Search

Introduction/aims The cutaneous silent period (CSP) reflects the function of A-delta sensory fibers. There are few studies on CSP in nerve entrapment syndromes. This study aims to evaluate the neurophysiological abnormalities of small-diameter sensory fibers in ulnar neuropathy at the elbow (UNE) by means of CSP. Methods We consecutively evaluated UNE patients at one electrodiagnostic laboratory. The CSP was obtained upon stimulating the fifth (D5) and third digits, recording from the first dorsal interosseous (FDI) and abductor pollicis brevis (APB) muscles. Results We enrolled 37 UNE patients (mean age 55.4 ± 11.2 y) and 30 controls (mean age 51.2 ± 11.1 y). The combinations of the D5-APB and D5-FDI mean onset latencies of CSP were significantly more prolonged in patients (83.7 ± 6.8 and 84.5 ± 8 ms, respectively) than in controls (78.2 ± 8.1 and 79.4 ± 7.6 ms, respectively). The D5-FDI duration of CSP was shorter in patients (52.2 ± 8.3 ms) than in controls (55.8 ± 7 ms). The mean of the onset latencies of D5-FDI and D5-APB was related to the clinical severity (P = .013 and .0025, respectively). D5-APB and D5-FDI onset latencies were more prolonged and the duration was shorter in the UNE group with absent ulnar sensory nerve action potentials (SNAPs) and axonal motor damage than in patients with preserved SNAPs and with demyelinating damage. Discussion CSP was able to demonstrate abnormalities of small-diameter myelinated sensory fibers. This damage was directly related to UNE severity and to axonal damage of motor fibers. Absence of a sensory large-diameter fiber response did not exclude preserved residual small fiber conduction.

Objective The aim of the study was to evaluate the clinical and electrodiagnostic testing in ulnar neuropathy at the elbow and differences according to site (humeroulnar arcade vs. retroepicondylar groove) and injury physiopathology (axonal vs. demyelinating), through prospective multicenter case-control study. Design Cases and controls were matched by age and sex. Ulnar neuropathy at the elbow diagnosis was made on symptoms. Statistical analysis was performed using Mann-Whitney, χ, and analysis of variance tests. Results One hundred forty-four cases and 144 controls were enrolled. Sensory loss in the fifth finger had the highest sensitivity (70.8%) compared with clinical findings. Motor conduction velocity across elbow reached the highest sensitivity (84.7%) in localizing ulnar neuropathy at the elbow recording from at least one of the two hand muscles (first dorsal interosseous and abductor digiti minimi). Abnormal sensory action potential amplitude from the fifth finger occurred more frequently in axonal than in demyelinating forms. Differences between retroepicondylar groove and humeroulnar arcade regarded conduction block and job type. Conclusions Clinical findings have less usefulness than electrodiagnostic testing in ulnar neuropathy at the elbow diagnosis. Motor conduction velocity across elbow recorded from both abductor digiti minimi and first dorsal interosseous increases diagnostic accuracy. Axonal forms have greater clinical and electrodiagnostic testing severity than demyelinating forms, which are more frequent in retroepicondylar groove. Manual workers prevailed in humeroulnar arcade. These findings may be helpful in prognostic and therapeutic approaches.

Introduction Alternatives to the classical medial parapatellar (MPP) approach for total knee arthroplasty (TKA) include the mini-medial parapatellar (MMPP), mini-subvastus (MSV), mini-midvastus (MMV) and quadriceps-sparing (QS) approaches. The best approach has been not fully clarified. The purpose of the present study was to conduct a Bayesian network meta-analysis comparing these approaches. Materials and methods The present analysis was carried out according to the PRISMA extension statement for reporting systematic reviews incorporating network meta-analyses of healthcare interventions. The databases search was performed in October 2019. All clinical trials comparing two or more approaches for primary TKA were considered for inclusion. The baseline comparability was evaluated through the analysis of variance (ANOVA) test. The statistical analysis was performed through the STATA software/MP. A Bayesian hierarchical random-effects model analysis was adopted in all the comparisons. Results Data from 52 articles (4533 patients) were collected. The mean follow-up was 20.38 months. With regard to diagnosis, gender, age and BMI, adequate baseline comparability was detected. The MSV approach ranked better concerning clinical scores (the lowest visual analogic scale, the higher KSS and KSFS) and functional outcomes (the shortest straight leg raise, the greatest degree of flexion and range of motion). Concerning perioperative data, the MSV evidenced the shortest hospital stay, while the MPP the shortest surgical duration and lowest estimated blood loss. Conclusion According to the main findings of the present study, the mini-subvastus approach for total knee arthroplasty demonstrated superior overall compared to the other approaches. Orthopaedic surgeons should consider this approach in the light of the evidence and limitations of this Bayesian network meta-analysis.

Objective The main objective is to investigate the diagnostic accuracy and the relation of touch sensation and subjective sensory symptoms in the medial aspect of the hand dorsum, and neurography of the dorsal ulnar cutaneous nerve (DUCN) in ulnar neuropathy at the elbow (UNE). Secondary objective is to report the electrophysiological occurrence of anatomical variant of sensory innervation of the medial aspect of the hand dorsum from superficial radial nerve (SRN). Design Prospective, cohort study. Setting Electromyography laboratory. Participants Consecutive participants (N=282), those with UNE (n=81) and those without UNE (n=201), were enrolled. Interventions Not applicable. Main Outcome Measures Accuracy and agreement between sensory clinical findings of the medial hand dorsum and neurography of DUCN in UNE diagnosis. Results DUCN neurographic and sensory findings had high specificity and relatively low sensitivity. Normal or abnormal sensory nerve action potential (SNAP) of DUCN matched with normal or abnormal touch sensation of the medial aspect of hand dorsum. Abnormal DUCN SNAP was related to the clinical severity of UNE and to the axonal damage of the ulnar nerve. Anatomical variant of the innervation of hand dorsum from SRN was demonstrated in 31 of 564 hands (6.2%) belonging to 26 of 282 participants (9.2%). If the variant was present, DUCN SNAP of the same side was more frequently absent or of low amplitude. Conclusions The utility of DUCN neurography and sensory findings of the medial aspect of the dorsum of the hand is limited in the diagnosis of UNE. However, if DUCN SNAP is absent or low in amplitude, it is advisable to check the presence of the anatomical variant of the innervation of the medial aspect of the hand dorsum from SRN.

Background: Malignant pleural mesothelioma (MPM) is a fatal tumor with a poor prognosis. The recent developments of liquid biopsies could provide novel diagnostic and prognostic tools in oncology. However, there is limited information about the feasibility of this technique for MPMs. Here, we investigate whether cancer-specific DNA sequences can be detected in pleural fluids and plasma of MPM patients as free circulating tumor DNA (ctDNA). Methods: We performed whole-exome sequencing on 14 tumor biopsies from 14 patients, and we analyzed 20 patient-specific somatic mutations with digital droplet PCR (ddPCR) in pleural fluids and plasma, using them as cancer-specific tumor biomarkers. Results: Most of the selected mutations could be detected in pleural fluids (94%) and, noteworthy, in plasma (83%) with the use of ddPCR. Pleural fluids showed similar levels of somatically mutated ctDNA (median = 12.75%, average = 16.3%, standard deviation = 12.3) as those detected in solid biopsies (median = 21.95%, average = 22.21%, standard deviation = 9.57), and their paired difference was weakly statistically significant (p = 0.048). On the other hand, the paired difference between solid biopsies and ctDNA from plasma (median = 0.29%, average = 0.89%, standard deviation = 1.40) was highly statistically significant (p = 2.5 × 10−7), corresponding to the important drop of circulating somatically mutated DNA in the bloodstream. However, despite the tiny amount of ctDNA in plasma, varying from 5.57% down to 0.14%, the mutations were detectable at rates similar to those possible for other tumors. Conclusions: We found robust evidence that mutated DNA is spilled from MPMs, mostly into pleural fluids, proving the concept that liquid biopsies are feasible for MPM patients.

