The influence of sex and menstrual cycle over the pain and electromyographic activity of masticatory muscles in subjects with temporomandibular disorders

Orientador: Maria Cecilia Ferraz de Arruda VeigaTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Odontologia de PiracicabaResumo: A mialgia mastigatória, é um dos principais sintomas em pacientes com disfunção temporomandibular (DTM); entretanto, sua patofisiologia ainda é pouco compreendida. Por isso, os objetivos deste trabalho foram investigar o efeito do sexo e do ciclo menstrual na atividade eletromiográfica (EMG) de pacientes com DTM, e a sensibilidade dolorosa, assim como os aspectos psicológicos destes mesmos pacientes. As respostas avaliadas, foram comparadas com as respostas do grupo controle. Os grupos DTM, foram compostos por 30 mulheres com ciclo menstrual regular; e por 23 homens. Os grupos controle, foram compostos por 30 mulheres com ciclo menstrual regular e por 30 homens, ambos sem DTM ou outras dores crÃ'nicas. Os voluntários foram avaliados, com base no Critério Diagnóstico de Pesquisa para DTM, (RDC/TMD) tanto para dor miofascial, como para artralgia (Eixo I). Os voluntários preencheram a Escala do Grau de Dor CrÃ'nica (GCPS), e as escalas de depressão e de sintomas físicos não-específicos (somatização) do RDC/TMD (Eixo II). A atividade EMG no repouso, foi registrada bilateralmente, nos músculos temporal anterior e músculos masseteres. A raiz quadrada da média (RMS) foi gerada a partir dos sinais EMG e foram normalizados, a partir dos valores obtidos durante a contração voluntária máxima. Os resultados mostraram diferenças EMG apenas nos músculos do lado esquerdo dos homens com DTM. Não houve diferenças significativas na atividade EMG dos músculos mastigatórios entre mulheres com e sem DTM. A dor miofascial foi maior na fase menstrual, comparada com as outras fases do ciclo menstrual. Além disso, as mulheres com DTM apresentaram maior GCPS, maior grau de depressão (moderado a severo), e pontuaram maiores itens de somatização (moderado a severo), comparado aos homens com DTM. Concluiu-se portanto, que: 1) Os homens com DTM apresentaram maior atividade EMG nos músculos do lado esquerdo da face, onde a dor foi mais prevalente. Não houve alteração na atividade EMG dos músculos mastigatórios de mulheres com DTM, sugerindo que existam diferenças sexuais nas respostas musculares induzidas pela dor; 2) a dor por DTM, é freqüentemente acompanhada por aspectos psicológicos, como depressão e somatização, principalmente em mulheresAbstract: The masticatory myalgia is one of the most common symptoms in temporomandibular disorder (TMD) patients; however, its pathophysioloy is poorly understood. Thus, the aims of this study were to investigate the effect of sex and pain on electromyographic activity (EMG); the effect of menstrual cycle phases on EMG activity; the influence of menstrual cycle on pain sensitivity; and the psychological aspects of TMD and control group. TMD cases were 30 normally cycling women; and 23 men. Controls were 30 normally cycling women and 30 men, without TMD or other chronic pains. The subjects were assessed based on Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) for both myofascial pain and arthralgia (Axis I). Subjects completed the RDC/TMD (Axis II), for Graded Chronic Pain Scale (GCPS), and measures of depression and nonspecific physical symptoms. EMG signals at rest were recorded bilaterally from the anterior temporal and masseter muscles. The root mean square (RMS) were computed from the EMG signals and normalized to the values obtained during maximal voluntary contractions. The results showed that were EMG differences only on the menâ?¿s TMD left masticatory muscles. There were no statistically significant differences in the EMG activity of masticatory muscles between women with and without TMD. The myofascial pain was significantly higher in menstrual phase compared with all of other phases of the menstrual cycle. Moreover, TMD women experienced higher GCPS, more moderately to severely graded depression, and scored greater moderate and severe somatization items than men TMD patients. It was concluded that: 1) The TMD men, presented higher EMG activity on the left side of the face, where pain was more prevalent. There was no significantly differences in EMG activity of womenâ?¿s TMD masticatory muscles, which indicates that the pain-induced changes in muscular responses could differ in men and women; 2) TMD pain is frequently accompanied by psychological aspects, like depression and somatization mainly in womenDoutoradoFisiologia OralDoutor em Odontologi

Mechanisms of Primary and Acquired Resistance to Immune Checkpoint Inhibitors in Patients with Hepatocellular Carcinoma

Simple Summary Immune checkpoint inhibitors (ICIs) are now a cornerstone of systemic treatment for hepatocellular carcinoma (HCC). However, their efficacy is blunted by mechanisms of tumour resistance in many patients. This review reports on the state of the art of resistance to ICIs, focusing on HCC, with the aim to provide clear and direct information to clinicians and researchers. Growing knowledge on the mechanisms of resistance to immunotherapy can indeed guide the choice of and expand the application of novel combined treatments. Hepatocellular carcinoma (HCC) is the most common liver cancer and a relevant global health problem. Immune checkpoint inhibitors (ICIs) represent the most effective systemic treatment for HCC. However, due to primary resistance, approximately 40% of HCC patients do not achieve a disease control with ICIs. Moreover, a similar proportion will experience disease progression after an initial response caused by secondary resistance. This review describes the mechanisms of primary and secondary resistance and reports the ongoing therapeutic strategies to overcome these obstacles

Treatment allocation in patients with hepatocellular carcinoma: Need for a paradigm shift?

