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To date, the virtual multidisciplinary tumor boards (vMTBs) are increasingly used to achieve high-quality treatment recommendations across health-care regions, which expands and develops the local MTB team to a regional or national expert network. This review describes the process of lung cancer-specific MTBs and the transition process from face-to-face tumor boards to virtual ones. The review also focuses on the project organization's description, advantages, and disadvantages. Semi-structured interviews identified five major themes for MTBs: current practice, attitudes, enablers, barriers, and benefits for the MTB. MTB teams exhibited positive responses to modeled data feedback. Virtualization reduces time spent for travel, allowing easier and timely patient discussions. This process requires a secure web platform to assure the respect of patients’ privacy and presents the same unanswered problems. The implementation of vMTB also permits the implementation of networks especially in areas with geographical barriers facilitating interaction between large referral cancer centers and tertiary or community hospitals as well as easier access to clinical trial opportunities. Studies aimed to improve preparations, structure, and conduct of MTBs, research methods to monitor their performance, teamwork, and outcomes are also outlined in this article. Analysis of literature shows that MTB participants discuss 5–8 cases per meeting and that the use of a vMTB for lung cancer and in particular stage III NSCLC and complex stage IV cases is widely accepted by most health professionals.Despite still-existing gaps, overall vMTB represents a unique opportunity to optimize patient management in apatient-centeredapproach.

We present a cohort of 100 subjects [43 men and 57 women; median age 66.00(25)] who were tested using carotid ultrasound to identify subclinical carotid atherosclerosis (SCA). We have evaluated the behaviour of whole blood viscosity (WBV) at high (450 s–1) and low (0.51 s–1) shear rates, plasma viscosity (450–1), hematocrit and mean erythrocyte aggregation. When compared to normal control subjects, using the Mann-Whitney test, we observed in SCA patients a significant increase in WBV only. The results were substantial after having divided the SCA subjects according to the cardiovascular risk factors (CRFs) and the degree of insulin resistance; the research was performed using two surrogate indexes such as TG/HDL-C and TyG. With the division carried out according to CRFs, employing the Kruskal-Wallis test, results show a significant increase in WBV (at high and low shear rates), in plasma viscosity, in erythrocyte aggregation and plasma fibrinogen level. Whereas by dividing them into the median of TG/HDL-C and TyG, we noticed a significant increase in WBV (at high and low shear rates) and in erythrocyte aggregation in the two groups with high TG/HDL-C ratio and with high TyG; having found an increased level of plasma fibrinogen in the latter. The data underlines the role of the main hemorheologic aspects in subclinical carotid atherosclerosis being closely correlated to the CRFs and different degrees of insulin resistance.

Background/aim Upper limb breast cancer-related lymphedema (BCRL) is a chronic and severe condition affecting a significant percentage of breast cancer survivors. Even though its physiopathology is well-known, there is no worldwide consensus on BCRL evaluation and a gold-standard treatment. This narrative review aims at providing a brief descriptive overview with regard to BCRL treatment modalities. Materials and methods We conducted a literature search within the PubMed database, and 33 articles out of 56 were selected, including reviews, systematic reviews, and meta-analyses aiming find the most updated evidence regarding BCRL treatment modalities. Results Physical exercise (aerobic exercise, resistance exercise, aquatic therapy), bandages, and intermittent pneumatic compression were shown to be most effective in BCRL patients, in terms of swelling reduction in the acute-intensive phase. Furthermore, physical exercise was beneficial also as a maintenance tool. Manual lymphatic drainage demonstrated efficacy in preventing secondary lymphedema if applied immediately after breast cancer surgery or in early phases of BCRL or as a maintenance tool. Complementary procedures such as acupuncture, reflexology, yoga and photo-biomodulation therapy did not show conclusive results in BCRL treatment. Surgery was shown effective in managing symptoms (liposuction), preventing (lymphaticovenular anastomosis) and treating BCRL (vascularized lymph node transfer). Conclusion BCRL is still a challenging condition either for breast cancer survivors and clinicians, deeply impacting patient functioning and quality of life. Due to the lack of globally accepted criteria in evaluating BCRL, to date a gold standard treatment for this widespread issue is still needed.

In 2013, the Italian Society of Nephrology joined forces with Nephrocare-Italy to create a clinical research cohort of patients on file in the data-rich clinical management system (EUCLID) of this organization for the performance of observational studies in the hemodialysis (HD) population. To see whether patients in EUCLID are representative of the HD population in Italy, we set out to compare the whole EUCLID population with patients included in the regional HD registries in Emilia-Romagna (Northern Italy) and in Calabria (Southern Italy), the sole regions in Italy which have systematically collected an enlarged clinical data set allowing comparison with the data-rich EUCLID system. An analysis of prevalent and incident patients in 2010 and 2011 showed that EUCLID patients had a lower prevalence of coronary heart disease, peripheral vascular disease, heart failure, valvular heart disease, liver disease, peptic ulcer and other comorbidities and risk factors and a higher fractional urea clearance (Kt/V) than those in the Emilia Romagna and Calabria registries. Accordingly, survival analysis showed a lower mortality risk in the EUCLID 2010 and 2011 cohorts than in the combined two regional registries in the corresponding years: for 2010, hazard ratio (HR) EUCLID vs. Regional registries: 0.80 [95% confidence interval: 0.71–0.90]; for 2011, HR: 0.76 [0.65–0.90]. However, this difference was nullified by statistical adjustment for the difference in comorbidities and risk factors, indicating that the longer survival in the EUCLID database was attributable to the lower risk profile of patients included in that database. This preliminary analysis sets the stage for future observational studies and indicates that appropriate adjustment for difference in comorbidities and risk factors is needed to generalize to the Italian HD population analyses based on the data-rich EUCLID database.

