Expression of the 70 kDa Heat shock protein family in Alpine freshwater chironomids (Diptera, Chironomidae) under natural conditions.

Chironomidae represent up to 100% of the fauna of Alpine streams. Because they survive stress conditions such as extremely low temperature (annual mean < 4°C), these organisms represent a good organism model to analyze the relationship between adaptations to cold and expression of stress proteins such as the 70 kDa Heat shock protein family. Fourth instar larvae of ten species of cold-stenothermal chironomids (Pseudodiamesa branickii, Diamesa latitarsis, Diamesa laticauda, Diamesa cinerella, Diamesa insignipes, Diamesa zernyi, Diamesa vaillanti, Orthocladius (Orthocladius) frigidus, Orthocladius (Euorthocladius) thienemanni and Paratriclocladius nivalis) were collected in a glacier-fed stream in N.E. Italy at two stations (1300 and 2600 m a.s.l.) and in two seasons (summer 2005 and spring 2006). Immunodetection and quantification of therelative levels of Hsp70 family were performed via Western blotting. Significantly different levels of Hsp70 were detected among species. The highest amounts were recorded in P. nivalis and D. insignipes, the lowest in P. branickii. Within the genus Diamesa, lower levels of Hsp70 were observed in the most cold stenothermal species than in the less cold stenothermal ones. These differences are explained by different autoecology. The results provide information on biochemical strategies of alpine midges to face cold temperatures under natural conditions and new insights into their possible response to global warming

Multimodality Treatment with Conventional Transcatheter Arterial Chemoembolization and Radiofrequency Ablation for Unresectable Hepatocellular Carcinoma

Background/Aims: To evaluate the efficacy of multimodality treatment consisting of conventional transcatheter arterial chemoembolization (TACE) and radiofrequency ablation (RFA) in patients with non-resectable and non-ablatable hepatocellular carcinoma (HCC). Methods: In this retrospective study, 85 consecutive patients with HCC (59 solitary, 29 multifocal HCC) received TACE followed by RFA between 2001 and 2010. The mean number of tumors per patient was 1.6 +/- 0.7 with a mean size of 3.0 +/- 0.9 cm. Both local efficacy and patient survival were evaluated. Results: Of 120 treated HCCs, 99 (82.5%) showed a complete response (CR), while in 21 HCCs (17.5%) a partial response was depicted. Patients with solitary HCC revealed CR in 91% (51/56); in patients with multifocal HCC (n = 29) CR was achieved in 75% (48 of 64 HCCs). The median survival for all patients was 25.5 months. The 1-, 2-, 3- and 5-year survival rates were 84.6, 58.7, 37.6 and 14.6%, respectively. Statistical analysis revealed a significant difference in survival between Barcelona Clinic Liver Cancer (BCLC) A (73.4 months) and B (50.3 months) patients, while analyses failed to show a difference for Child-Pugh score, Cancer of Liver Italian Program (CLIP) score and tumor distribution pattern. Conclusion: TACE combined with RFA provides an effective treatment approach with high local tumor control rates and promising survival data, especially for BCLC A patients. Randomized trials are needed to compare this multimodality approach with a single modality approach for early-stage HCC. Copyright (C) 2011 S. Karger AG, Base

Stress response of a boreo-alpine species of tardigrade, Borealibius zetlandicus (Eutardigrada, Hypsibiidae)

Invertebrates living in extreme environments as well as those living under unpredictable habitat conditions must be able to survive severe environmental stresses bound to their habitats. Tardigrades represent a good animal model to analyze responses evolved by organisms to overcome extreme environmental stresses or to colonize extreme environments because they respond to desiccation or freezing in their habitats by entering cryptobiosis. The responses to environmental stresses have been evaluated almost exclusively in terrestrial tardigrades, while very little is known about the ability of limnic species to tolerate those stresses. This study evaluates the responses of the limnic boreo-alpine species Borealibius zetlandicus, under lab conditions, to stresses imposed by desiccation and temperature variation (freezing and heating). Our results indicate that active specimens are able to freeze, confirming the cryobiotic ability of this species. There is a negative correlation between survival and cooling rates. In contrast, no specimens of B. zetlandicus are able to survive desiccation. With regard to thermal tolerance, the animals show a high ability to resist heat-shock (LT50 = 33.0 0.5°C) for a short time. This wide tolerance to different environmental parameters could be the reason for the wide distribution of the species. Due to the disjunct distribution of the species and to the presence of cryptic tardigrade species that could have different ecological and physiological responses, we decided to characterize the population studied from a molecular point of view by investigating its COI mtDNA sequences

