Tumor and circulating biomarkers in patients with second-line hepatocellular carcinoma from the randomized phase II study with tivantinib

ARQ 197-215 was a randomized placebo-controlled phase II study testing the MET inhibitor tivantinib in second-line hepatocellular carcinoma (HCC) patients. It identified tumor MET as a key biomarker in HCC. Aim of this research was to study the prognostic and predictive value of tumor (MET, the receptor tyrosine kinase encoded by the homonymous MNNG-HOS transforming gene) and circulating (MET, hepatocyte growth factor [HGF], alpha-fetoprotein [AFP], vascular endothelial growth factor [VEGF]) biomarkers in second-line HCC. Tumor MET-High status was centrally assessed by immunohistochemistry. Circulating biomarkers were centrally analyzed on serum samples collected at baseline and every 4-8 weeks, using medians as cut-off to determine High/Low status. Tumor MET, tested in 77 patients, was more frequently High after (82%) versus before (40%) sorafenib. A significant interaction (p = 0.04) between tivantinib and baseline tumor MET in terms of survival was observed. Baseline circulating MET and HGF (102 patients) High status correlated with shorter survival (HR 0.61, p = 0.03, and HR 0.60, p = 0.02, respectively), while the association between AFP (104 patients) or VEGF (103 patients) status and survival was non-significant. Conclusions: Tumor MET levels were higher in patients treated with sorafenib. Circulating biomarkers such as MET and HGF may be prognostic in second-line HCC. These results need to be confirmed in larger randomized clinical trials

Oral Versus Standard Antimicrobial Treatment for Pyogenic Native Vertebral Osteomyelitis: A Single-Center, Retrospective, Propensity Score-Balanced Analysis

Background: Interest in shorter antimicrobial regimens and oral treatment for osteoarticular infections is growing. The aim of this study is to assess whether there is an association between the administration of an entirely oral antibiotic therapy (OT) and the clinical outcome of native vertebral osteomyelitis (NVOs). Methods: We conducted a single-center, retrospective, observational study on consecutive patients with pyogenic NVOs over a 10-year period (2008-2018). We performed multivariate logistic regression analysis to identify risk factors for clinical failure, both in the whole population and in subgroups. The impact of OT versus standard treatment (intravenous induction followed by oral treatment whenever possible) was assessed in patients with a non-multidrug-resistant microorganism (MDRO) etiology, and the impact of a rifampin-containing regimen was assessed in patients affected by NVOs caused by staphylococci or of unknown etiology. Results: The study population included 249 patients, and 33 (13.3%) experienced clinical failure; the OT group consisted of 54 patients (21.7%). Multivariate regression analysis of the whole population selected Charlson comorbidity index (adjusted odds ratio [aOR], 1.291; 95% confidence interval [CI], 1.114-1.497; P =. 001) and MDRO etiology (aOR, 3.301; 95% CI, 1.368-7.964; P =. 008) as independent factors for clinical failure. Among patients affected by a non-MDRO NVO, OT was not associated with an increased risk of clinical failure (aOR, 0.487; 95% CI,. 133-1.782; P =. 271), even after adjustment for the propensity score of receiving OT. In the subgroup of patients with staphylococcal or unknown etiology, NVO rifampin was independently associated with favorable outcome (aOR, 0.315; 95% CI,. 105-.949; P =. 040). Conclusions: An entirely oral, highly bioavailable treatment, including rifampin, may be as effective as parenteral treatment in selected patients with NVOs

National multi-stakeholder meetings: a tool to support development of integrated policies and practices for testing and prevention of HIV, viral hepatitis, TB and STIs

