 2 Spinal Muscular Atrophy (SMA) patients with multiple assessments. We included 652 Hammersmith Functional Motor Scale Expanded (HFMSE) assessments at 12 month- and 305 at 24 month- intervals. The cohort was subdivided by functional level, Survival of Motor Neuron copy number and age. Stable scores (± 2 points) were found in 68% at 12 months and in 55% at 24 months. A decrease =2 points was found in 21% at 12 months and in 35% at 24 months. An increase =2 points was found in 11% at 12 months and 9.5% at 24 months. The risk of losing =2 points increased with age and HFMSE score at baseline both at 12 and 24-month. For each additional HFMSE point at baseline, the relative risk of a >2 point decline at 12 months increases by 5% before age 5 years (p?=?0.023), by 8% between 5 and 13 (p

Late-onset Pompe disease (LOPD) is characterized by progressive muscle weakness, respiratory muscle dysfunction, and minor cardiac involvement. Although in LOPD, as in other neuromuscular diseases, controlled low impact sub-maximal aerobic exercise and functional ability exercise can improve general functioning and quality of life, as well as respiratory rehabilitation, the bulk of evidence on that is weak and guidelines are lacking. To date, there is no specific focus on rehabilitation issues in clinical recommendations for the care of patients with Pompe disease, and standard practice predominantly follows general recommendation guidelines for neuromuscular diseases. The Italian Association of Myology, the Italian Association of Pulmonologists, the Italian Society of Neurorehabilitation, and the Italian Society of Physical Medicine and Rehabilitation, have endorsed a project to formulate recommendations on practical, technical, and, whenever possible, disease-specific guidance on rehabilitation procedures in LOPD, with specific reference to the Italian scenario. In this first paper, we review available evidence on the role of rehabilitation in LOPD patients, particularly addressing the unmet needs in the management of motor and respiratory function for these patients. Late-onset Pompe disease (LOPD) is characterized by progressive muscle weakness, respiratory muscle dysfunction, and minor cardiac involvement. Although in LOPD, as in other neuromuscular diseases, controlled low impact sub-maximal aerobic exercise and functional ability exercise can improve general functioning and quality of life, as well as respiratory rehabilitation, the bulk of evidence on that is weak and guidelines are lacking. To date, there is no specific focus on rehabilitation issues in clinical recommendations for the care of patients with Pompe disease, and standard practice predominantly follows general recommendation guidelines for neuromuscular diseases. The Italian Association of Myology, the Italian Association of Pulmonologists, the Italian Society of Neurorehabilitation, and the Italian Society of Physical Medicine and Rehabilitation, have endorsed a project to formulate recommendations on practical, technical, and, whenever possible, disease-specific guidance on rehabilitation procedures in LOPD, with specific reference to the Italian scenario. In this first paper, we review available evidence on the role of rehabilitation in LOPD patients, particularly addressing the unmet needs in the management of motor and respiratory function for these patients.

This study regards the total articulating cementless knee. This is a mobile-bearing knee, the tibial component of which consists of 2 parts: a highly conforming polyethylene insert freely rotating on a metal tray. Our case study relating to the implant of the first 110 knees operated on consecutively from 1991 to 1995 is reported, with an average follow-up of 6.3 years (range, 5-9 years). The average preoperative Knee Society Score was 78 points, and the average postoperative score was 156 points. The complications specifically related to the prosthetic components and which required revision surgery were 4: 2 cases of instability, 1 aseptic loosening of the tibial tray, and 1 traumatic dislocation of the tibial insert. A further 3 patients underwent reoperation for causes not strictly related to the implant: 2 because of intractable patellar pain and 1 because of periprosthetic ossifications that limited flexion. All of the complications were observed in patients operated on during the first 3 years of our experience, thus suggesting a definite learning curve with this prosthesis. No evidence of progressive radiographic periprosthetic osteolysis was recorded, and no relevant polyethylene wear was observed over time. Kaplan-Meier survival curves show the probability of survival to be 93.7% with revision surgery for any reason as an endpoint, and 96.3% with revision surgery for a mechanical reason as an endpoint. Certainty that mobile-bearing total knees are able to assure a longer life of the implant than the conventional models would require an evaluation of results over 15 to 20 years. However, in the meantime, these good preliminary results at least justify continuing the use of this type of prosthesis, which still awaits confirmation of the, as-yet-theoretical, advantage compared with fixed-bearing total knees.