Background Plasminogen activator inhibitor-1 (PAI-1) is the most important inhibitor of plasminogen activator. The functional 4G/5G polymorphism of the gene coding for PAI-1 may affect PAI-1 plasmatic activity, influencing the imbalance between coagulation and fibrinolysis cascades. In this prospective cohort analytic study, we investigated the role of this single nucleotide polymorphism in the persistence of thrombotic lesion and the occurrence of post-thrombotic syndrome. Patients/Methods In a group of 168 patients with post-surgical deep vein thrombosis of the legs, we analyzed the 4G/5G polymorphism in the promoter of PAI-1 gene and plasmatic PAI-1 activity. Enrolled patients were divided in two groups: patients with 4G/5G polymorphism and increased PAI-1 activity (n = 85) and patients without 4G/5G polymorphism and normal PAI-1 activity (n = 83). All patients were treated according to current protocols and re-examined after 3, 12 and 36 months in order to evaluate the persistence of thrombotic lesion and the occurrence of post-thrombotic syndrome. Results We found a significantly increased PAI activity in carrier of the 4G allele, who experienced much more frequently a persistence of thrombosis after 3, 12 and 36 months and/or the development of post-thrombosis syndrome, in spite of the anticoagulant treatment. Conclusions These data not only confirm the role played by PAI-1 activity and by the 4G/5G SNP of the PAI-1 gene, but also suggest that current therapeutic protocols, recommending the administration of low weight molecular heparin and oral anticoagulant for the treatment of deep vein thrombosis, could be non sufficient for patients genetically predisposed to a less efficient clot lysis.

Residual vein thrombosis (RVT) indicates a prothrombotic state and is useful for evaluating the optimal duration of oral anticoagulant treatment (OAT). Patients with a first episode of deep vein thrombosis, treated with OAT for 3 months, were managed according to RVT findings. Those with RVT were randomized to either stop or continue anticoagulants for 9 additional months, whereas in those without RVT, OAT was stopped. Outcomes were recurrent venous thromboembolism and/or major bleeding. Residual thrombosis was detected in 180 (69.8%) of 258 patients; recurrent events occurred in 27.2% of those who discontinued (25/92; 15.2% person-years) and 19.3% of those who continued OAT (17/88; 10.1% person-years). The relative adjusted hazard ratio (HR) was 1.58 (95% confidence interval [CI], 0.85-2.93; P = .145). Of the 78 (30.2%) patients without RVT, only 1 (1.3%; 0.63% person-years) had a recurrence. The adjusted HR of patients with RVT versus those without was 24.9 (95% CI, 3.4-183.6; P = .002). One major bleeding event (1.1%; 0.53% person-years) occurred in patients who stopped and 2 occurred (2.3%; 1.1% person-years) in those who continued OAT. Absence of RVT identifies a group of patients at very low risk for recurrent thrombosis who can safely stop OAT. This trial was registered at http://www.ClinicalTrials.gov as no. NCT00438230.

Venous leg ulcers are common in subjects with chronic venous insufficiency. The increased intraluminal pressure causes alteration of the skin microcirculation, leukocyte activation and release of proteolytic enzymes leading to ulceration. An impaired expression and activity of matrix metalloproteases (MMPs) and their tissue inhibitors (TIMPs) might influence extracellular matrix degradation and deposition in chronic venous ulcers with the failure of the healing process. Our aim was to evaluate plasma concentration of gelatinases (MMP-2 and MMP-9) and their inhibitors (TIMP-1 and TIMP-2) in subjects with venous leg ulcers before and after the compression therapy. We enrolled 36 subjects (12 men and 24 women, mean age 67.38 ± 12.7 yrs) with non-infected venous leg ulcers (CEAP C6), which underwent a color Duplex scan examination of the veins and arteries of the inferior limbs and were treated with a multi-layer bandaging system. The ulcer healing was obtained in 23 subjects only (9 men and 14 women). We evaluated, on fasting venous blood, the plasma levels of MMP-2, MMP-9, TIMP-1 and TIMP-2 using ELISA kit, before and after the treatment. We observed a significant increase in plasma concentration of gelatinases and their inhibitors and in MMP-2/TIMP-2 ratio in subjects with leg ulcers in comparison with normal controls. In subjects with healed ulcers we found a decrease in MMP-9 and TIMP-1 levels and in MMP-2/TIMP-2 ratio compared to the baseline values, although higher levels of all the examined parameters in comparison with normal controls. In conclusion, plasma MMPs profile is impaired in subjects with venous leg ulcers and it improves after the healing, persisting anyway altered in respect to healthy controls.