The aim of the study was to demonstrate abnormalities of motor conduction of the tibial nerve across the tarsal tunnel in type 2 diabetes.One hundred twenty-four consecutive patients (mean age = 66.6 yrs, 62.1% male) with distal symmetric diabetic polyneuropathy clinically diagnosed were prospectively enrolled. Nerve conduction studies of deep peroneal, tibial, superficial peroneal, medial plantar, and sural nerves and standard needle electromyography in the lower limbs were performed. Demographic, anthropometric, and clinical findings were collected.Motor conduction velocity of the tibial nerve across tarsal tunnel was slowed in 60.5% of patients; another 4% showed conduction block across tarsal tunnel without reduction of motor conduction velocity. Overall percentage of abnormalities across tarsal tunnel (64.5%) exceeds that of the sensory conduction velocities of proximal sural and superficial peroneal nerves. Abnormal tibial motor conduction velocity across tarsal tunnel represents the most common abnormality among all motor nerve conduction study parameters and significantly correlates with hemoglobin level, diabetic neuropathic index score, and diabetic complications frequency.Tibial conduction abnormalities across tarsal tunnel are the most sensitive motor parameter in distal symmetric diabetic polyneuropathy, second only to conduction abnormalities of sensory/mixed distal nerves of the feet. The use of nerve conduction studies across tarsal tunnel of the tibial nerve may be useful in the electrophysiological protocol to confirm the diagnosis of distal symmetric diabetic polyneuropathy.

Introduction: Increasing evidence demonstrates a crucial role of inflammation in inducing and promoting several cancers. Pro-inflammatory upregulation of cytokines such as IL-6 has been implicated in cervical cancer development and progression through several mechanisms, for example, by inducing platelet production, activation, and aggregation. The aim of the study was to evaluate the effective prognostic impact of inflammatory biomarkers such as platelet count, platelet to lymphocyte ratio (PLR), and IL-6 in cervical cancer patients. Materials and Methods: Between 2016 and 2019, 108 out of 159 patients with cervical cancer have been enrolled. Cutoff level of pretreatment platelet count and PLR was identified by using the ROC curve. IL-6 tumoral and peritumoral expression was analyzed and stratified as low and high (low expression: 0 and +1; marked expression: +2 and +3). Results: Median follow-up duration was 30 months (range 16–44). Patients with higher platelet counts showed worse DFS and OS (DFS p < 0.001; OS p < 0.001). Cumulative rates of DFS and OS in patients with lower PLR were higher than in patients with higher values of PLR (DFS p = 0.032; OS p < 0.001). Survival analysis showed a better prognosis in patients with lower IL-6 expression (DFS p < 0.001; OS p < 0.001). Conclusion: Nowadays, causal relationship between inflammation, innate immunity, and cancer is more widely accepted. However, many of the molecular and cellular mechanisms mediating this relationship remain unresolved. Ongoing inflammatory response was associated with poor outcomes in cervical cancer patients. A higher pretreatment platelet count and PLR value associated with higher IL-6 tumoral expression could be used to predict poor prognosis in cervical cancer patients.

We performed a prospective multicenter case-control study to explore the association between ulnar neuropathy at elbow (UNE) and body and elbow anthropometric measures, demographic and lifestyle factors, and comorbidities. Cases and controls were consecutively enrolled among subjects admitted to four electromyography labs. UNE diagnosis was made on clinical and neurographic findings. The control group included all other subjects without signs/symptoms of ulnar neuropathy and with normal ulnar nerve neurography. Anthropometric measurements included weight, height, waist, hip circumferences, and external measures of elbow using a caliper. The participants filled in a self-administered questionnaire on personal characteristics, lifestyle factors, and medical history. We estimated odds ratios (ORs) and 95% confidence intervals (CIs) by fitting unconditional logistic regression models adjusted by center and education level. We enrolled 220 cases (males 61.8%; mean age 51.7 years) and 460 controls (47.4% males; mean age 47.8 years). At multivariable analysis, UNE was associated to male gender (OR = 2.4, 95%CI = 1.6-3.7), smoking habits (>25 pack-years (OR = 2.3, 95%CI = 1.3-4.1), body mass index (OR = 1.05, 95%CI 1.01-1.10), polyneuropathies (OR = 4.1, 95%CI 1.5-11.5), and leaning with flexed elbow on a table/desk (OR = 1.5, 95%CI 1.0-2.2). Cubital groove width (CGW) turned out to be negatively associated with UNE (OR = 0.80, 95%CI = 0.74-0.85). Our study suggests that some personal factors especially anthropometric measures of the elbow may play a role in UNE pathogenesis as the measures of wrist in CTS. We demonstrated that for each millimeter of smaller CGW the risk of idiopathic UNE increases of 25%.

Introduction In this study we collected reference values for the across-tarsal-tunnel conduction of the motor tibial nerve (mTN). Methods The mTN compound muscle action potentials (CMAPs) from the abductor hallucis muscle were obtained by stimulating below/above the malleolus and the popliteal fossa. The effect of weight, height, body mass index (BMI), foot and leg length, sex, and age were evaluated using univariate and multivariate correlation analyses, and predictive equations for each mTN conduction parameter were developed. Results On the basis of data from 185 subjects, there were differences between women and men in all anthropometric parameters and for some nerve conduction values. Through multivariate analysis, age, but not sex, was found to have a significant impact. Height affected both distal and proximal conduction velocity. BMI affected CMAP amplitude. Discussion mTN conduction is influenced by various demographic and anthropometric factors. For all intrinsic factors, height demonstrated the greatest effect on mTN conduction across the tarsal tunnel.

Drug-eluting bioresorbable vascular scaffolds (BVSs) have emerged as a potential breakthrough for the treatment of coronary artery stenosis, providing mechanical support and drug delivery followed by complete resorption. Restenosis and thrombosis remain the primary limitations in clinical use. The study aimed to identify potential markers of restenosis and thrombosis analyzing the vascular wall cell transcriptomic profile modulation triggered by BVS at different values of shear stress (SS). Human coronary artery endothelial cells and smooth muscle cells were cultured under SS (1 and 20 dyne cm−2) for 6 h without and with application of BVS and everolimus 600 nM. Cell RNA-Seq and bioinformatics analysis identified modulated genes by direct comparison of SS conditions and Gene Ontology (GO). The results of different experimental conditions and GO analysis highlighted the modulation of specific genes as semaphorin 3E, mesenchyme homeobox 2, bone morphogenetic protein 4, (heme oxygenase 1) and selectin E, with different roles in pathological evolution of disease. Transcriptomic analysis of dynamic vascular cell cultures identifies candidate genes related to pro-restenotic and pro-thrombotic mechanisms in an in-vitro setting of BVS, which are not adequately contrasted by everolimus addition.

Recent evidence suggests that a loss of expression of caveolin in the stromal compartment (sCav-1) of human invasive breast carcinoma (IBC) may be a predictor of disease recurrence, metastasis and poor outcome. At present, there is little knowledge regarding the expression of sCav-1 at the metastatic sites. We therefore studied sCav-1 expression in IBCs and in their axillary lymph nodes to seek a correlation with cancer metastasis. 189 consecutive invasive IBCs (53 with axillary lymph node metastases and 136 without) were studied by immunohistochemistry, using a rabbit polyclonal anti-Cav-1 antibody. In IBCs sCav-1 was evaluated in fibroblasts scattered in the tumor stroma whereas in lymph nodes sCav-1 was assessed in fibroblast-like stromal cells. For the first time, we observed a statistically significant progressive loss of sCav-1 from normal/reactive axillary lymph nodes of tumors limited to the breast to metastatic axillary lymph nodes, through normal/reactive axillary lymph nodes of tumors with axillary metastatic spread. These data indicate that Cav-1 expressed by the stromal compartment of lymph nodes, somehow, may possibly contribute to metastatic spread in IBC.