To identify a set of sonomorphological parameters to evaluate the outcome of arthroscopic surgery for popliteal cysts by sonography.We examined 30 patients (18 males, 12 females) before treatment and 3/6 months after arthroscopy. Patients were classified by clinical (4 groups) and sonographic criteria. The sonographic criteria were the morphological classification of the cysts (beak-shaped, X-shaped, grape-like, slit-shaped) and the volume measurement.Sonography identified beak-shaped popliteal cysts (the most frequent Baker cyst shape), 5 grape-like (the usual shape of complicated Baker cysts) and 1 X-shaped . The volume of cysts before treatment ranged from 5 to 38 cl. Most cysts were clinically rated as grade 2 (symptomatic and evident at physical examination, with a reduction of range of motion up to 20 degrees of flexion). No patient was rated as grade 0 (normal). After surgery the cyst was still evident at sonography. After 3 months we recorred a cyst volume decrease in all cases. Six months after surgery 29/30 cysts had a volume5 cl with an almost virtual cavity that changed their appearance in to slit-shaped . In one case cyst volume increased. The clinical classification showed an increase of the grade 0 group unsymptomatic cysts (not detectable at physical examination).Sonographic evaluation of popliteal cysts after arthroscopic surgical treatment allowed to recognize the cysts, which are not removed by this approach. The follow-up at 3 months showed a reduction in cyst volume. After six months, in the cases with a good surgical response, the cysts reached a volume5 cl regardless of their original volume. The morphology of the cysts with a good surgical result, is slit-shaped with virtual cavity regardless of their original appearance. There is a high correlation between sonographic and clinical data. We believe that the volume reduction of the cyst three months after surgery is a good predictive element. After six months the preesence of a cyst with a volume5 cl and a slit-shape with virtual cavity is a sign of good surgical result.

The dimensional changes of the muscle fibres of the active motor units generate a signal, labelled as mechanomyogram (MMG), related to the number and firing rate of the active fibres. Aim of the study was to evaluate if the root mean square (RMS) of the surface EMG, of the MMG and their relationship (electromechanical coupling efficiency, EMCE) are related to the clinical stage of patients affected by myotonic dystrophy. The EMG and the MMG were recorded during isometric contractions at 20%, 40% and 60% of the maximal voluntary contraction (MVC), in less (elbow flexors, EF) and more (finger flexors, FF) affected muscles in 10 myotonic dystrophy (DM) patients (duration of disease: 15-22 yr.; MDRS scale: 3-4) and in 10 age matched controls (C). It resulted that I) the MVC was only 30% lower in DM than in C (P0.05) for the EF but 74% lower (P0.001) for the FF; II) at the same relative force the MMG-RMS and the EMG-RMS in DM were significantly lower than in C (P0.05); III) the EMCE was almost the same in DM and C for EF but dramatically lower for FF. In conclusion these findings provide evidence that the EMCE changes due to the dystrophic process can be monitored by this new and non invasive technique. A good concurrence of clinical findings and experimental results was observed.

In a 48-year-old female, the first symptoms apparently manifested themselves 18 years before, with occasional tripping and weakness in both legs. During the next 18 years, weakness progressed and the patient developed a waddling gait; she became unable to rise from a lying or seated position unassisted and the shoulder girdle also became affected. Neurological examination revealed limb and shoulder girdle predominantly involving the lower extremities. We established cell cultures from muscle biopsy specimens obtained from our patient and carried out morphological analysis which, although aspecific, demonstrated clear signs of neurogenic suffering. This was confirmed in EMG studies performed. Biochemical analysis revealed very low acid maltase residual activity. We describe an unusual case of adult-onset acid maltase deficiency (AMD) with neurogenic atrophy and low residual activity. Innervated myofibres prepared by co-culturing the patient's myoblasts, with spinal cord foetal mouse explants were not associated with an abnormal in vitro maturation of the innervated myofibres as expected by the very low residual enzymatic activity found both in the muscle biopsy specimens and in the muscle cultures. There is strong suggestion that factors other than the amount of residual activity must be involved to determine the clinical manifestation of this disease.