Objectives: to evaluate the clinical efficacy and the effects on the quality of life of Iloprost, a prostacyclin analogue, used, according to a new protocol, in patients with Raynaud’s phenomenon secondary to Systemic Sclerosis. Methods: in this randomized study we treated 30 patients with Iloprost given by intravenous infusion, at progressively increasing doses (starting from 0.5 ng/Kg/min up 2 ng/Kg/min) over a period of 6 hours a day for ten days in two consecutive weeks, with repeated cycles at regular intervals of three months for 18 months. The results were compared with those obtained in 30 other patients, who had received the same drug but with different posologic schemes. Results: the total average daily duration of the attacks, the average duration of a single attack and the average daily frequency of the attacks were reduced significantly in all groups of treatment, but the comparison between the groups demonstrated significant differences between patients treated with the new protocol and the others at later times (T12 and T18). The effects on the quality of life, evaluated by SF-36, demonstrate, in the group treated with the new protocol, a marked improvement both regarding the scale relative to the physical aspect of the illness, and especially regarding the scale relative to the mental aspect. Conclusions: in SSc patients, cyclic intravenous Iloprost infusion is efficacious in the treatment of Raynaud’s phenomenon. The protocol that we used, compared with others, is able to determine not only favourable clinical effects but also a marked improvement in the quality of life.

Summary Over the last few years, there has been an enormous increase in the use of needle core biopsy (CB) for the histopathological characterisation of suspect lesions of the breast. The aim of this study was to verify the diagnostic reliability of CB by comparing the histological results obtained with the use of this technique with those obtained from the whole of the surgically resected specimen. We studied 198 out of 426 patients with clinically and/or radiologically suspect breast lesions. We found correspondence between the histological examination of the whole of the excised specimen and that of the CB in 94.9% of the cases of infiltrating carcinoma and in 71.4% of those involving ductal carcinomas in situ. The predictive value of CB was 98.9%, sensitivity was 96.1% and specificity 93.3%. These results confirmed that CB is an extremely reliable diagnostic tool in the definition of breast lesions.

There are only a few published studies on the association between subclavian steal syndrome and ischemic heart disease. The objective of this report is to evaluate the efficacy of subclavian stenoocclusion treatment in patients with subclavian steal syndrome (SSS) and previous cor- onary bypass. Over the last 8 years we observed 207 patients who underwent left internal mammary artery–intraventricular artery (LIMA–IVA) bypass graft. Of these, 31 patients were affected by steno-occlusion of the homolateral subclavian artery. Ten patients (group 1) showed latent vertebral-SSS and were pharmacologically treated. Seven patients (group 2) had an intermittent vertebral-SSS; four patients were treated with angioplasty and stent application and three were pharmacologically treated. Fourteen patients (group 3) with complete vertebral-SSS were treated with angioplasty and stent application or carotid-subclavian bypass graft. All pa- tients were followed up every 3 months for a period of 5 years after the diagnosis. The first group of patients showed no angina and no sign of subclavian restenosis. In the second group only two patients, who were affected by angina, showed subclavian restenosis at angiography. In the third group only one patient underwent further angioplasty for restenosis. The results of this study show that the SSS may be an adverse event in patients with a LIMA-IVA bypass graft. Identification of the steal is essential to choose an appropriate therapeutic approac

ISS-IP1, a multicenter, randomized, 48-week open trial, was designed to compare the introduction of ritonavir or indinavir in patients with previous nucleoside experience and CD4+ cell counts below 50/mm3. Concomitant antiretroviral treatment with nucleoside analogs was allowed. Primary efficacy measures were survival and time to a new AIDS-defining event or death, analyzed through the whole period of observation by the intention-to-treat approach. Primary toxicity measures were time to treatment discontinuation and adverse events, grade at least 3/serious, analyzed by an on-treatment approach. Evaluation-of efficacy also included CD4+ cell and RNA response. The trial enrolled 1251 patients in 5 months. At baseline, mean CD4+ cell count was about 20 cells/mm3 and mean HIV RNA copy number was 4.9 log10/ml in both groups. Overall, 402 patients in the ritonavir group and 250 patients in the indinavir group permanently discontinued the assigned treatment (relative risk, 1.96; 95% CI, 1.68-2.30; p = 0.0001), with most of this difference dependent on a higher number of discontinuation for adverse events in the ritonavir group. After a mean follow-up of 307 days (ritonavir, 304; indinavir, 309), 124 deaths (ritonavir, 61; indinavir, 63; relative risk, 0.96; 95% CI, 0.67-1.36; p = 0.80) and 330 new AIDS-defining events (ritonavir, 170; indinavir, 160; relative risk, 1.05; 95% CI, 0.85-1.31; p = 0.60) were observed. CD4+ cell counts increased in both groups in patients still receiving treatment, with about 100 cells gained by week 24 and 150 cells gained by week 48. Body weight also increased over time in both groups. Analysis of RNA response showed a decrease of 1.5 log10 or higher in both treatment groups. Overall, 400 patients in the ritonavir group and 338 patients in the indinavir group developed at least one grade 3/serious new adverse event during follow-up (relative risk, 1.48; 95% CI, 1.28-1.72; p = 0.0001). Favorable CD4+ cell and RNA responses at 24 and 48 weeks were observed in both groups of patients remaining on treatment. Indinavir showed slightly better effects in sustaining RNA, CD4+ cell, and body weight responses. Ritonavir and indinavir results were comparable in terms of clinical outcome (survival and AIDS-defining events).