Introduction The role of tourniquet during knee arthroplasty is controversial. The present study compares various tourniquet protocols using a Bayesian network meta-analysis of peri-operative data. Material and methods The present study was conducted in accordance with the PRISMA extension statement for reporting systematic reviews incorporating network meta-analyses of health interventions. The literature search was conducted in September 2020. All clinical trials investigating the role of tourniquet in knee arthroplasty were considered for inclusion. Methodological quality was assessed using Review Manager 5.3. A Bayesian hierarchical random-effects model analysis was used in all comparisons. Results Ultimately, pooled data from 68 studies (7413 procedures) were analysed. Significant inconsistency was found in the data relating to total estimated blood lost; no assumption could be made on this outcome. Full-time tourniquet resulted in the shortest surgical duration and lowest intra-operative blood lost, in both cases followed by incision-to-suture. The incision-to-suture protocol achieved the smallest drop in haemoglobin during the first 72 h post-operatively and the lowest rate of blood transfusion, both followed by full-time tourniquet. Hospitalisation was shortest in the absence (no-tourniquet) group, followed by the cementation-to-end group. Conclusion For knee arthroplasty, longer tourniquet use is associated with the shorter duration of surgery, lower intra-operative blood lost, lower drops in haemoglobin and fewer transfusion units. The shortest average hospitalisation was associated with no tourniquet use.

Postoperative ileus (POI) impairs patient recovery, prolonging hospital stay after major surgery in ovarian cancer (OvCa) patients. Thus, intraoperative bowel isolation is expected to reduce manipulation-related impairment. The aim of this study was to investigate the impact of intraoperative intestinal isolation bag on POI in OvCa patients submitted to primary surgery. A randomized trial including patients managed with or without isolation bag during OvCa primary surgery was conducted. Patients were selected by consecutive randomization. Primary endpoints were the time between surgery and resumption of bowel motility (as passage of first/continued flatus), assessing of postoperative nausea or vomiting and return to regular diet. Secondary endpoint was the impact of intestinal isolation bag on length of hospitalization in the two groups. Ninety-two patients respecting inclusion criteria were eligible to be enrolled in the study (48 patients as Group 1 and 44 patients as Group 2). Thirty-eight (79.2%) patients, in which intraoperative isolation bag was used, experienced first/continued flatus within 3 days from surgery and they were susceptible to be discharged within 5 days, compared, respectively, to 34.3% of Group 2 (n = 15). Advantages were more evident in patients whose surgery took over 220 min (OR 0.02, CI 95% 0.001–0.57; p

The objective of the study is to investigate the effects of age, height, gender, body mass index (BMI), waist-to-hip ratio (WHR), arm and elbow measures on ulnar nerve conduction. We enrolled 261 "disease-free" subjects. We analyzed motor conduction velocity (MCV) in across elbow (AE) and forearm tracts, and sensory conduction velocity in 4th, 5th digit-wrist tracts (U4, U5) and in dorsal ulnar cutaneous nerve (DUC). We calculated the amplitudes of sensory and motor potentials (CMAPa and SNAPa), % of CMAPa drop AE, MCV drop and distal motor latency (DML). Univariate and multivariate analyses were performed. We estimated the predictive equations. The median nerve was examined for comparison. Age was negatively correlated with all conduction parameters. Forearm and AE MCV, % of CMAPa drop, DML, U4 and U5 SCV also depended upon height. Females had higher U4 and U5 SNAPa than males. BMI showed inverse relationship with U4 and U5 SNAPa. DUC parameters depended upon BMI and arm length. Similar trends were observed for the median nerve. "Normative" ulnar conduction parameters should be adjusted for demographic and anthropometric measures to improve diagnostic sensitivity.

Background Sudden unexplained death (SUD) refers to cases of sudden death where autopsy fails to identify any cardiac or extracardiac underlying cause. Guideline‐directed standard genetic testing identifies a disease‐causing mutation in less than one‐third of cases of SUD. Conversely, whole exome sequencing (WES) may provide the key to solve most cases of SUD even after several years from the subject's death. Methods We report on a case of sudden unexpected death of a 37‐year‐old male, with inconclusive autopsy conducted 14 years ago. A recent reevaluation through WES was performed on DNA extracted from left ventricular samples. A multiple step process including several “in silico” tools was applied to identify potentially pathogenic variants. Data analysis was based on a 562 gene panel, including 234 candidate genes associated with sudden cardiac death or heart diseases, with the addition of 328 genes highly expressed in the heart. WebGestalt algorithms were used for association enrichment analysis of all genes with detected putative pathogenic variants. Results WES analysis identified four potentially pathogenic variants: RYR2:c.12168G>T, TTN:c.11821C>T (rs397517804), MYBPC3:c.1255C>T (rs368770848), and ACADVL:c.848T>C (rs113994167). WebGestalt algorithms indicated that their combination holds an unfavorable arrhythmic susceptibility which conceivably caused the occurrence of the events leading to our subject's sudden death. Conclusion Associating WES technique with online prediction algorithms may allow the recognition of genetic mutations potentially responsible for otherwise unexplained deaths., We report on a case of sudden unexpected death of a 37‐year‐old male, with inconclusive autopsy conducted 14 years ago, where recent reevaluation through whole exome sequencing (WES) and WebGestalt algorithms allowed the recognition of four genetic mutations (RYR2‐K4056N, TTN‐R3941C, MYBPC3‐R419C, and ACADVL‐V283A) potentially responsible for the subject's sudden death.

// Sara Franceschi 1 , Francesca Lessi 1 , Paolo Aretini 1 , Valerio Ortenzi 2 , Cristian Scatena 2 , Michele Menicagli 1 , Marco La Ferla 1 , Prospero Civita 1 , Katia Zavaglia 3 , Claudia Scopelliti 1 , Alessandro Apollo 4 , Francesco Giovanni Carbone 2 , Riccardo Vannozzi 5 , Generoso Bevilacqua 6 , Francesco Pasqualetti 7 , Antonio Giuseppe Naccarato 2 and Chiara Maria Mazzanti 1 1 Fondazione Pisana per la Scienza, Onlus, Pisa, Italy 2 Department of Translational Research and New Technologies in Medicine, University Hospital of Pisa, Pisa, Italy 3 SOD Molecular Genetics, University Hospital of Pisa, Pisa, Italy 4 Tumor Cell Biology Unit, Istituto Tumori Toscana, Florence, Italy 5 Neurosurgery Department, University Hospital of Pisa, Pisa, Italy 6 Pathological Anatomy Section, San Rossore Clinic, Pisa, Italy 7 Radiotherapy Department, University Hospital of Pisa, Pisa, Italy Correspondence to: Chiara Maria Mazzanti, email: c.mazzanti@fpscience.it Keywords: glioblastoma; next generation sequencing (NGS); recurrence free survival (RFS); onco-drivers; tumor suppressors Received: November 17, 2017 Accepted: April 02, 2018 Published: May 08, 2018 ABSTRACT Glioblastoma is a devastating disease that despite all the information gathered so far, its optimal management remains elusive due to the absence of validated targets from clinical studies. A better clarification of the molecular mechanisms is needed. In this study, having access to IDH1 wild-type glioblastoma of patients with exceptionally long recurrence free survival (RFS), we decided to compare their mutational and gene expression profile to groups of IDH1 wild-type glioblastoma of patients with shorter RFS, by using NGS technology. The exome analysis revealed that Long-RFS tumors have a lower mutational rate compared to the other groups. A total of 158 genes were found differentially expressed among the groups, 112 of which distinguished the two RFS extreme groups. Overall, the exome data suggests that shorter RFS tumors could be, chronologically, in a more advanced state in the muli-step tumor process of sequential accumulation of mutations. New players in this kind of cancer emerge from the analysis, confirmed at the RNA/DNA level, identifying, therefore, possible oncodrivers or tumor suppressor genes.