Letter

TACE treatment in hepatocellular carcinoma: What should we do now?

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A Liver Index and its Relationship to Indices of HCC Aggressiveness

A Hepatocellular (HCC) Aggressiveness Index was recently constructed, consisting of the sum of the scores for the 4 clinical parameters of maximum tumor size, multifocality, presence of portal vein thrombus and blood alphafetoprotein levels. It was observed that there was an association with several liver function tests. We have now formed a Liver Index from the 4 liver parameters with the highest hazard ratios with respect to HCC aggressiveness, namely: blood total bilirubin, gamma glutamyl transpeptidase (GGTP), albumin and platelet levels (cirrhosis surrogate). We found that the scores for the Liver Index related significantly to survival, but also to the Aggressiveness Index and to its individual HCC components as well as showing significant trends with the components. These results support the hypothesis that liver function is not only an important prognostic factor in HCC patients, but may also be involved in HCC biology and aggressiveness. Blood albumin, GGTP, albumin and platelet levels were used to create a Liver Index that related significantly to parameters of HCC aggressiveness

Development and Validation of a New Prognostic System for Patients with Hepatocellular Carcinoma

BACKGROUND: Prognostic assessment in patients with hepatocellular carcinoma (HCC) remains controversial. Using the Italian Liver Cancer (ITA.LI.CA) database as a training set, we sought to develop and validate a new prognostic system for patients with HCC. METHODS AND FINDINGS: Prospective collected databases from Italy (training cohort, n = 3,628; internal validation cohort, n = 1,555) and Taiwan (external validation cohort, n = 2,651) were used to develop the ITA.LI.CA prognostic system. We first defined ITA.LI.CA stages (0, A, B1, B2, B3, C) using only tumor characteristics (largest tumor diameter, number of nodules, intra- and extrahepatic macroscopic vascular invasion, extrahepatic metastases). A parametric multivariable survival model was then used to calculate the relative prognostic value of ITA.LI.CA tumor stage, Eastern Cooperative Oncology Group (ECOG) performance status, Child-Pugh score (CPS), and alpha-fetoprotein (AFP) in predicting individual survival. Based on the model results, an ITA.LI.CA integrated prognostic score (from 0 to 13 points) was constructed, and its prognostic power compared with that of other integrated systems (BCLC, HKLC, MESIAH, CLIP, JIS). Median follow-up was 58 mo for Italian patients (interquartile range, 26-106 mo) and 39 mo for Taiwanese patients (interquartile range, 12-61 mo). The ITA.LI.CA integrated prognostic score showed optimal discrimination and calibration abilities in Italian patients. Observed median survival in the training and internal validation sets was 57 and 61 mo, respectively, in quartile 1 (ITA.LI.CA score 64 1), 43 and 38 mo in quartile 2 (ITA.LI.CA score 2-3), 23 and 23 mo in quartile 3 (ITA.LI.CA score 4-5), and 9 and 8 mo in quartile 4 (ITA.LI.CA score > 5). Observed and predicted median survival in the training and internal validation sets largely coincided. Although observed and predicted survival estimations were significantly lower (log-rank test, p < 0.001) in Italian than in Taiwanese patients, the ITA.LI.CA score maintained very high discrimination and calibration features also in the external validation cohort. The concordance index (C index) of the ITA.LI.CA score in the internal and external validation cohorts was 0.71 and 0.78, respectively. The ITA.LI.CA score's prognostic ability was significantly better (p < 0.001) than that of BCLC stage (respective C indexes of 0.64 and 0.73), CLIP score (0.68 and 0.75), JIS stage (0.67 and 0.70), MESIAH score (0.69 and 0.77), and HKLC stage (0.68 and 0.75). The main limitations of this study are its retrospective nature and the intrinsically significant differences between the Taiwanese and Italian groups. CONCLUSIONS: The ITA.LI.CA prognostic system includes both a tumor staging-stratifying patients with HCC into six main stages (0, A, B1, B2, B3, and C)-and a prognostic score-integrating ITA.LI.CA tumor staging, CPS, ECOG performance status, and AFP. The ITA.LI.CA prognostic system shows a strong ability to predict individual survival in European and Asian populations

Metronomic capecitabine vs. best supportive care in Child-Pugh B hepatocellular carcinoma: A proof of concept