Background: We conducted a study using an intravenous (i.v.) infusion of iloprost in the treatment of venous ulcers to verify whether the association of i.v. iloprost + local therapy + elastic compression has a favorable effect when compared with traditional treatment with local therapy and elastic compression. Study Design: We evaluated the effects of iloprost in 98 consecutive patients with noncomplicated venous ulcers of lower limbs subdivided into 2 groups: the first group (48 patients) received iloprost in saline solution for 3 weeks and the second group (50 patients) received a venous infusion of a saline solution. The patients were examined at baseline time 0 (first visit) and then after 15, 30, 45, 60, 75 90, 105 120, 135, and 150 days. Results: In the first group, after 90 days, all the ulcers had healed, whereas in the second group only 50% of ulcers had healed after 105 days. At the end of the study, in the second group only 84.09% of ulcers had healed. The statistical analysis showed a significant difference between the first (iloprost group) and the second group (placebo group). Besides, in the first group the cicatrization of the ulcer happened in a shorter period (27.90% after 60 days; 41.86% after 75 days; and 100% after 100 days) whereas in the second group, at the end of the study, in 15.91 % of patients the ulcers had not recovered. Conclusion: Iloprost can significantly reduce healing time for venous leg ulcers through several actions.

The authors describe one case of a rare primitive non-Hodgkin lymphoma of the uterus, and two cases of primary non-Hodgkin lymphoma of the breast. Histologically, the uterine lymphoma, although clinically confined to the uterus, was a diffuse large cell lymphoma, group G according to the Working formulation for Clinical Usage. The two cases of breast lymphoma were a centrocytic-centroblastic and a lymphoplasmocytoid non-Hodgkin lymphoma, respectively. All cases were initally treated with radical surgery plus radiotherapy, but the first patient showed an early recurrence at distant sites, which required systemic cytotoxic chemotherapy. The patient with uterine non-Hodgkin lymphoma received a very intense regimen-i.e. the ProMACE-Cytabom-because of the unfavourable histology, while the two patients with primary breast non-Hodgkin lymphoma received less aggressive CHOP and CVP chemotherapy. All patients are still alive and free of disease 3 to 6 years after initial diagnosis. These cases stress the systemic nature of non-Hodgkin lymphomas even if apparently localized to a single extranodal organ. Thus, although a definitive therapeutic strategy cannot be drawn from the rare and occasional reports in the medical literature, primary extranodal lymphomas require integrated multimodality therapy with radiotherapy and/or chemotherapy. © 1995 W.B. Saunders Company Limited.

Extensive research activities are recently directed towards the Semantic Web as a future form of the Web. Consequently, Web search as the key technology of the Web is evolving towards some novel form of Semantic Web search. A very promising recent approach to such Semantic Web search is based on combining standard Web search with ontological background knowledge and using standard Web search engines as the main inference motor of Semantic Web search. In this paper, we propose to further enhance this approach to Semantic Web search by the use of inductive reasoning. This adds the important ability to handle inconsistencies, noise, and incompleteness, which often occur in distributed and heterogeneous environments, such as the Web. We report on a prototype implementation of the new approach and extensive experimental results. © 2010 ACM.

Introduction. Superficial venous thrombosis (SVT) has been considered for a long time a limited clinical condition with a low importance, but this approach has changed in recent years, when several studies demonstrated spreading to deep veins occurring from 7.3 to 44%, with high prevalence of pulmonary embolism . Materials and Methods. To evaluate the prevalence of genetic risk factors for VTE in patients suffering from SVT on both normal and varicose vein, and to evaluate their role on spreading to deep veins, we studied 107 consecutive outpatients with symptomatic SVT. Ultrasound examination was performed, and the presence of FV Leiden, Prothrombin G20210A mutation, MTHFR C677T mutation were researched. Results. In patients with SVT on healthy veins, the prevalence of thrombophilic conditions was consistent among all three mutations. In particularly, FV Leiden was more frequent in patients with venous progression to the deep system (60%) than in those without venous extension (23.6%). Similar results were found regarding FII G20210A and MTHFR C677T mutations in patients with (23.7% and 40%, respectively) or without thrombotic progression to the venous system (7.9% and 20%, respectively). Instead, in patients with SVT on varicose veins, the prevalence of FVL, FII and MTHFR mutations was low (6.7%, 4.4% and 6.7% respectively). However, even in these patients, the prevalence of FVL, FII and MTHFR C677T was higher in those with thrombus extension to the deep system (35.7%, 7.4% and 21.4% respectively) in comparison to those without. (6.7%, 4.4% and 6.7% respectively). Conclusions. Our data show the high prevalence of inherited thrombophilic states in patients with SVT on normal veins and their role in the progression to the deep vein system.