The role of tourniquet during knee arthroplasty is controversial. The present study compares various tourniquet protocols using a Bayesian network meta-analysis of peri-operative data.The present study was conducted in accordance with the PRISMA extension statement for reporting systematic reviews incorporating network meta-analyses of health interventions. The literature search was conducted in September 2020. All clinical trials investigating the role of tourniquet in knee arthroplasty were considered for inclusion. Methodological quality was assessed using Review Manager 5.3. A Bayesian hierarchical random-effects model analysis was used in all comparisons.Ultimately, pooled data from 68 studies (7413 procedures) were analysed. Significant inconsistency was found in the data relating to total estimated blood lost; no assumption could be made on this outcome. Full-time tourniquet resulted in the shortest surgical duration and lowest intra-operative blood lost, in both cases followed by incision-to-suture. The incision-to-suture protocol achieved the smallest drop in haemoglobin during the first 72 h post-operatively and the lowest rate of blood transfusion, both followed by full-time tourniquet. Hospitalisation was shortest in the absence (no-tourniquet) group, followed by the cementation-to-end group.For knee arthroplasty, longer tourniquet use is associated with the shorter duration of surgery, lower intra-operative blood lost, lower drops in haemoglobin and fewer transfusion units. The shortest average hospitalisation was associated with no tourniquet use.

Trastuzumab is an effective therapeutic treatment for Her2-like breast cancer; despite this most of these tumors develop resistance to therapy due to specific gene mutations or alterations in gene expression. Understanding the mechanisms of resistance to Trastuzumab could be a useful tool in order to identify combinations of drugs that elude resistance and allow a better response for the treated patients. Twelve primary biopsies of Her2+/hormone receptor negative (ER-/PgR-) breast cancer patients were selected based on the specific response to neoadjuvant therapy with Trastuzumab and their whole exome was sequenced leading to the identification of 18 informative gene mutations that discriminate patients selectively based on response to treatment. Among these genes, we focused on the study of the ANKRD44 gene to understand its role in the mechanism of resistance to Trastuzumab. The ANKRD44 gene was silenced in Her2-like breast cancer cell line (BT474), obtaining a partially Trastuzumab-resistant breast cancer cell line that constitutively activates the NF-kb protein via the TAK1/AKT pathway. Following this activation an increase in the level of glycolysis in resistant cells is promoted, also confirmed by the up-regulation of the LDHB protein and by an increased TROP2 protein expression, found generally associated with aggressive tumors. These results allow us to consider the ANKRD44 gene as a potential gene involved in Trastuzumab resistance.

We describe a unique case of skeletal and extraskeletal angiomatosis complicated by Kasabach-Merritt syndrome. The patient was a 3-year-old boy, who presented with involvement of both femurs and left tibia, as well as with soft tissue lesions of the left thigh. At birth, multiple hemangiomas of the soft tissues of the frontal and parietal scalp had been identified, together with a space-occupying lesion of the lung. Histologically, the skeletal and soft tissue lesions consisted of a proliferation of thin-walled, dilated blood vessels, with an endothelial lining devoid of atypia and exhibiting immunoreactivity for CD31 and CD34, while podoplanin and GLUT1 were negative. Whole exome sequencing performed on samples from the lesion of the femur, the tibia and the skin of the thigh, showed a GNAQ (c.286A>T:p.T96S) variant in all specimens, that was confirmed with digital droplet PCR. This case expands the clinical and pathologic spectrum of vascular proliferations showing similar molecular biology, characterized by GNAQ, GNA11 or GNA14 mutations.

Unfortunately, the 13th author name has been published incorrectly in the original publication.

Total hip arthroplasty (THA) is one of the most performed intervention in orthopaedics surgery. Currently, there is no unanimous approval concerning the best approach for THA in terms of nerve palsies, dislocations and further revisions. Hence, a Bayesian network meta-analysis was conducted. The present study was conducted according to the PRISMA extension statement for reporting of systematic reviews incorporating network meta-analyses of healthcare interventions. The literature search was performed in September 2019. The NMA was performed through the STATA Software/MP routine for Bayesian hierarchical random-effects model analysis. Data from 10,675 THA were collected. The mean follow-up was 10 months. The anterior approach reported the lowest risk to incur a post-operative dislocation (overall inconsistency P = 0.99). The posterolateral approach reported the lowest risk to incur a nerve palsy (overall inconsistency P = 0.77). The funnel plot revealed a low risk of publication bias. The lateral approach was found to have the lowest risk of resulting in a revision surgery (overall inconsistency P = 0.90). According to our network comparisons, the posterolateral approach for THA represent the favourable exposure with regards to nerve palsy, further dislocations and revision surgeries.

A correction to this paper has been published: https://doi.org/10.1007/s00590-021-03026-9

BackgroundBladder cancer (BC) is the 9th most common cancer diagnosis worldwide. Low grade (LG) represents 70% of all BCs, characterized by recurrence and rare ability (10-15%) to progress to high grade (HG) and invade. The remaining 30% is high grade (HG), fast invasive BC, which is resistant to therapy. Identifying biomarkers for predicting those tumors able to progress is a key goal for patient outcome improvement. This study focuses on the most promising prognostic markers.Materials and methodsTP53 and FGFR3 mutational status, Survivin, CK19, CK20, E-cadherin and CD44 gene expression analysis were performed on 66 BCs.ResultsSurvivin was found associated to tumor grade (pConclusionWe suggest Survivin, both as a biomarker associated to G3 BCs but negatively related to TP53 mutational status, and as a potential novel therapeutic target.

Objectives To evaluate sensitivity, specificity and predictive values of sensory findings in ulnar neuropathy at the elbow (UNE), differences according to UNE localization and pathophysiology, and relation between the sites of sensory symptoms, abnormal evaluation of sensation and neurographic findings of ulnar sensory nerve. Methods Hand diagram and Semmes-Weinstein monofilaments were used for clinical evaluation in four ulnar hand territories. Sensory neurography was measured in the fourth and fifth digits-wrist segments (U5) and in the dorsal ulnar cutaneous nerve. Results We enrolled 75 idiopathic UNE cases and 180 controls. Symptoms in the fifth digit, reduction of touch sensation and U5 sensory nerve action potential amplitude (SNAPa) had the highest sensitivity, specificity and predictivity in UNE diagnosis. The normal/abnormal sensory clinical findings of the fifth digit matched with normal/abnormal U5 SNAP more than the matching of sensory parameters in the other ulnar hand sites. Sensory anomalies were more frequent in predominantly axonal than demyelinating UNE. There were no differences according to UNE location. Conclusion Sensory anomalies of the fifth digit are constant findings in UNE more than anomalies of the other ulnar nerve hand regions. Significance Probably the fascicles from fifth digit are the most liable to damage at elbow.

Background and objectives: Cancer stem cells (CSCs) have been implicated in tumor initiation, recurrence, metastatic spread and poor survival in multiple tumor types, breast cancers included. CSCs selectively overexpress key mitochondrial-related proteins and inhibition of mitochondrial function may represent a new potential approach for the eradication of CSCs. Because mitochondria evolved from bacteria, many classes of FDA-approved antibiotics, including doxycycline, actually target mitochondria. Our study aimed to determine whether short-term pre-operative treatment with oral doxycycline results in reduction of CSCs in early breast cancer patients.\ud \ud Methods: Doxycycline was administered orally for 14 days before surgery for a daily dose of 200 mg. Immuno-histochemical analysis of formalin-fixed paraffin-embedded (FFPE) samples from 15 patients, of which 9 were treated with doxycycline and 6 controls (no treatment), was performed with known biomarkers of “stemness” (CD44, ALDH1), mitochondrial mass (TOMM20), cell proliferation (Ki67, p27), apoptosis (cleaved caspase-3) and neo-angiogenesis (CD31). For each patient, the analysis was performed both on pre-operative specimens (core-biopsies) and surgical specimens. Changes from baseline to post-treatment were assessed with MedCalc 12 (unpaired t-test). \ud \ud Results: Post-doxycycline tumor samples demonstrated a statistically significant decrease in the stemness marker CD44 (p-value < 0.005), when compared to pre-doxycycline tumor samples. More specifically, CD44 levels were reduced between 17.65% and 66.67%, in 8 out of 9 patients treated with doxycycline. In contrast, only one patient showed a rise in CD44, by 15%. Overall, this represents a positive response rate of nearly 90%. Similar results were also obtained with ALDH1, another marker of stemness. In contrast, markers of mitochondrial mass, proliferation, apoptosis and neo-angiogenesis, were all similar between the two groups. \ud \ud Conclusions: Quantitative decreases in CD44 and ALDH1 expression are consistent with pre-clinical experiments and suggest that doxycycline can selectively eradicate CSCs in breast cancer patients in vivo. Future studies (with larger numbers of patients) will be conducted to validate these promising pilot studies.