Background Country level policies and practices of testing and care for HIV, viral hepatitis and sexually transmitted infections are lagging behind European recommendations on integration across diseases. Building on previous experiences and evidence, the INTEGRATE Joint Action arranged four national stakeholder meetings. The aim was to foster cross-disciplinary and cross-disease collaborations at national level as a vehicle for strengthened integration of testing and care services. This article presents the methodology and discusses main outcomes and recommendations of these meetings. Methods Local partners in Croatia, Italy, Lithuania and Poland oversaw the planning, agenda development and identification of key persons to invite to ensure that meetings addressed main challenges and issues of the respective countries. Invited national stakeholders represented policy and public health institutions, clinical settings, testing sites and community organisations. National experts and experts from other European countries were invited as speakers and facilitators. Main topic discussed was how to increase integration across HIV, viral hepatitis and sexually transmitted infections in testing and care policies and practice; tuberculosis was also addressed in Lithuania and Italy. Results The agendas reflected national contexts and the meetings provided a forum to engage stakeholders knowledgeable of the national prevention, testing and care systems in interaction with international experts who shared experiences of the steps needed to achieve integration in policies and practice. The evaluations showed that participants found meetings relevant, important and beneficial for furthering integration. Of the respondents 78% agreed or strongly agreed that there was a good representation of relevant national stakeholders, and 78% that decision/action points were made on how to move the agenda forward. The importance of securing participation from high level national policy makers was highlighted. Outcomes were nationally tailored recommendations on integrated policies and strategies, diversification of testing strategies, stigma and discrimination, key populations, cost effectiveness, surveillance and funding. Conclusions Shifting from single to multi-disease approaches require collaboration among a broad range of actors and national multi-stakeholder meetings have proven excellent to kick-start this. Face-to-face meetings of key stakeholders represent a unique opportunity to share cross-sectoral perspectives and experiences, identify gaps in national policies and practices and agree on required next steps.The INTEGRATE Joint Action was co-funded by the 3rd Health Programme of the European Union under grant agreement no 761319. National meetings and trainings were co-funded by EuroTEST’s grants from Merck and Janssen. Daniel Simões is the recipient of PhD Grant PD/BD/128008/2016 from Fundação para a Ciência e Tecnologia (FCT). All funders had no role in the study design, analysis, decision to publish, or preparation of the manuscript

Increasing integrated testing in community settings through interventions for change, including the Spring European Testing Week

Background: Maximising access to testing by targeting more than one infection is effective in identifying new infections in settings or populations. Within the EU funded Joint Action INTEGRATE, this paper examined the feasibility and impact of expanding integrated testing for HIV, hepatitis C (HCV), chlamydia, gonorrhoea and/or syphilis in four community-based pilots through targeted interventions in Croatia, Italy and Poland and the Spring European Testing Week since community settings are key in detecting new infections and reaching key populations. Methods: Pilots led by local INTEGRATE partners prioritised testing for other infections or key populations. The Croatian pilot expanded testing for men who have sex with men to syphilis, chlamydia and gonorrhoea. Italian partners implemented a HIV and HCV testing/information event at a migrant centre. A second Italian pilot tested migrants for HIV and HCV through outreach and a low-threshold service for people who use drugs. Polish partners tested for HIV, HCV and syphilis among people who inject drugs in unstable housing via a mobile van. Pilots monitored the number of individuals tested for each infection and reactive results. The pilot Spring European Testing Week from 18 to 25 May 2018 was an INTEGRATE-driven initiative to create more testing awareness and opportunities throughout Europe. Results: The Croatian pilot found a high prevalence for each syphilis, chlamydia and gonorrhoea respectively, 2.1%, 12.4% and 6.7%. The Italian migrant centre pilot found low proportions who were previously tested for HIV (24%) or HCV (11%) and the second Italian pilot found an HCV prevalence of 6.2%, with low proportions previously tested for HIV (33%) or HCV (31%). The Polish pilot found rates of being previously tested for HIV, HCV and syphilis at 39%, 37%, and 38%, respectively. Results from the Spring European Testing Week pilot showed it was acceptable with increased integrated testing, from 50% in 2018 to 71% in 2019 in participants. Conclusions: Results show that integrated testing is feasible and effective in community settings, in reaching key populations and minimising missed testing opportunities, and the pilots made feasible because of the European collaboration and funding. For sustainability and expansion of integrated community testing across Europe, local government investment in legislation, financial and structural support are crucial.The INTEGRATE Joint Action was co-funded by the 3rd Health Programme of the European Union under grant agreement no 761319. The EuroTEST/European Testing Week initiative has received funding and grants from Gilead Sciences, ViiV Healthcare, Janssen, Merck/MSD and the European Commission under the 3rd and 2nd Health Programmes. HUHIV: CheckPoint Zagreb is funded by cooperation programs by the City of Zagreb and Ministry of Health incl. HIV, HCV and syphilis rapid tests, CT/NG tests are donated by Cepheid with the contribution of the Department of Immunological and Molecular Diagnostics of the Clinic for Infectious Diseases Dr Fran Mihaljević during the pilot project. CRI/FVM: For the pilot activity in the migrant centre, HIV and HCV rapid tests were donated by FVM/CRI. Moreover, FVM contributed with the staff and equipment (mobile unit). FVM: The medical centre and outreach street unit are funded by the Health Department of Lazio Regional Administration of Italy. NAC/FES: Funding for FES pilot in 2019 was provided by NAC. FES secured their staff, mobile unit and tests. Daniel Simões is the recipient of PhD Grant PD/BD/128008/2016 from Fundação para a Ciência e Tecnologia (FCT). All funders had no role in the study design, analysis, decision to publish, or preparation of the manuscript