The aim of this study was to evaluate different durations of treatment in patients with calf venous thrombosis (CVT) involving 1 or more deep veins. The authors studied 2 groups of patients with postsurgical CVT diagnosed by echo-color Doppler. The first group consisted of 68 patients with CVT involving a single vein, and the second group consisted of 124 patients with CVT involving 2 or more veins. Immediately after diagnosis, all patients were treated with nadroparin calcium and sodium warfarin. Heparin treatment was withdrawn after 5–6 days of treatment, when the international normalized ratio (INR) was stabilized between 2 and 3. Each group was divided into 2 subgroups receiving anticoagulation treatment for 6 or 12 weeks, respectively. The endpoint was proximal extension of the thrombotic lesion, defined as the extension of the thrombus to the popliteal and/or femoral vein. In patients with single-vessel CVT there was no significant difference between the 2 subgroups, whereas in patients with CVT involving 2 or more vessels, a statistically significant difference was observed, the number of cases showing proximal extension of the thrombus being higher among patients treated for 6 weeks. Twelve weeks of anticoagulation treatment is better than 6 weeks only in patients with postsurgical CVT involving 2 or more veins.

Thirty patients with measurable metastatic breast carcinoma were treated with a combination of cyclophosphamide 600 mg/m2 on day 1, levofolinic acid 100 mg/m2 plus 5-fluorouracil 375 mg/m2 on days 1-3, and epidoxorubicin (EDXR) in three refracted doses on days 1-3 with G-CSF rescue for 10 days. In the phase I part of the study, groups of 3 patients received EDXR 20, 25, 30, 35, and 40 mg/m2/day until the dose limiting toxicity (DLT) was reached. At the dose of 40mg/m2/day prolonged grade 4 leukopenia, severe proctitis, and grade 3 diarrhea represented the DLT. All subsequent partients were treated at the maximal tolerated dose of EDXR (35 mg/m2/day). In the group of 18 patients treated at 35 mg/m2/day the overall response rate was 78% with 22% CR and 56% PR. Four patients did not respond. Objective responses were seen at all tumor sites including bone and viscera, which usually are rather chemotherapy insensitive. Toxicity was generally acceptable. Although the response rate was quite high, the duration of objective tumor regression and patients' survival were not impressive. In conclusion, we do not recommend routine use of such an aggressive regimen for palliation of advanced breast cancer. Results of the present and similar studies may, however, be useful for planning of neoadjuvant or adjuvant trials with curative intent. ©1994 Informa UK Ltd All rights reserved: reproduction in whole or part not permitted.

Objectives: To determine whether highly active antiretroviral therapy (HAART) is effective in HIV-associated neurocognitive impairment. Design: An open label, prospective, observational study. Methods: Since April 1996, 116 patients with advanced HIV infection, reverse transcriptase inhibitor (nRTI) experienced but protease inhibitor (PI) naive, were screened for the presence of neurocognitive impairment. Ninety patients with confounding neurological illness, opportunistic infections or drug abuse were excluded. The remaining 26 patients underwent comprehensive neuropsychological testing, and laboratory measures before, after 6 and after 15 months of treatment with one PI plus two nRTI. Results: The prevalence of neurocognitive impairment decreased from 80.8% (baseline) to 50.0% (P < 0.05) (sixth month) and to 21.7% (P < 0.001) (15th month). Among the functions explored, the impairment of concentration and speed of mental processing decreased from 65.4 to 21.7% (P < 0.01) and of memory impairment from 50 to 8.7% (P < 0.01). Comparing baseline with the sixth and 15th month raw scores, a statistically significant improvement was seen in measures exploring concentration and speed of mental processing (P < 0.05), mental flexibility (P < 0.05), memory (P < 0.05), fine motor functions (P < 0.05) and visuospatial and constructional abilities (P < 0.01). After 6 months of HAART patients with a normal neuropsychological examination had lower mean plasma viraemia (2.95 versus 3.97 log copies/ml, P < 0.05) and greater mean log plasma HIV RNA changes from baseline (-1.84 versus -0.83 log copies/ml, P < 0.05) than neuropsychologically impaired subjects. Conclusion: HAART produces a positive and sustained effect on neurocognitive impairment in HIV-infected patients. A reduction of plasma viral load was associated with the regression of neuropsychological test abnormalities.

Objective To report a case of ovarian hyperstimulation syndrome with methylenetetrahydrofolate reductase (MTHFR) gene 677T homozygosis mutation and A1298C gene heterozygosis mutation. Design Case report. Setting A pregnant woman in an academic hospital. Patient(s) A woman with ovarian hyperstimulation syndrome. Intervention(s) Nadroparin was administered for 2 weeks at a dosage of 200 IU/kg twice per day and then once per day; also administered once per day were folates, 5 mg; B6 vitamin, 15 mg; and B12 vitamin, 1 mg. Main Outcome Measure(s) Clinical follow-up. Result(s) Delivery was regular within the set time limits, and the fetus was born alive and in good health. Conclusion(s) We believe that MTHFR mutation research could be executed in women before ovarian stimulation treatment, but other observations are necessary to support this recommendation.