Glioblastoma (GB) is the most aggressive type of primary brain tumor. Despite the progress in recent years regarding the diagnosis and treatment of GB, the recurrence rate remains high, due to the infiltrative and dispersive nature of the tumor, which typically results in poor patient prognosis. In the present study, 19 formalin-fixed, paraffin-embedded GB samples were selected from patients with GB tumors. The samples were classified into a short or long recurrence-free survival (RFS) group, based on the time of first recurrence of the disease in the patients. The 19 samples were molecularly characterized for mutations in the isocitrate dehydrogenase 1 (IDH1) gene, amplification of the epidermal growth factor receptor (EGFR) gene, presence of the EGFR variant III, and methylation of the promoter region of the O6-methylguanine-DNA methyltransferase (MGMT) gene. Then, the expression of 84 genes involved in cell-cell and cell-matrix interactions, and that of 84 microRNAs (miRNAs) associated with brain cancer, was profiled. In addition, a copy number variation analysis of 23 genes reported to undergo frequent genomic alterations in human glioma was also performed. Differences in the expression levels of a number of genes were detected across the short and long RFS groups. Among these genes, 5 in particular were selected, and a 5-genes combination approach was developed, which was able to differentiate between patients with short and long RFS outcome. The high levels of sensitivity and precision displayed by this 5-genes combination approach, which were confirmed with a cross-validation method, provide a strong foundation for further validation of the involvement of the aforementioned genes in GB in a larger patient population. In conclusion, the present study has demonstrated how the expression pattern of miRNAs and mRNAs in patients with GB defines a particular molecular hallmark that may increase or reduce the aggressive behavior of GB tumors, thus influencing the survival rates of patients with GB, their response to therapy and their tendency to suffer a relapse.

Objective To identify optimal cutoff values for body, hand, and wrist measurements in order to correctly identify individuals with carpal tunnel syndrome (CTS), using receiver operating characteristic (ROC) curves. Methods We enrolled patients with CTS and control subjects at a 1:2 ratio, regardless of age and sex. The diagnosis of CTS was based on clinical findings and delayed distal conduction velocity of the median nerve. The anthropometric measurements included weight, height, waist circumference, hip circumferences, wrist depth/width, third digit length, and palm length/width. Obesity indicators and hand/wrist ratios were calculated. Area under the ROC curve (AUC), sensitivity, specificity, and likelihood ratios were calculated separately according to sex. To assess the role of multiple anthropometric measurements, we fit multivariable logistic regression models including age, wrist ratio, shape index, body mass index, and waist-to-hip ratio. Results The study group comprised 1,117 subjects (250 female patients and 474 female controls; 120 male patients and 273 male controls). In women, the accuracy of all anthropometric measures was low (AUC ≤0.64). In men, the accuracy of the hand ratio, shape index, and wrist-to-palm ratio was moderate (AUC = 0.75). The estimates from the multivariable models confirmed the well-known associations between the selected variables and the risk of CTS, but the use of multiple predictors did not dramatically improve the diagnostic performance observed for single anthropometric indexes. Conclusion In clinical practice, the cutoff values for many anthropometric measurements have limited value as tools for the diagnosis of CTS.

CIMBA Consortium et al., PMID: 25849179, [Importance]: Limited information about the relationship between specific mutations in BRCA1 or BRCA2 (BRCA1/2) and cancer risk exists. [Objective]: To identify mutation-specific cancer risks for carriers of BRCA1/2. [Design, Setting, and Participants]: Observational study ofwomen whowere ascertained between 1937 and 2011 (median, 1999) and found to carry disease-associated BRCA1 or BRCA2 mutations. The international sample comprised 19 581 carriers of BRCA1 mutations and 11 900 carriers of BRCA2 mutations from 55 centers in 33 countries on 6 continents.We estimated hazard ratios for breast and ovarian cancer based on mutation type, function, and nucleotide position.We also estimated RHR, the ratio of breast vs ovarian cancer hazard ratios. A value of RHR greater than 1 indicated elevated breast cancer risk; a value of RHR less than 1 indicated elevated ovarian cancer risk. [Exposures]: Mutations of BRCA1 or BRCA2. [Main Outcomes and Measures]: Breast and ovarian cancer risks. [Results]: Among BRCA1 mutation carriers, 9052 women (46%) were diagnosed with breast cancer, 2317 (12%) with ovarian cancer, 1041 (5%) with breast and ovarian cancer, and 7171 (37%) without cancer. Among BRCA2 mutation carriers, 6180 women (52%) were diagnosed with breast cancer, 682 (6%) with ovarian cancer, 272 (2%) with breast and ovarian cancer, and 4766 (40%) without cancer. In BRCA1, we identified 3 breast cancer cluster regions (BCCRs) located at c.179 to c.505 (BCCR1; RHR = 1.46; 95%CI, 1.22-1.74; P = 2 × 10-6), c.4328 to c.4945 (BCCR2; RHR = 1.34; 95%CI, 1.01-1.78; P = .04), and c. 5261 to c.5563 (BCCR2', RHR = 1.38; 95%CI, 1.22-1.55; P = 6 × 10-9).We also identified an ovarian cancer cluster region (OCCR) from c.1380 to c.4062 (approximately exon 11) with RHR = 0.62 (95%CI, 0.56-0.70; P = 9 × 10-17). In BRCA2, we observed multiple BCCRs spanning c.1 to c.596 (BCCR1; RHR = 1.71; 95%CI, 1.06-2.78; P = .03), c.772 to c.1806 (BCCR1'; RHR = 1.63; 95%CI, 1.10-2.40; P = .01), and c.7394 to c.8904 (BCCR2; RHR = 2.31; 95%CI, 1.69-3.16; P = .00002).We also identified 3 OCCRs: the first (OCCR1) spanned c.3249 to c.5681 that was adjacent to c.5946delT (6174delT; RHR = 0.51; 95%CI, 0.44-0.60; P = 6 × 10-17). The second OCCR spanned c.6645 to c.7471 (OCCR2; RHR = 0.57; 95%CI, 0.41-0.80; P = .001). Mutations conferring nonsense-mediated decay were associated with differential breast or ovarian cancer risks and an earlier age of breast cancer diagnosis for both BRCA1 and BRCA2 mutation carriers. [Conclusions and Relevance]: Breast and ovarian cancer risks varied by type and location of BRCA1/2 mutations. With appropriate validation, these data may have implications for risk assessment and cancer prevention decision making for carriers of BRCA1 and BRCA2 mutations., Dr Antoniou and the CIMBA data management are funded by Cancer Research UK. Dr Easton is a Principal Research Fellow of Cancer Research UK. Dr Rebbeck is supported by R01-CA083855, R01-CA102776, and P50-CA083638 from the National Institutes of Health (NIH). Dr Rebbeck, Dr Nathanson, Ms Friebel, and Dr Domchek are supported by the Basser Research Center at the University of Pennsylvania. Dr Nathanson is supported by the Breast Cancer Research Foundation. Drs Domchek and Nathanson are supported by the Rooney Family Foundation. Dr Poppe is supported by R01-CA112520 from NIH. Cancer Research UK provided financial support for this work. Dr Antoniou is a Senior Cancer Research UK Cancer Research Fellow. Dr Phillips is a National Breast Cancer Foundation (Australia) Practitioner Fellow.