Efficacy and safety of combination therapy with everolimus and sorafenib for recurrence of hepatocellular carcinoma after liver transplantation.

Background Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. Methods This was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVL+SORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received ≥1 dose of the study drug. Results Seven patients (100% male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVL+SORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6%), cyclosporine (CsA) in 2 (28.6%), and EVL monotherapy in 3 (42.8%). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 of them (57.1%) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), whereas 1patient (14.3%) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). Adverse events led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%). Conclusions Treatment of HCC recurrence after LT with a combination regimen of EVL+ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival.BACKGROUND: Recurrence of hepatocellular carcinoma (HCC) after liver transplantation (LT) is still associated with a dismal outcome. Combination therapy with everolimus (EVL) and vascular endothelial growth factor inhibitor sorafenib (SORA) is based on the role of both b-Raf and mammalian target of rapamycin/protein kinase B pathways in the pathogenesis of HCC and is being investigated in clinical practice. METHODS: This was a single-center retrospective analysis on LT recipients with unresectable HCC recurrence and undergoing combination therapy with EVL and SORA. Patients were included if they were switched to EVL+SORA at any time after surgery. Primary endpoint was overall survival (OS) after both LT and recurrence, and response to treatment based on the modified Response Evaluation Criteria in Solid Tumors (mRECIST) in the intention-to-treat (ITT) population. Secondary analysis was safety of combination therapy with EVL and SORA in the population of patients who received ≥1 dose of the study drug. RESULTS: Seven patients (100% male; median age 53 years [interquartile range (IQR) 9 years]) were considered for analysis. HCC recurrence was diagnosed at a median (IQR) interval since LT of 9 (126) months, and patients were administered EVL+SORA at a median interval since LT of 11 (126) months. Baseline immunosuppression was with tacrolimus (TAC) in 2 patients (28.6%), cyclosporine (CsA) in 2 (28.6%), and EVL monotherapy in 3 (42.8%). At a median (IQR) follow-up of 6.5 (14) months, 5 patients (71.4%) were alive, 4 of them (57.1%) with tumor progression according to the mRECIST criteria. Median (IQR) time to progression was 3.5 (12) months. Two patients died at a median (IQR) follow-up of 5 (1) months owing to tumor progression in 1 patient (14.3%) and sepsis in the other (14.3%). EVL monotherapy was achieved in 6 patients (85.7%), whereas 1patient (14.3%) could not withdraw from calcineurin inhibitor owing to acute rejection. Treatment complications were: hand-foot syndrome in 5 patients (71.4%), hypertension in 1 (14.3%), alopecia in 1 (14.3%), hypothyroidism in 1 (14.3%), diarrhea in 2 (28.6%), pruritus in 1 (14.3%), abdominal pain in 1 (14.3%), rash in 1 (14.3%), asthenia in 3 (42.8%), anorexia in 3 (42.8%), and hoarseness in 2 (28.6%). Adverse events led to temporary SORA discontinuation in 2 patients (28.6%) and to SORA dose reduction in 3 (42.8%). CONCLUSIONS: Treatment of HCC recurrence after LT with a combination regimen of EVL+ SORA is challenging because of SORA-related complications. Longer follow-up periods and larger series are needed to better capture the impact of such combination treatment on tumor progression and patient survival

A New SteatoScore in the Evaluation of Non-Alcoholic Liver Disease in Oncologic Patients