Background Acute flaccid paralysis (AFP) surveillance has been adopted globally as a key strategy for monitoring the progress of the polio eradication initiative. Hereby, to evaluate the completeness of the ascertainment of AFP cases in Italy, a hospital-discharges based search was carried out. Methods AFP cases occurring between 2007 and 2016 among children under 15 years of age were searched in the Italian Hospital Discharge Records (HDR) database using specific ICD-9-CM diagnostic codes. AFP cases identified between 2015 and 2016 were then compared with those notified to the National Surveillance System (NSS). Results Over a 10-year period, 4163 hospital discharges with diagnosis of AFP were reported in Italy. Among these, 956 (23.0%) were acute infective polyneuritis, 1803 (43.3%) myopathy, and 1408 (33.8%) encephalitis, myelitis and encephalomyelitis. During the study period, a decreasing trend was observed for all diagnoses and overall the annual incidence rate (IR) declined from 5.5 to 4.5 per 100,000 children. Comparing NSS with HDR data in 2015–2016, we found a remarkable underreporting, being AFP cases from NSS only 14% of those recorded in HDR. In particular, the acute infective polyneuritis cases reported to NSS accounted for 42.6% of those detected in HDR, while only 0.9% of myopathy cases and 13.1% of encephalitis/myelitis/encephalomyelitis cases have been notified to NSS. The highest AFP IRs per 100,000 children calculated on HDR data were identified in Liguria (17.4), Sicily (5.7), and Veneto (5.1) Regions; regarding the AFP notified to the NSS, 11 out of 21 Regions failed to reach the number of expected cases (based on 1/100,000 rate), and the highest discrepancies were observed in the Northern Regions. Overall, the national AFP rate was equal to 0.6, therefore did not reach the target value. Conclusions AFP surveillance data are the final measure of a country’s progress towards polio eradication. The historical data obtained by the HDR have been useful to assess the completeness of the notification data and to identify the Regions with a low AFP ascertainment rate in order to improve the national surveillance system.

Background: Multiple lines of evidence support that the Hedgehog (Hh) signalling has a role in the maintenance and progression of different human cancers. Therefore, inhibition of the Hh pathway represents a valid anticancer therapeutic approach for renal cell carcinoma (RCC) patients. NVP-LDE225 is a Smoothened (Smo) antagonist that induces dose-related inhibition of Hh and Smo-dependent tumour growth. Methods: We assayed the effects of NVP-LDE225 alone or in combination with everolimus or sunitinib on the growth and invasion of human RCC models both in vitro and in vivo. To this aim, we used a panel of human RCC models, comprising cells with acquired resistance to sunitinib - a multiple tyrosine kinase inhibitor approved as a first-line treatment for RCC. Results: NVP-LDE225 cooperated with either everolimus or sunitinib to inhibit proliferation, migration, and invasion of RCC cells even in sunitinib-resistant (SuR) cells. Some major transducers involved in tumour cell motility, including paxillin, were also efficiently inhibited by the combination therapy, as demonstrated by western blot and confocal microscopy assays. Moreover, these combined treatments inhibited tumour growth and increased animal survival in nude mice xenografted with SuR RCC cells. Finally, lung micrometastasis formation was reduced when mice were treated with NVP-LDE225 plus everolimus or sunitinib, as evidenced by artificial metastatic assays. Conclusions: Hedgehog inhibition by NVP-LDE225 plus sunitinib or everolimus bolsters antitumour activity by interfering with tumour growth and metastatic spread, even in SuR cells. Thus, this new evidence puts forward a new promising therapeutic approach for RCC patients.

Within the initiatives for poliomyelitis eradication by WHO, Italy activated an environmental surveillance (ES) in 2005. ES complements clinical Acute Flaccid Paralysis (AFP) surveillance for possible polio cases, detects poliovirus circulation in environmental sewage, and is used to monitor transmission in communities. In addition to polioviruses, the analyses comprised: (i) the monitoring of the presence of non-polio enteroviruses in sewage samples and (ii) the temporal and geographical distribution of the detected viruses. From 2009 to 2015, 2880 sewage samples were collected from eight cities participating in the surveillance. Overall, 1479 samples resulted positive for enteroviruses. No wild-type polioviruses were found, although four Sabin-like polioviruses were detected. The low degree of mutation found in the genomes of these four isolates suggests that these viruses have had a limited circulation in the population. All non-polio enteroviruses belonged to species B and the most frequent serotype was CV-B5, followed by CV-B4, E-11, E-6, E-7, CV-B3, and CV-B2. Variations in the frequency of different serotypes were also observed in different seasons and/or Italian areas. Environmental surveillance in Italy, as part of the 'WHO global polio eradication program', is a powerful tool to augment the polio surveillance and to investigate the silent circulation or the re-emergence of enteroviruses in the population.