Objective Previous studies showed "F-wave inversion" (F-INV) as a sensitive method in the electrodiagnosis of early stage of carpal tunnel syndrome (CTS). This study aimed at evaluating the sensitivity and specificity of F-wave and nerve conduction velocity (NCV) testing in CTS. Methods We consecutively enrolled 244 cases and 108 controls. F-waves analysis included: Fwave minimum and mean latencies, F-wave persistence and chronodispersion, mean-F/CMAP amplitude ratio, F-INV. Specificity and sensitivity of F-waves parameters were calculated in the whole sample of CTS patients and by grouping the patients according to CTS severity. Multivariate logistic regression was also performed using F-INV as a dependent variable. Results In the whole sample the sensitivity of F-mean-INV and of median–ulnar NCV comparative testing was 50.8% and 93.7%, respectively. F-INV sensitivity dropped to 8% in CTS early stage. F-INV could be predicted only by distal motor latency of the median nerve. The sensitivity of all F-wave parameters increased only in the most severe stages of CTS. Conclusions This study does not confirm the electrodiagnostic usefulness of F-INV in early stage of CTS. All F-wave parameters, including F-INV, are much less sensitive than conventional NCV in CTS electrodiagnosis. F-wave does not add further useful information specifically related to CTS.

Objective To assess the associations between carpal tunnel syndrome (CTS) severity and selected anthropometric and obesity indexes. Design We performed a case-control study. Clinical and electrophysiological severity of CTS was classified as mild, moderate, or severe based on validated scales. Body and hand anthropometric characteristics were measured at the time of the electrodiagnostic study. We estimated the relative risk ratios (RRRs) of CTS severity by fitting multinomial logistic regression models adjusted by age and sex. In addition, we fitted multivariable models, including age, sex, wrist ratio, hand ratio, body mass index (BMI), and waist/stature ratio. Setting Electromyography laboratories. Participants Consecutive patients (N=1087), those with CTS (n=340) and those without CTS (n=747), were enrolled. Interventions Not applicable. Main Outcome Measures Associations between CTS severity and selected anthropometric and obesity indexes. Results We observed associations between many anthropometric indexes and CTS severity. Among obesity indexes, the waist/stature ratio, and among hand anthropometric indexes, the wrist/palm ratio, showed the highest RRRs for the clinical and electrophysiological severity scales. The RRRs of severe CTS (adjusted for age and sex) for the wrist/palm ratio were 3.5 for the clinical scale and 2.4 for the electrophysiological scale. The RRRs of severe CTS for the waist/stature ratio were 2.3 for the clinical scale and 2.0 for the electrophysiological scale. In the multivariable models, both BMI and the waist/stature ratio were associated with the outcomes. Conclusions Different configurations of the body and, in particular, the hand and wrist system may influence the occurrence and severity of CTS. Multiple obesity indexes, possibly including the waist/stature ratio, should be considered when investigating the association between body composition and CTS. Future studies should determine whether in obese subjects with CTS the weight and waist circumference loss produces an improvement in CTS symptoms and recovery of distal conduction velocity of the median nerve.

Objective: To study the diagnostic properties of hand/wrist and body measures according to validated clinical and electrophysiological carpal tunnel syndrome (CTS) severity scales. Methods: We performed a prospective case-control study. For each case, two controls were enrolled. Two five-stage clinical and electrophysiological scales were used to evaluate CTS severity. Anthropometric measurements were collected and obesity indicators and hand/wrist ratios were calculated. Area under the receiver operating characteristic curves (AUC), sensitivity, specificity, and likelihood ratios were calculated separately by gender. Results: We consecutively enrolled 370 cases and 747 controls. The wrist-palm ratio, waist-hipheight ratio and waist-stature ratio showed the highest proportion of cases with abnormal values in the severe stages of CTS for clinical and electrophysiological severity scales in both genders. Accuracy tended to increase with CTS severity for females and males. In severe stage, most of the indexes presented moderate accuracy in both genders. Among subjects with severe CTS, the wrist-palm ratio presented the highest AUC for hand measures in the clinical and electrophysiological severity scales both in females (AUC 0.83 and 0.76, respectively) and males (AUC 0.91 and 0.82, respectively). Among subjects with severe CTS, the waist-stature ratio showed the highest AUC for body measures in the clinical and electrophysiological severity scales both in females (AUC 0.78 and 0.77, respectively) and males (AUC 0.84 and 0.76, respectively). The results of waist-hip-height ratio AUC were similar. Conclusions: Wrist-palm ratio, waist-hip-height ratio and waist-stature ratio could contribute to support the diagnostic hypothesis of severe CTS that however has to be confirmed by nerve conduction study.

ObjectiveCarpal tunnel syndrome (CTS) is a socially relevant condition. This case-control study aims to investigate the association between CTS severity and manual work considering personal anthropometric risk factors as well.MethodsWe consecutively enrolled one CTS case for two controls (subjects without clinical and electrophysiological CTS signs) regardless of age and gender who were admitted to the same three outpatient electromyography labs.CTS cases were grouped in three classes of progressive „clinical and electrophysiological severity according to two „validated five-stage scales. Anthropometric measures and „occupational history were collected. Job titles were coded according to the International Standard Classification of Occupations (ISCO 88) by two occupational physicians who were blind to case/control status. Job titles were grouped in two main occupational categories: manual workers and non-manual workers.To assess the association between CTS severity and manual work, ordered logistic regression models (adjusted for age, sex, wrist-palm ratio and waist-stature ratio) were performed. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated.ResultsThis case-control study enrolled 370 cases and 747 controls. After the exclusion of retired subjects, subjects older than 65 years and subjects with no information about occupational history, we included 183 cases and 445 controls in the main analysis.For manual workers with respect to non-manual workers, the OR for the electrophysiological severity scale was 2.4 (95%CI 1.5–3.7). Regarding the clinical severity scale, the OR for manual workers compared to non-manual workers were 2.3 (95%CI 1.5–3.7).ConclusionThis study confirms that manual work is an important risk factor for CTS. The association between manual work and CTS severity tends to increase from mild to severe stage of both electrophysiological and clinical scale.

The aims are to evaluate electrodiagnostic testing (EDX) requests and verify if presence, consistency and agreement of referral diagnosis could be predicted by patient demographic findings and referring physician typology, and if there were differences in respect to our previous study performed 16 years ago. The study concerns EDX requests referred to two electromyography labs during the year 2011. Differences between findings of general practitioners (GPs) versus specialists' requests and between this study with the previous were assessed. Multivariate logistic regression was performed to calculate odds ratio to assess the strength of association between presence, consistency and agreement of referral diagnosis with patient demographic findings and referring physician typology. We evaluated EDX requests of 1,586 patients (mean age 56 ± 16.7 years, 58.8 % women), 1,050 (66.2 %) were referred by GPs and 536 (33.8 %) by specialists. The suspected diagnosis was reported in 1,033 (65.1 %) requests, the overall consistency was 79.9 % and agreement was 71.9 %. Presence, consistency and agreement of referral diagnosis were predicted by physician's typology (specialist). Only if the suspected diagnosis was carpal tunnel syndrome, consistency and agreement were high regardless of doctor's typology. The physicians, especially GPs, who reported the referral diagnosis decreased during the past 16 years. A diagnostic test, including EDX, should be considered mainly if it fits into the best diagnostic strategy. The neurophysiologist should decide if EDX is useful, make the best decision on further management, and not submit patients to unnecessary and uncomfortable procedures. This choice of behaviour could be questionable and may lead to ethical and deontological problems.