In the present series of experiments, we studied the effects of developmental neural control on morphological differentiation and on the activity of muscle-specific (creatine kinase, CK; phosphoglycerate mutase, PGAM; phosphorylase, PPL; and phosphofructokinase, PFK) and non-specific (acid maltase, AM; glucose-6-phosphate dehydrogenase, G6PD), human muscle enzymes in de novo innervated muscle cultures. Following innervation of muscle cultures, we noted an increase in the activity of CK, PPL, PFK and AM along with a reduction in G6PD activity. There was also a change of the CK isoenzymes present in the myotubes, i.e. BB and MB are the major isoenzymes in non innervated cultures, but MM becomes predominant following innervation. In the case of PGAM, the only isoenzyme present in the non innervated cultures was BB while the MM isoform appeared only after a prolonged innervation period in most cases--with the exception of AM--these changes in enzyme activity and in the type of isoenzymes present, demonstrate that innervated cultures are more similar to mature muscle. This maturation of enzymatic activity correlates well with the morphological maturation of the myotubes observed following innervation. Such innervated cultures therefore represent a better model with which to study the morphological and biochemical abnormalities associated with neuromuscular diseases.

In previous experiments, we obtained an in vitro restoration of a cytosolic enzyme glucose-6-phosphate dehydrogenase (G6PD) in hybrid myotubes formed between G6PD-deficient and human or murine myoblasts. In the present series of experiments, the degree of restoration was observed and the persistence of the restored activity was evaluated in the hybrids formed. Quantitative measurements of enzymatic activity in single human-human or human-mouse myotubes, identified by using either fluorescent latex microspheres or Hoechst stain 33258, were made by using a computer-controlled Leitz photometer. Histospectrophotometry and statistical analysis showed a 50% restoration of enzymatic activity in human-human hybrids compared to deficient and normal myotubes. The restored activity was uniformly distributed throughout the cytoplasm and persisted in long-term cultures. No nuclear domain was observed for G6PD. Knowledge of the degree of restoration, of the extent of distribution of the products of "competent" nuclei and the demonstration that the correction is not a transitory event in vitro, supports the potential usefulness of myoblast transfer therapy for this type of myopathy.

The large use of double block of sciatic and femoral nerves (bibloc) with high mepivacaine 2% doses (10 mg/kg) has pointed out some cases of toxicity. We found a relationship between shiver and mepivacaine arterious plasma levels higher than 6 micrograms/ml. These symptoms were self-limited and statistically not significant.

A new technique for regional anaesthesia for arthroscopy of the knee is presented. The method includes sciatic nerve block according to the technique proposed by Labat, through a posterior approach and the block of the femoral and lateral cutaneous nerves using a single anterior approach. Results obtained in 30 patients are presented: they include good stability of the cardiovascular and respiratory parameters, high efficiency and duration of anaesthesia resulting in a satisfactory surgical procedure.

Myotonic dystrophies (DM) are repeat expansion diseases in which expanded CTG (DM1) and CCTG (DM2) repeats cause the disease. Mutant transcripts containing CUG/CCUG repeats are retained in muscle nuclei producing ribonuclear inclusions, which can bind specific RNA-binding proteins, leading to a reduction in their activity. The sequestration of muscleblind- like proteins (MBNLs), a family of alternative splicing factors, appears to be involved in splicing defects characteristic of DM pathologies. To determine whether MBNL1 nuclear sequestration is a feature of DM pathologies, we have examined the in vivo distribution of MBNL1 in muscle sections from genetically confirmed DM1 (n=7) and DM2 (n=9) patients, patients with other myotonic disorders (n=11) and from patients with disorders caused by repeat expansions, but not DM1/DM2 (n=3). The results of our immunofluorescence study indicate that, among patients examined, MBNL1 nuclear sequestration in protein foci is a molecular pathology marker of DM1 and DM2 patients where ribonuclear inclusions of transcripts with expanded CUG/CCUG repeats are also present. These findings indicate that MBNLs might be important targets for therapeutic interventions to correct some of the specific features of DM pathology.