Aim: To validate the Composite Autonomic Symptom Score (COMPASS) 31, in its Italian version, for the diagnosis of diabetic cardiovascular autonomic neuropathy in a clinic-based, single-centre study. Methods: A total of 73 participants with diabetes (age 55 ± 14 years) completed the COMPASS 31 questionnaire before undergoing cardiovascular autonomic neuropathy and diabetic polyneuropathy assessment according to cardiovascular reflex tests, neuropathic symptoms and signs, and vibration and thermal thresholds. Results: The COMPASS 31 total weighted score differed between participants with and without cardiovascular autonomic neuropathy (29.9 ± 19.5 vs 16.1 ± 14.7; P = 0.003) and with and without diabetic polyneuropathy (28.9 ± 19.1 vs 12.7 ± 11.3; P < 0.0001). It was related to cardiovascular reflex tests score (rho = 0.38, P = 0.0013) as well as diabetic polyneuropathy symptoms (rho=0.61, P < 0.0001) and signs scores (rho = 0.49, P < 0.0001). Receiver-operating curve analysis showed a fair diagnostic accuracy of total score for cardiovascular autonomic neuropathy (area under the curve 0.748 ± 0.068, 95% CI 0.599-0.861) and diabetic polyneuropathy (area under the curve 0.742 ± 0.061, 95% CI 0.611-0.845). The best score thresholds were 16 for early cardiovascular autonomic neuropathy (sensitivity 75.0%, specificity 64.9%, positive predictive value 37.5% and negative predictive value 90.2%), and 17 for both confirmed cardiovascular autonomic neuropathy and diabetic polyneuropathy (sensitivity 70.0% and 65.5%, respectively; specificity 66.7% and 79.5%, respectively; positive predictive value 25.0% and 67.9%, respectively; and negative predictive value 93.0% and 77.8%, respectively). COMPASS 31 had a good internal consistency according to Cronbach's α coefficient of 0.73. Conclusions: COMPASS 31 can represent a valid, easy-to-use, quantitative assessment tool for autonomic symptoms in diabetic neuropathy, with a fair diagnostic accuracy for both cardiovascular autonomic neuropathy and diabetic polyneuropathy.

Hereby, the partial Viral Protein 1 sequences of Coxsackievirus B5 (CV-B5) from sewage samples, collected in Italy from 2016 to 2017, were compared with those available in GenBank from clinical samples. Phylogenetic analysis highlighted: (I) the predominant circulation of CV-B5 genogroup B in Italy, and (II) the presence of two new sub-genogroups.

Background:Cetuximab is the only targeted agent approved for the treatment of head and neck squamous cell carcinomas (HNSCC), but low response rates and disease progression are frequently reported. As the phosphoinositide 3-kinase (PI3K) and the mammalian target of rapamycin (mTOR) pathways have an important role in the pathogenesis of HNSCC, we investigated their involvement in cetuximab resistance.Methods:Different human squamous cancer cell lines sensitive or resistant to cetuximab were tested for the dual PI3K/mTOR inhibitor PF-05212384 (PKI-587), alone and in combination, both in vitro and in vivo.Results:Treatment with PKI-587 enhances sensitivity to cetuximab in vitro, even in the condition of epidermal growth factor receptor (EGFR) resistance. The combination of the two drugs inhibits cells survival, impairs the activation of signalling pathways and induces apoptosis. Interestingly, although significant inhibition of proliferation is observed in all cell lines treated with PKI-587 in combination with cetuximab, activation of apoptosis is evident in sensitive but not in resistant cell lines, in which autophagy is pre-eminent. In nude mice xenografted with resistant Kyse30 cells, the combined treatment significantly reduces tumour growth and prolongs mice survival.Conclusions:Phosphoinositide 3-kinase/mammalian target of rapamycin inhibition has an important role in the rescue of cetuximab resistance. Different mechanisms of cell death are induced by combined treatment depending on basal anti-EGFR responsiveness. © 2014 Cancer Research UK.

Summary: Purpose: Mental retardation, facial dysmorphisms, and neurologic and brain abnormalities are features of 6q terminal deletions. Epilepsy is frequently associated with this chromosome abnormality, but electroclinical findings are not well delineated. We report five unrelated patients with 6q terminal deletions and a peculiar clinical, EEG, and neuroradiologic picture of epilepsy, mental retardation, and colpocephaly. Methods: These three male and two female patients underwent general and neurologic examinations, repeated awake and sleep EEGs, and brain magnetic resonance imaging (MRI). A cytogenetic study and fluorescent in situ hybridization (FISH) with chromosome-specific subtelomeric probes were carried out in all cases. Results: All subjects had seizures characterized by vomiting, cyanosis, and head and eye version, with and without loss of consciousness. In four cases, EEGs showed posterior spike-andwave complexes, which were activated by sleep. No patient had status epilepticus or prolonged seizures. Brain MRI revealed colpocephaly and dysgenesis of the corpus callosum and brainstem in four patients; three of them also had hypertrophic massa intermedia. FISH analysis revealed a 6q terminal deletion in all patients, which ranged between 9 Mb (cases 2 and 3) and 16 Mb (case 4). Conclusions: We suggest that epilepsy associated with 6q terminal deletions is a new entity. Patients with dysmorphic features associated with focal occipital epilepsy, colpocephaly, and dysgenesis of the corpus callosum, thalami, and brainstem should be considered candidates for testing for 6q subtelomere deletions. Key Words: 6q Deletion—Epilepsy—EEG— Colpocephaly—Chromosome abnormalities.