Summary Study aim This prospective study aim to examine whether clinical findings and electrodiagnostic testing (EDX) in patients with lumbosacral monoradiculopathy due to herniated disc (HD) differ as a function of root involvement level (L5 vs. S1) and HD zone (paramedian vs. intraforaminal). Patients and methods All patients with L4, L5 or S1 monoradiculopathy were prospectively enrolled at four electromyography (EMG) labs over a 2-year period. The diagnosis was based on a congruence between patient history and MRI evidence of HD. We compared the sensitivities of clinical findings and EDX with respect to both root involvement level and HD zone. Multivariate logistic regression was performed in order to verify the association between abnormal EMG, clinical, and neuroradiological findings. Results One hundred and eight patients (mean age 47.7 years, 55% men) were consecutively enrolled. Sensory loss in the painful dermatome was the most frequent finding at physical examination (56% of cases). EMG was abnormal in at least one muscle supplied by femoral and sciatic nerves in 45 cases (42%). Inclusion of paraspinal muscles increased sensitivity to only 49% and that of proximal muscles was useless. Motor and sensory neurography was seldom abnormal. The most frequent motor neurographic abnormalities were a delay of F-wave minimum latency and decrease in the compound muscle action potential amplitude from extensor digitorum brevis and abductor hallucis in L5 and S1 radiculopathies, respectively. Sensory neurography was usually normal, the amplitude of sensory nerve action potential was seldom reduced when HD injured dorsal root ganglion or postganglionic root fibres. Multivariate logistic regression analysis showed that EMG abnormalities could be predicted by myotomal muscular weakness, abnormal deep reflexes, and paraesthesiae. The only clinical and electrophysiological differences with respect to root involvement level concerned deep reflexes and motor neurography of deep peroneal and tibial nerves. Conclusions Only some EDX parameters are helpful for the diagnosis of lumbosacral radiculopathy. EMG was abnormal in less than 50% of cases and its abnormalities could be predicted by some clinical findings. However, neurography is useful as a tool for differential diagnosis between radiculopathy and more diffuse disorders of the peripheral nervous system (polyneuropathy, plexopathy).

// Caterina Chiappetta 1 , Massimiliano Mancini 1 , Francesca Lessi 2 , Paolo Aretini 2 , Veronica De Gregorio 2 , Chiara Puggioni 1 , Raffaella Carletti 1 , Vincenzo Petrozza 1 , Prospero Civita 2 , Sara Franceschi 2 , Antonio G. Naccarato 3 , Carlo Della Rocca 1 , Chiara M. Mazzanti 2, * and Claudio Di Cristofano 1, * 1 UOC of Pathology, Department of Medical-Surgical Sciences and Bio-Technologies, Sapienza University of Rome, Latina, Italy 2 Pisa Science Foundation, Pisa, Italy 3 Department of Pathology, University of Pisa, Pisa, Italy * These authors contributed equally to this work Correspondence to: Carlo Della Rocca, email: carlo.dellarocca@uniroma1.it Keywords: osteosarcoma, next generation sequencing, carcinogenesis, metastasis, drug resistance Received: March 31, 2017 Accepted: June 20, 2017 Published: July 05, 2017 ABSTRACT Osteosarcoma is the most common pediatric primary non-hematopoietic bone tumor. Survival of these young patients is related to the response to chemotherapy and development of metastases. Despite many advances in cancer research, chemotherapy regimens for osteosarcoma are still based on non-selective cytotoxic drugs. It is essential to investigate new specific molecular therapies for osteosarcoma to increase the survival rate of these patients. We performed exomic sequence analyses of 8 diagnostic biopsies of patients with conventional high grade osteosarcoma to advance our understanding of their genetic underpinnings and to correlate the genetic alteration with the clinical and pathological features of each patient to identify a personalized therapy. We identified 18,275 somatic variations in 8,247 genes and we found three mutated genes in 7/8 (87%) samples (KIF1B, NEB and KMT2C). KMT2C showed the highest number of variations; it is an important component of a histone H3 lysine 4 methyltransferase complex and it is one of the histone modifiers previously implicated in carcinogenesis, never studied in osteosarcoma. Moreover, we found a group of 15 genes that showed variations only in patients that did not respond to therapy and developed metastasis and some of these genes are involved in carcinogenesis and tumor progression in other tumors. These data could offer the opportunity to get a key molecular target to identify possible new strategies for early diagnosis and new therapeutic approaches for osteosarcoma and to provide a tailored treatment for each patient based on their genetic profile.

To demonstrate whether in distal symmetric polyneuropathy (DSPN) in diabetes there are differences between patients with and without neuropathic pain and whether pain is associated with demographic, clinical and electrophysiological variables.We prospectively enrolled 154 consecutive patients (mean age 67 years, 64% men) in an electromyography (EMG) lab. The differences were calculated between DSPN patients with (no.78) and without neuropathic pain (no.76) relating to age, sex, BMI, type, duration, treatment and complications of diabetes, HbA1c, type and duration of DSPN symptoms, DSPN clinical severity score (with Diabetic Neuropathic Index-DNI), electrophysiological findings of lower limb muscles and nerves.The differences between DSPN patients with and without pain included the presence of symptoms (burning and weakness), DNI score and neurographic findings of all nerves and neurogenic EMG. But in the logistic regression models enter only the following variables: DNI score, neurogenic EMG, and among symptoms “burning-.The presence of pain in DSPN is associated with DSPN clinical severity, neurogenic EMG and presence of “burning- symptom but not with demographic or neurographic findings, or diabetes related variables. Therefore, the neuropathic pain in DSPN does not associate with the degree of involvement of large diameter sensory fibres or diabetes severity.

To report an electrophysiological study on thenar motor neuropathy of the median nerve.Twenty-eight consecutive patients (mean age, 48.8 years; 17 men) with dominant hand thenar muscle weakness without sensory symptoms were enrolled in this study. Electromyography of hand and forearm muscles and neurography of median, ulnar, radial, and palmar nerves, including distal motor latency recording from the second interosseous-lumbrical muscles, were performed.Complete denervation of the abductor pollicis brevis muscle was observed in one case and delayed median abductor pollicis brevis-distal motor latency was observed in the others. Other neurographic findings were normal.Thenar motor neuropathy may have different pathogeneses. It may be considered a variant of carpal tunnel syndrome involving the motor branch only or more likely due to chronic direct compression of the branch, because it preferentially affects males, dominant hand, and persons doing manual work. In both cases, anatomic origin and variations in the course of the branch may favor thenar motor neuropathy.

Objective Carpal tunnel syndrome (CTS) has a high prevalence in agricultural workers, especially those engaged in vineyards. We postulated that vineyard CTS was electrophysiologically different from CTS of other subjects. We performed a retrospective cross-sectional electrophysiological study of two cohorts of consecutive patients with CTS, the first consisting of vineyard workers and the second, of other unselected types of workers, housewives and pensioners. Methods Thirty-three vineyard workers (mean age 46.8 years, 42% women) and 205 patients with other occupations (mean age 53.7 years; 66% women) were enrolled. All patients underwent sensory and motor neurography of the median and ulnar nerves. Differences in demographic and electrophysiological findings between groups were calculated and multiple linear regression analysis was performed to eliminate the influence of potential confounding factors (age, sex, BMI, clinical severity of CTS) on the results of univariate difference analysis. Results Univariate analysis showed that DML was longer and compound muscle action potential amplitude of the median nerve, recorded from the abductor pollicis brevis muscle, was smaller in vineyard workers than in the other CTS patients. These differences remained significant after adjusting the results for confounding factors. Conclusions The vineyard workers showed a different pattern of CTS than the other patients: thenar motor fibres were more affected, presumably due to chronic compression on the thenar branch. This suggests an association between “common” CTS and thenar mononeuropathy. Significance Occupational physiologists should clarify the mechanisms of neuromuscular engagement in particular jobs and ergonomists design suitable working tools, because many “individual” risk factors are difficult to change, but workplace-related risk factors can be modified.