Impact of patients nutritional status on major surgery outcome

Abstract. – OBJECTIVE: Surgery is a major stress factor that activates several inflammatory and catabolic pathways in man. An appropriate nutritional status allows the body to react properly to this stressor and recover in a faster and more efficient manner. On the other hand, malnutrition is related to a worse surgery outcome and to a higher prevalence of comorbidities and mortality. The aims of this study were to evaluate the nutritional status of patients undergoing major surgery and investigate the potential correlation between malnutrition and surgical outcomes. PATIENTS AND METHODS: Mini Nutritional Assessment (MNA) and global clinical examination (including biochemical parameters and comorbidities existence) were undertaken in 50 consecutive patients undergoing major surgery. Patients’ clinical conditions were re-evaluated at 3 and 6 days after surgery, recording biochemical parameters and systemic and/or wound-related complications. RESULTS: A compromised nutritional status was present in more than half (54%) of patients (malnutrition in 10% and risk of malnutrition in 44% of patients, respectively). Females were slightly more at risk of malnutrition (48% vs. 41%, p=NS, females vs. males) and clearly malnourished (14% vs. 7%, p<0.05, females vs. males). Age was an independent risk factor for malnutrition and within the elders’ group (> 80 years old) 16.70% of patients was diagnosed with malnutrition and 58.3% was at risk of malnutrition. Systemic complications were registered in all patients both at 3 and 6 days after surgery. However, well-nourished and at-risk of malnutrition patients had earlier complications that only partially resolved within six days after the operation. Malnourished patients showed fewer complications at the 3rd post-surgery follow-up day but had a worse outcome six days after surgery. CONCLUSIONS: Older age and but not female sex are independent risk factors for malnutrition development in patients undergoing major surgery. More interestingly, more than half of patients with an impaired nutritional status presented a less appropriated stress response to surgery. These data suggest that nutritional status assessment may be important to recognize patients at potential risk of surgical complications and that early nutritional interventions must be promptly arranged

The Role of Diet, Micronutrients and the Gut Microbiota in Age-Related Macular Degeneration: New Perspectives from the Gut\u207bRetina Axis.

Age-related macular degeneration (AMD) is a complex multifactorial disease and the primary cause of legal and irreversible blindness among individuals aged 6565 years in developed countries. Globally, it affects 30\u207b50 million individuals, with an estimated increase of approximately 200 million by 2020 and approximately 300 million by 2040. Currently, the neovascular form may be able to be treated with the use of anti-VEGF drugs, while no effective treatments are available for the dry form. Many studies, such as the randomized controlled trials (RCTs) Age-Related Eye Disease Study (AREDS) and AREDS 2, have shown a potential role of micronutrient supplementation in lowering the risk of progression of the early stages of AMD. Recently, low-grade inflammation, sustained by dysbiosis and a leaky gut, has been shown to contribute to the development of AMD. Given the ascertained influence of the gut microbiota in systemic low-grade inflammation and its potential modulation by macro- and micro-nutrients, a potential role of diet in AMD has been proposed. This review discusses the role of the gut microbiota in the development of AMD. Using PubMed, Web of Science and Scopus, we searched for recent scientific evidence discussing the impact of dietary habits (high-fat and high-glucose or -fructose diets), micronutrients (vitamins C, E, and D, zinc, beta-carotene, lutein and zeaxanthin) and omega-3 fatty acids on the modulation of the gut microbiota and their relationship with AMD risk and progression

Early tumor shrinkage and response assessment according to mRECIST predict overall survival in hepatocellular carcinoma patients under sorafenib.