PurposeThe aims of this study were to evaluate the reproducibility of a new multi-parametric steatoscore (new SteatoScore) in oncologic patients with non-alcoholic fatty liver disease (NAFLD) and to compare it with computed tomography (CT). Materials and MethodsFifty-one (31 men, 20 women) oncologic patients, with a mean age and weight of 63.9 years and 78.33 kg, respectively, were retrospectively enrolled in the study. Patients underwent ultrasound (US) and computed tomography (CT) examinations as part of their oncologic follow-up protocol. US examinations were performed by using a 3.5-MHz convex probe. During the US examination, three standardized clips were obtained in each patient. Two operators performed all measurements, one of whom repeated the processing twice in 1 year. Hepatic/renal ratio (HR), attenuation rate (AR), diaphragm visualization (DV), hepatic/portal vein ratio (HPV), and portal vein wall visualization (PVW) were acquired and calculated by using Matlab and inserted in a multi-parametric algorithm called new SteatoScore. On unenhanced CT scan, hepatic attenuation (HA), liver-spleen difference (L-S), and liver/spleen ratio (L/S) were measured by placement of a region of interest (ROI) within liver and spleen parenchyma, avoiding areas with vessels and biliary ducts. ResultsThe intra-observer variability was greater than the inter-observer one, with intraclass correlation coefficient (ICC) values of 0.94 and 0.97, respectively. Correlation between single US and CT parameters provided an agreement in no case exceeding 50%. New SteatoScore showed high reproducibility, and high coefficient of correlation with L-S (R = -0.64; p < 0.0001) and L/S (R = -0.62; p < 0.0001) at CT. ConclusionNew SteatoScore has a high reproducibility and shows a good correlation with unenhanced CT in evaluation of oncologic patients with NAFLD

Baseline computed-tomography (CT)-evaluated sarcopenia predicts toxicity from first-line chemotherapy in metastatic gastric cancer (mGC) patients

Introduction: The impact of sarcopenia as a predictor of poor prognosis and its association with chemotherapy toxicity have been explored in different cancer types but remain controversial in mGC. Our aim was to explore the correlation between sarcopenia, evaluated at baseline CT scan, and toxicity and efficacy of first-line therapy. Methods: We retrospectively analyzed pre-treatment CT scans from 78 mGC patients treated with first-line doublet chemotherapy comprising oxaliplatin and 5-fluorouracil/leucovorin or capecitabine (trastuzumab was administered in case of HER2-positive disease). Sarcopenia was defined according to previously published criteria (Martin L et al. J Clin Oncol 2013) by the use of the skeletal muscle index (SMI) and body mass index (BMI), according to gender-specific cut-off values. SMI was calculated as follows: cross-sectional skeletal muscle area (SMA) measured at the level of the third lumbar vertebra / (height)2 (m2). Toxicities were graded according to NCI CTCAE v.4.0. Association between the presence of sarcopenia and different adverse events was evaluated by Chi-square test. Correlation with response rate (RR, evaluated according to RECIST criteria 1.1), progression-free survival (PFS) and overall survival (OS) was assessed by the use of the log-rank test. Results: Sarcopenia was evident in 34 (44%) patients. We observed a significant association between the presence of sarcopenia at baseline assessment and a higher risk of severe (i.e. grade 3-4) neutropenia (38% versus 18%; p = 0.048) and a higher risk of any grade mucosal toxicities (56% versus 34%; p = 0.045). None of the other investigated clinical factors (comprising age, gender, performance status, sites of metastases and previous surgery on primary tumor) was associated with the risk of toxicity. Neither sarcopenia nor the other evaluated clinical parameters were associated with outcome as measured by RR, PFS, and OS: the only exception was performance status, which was confirmed a major prognostic determinant in terms of PFS and OS. Conclusion: Our experience identified sarcopenia as a potential determinant of the risk of hematologic and mucosal toxicities from first-line platinum plus fluoropyrimidine chemotherapy in mGC patients. Sarcopenia was apparently not associated with benefit from treatment and survival, but larger studies are needed to address this issue. Strategies aiming at improving the nutritional status of mGC patients are warranted to optimize the risk-to-benefit ratio of available treatments