Diabetes mellitus is a main risk factor for vascular diseases. Vascular injury induced by diabetes mellitus is characterized by endothelial dysfunction attributable to an increased oxidative stress. So far, the molecular mechanisms involved in the vasculotoxic effects of diabetes are only partially known. We examined the effect of diabetes mellitus on oxidative stress and Rac-1 activation, a small G -protein involved in the activation of NADPH oxidase. Our results show that oxidative stress in vessels of different murine models of diabetes mellitus and in endothelial cells treated with high glucose is associated with an increased Rac-1/PAK binding and Rac-1 translocation from cytosol to plasma membrane, thus demonstrating an enhanced Rac-1 activity. More important, selective Rac-1 inhibition by an adenoviral vector carrying a dominant negative mutant of Rac-1 protected from oxidative stress and vascular dysfunction induced by diabetes mellitus. Our study demonstrates that Rac-1 plays a crucial role in diabetes-induced vascular injury, and it could be a target of novel therapeutic approaches to reduce vascular risk in diabetes mellitus. © 2006 American Heart Association, Inc.

The pathogenetic hypotheses of Raynaud’s phenomenon include increased activation of sympathetic noradrenergic nerves controlling muscle tone of digit arteriolar walls. Because acral sympathetic fibres contain vasoactive adrenergic and cholinergic fibres for sweat glands, we tested cholinergic sympathetic fibre function in primary Raynaud’s phenomenon (PRP) patients by sympathetic skin response (SSR). Twenty-six consecutive patients (19 women, 7 men, mean age 37.8 years) with PRP were enroled prospectively. SSR was obtained by random electrical stimulation of the left ulnar nerve at the wrist recording from the palm (PSSR), third (M3SSR) and fifth fingers (U5SSR) on the right side. For each subject latency of shortest response, area of largest response and grand mean latencies and areas of 12 consecutive responses were calculated. The differences between patients and a control group (15 women, 6 men, mean age 38.9 years) were calculated. SSR habituation was also compared between patients and controls. PSSRs were recorded in all patients and no difference in any PSSR parameter was found between patients and controls. U5SSRs and M3SSRs were absent in two patients. Grand mean area and mean of largest M3SSRs and U5SSRs were significantly lower in patients than in controls. Grand mean latency and mean of shortest M3SSRs and U5SSRs were significantly slower in patients than in controls. M3 and U5SSRs habituated less in patients than in controls. Dysregulation of cholinergic sympathetic fibres innervating the fingers was found in PRP. Abnormal peripheral mechanisms may be the cause. Since SSR habituation was also not normal, even central mechanisms may be implicated.

Background The association between carpal tunnel syndrome (CTS) and high body mass index (BMI) and some hand measures is well known. No study has been specifically focused on waist circumference (WC) and waist-to-hip-ratio (WHR). The aim of this prospective case–control study is to evaluate the association between CTS and WC, WHR and other body and hand anthropometric measures. Methods We consecutively enrolled one “idiopathic” CTS case for two controls in 3 outpatient electromyography labs. The main anthropometric measures were BMI, WC, WHR, wrist ratio (WR) and hand ratio (HR). We performed univariate and multivariate analyses. Results Female cases and controls were 250 and 474 and male cases and controls were 120 and 273, respectively. At univariate analysis there were differences in many anthropometric measures between cases and controls. At multivariate logistic regression analyses high BMI, WC and WHR and abnormal HR and WR were independent risk factors for CTS. Crossing two categories between BMI, WC and WHR, the overweight subjects, especially females, were at risk only if they had very high WC or high WHR. The risk increased if they were obese. Conclusions High WC/WHR doubles the risk of CTS, the risk further increased if overweight/obese subjects have also very high WC or high WHR. The obese subjects were always at risk regardless of WC and WHR values. Metabolic causes of this association with CTS were hypothesised. BMI is not the only and most powerful body predictor of “idiopathic” CTS, but also WHR and WC should be considered. These measures may not be interchangeable and it may be desirable to consider the utility of their joint use.

Background Papillary thyroid cancer is the most common endocrine malignancy. The most sensitive and specific diagnostic tool for thyroid nodule diagnosis is fine-needle aspiration (FNA) biopsy with cytological evaluation. Nevertheless, FNA biopsy is not always decisive leading to “indeterminate” or “suspicious” diagnoses in 10 %–30 % of cases. BRAF V600E detection is currently used as molecular test to improve the diagnosis of thyroid nodules, yet it lacks sensitivity. The aim of the present study was to identify novel molecular markers/computational models to improve the discrimination between benign and malignant thyroid lesions. Methods We collected 118 pre-operative thyroid FNA samples. All 118 FNA samples were characterized for the presence of the BRAF V600E mutation (exon15) by pyrosequencing and further assessed for mRNA expression of four genes (KIT, TC1, miR-222, miR-146b) by quantitative polymerase chain reaction. Computational models (Bayesian Neural Network Classifier, discriminant analysis) were built, and their ability to discriminate benign and malignant tumors were tested. Receiver operating characteristic (ROC) analysis was performed and principal component analysis was used for visualization purposes. Results In total, 36/70 malignant samples carried the V600E mutation, while all 48 benign samples were wild type for BRAF exon15. The Bayesian neural network (BNN) and discriminant analysis, including the mRNA expression of the four genes (KIT, TC1, miR-222, miR-146b) showed a very strong predictive value (94.12 % and 92.16 %, respectively) in discriminating malignant from benign patients. The discriminant analysis showed a correct classification of 100 % of the samples in the malignant group, and 95 % by BNN. KIT and miR-146b showed the highest diagnostic accuracy of the ROC curve, with area under the curve values of 0.973 for KIT and 0.931 for miR-146b. Conclusions The four genes model proposed in this study proved to be highly discriminative of the malignant status compared with BRAF assessment alone. Its implementation in clinical practice can help in identifying malignant/benign nodules that would otherwise remain suspicious. Electronic supplementary material The online version of this article (doi:10.1186/s12885-015-1917-2) contains supplementary material, which is available to authorized users.

To analyze the relationship between pain and presence, site, and type of adhesions in women with endometriosis.This was a multicenter, observational cross-sectional study. Eligible for the study were women with endometriosis and pelvic pain, consecutively observed during the study period at the collaborating centers. A total of 574 women entered the study.Adhesions were observed in 81.9% of cases (470 women). The frequency was lower in women with endometriosis at stage I-II (65%) and higher in women with stage III-IV (88%); this difference was statistically significant (p.01). The frequency of adhesions was lower in women with ovarian endometriosis (74%) and higher in those with ovarian and peritoneal endometriosis (87%) or other sites (96%) (p.01). The presence of adhesions was associated with higher mean visual analog scale (VAS) scores and median multidimensional scale ratings in women with ovarian disease and with stage I-II disease. Women with ovarian adhesions reported higher VAS and multidimensional scale scores (p.05) than women with peritoneal adhesions or adhesions in other sites.The results of this study suggest that there is no overall association between the presence of adhesions and the degree of pain in women with endometriosis. The data suggests that there may be an association between adhesions and pain in women with ovarian and Type I-II endometriosis. However, these associations were no longer significant after correction for multiple comparisons. Further research is indicated to test these associations.

In order to assess barriers and the attitudes of gynecologists toward randomized controlled trials (RCT) in surgery for endometriosis, we identified 62 gynecologists affiliated with the Gruppo Italiano di Studio sull'Endometriosi and sent them a questionnaire. A total of 52 (83.9%) gynecologists completed and sent it back to the coordinating center. Most gynecologists strongly agreed or agreed that RCTs should be the study design of choice for evaluating surgical procedures, but 66% also strongly agree/agree that RCTs are best suited to nonsurgical setting. With regard to the feasibility of RCT in surgery, there was a high level (>50%) of agreement with the statement: RCTs are insufficiently funded; the surgical community gives to RCTs too low priority; patients are unlikely to accept random allocation. A total of 43% agree or strongly agree that there is often consensus on new procedures without the need for RCTs, but 49% disagree or strongly disagree. Considering the statements on methodological problem...