Serum alpha-fetoprotein and clinical outcomes in patients with advanced hepatocellular carcinoma treated with ramucirumab

Background Post hoc analyses assessed the prognostic and predictive value of baseline alpha-fetoprotein (AFP), as well as clinical outcomes by AFP response or progression, during treatment in two placebo-controlled trials (REACH, REACH-2).Methods Serum AFP was measured at baseline and every three cycles. The prognostic and predictive value of baseline AFP was assessed by Cox regression models and Subpopulation Treatment Effect Pattern Plot method. Associations between AFP (≥ 20% increase) and radiographic progression and efficacy were assessed.Results Baseline AFP was confirmed as a continuous (REACH, REACH-2; p < 0.0001) and dichotomous (≥400 vs. <400 ng/ml; REACH, p < 0.01) prognostic factor, and was predictive for ramucirumab survival benefit in REACH (p = 0.0042 continuous; p < 0.0001 dichotomous). Time to AFP (hazard ratio [HR] 0.513; p < 0.0001) and radiographic (HR 0.549; p < 0.0001) progression favoured ramucirumab. Association between AFP and radiographic progression was shown for up to 6 (odds ratio [OR] 5.1; p < 0.0001) and 6–12 weeks (OR 1.8; p = 0.0065). AFP response was higher with ramucirumab vs. placebo (p < 0.0001). Survival was longer in patients with an AFP response than patients without (13.6 vs. 5.6 months, HR 0.451; 95% confidence interval, 0.354–0.574; p < 0.0001).Conclusions AFP is an important prognostic factor and a predictive biomarker for ramucirumab survival benefit. AFP ≥ 400 ng/ml is an appropriate selection criterion for ramucirumab.Clinical Trial Registration ClinicalTrials.gov, REACH ({"type":"clinical-trial","attrs":{"text":"NCT01140347","term_id":"NCT01140347"}}NCT01140347) and REACH-2 ({"type":"clinical-trial","attrs":{"text":"NCT02435433","term_id":"NCT02435433"}}NCT02435433).Subject terms: Oncology, Biomarkers     

The bruxism construct: From cut‐off points to a continuum spectrum

This commentary discusses the need to move on from the adoption of cut‐off points for the definition of the presence/absence of bruxism and justifies the need to embrace an evaluation based on the continuum of jaw motor behaviours. Currently, the number of events per hour, as identified by polysomnography (PSG), is used to define the presence of sleep bruxism (SB). Whilst PSG still remains the indispensable equipment to study the neurophysiological correlates of SB, the scoring criteria based on a cut‐off point are of questionable clinical usefulness for the study of oral health outcomes. For awake bruxism (AB), criteria for a definite diagnosis have never been proposed. Some goal‐oriented strategies are proposed to identify bruxism behaviours that increase the risk of negative oral health outcomes (eg, tooth wear, muscle and/or temporomandibular joint [TMJ] pain, restorative complications). One possible strategy would embrace an improved knowledge on the epidemiology and natural variability of bruxism, even including study of the amount of PSG/SB and electromyography masticatory muscle activity (EMG/MMA) during sleep and the frequency/prevalence of bruxism behaviours during wakefulness that are needed to represent a risk factor for clinical consequences, if any. There should not be any preclusion about the diagnostic strategies to pursue that goal, and a combination of instrumental and non‐instrumental approaches may even emerge as the best available option. Once data are available, large‐scale, non‐selected population samples representing the entire continuum of EMG/MMA activities are also needed, in the attempt to estimate untreated health risks in the population.     

Saporin-S6: A Useful Tool in Cancer Therapy

Thirty years ago, the type 1 ribosome-inactivating protein (RIP) saporin-S6 (also known as saporin) was isolated from Saponaria officinalis L. seeds. Since then, the properties and mechanisms of action of saporin-S6 have been well characterized, and it has been widely employed in the construction of conjugates and immunotoxins for different purposes. These immunotoxins have shown many interesting results when used in cancer therapy, particularly in hematological tumors. The high enzymatic activity, stability and resistance to conjugation procedures and blood proteases make saporin-S6 a very useful tool in cancer therapy. High efficacy has been reported in clinical trials with saporin-S6-containing immunotoxins, at dosages that induced only mild and transient side effects, which were mainly fever, myalgias, hepatotoxicity, thrombocytopenia and vascular leak syndrome. Moreover, saporin-S6 triggers multiple cell death pathways, rendering impossible the selection of RIP-resistant mutants. In this review, some aspects of saporin-S6, such as the chemico-physical characteristics, the structural properties, its endocytosis, its intracellular routing and the pathogenetic mechanisms of the cell damage, are reported. In addition, the recent progress and developments of saporin-S6-containing immunotoxins in cancer immunotherapy are summarized, including in vitro and in vivo pre-clinical studies and clinical trials.     