BACKGROUND: The aim of this study was to explore the relationship between follow-up imaging characteristics and overall survival (OS) in advanced hepatocellular carcinoma (HCC) patients under sorafenib treatment. METHODS: Associations between OS and objective response (OR) by mRECIST or early tumor shrinkage (ETS; ≥20% reduction in enhancing tumor diameter at the first follow-up imaging) were analyzed in HCC patients treated with sorafenib within a multicenter phase II trial (SORAMIC). 115 patients were included in this substudy. The relationship between survival and OR or ETS were explored. Landmark analyses were performed according to OR at fixed time points. Cox proportional hazards models with OR and ETS as a time-dependent covariate were used to compare survival with factors known to influence OS. RESULTS: The OR rate was 29.5%. Responders had significantly better OS than non-responders (median 30.3 vs. 11.4 months; HR, 0.38 [95% CI, 0.22-0.63], p < 0.001), and longer progression-free survival (PFS; median 10.1 vs. 4.3 months, p = 0.015). Patients with ETS ≥ 20% had longer OS (median 22.1 vs. 11.4 months, p = 0.002) and PFS (median 8.0 vs. 4.3 months, p = 0.034) than patients with ETS < 20%. Besides OR and ETS, male gender, lower bilirubin and ALBI grade were associated with improved OS in univariate analysis. Separate models of multivariable analysis confirmed OR and ETS as independent predictors of OS. CONCLUSION: OR according to mRECIST and ETS in patients receiving sorafenib treatment are independent prognostic factors for OS. These parameters can be used for assessment of treatment benefit and optimal treatment sequencing in patients with advanced HCC

Dynamics in Circulating y -55Proinflammatory Biomarkers for Prognostic Assessment of Patients With Advanced HCC – A Substudy From the SORAMIC Trial

Introduction: Prediction of response to treatment in patients with advanced hepatocellular carcinoma (HCC) may assist in the selection of personalized management. Objective: This exploratory analysis of the palliative arm of the SORAMIC trial (ClinicalTrials.gov NCT01126645) evaluated the prognostic potential of basal and dynamic changes in systemic levels of interleukin 6 (IL-6), interleukin 8 (IL-8), systemic vascular endothelial growth factor (VEGF), and lipopolysaccharide (LPS). Methods: We evaluated the correlations between overall survival (OS) and concentrations of IL-6, IL-8, VEGF, and LPS at follow-up approximately 7-9 weeks after treatment initialization (FU) compared to baseline (BL) in 90 patients treated either with 90Yttrium (90Y) microspheres combined with sorafenib (n = 44) or with sorafenib (n = 46) alone. Results: Changes in IL-6 concentration during treatment showed correlations with the outcome. An increase in IL-6 concentration of less than 16.8 pg/mL over baseline readings was associated with better survival [median OS 16.3 months compared with 8.9 months (p = 0.0354)]. Correlations with survival were not observed for VEGF or LPS concentrations at baseline, at FU, or changes between these time points. Conclusions: Changes in IL 6 serum levels at 7-9 weeks after treatment initialization but not in IL 8, VEGF, or LPS add important information on the outcome of advanced HCC patients treated palliatively within the SORAMIC trial

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

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Helicobacter species are associated with possible increase in risk of biliary lithiasis and benign biliary diseases

<p>Abstract</p> <p>Background</p> <p>Hepato-biliary tract lithiasis is common and present either as pain or as asymptomatic on abdominal ultrasonography for other causes. Although the DNA of <it>Helicobacter </it>species are identified in the gallbladder bile, tissue or stones analyzed from these cases, still a causal relationship could not be established due to different results from different geographical parts.</p> <p>Methods</p> <p>A detailed search of pubmed and pubmedcentral was carried out with key words <it>Helicobacter </it>and gallbladder, gallstones, hepaticolithiasis, cholelithiasis and choledocholithiasis, benign biliary diseases, liver diseases. The data was entered in a data base and meta analysis was carried out. The analysis was carried out using odds ratio and a fixed effect model, 95% confidence intervals for odds ratio was calculated. Chi square test for heterogeneity was employed. The overall effect was calculated using Z test.</p> <p>Results</p> <p>A total of 12 articles were identified. One study used IgG for diagnosis while others used the PCR for Ure A gene, 16 S RNA or Cag A genes. A couple of studies used culture or histopathology besides the PCR. The cumulative results show a higher association of <it>Helicobacter </it>with chronic liver diseases (30.48%), and stone diseases (42.96%)(OR 1.77 95% CI 1.2–2.58; Z = 2.94, p = 0.003), the effect of each could not be identified as it was difficult to isolate the effect of helicobacter due to mixing of cases in each study.</p> <p>Conclusion</p> <p>The results of present meta analysis shows that there is a slight higher risk of cholelithiasis and benign liver disease (OR 1.77), however due to inherent inability to isolate the effect of stone disease from that of other benign lesions it is not possible to say for sure that <it>Helicobacter </it>has a casual relationship with benign biliary disease or stone disease or both.</p