Myotonic dystrophies, the most common form of adult muscular dystrophy, comprise at least two forms, clinically and genetically heterogeneous. Myotonic dystrophy type 1 and type 2 are both caused by unstable repetitions in untranslated gene regions: a [CTG]n expansion in the 3' region of the DMPK gene on chromosome 19q13 (DM1) and [CCTG]n tetranucleotide repeat located in the first intron of the ZNF9 gene on chromosome 3q21 (DM2). DM clinical features are caused by a gain of functions RNA mechanism in which the CUG and CCUG repeats alter nuclear functions, including alternative splicing of shared genes. Southern blot and/or polymerase chain reaction PCR-based approaches allow the detection of DM mutations in almost 100% of cases, however, the expansion size and the elevated grade of somatic instability make molecular testing for DM a diagnostic challenge. The increased use of DNA testing for DM generates many questions regarding the indications and interpretations of the test which require standardized methods, routinely available in molecular genetic laboratories. Here, we propose Guidelines for the molecular diagnosis of DM1 and DM2 approved by the Italian Ministry of Health in 2005 (Piano Nazionale Linee Guida, PNLG). Best practice for DM molecular analysis in diagnostic application, presymptomatic and prenatal testing, using direct and indirect approaches are described, with particular attention focused on ethical, legal and social issues. Overviews of materials used in the molecular diagnosis, as well as internet resources, are also included.

Large scale deletions of mitochondrial DNA (mtDNA) or altered inter-genomic regulation in skeletal muscle have been demonstrated in patients with mitochondrial encephalomyopathies due to Cytochrome C oxidase (COx) deficiency. We have analyzed by Southern blotting and Polymerase Chain Reaction (PCR) the mtDNA in primary muscle cultures (myoblast-myotube stages and at clonal densities) and in fibrogenic subclones obtained from 9 patients with partial COx deficiency who had in their muscle biopsy a subpopulation of mtDNA showing deletions of variable size (between 2.1 and 6.5 Kb). Only in the cultures from one patient, southern analysis revealed in myoblasts and myotubes a mtDNA almost identical to that found in the original muscle biopsy and persistence of deletion in muscle cells grown at clonal densities. The deletion was detectable in fibrogenic lineage only by PCR amplification. The deleted mtDNA molecules were detectable in myogenic or fibrogenic cultures from other patients only by PCR amplification. The different amounts of deleted mtDNA in the various tissues could be due either to an unequal distribution of the altered mtDNA during embryogenesis with amplification of deleted molecules in myogenic lineage or could result from negative selection against the altered mtDNA in rapidly proliferating cells, such as fibroblasts.

Aim: A link has been established between malnutrition, immunological status, and hepatocellular carcinoma (HCC). The prognostic nutritional index (PNI) has been recognized as a prognostic indicator in early-stage HCC and in patients treated with first-line therapy. However, to date, the role of the PNI in HCC patients treated with regorafenib has not been reported. Methods: We undertook a multicentric analysis on a cohort of 284 patients affected by advanced HCC treated with regorafenib. The PNI was calculated as follows: 10×serum albumin concentration (g/dl)+0.005×peripheral lymphocyte count (number/mm3). Univariate and multivariate analyses were used to investigate the association between PNI and survival outcomes. Results: A PNI cut-off value of 44.45 was calculated by a receiver operating characteristic analysis. The median overall survival was 12.8 and 7.8 months for patients with high (>44.45) and low (≤44.45) PNI, respectively (hazard ratio, 0.58; 95% confidence interval, 0.43–0.77; p=0.0002). In the univariate and multivariate analyses, low PNI value and increased serum bilirubin level emerged as independent prognostic factors for overall survival. No differences were found between high and low PNI in terms of progression-free survival (p=0.14). Conclusion: If validated, the PNI could represent an easy-to-use prognostic tool able to guide the clinical decision-making process in HCC patients treated with regorafenib.

Objective: To comprehensively assess whether neopterin in urine could be a candidate biomarker for determining the neuroinflammatory status in ALS. Methods: We performed an observational, cross-sectional study in 81 pALS, 68 age- and sex-comparable healthy controls (HC), 14 patients affected by MS and 24 OND patients. ALS patients underwent a neurological evaluation to assess the global functional status evaluated by Amyotrophic Lateral Sclerosis Functional Rating Scale—Revised (ALSFRS-R) and the disease progression rate. Urinary neopterin concentrations were determined by high-performance liquid chromatography method and were recorded at the time of first examination to assess their effect on disease severity and survival. Results: Urinary neopterin was significantly higher in pALS (263.90 [198.71–474.90]) compared to MS (155.28 [131.74–190.38], p =