Serum proinflammatory cytokines and nutritional status in pediatric chronic liver disease

AIM: To evaluate the nutritional status and its association with proinflammatory cytokines in children with chronic liver disease.METHODS: We performed a cross-sectional study with 43 children and adolescents, aged 0 to 17 years, diagnosed with chronic liver disease. All patients regularly attended the Pediatric Hepatology Unit and were under nutritional follow up. The exclusion criteria were fever from any etiology at the time of enrollment, inborn errors of the metabolism and any chronic illness. The severity of liver disease was assessed by Child-Pugh, Model for End-stage Liver Disease(MELD) and Pediatric End Stage Liver Disease(PELD) scores. Anthropometric parameters were height/age, body mass index/age and triceps skinfold/age according to World Health Organization standards. The cutoff points for nutritional status were risk of malnutrition(Z-score -1.00) and malnutrition(Z-score -2.00). Interleukin-1β(IL-1β), IL-6 and tumor necrosis factor-α levels were assessed by commercial ELISA kits. For multivariate analysis, linear regression was applied to assess the association between cytokine levels, disease severity and nutritional status. RESULTS: The median(25th-75 th centile) age of the study population was 60(17-116)-mo-old, and 53.5% were female. Biliary atresia was the main cause of chronic liver disease(72%). With respect to Child-Pugh score, cirrhotic patients were distributed as follows: 57.1% Child-Pugh A, a mild presentation of the disease, 34.3% Child-Pugh B, a moderate stage of cirrhosis and 8.6% Child-Pugh C, were considered severe cases. PELD and MELD scores were only above the cutoff point in 5 cases. IL-6 values were increased in patients at nutritional risk(34.9%) compared with those who were well-nourished [7.12(0.58-34.23) pg/m L vs 1.63(0.53-3.43) pg/m L; P = 0.02], correlating inversely with triceps skinfold-for-age z-score(rs =-0.61; P 0.001). IL-6 levels were associated with liver disease severity assessed by Child-Pugh score(P = 0.001). This association remained significant after adjusting for nutritional status in a linear regression model. CONCLUSION: High IL-6 levels were found in children with chronic liver disease at nutritional risk. Inflammatory activity may be related to nutritional status deterioration in these patients.     

Validity and reliability of the Unified Classification System applied to periprosthetic femur fractures: a comparison with the Vancouver system

Abstract

Objective: The Unified Classification System (UCS) presents itself as an evolution of the Vancouver Classification (VCS) for the evaluation of periprosthetic fractures of the proximal femur (PPF). The aim of our study was to highlight any loss of reproducibility or validity of the new classification system, compared to the previous one.

Material and methods: We tested the interobserver and intraobserver agreement using 40 PPF clinical cases. Each classifying subtype of the UCS and VCS was present in at least two cases. Six experienced hip surgeons (Senior Surgeon, SS) and 5 surgeons in training (Junior Surgeon, JS) classified the clinical cases, using VCS and UCS. The validity of both classifications was then tested with intraoperative surveys.

Results: The mean κ value for interobserver agreement for the VCS in the JS group was 0.65 and 0.81 for the SS group. The mean κ value for interobserver agreement for the UCS in the JS group was 0.63 and 0.65 for the SS group. The mean κ value for intraobserver agreement for the VCS in the JS group was 0.71 and 0.73 for the SS group. The mean κ value for intraobserver agreement for the UCS in the JS group was 0.72 and 0.7 for the SS group. Validity analysis showed a moderate agreement for the VCS and a good agreement for the UCS.

Conclusion: The UCS completes the Vancouver classification, expanding it. It is reliable, despite the increase in classification categories and number of parameters to evaluate, with a slightly higher validity.     

Diagnostic and prognostic value of magnetic resonance imaging in the detection of tumor depth of invasion and bone invasion in patients with oral cavity cancer

La radiologia medica - To evaluate the accuracy of preoperative contrast-enhanced magnetic resonance imaging (MRI) in the assessment of radiological depth of invasion (rDOI) and bone invasion in...     

Information diffusion,Facebook clusters,and the simplicial model of social aggregation: a computational simulation of simplicial diffusers for community health interventions

By integrating the simplicial model of social aggregation with existing research on opinion leadership and diffusion networks, this article introduces the constructs of simplicial diffusers (mathematically defined as nodes embedded in simplexes; a simplex is a socially bonded cluster) and simplicial diffusing sets (mathematically defined as minimal covers of a simplicial complex; a simplicial complex is a social aggregation in which socially bonded clusters are embedded) to propose a strategic approach for information diffusion of cancer screenings as a health intervention on Facebook for community cancer prevention and control. This approach is novel in its incorporation of interpersonally bonded clusters, culturally distinct subgroups, and different united social entities that coexist within a larger community into a computational simulation to select sets of simplicial diffusers with the highest degree of information diffusion for health intervention dissemination. The unique contributions of the article also include seven propositions and five algorithmic steps for computationally modeling the simplicial model with Facebook data.