Introduction: Src tyrosine kinase overactivation has been correlated with a poor response to human epidermal growth factor receptor 2 (HER2) inhibitors in breast cancer. To identify the mechanism by which Src overexpression sustains this resistance, we tested a panel of breast cancer cell lines either sensitive or resistant to lapatinib.Methods: To determine the role of Src in lapatinib resistance, we evaluated the effects of Src inhibition/silencing in vitro on survival, migration, and invasion of lapatinib-resistant cells. In vivo experiments were performed in JIMT-1 lapatinib-resistant cells orthotopically implanted in nude mice. We used artificial metastasis assays to evaluate the effect of Src inhibition on the invasiveness of lapatinib-resistant cells. Src-dependent signal transduction was investigated with Western blot and ELISA analyses.Results: Src activation was higher in lapatinib-resistant than in lapatinib-sensitive cells. The selective small-molecule Src inhibitor saracatinib combined with lapatinib synergistically inhibited the proliferation, migration, and invasion of lapatinib-resistant cells. Saracatinib combined with lapatinib significantly prolonged survival of JIMT-1-xenografted mice compared with saracatinib alone, and impaired the formation of lung metastases. Unexpectedly, in lapatinib-resistant cells, Src preferentially interacted with epidermal growth factor receptor (EGFR) rather than with HER2. Moreover, EGFR targeting and lapatinib synergistically inhibited survival, migration, and invasion of resistant cells, thereby counteracting Src-mediated resistance. These findings demonstrate that Src activation in lapatinib-resistant cells depends on EGFR-dependent rather than on HER2-dependent signaling.Conclusions: Complete pharmacologic EGFR/HER2 inhibition is required to reverse Src-dependent resistance to lapatinib in breast cancer. © 2014 Formisano et al.; licensee BioMed Central Ltd.

Background The EGFR tyrosine kinase inhibitors gefitinib and erlotinib are first-line therapy for NSCLCs harbouring EGFR-activating mutations. The intrinsic and acquired resistance to these agents is a relevant clinical issue. Although Src tyrosine kinase has been involved in such resistance in preclinical models, clinical development of these agents has been so far limited. Methods We used a panel of human NSCLC cell lines: PC9 and HCC827 (EGFR-activating mutation; highly sensitive to erlotinib), Calu3 (EGFR/Ras wild-type, wt; moderately sensitive), Calu3-ER (with acquired resistance), H1299 and A549 (Ras mutant; resistant), H1975 (EGFR T790M mutant; resistant). In these models, we tested three different Src inhibitors (saracatinib, dasatinib, and bosutinib), both in vitro and in vivo. Findings NSCLC cell lines showed different activation of EGFR-dependent and Src-dependent pathways and variable sensitivity to Src inhibitors. A kinase assay demonstrated that all the compounds are able to directly inhibit EGFR tyrosine kinase variants. In cell lysates only saracatinib and bosutinib efficiently reduced EGFR activation, while dasatinib was the more effective agent in inhibiting Src tyrosine kinase. Consistently, in EGFR-activating mutant, erlotinib sensitive cells, saracatinib and bosutinib showed anti-proliferative effects related to simultaneous EGFR/Src inhibition. In EGFR wt/Ras mutant cells Src inhibition by dasatinib interfered with cell proliferation and signal transduction. Since Src inhibitors had only moderate effects as single agents we tested the combination of saracatinib with EGFR inhibitors (erlotinib or cetuximab) in EGFR-addicted cells, and of dasatanib with MEK inhibitors (selumetinib) in Ras mutant, erlotinib resistant models. These combinations were effective both in vitro and in nude mice, inhibiting tumour growth, prolonging mice survival, and interfering with signal transduction. Importantly, the combination of saracatanib and cetuximab was effective also in the erlotinib resistant, EGFR T790M mutant model. Interpretation Src inhibitors may act with different mechanisms in NSCLC cell lines, depending on EGFR/Ras mutational profile. Integration of anti-Src agents with EGFR or MEK inhibitors could represent effective therapeutic options for different cohorts of NSCLC patients.

bjective: To evaluate the efficacy of subclavian stenosis percutaneous transfemoral angioplasty (PTA)-treatment in patients with intermittent or complete subclavian steal syndrome (SSS), and coronary-subclavian steal syndrome (C-SSS) after left internal mammary artery-interventricular anterior artery (LIMA-IVA) by pass graft. Methods: We studied 42 patients with coronary subclavian steal syndrome subdivided in two groups; the first group consisted of 15 patients who presented an intermittent vertebral-subclavian steal, while the second group consisted of 27 patients with a complete vertebral-subclavian steal. All patients were treated with angioplasty and stent application and were followed up for a period of 5 years by echocolor-doppler examination to evaluate any subclavian restenosis. Results: Subclavian restenosis was significantly increased in patients with a complete subclavian steal syndrome. The restenosis rate was 6.67% in the first group and 40.75% in the second group, These patients had 9.1 fold-increase risk (CI confidence interval 0.95-86.48) in restenosis. Conclusion: Patients with a complete subclavian and coronary steal syndrome present a higher risk of subclavian restenosis