The risk stratification of adverse neonatal outcomes in women with gestational diabetes (STRONG) study

Aims: To assess the risk of adverse neonatal outcomes in women with gestational diabetes (GDM) by identifying subgroups of women at higher risk to recognize the characteristics most associated with an excess of risk. Methods: Observational, retrospective, multicenter study involving consecutive women with GDM. To identify distinct and homogeneous subgroups of women at a higher risk, the RECursive Partitioning and AMalgamation (RECPAM) method was used. Overall, 2736 pregnancies complicated by GDM were analyzed. The main outcome measure was the occurrence of adverse neonatal outcomes in pregnancies complicated by GDM. Results: Among study participants (median age 36.8 years, pre-gestational BMI 24.8 kg/m2), six miscarriages, one neonatal death, but no maternal death was recorded. The occurrence of the cumulative adverse outcome (OR 2.48, 95% CI 1.59–3.87), large for gestational age (OR 3.99, 95% CI 2.40–6.63), fetal malformation (OR 2.66, 95% CI 1.00–7.18), and respiratory distress (OR 4.33, 95% CI 1.33–14.12) was associated with previous macrosomia. Large for gestational age was also associated with obesity (OR 1.46, 95% CI 1.00–2.15). Small for gestational age was associated with first trimester glucose levels (OR 1.96, 95% CI 1.04–3.69). Neonatal hypoglycemia was associated with overweight (OR 1.52, 95% CI 1.02–2.27) and obesity (OR 1.62, 95% CI 1.04–2.51). The RECPAM analysis identified high-risk subgroups mainly characterized by high pre-pregnancy BMI (OR 1.68, 95% CI 1.21–2.33 for obese; OR 1.38 95% CI 1.03–1.87 for overweight). Conclusions: A deep investigation on the factors associated with adverse neonatal outcomes requires a risk stratification. In particular, great attention must be paid to the prevention and treatment of obesity

Model-guided therapy for hepatocellular carcinoma: A role for information technology in predictive, preventive and personalized medicine

Predictive, preventive and personalized medicine (PPPM) may have the potential to eventually improve the nature of health care delivery. However, the tools required for a practical and comprehensive form of PPPM that is capable of handling the vast amounts of medical information that is currently available are currently lacking. This article reviews a rationale and method for combining and integrating diagnostic and therapeutic management with information technology (IT), in a manner that supports patients through their continuum of care. It is imperative that any program devised to explore and develop personalized health care delivery must be firmly rooted in clinically confirmed and accepted principles and technologies. Therefore, a use case, relating to hepatocellular carcinoma (HCC), was developed. The approach to the management of medical information we have taken is based on model theory and seeks to implement a form of model-guided therapy (MGT) that can be used as a decision support system in the treatment of patients with HCC. The IT structures to be utilized in MGT include a therapy imaging and model management system (TIMMS) and a digital patient model (DPM). The system that we propose will utilize patient modeling techniques to generate valid DPMs (which factor in age, physiologic condition, disease and co-morbidities, genetics, biomarkers and responses to previous treatments). We may, then, be able to develop a statistically valid methodology, on an individual basis, to predict certain diseases or conditions, to predict certain treatment outcomes, to prevent certain diseases or complications and to develop treatment regimens that are personalized for that particular patient. An IT system for predictive, preventive and personalized medicine (ITS-PM) for HCC is presented to provide a comprehensive system to provide unified access to general medical and patient-specific information for medical researchers and health care providers from different disciplines including hepatologists, gastroenterologists, medical and surgical oncologists, liver transplant teams, interventional radiologists and radiation oncologists. The article concludes with a review providing an outlook and recommendations for the application of MGT to enhance the medical management of HCC through PPPM

Prognostic value of the neutrophil-to-lymphocyte ratio in advanced hepatocellular carcinoma: An exploratory analysis from the ARQ197-215 study

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