There is a relative lack of evidence about systemic treatments in patients with hepatocellular carcinoma (HCC) and moderate liver dysfunction (Child-Pugh B). In this multicenter study we retrospectively analyzed data from Child-Pugh B-HCC patients na\uefve to systemic therapies, treated with MC or best supportive care (BSC). To reduce the risk of selection bias, an inverse probability of treatment weighting approach was adopted. Propensity score was generated including: extrahepatic spread; macrovascular invasion; performance status, alphafetoprotein > 400 ng/ml, Child- Pugh score [B7 vs. B8-9]. We identified 35 MC-treated patients and 70 controls. Median overall survival was 7.5 [95% CI: 3.733-11.267]in MC-patients and 5.1 months [95% CI: 4.098-6.102] in the BSC group (p = 0.013). In patients treated with MC, median progression-free survival was 4.5 months (95% CI: 2.5-6.5). The univariate unweighted Cox regression showed a 42% reduction in death risk for patients on MC (95%CI: 0.370-0.906; p = 0.017). After weighting for potential confounders, death risk remained essentially unaltered. In the MC group, 12 patients (34.3%) experienced at least one adverse event, the most common of which were: fatigue (17.1%), hand-foot syndrome (8.5%), thrombocytopenia (8.5%), and neutropenia (5.7%). MC seems a safe option for Child-Pugh B-HCC patients. Its potential antitumour activity warrants prospective evaluations

Plasma cholesterol and lipoprotein levels in relation to tumor aggressiveness and survival in HCC patients

open13Hepatocellular carcinoma is associated with several chronic liver diseases, especially chronic hepatitis B virus, hepatitis C virus, and alcoholism. It is increasingly appreciated that obesity/metabolic syndrome is also associated with chronic liver disease and subsequent hepatocellular carcinoma.openCarr, Brian I; Giannelli, Gianluigi; Guerra, Vito; Giannini, Edoardo G; Farinati, Fabio; Rapaccini, Gian Ludovico; Marco, Maria Di; Zoli, Marco; Caturelli, Eugenio; Masotto, Alberto; Virdone, Roberto; Sacco, Rodolfo; Trevisani, FrancoCarr, Brian I; Giannelli, Gianluigi; Guerra, Vito; Giannini, Edoardo G; Farinati, Fabio; Rapaccini, Gian Ludovico; Marco, Maria Di; Zoli, Marco; Caturelli, Eugenio; Masotto, Alberto; Virdone, Roberto; Sacco, Rodolfo; Trevisani, Franc

Pharmacological characterisation of capsaicin-induced relaxations in human and porcine isolated arteries

Capsaicin, a pungent constituent from red chilli peppers, activates sensory nerve fibres via transient receptor potential vanilloid receptors type 1 (TRPV1) to release neuropeptides like calcitonin gene-related peptide (CGRP) and substance P. Capsaicin-sensitive nerves are widely distributed in human and porcine vasculature. In this study, we examined the mechanism of capsaicin-induced relaxations, with special emphasis on the role of CGRP, using various pharmacological tools. Segments of human and porcine proximal and distal coronary arteries, as well as cranial arteries, were mounted in organ baths. Concentration response curves to capsaicin were constructed in the absence or presence of the CGRP receptor antagonist olcegepant (BIBN4096BS, 1 μM), the neurokinin NK1 receptor antagonist L-733060 (0.5 μM), the voltage-sensitive calcium channel blocker ruthenium red (100 μM), the TRPV1 receptor antagonist capsazepine (5 μM), the nitric oxide synthetase inhibitor Nω-nitro-l-arginine methyl ester HCl (l-NAME; 100 μM), the gap junction blocker 18α-glycyrrhetinic acid (10 μM), as well as the RhoA kinase inhibitor Y-27632 (1 μM). Further, we also used the K+ channel inhibitors 4-aminopyridine (1 mM), charybdotoxin (0.5 μM) + apamin (0.1 μM) and iberiotoxin (0.5 μM) + apamin (0.1 μM). The role of the endothelium was assessed by endothelial denudation in distal coronary artery segments. In distal coronary artery segments, we also measured levels of cyclic adenosine monophosphate (cAMP) after exposure to capsaicin, and in human segments, we also assessed the amount of CGRP released in the organ bath fluid after exposure to capsaicin. Capsaicin evoked concentration-dependent relaxant responses in precontracted arteries, but none of the above-mentioned inhibitors did affect these relaxations. There was no increase in the cAMP levels after exposure to capsaicin, unlike after (exogenously administered) α-CGRP. Interestingly, there were significant increases in CGRP levels after exposure to vehicle (ethanol) as well as capsaicin, although this did not induce relaxant responses. In conclusion, the capsaicin-induced relaxations of the human and porcine distal coronary arteries are not mediated by CGRP, NK1, NO, vanilloid receptors, voltage-sensitive calcium channels, K+ channels or cAMP-mediated mechanisms. Therefore, these relaxant responses to capsaicin are likely to be attributed to a non-specific, CGRP-independent mechanism

Efficacy of radioembolization according to tumor morphology and portal vein thrombosis in intermediate–advanced hepatocellular carcinoma

Purpose: We analyzed overall survival (OS) following radioembolization according to macroscopic growth pattern (nodular vs infiltrative) and vascular invasion in intermediate-advanced hepatocellular carcinoma (HCC). Methods: Between September 2005 and November 2013, 104 patients (50.0% portal vein thrombosis [PVT], 29.8% infiltrative morphology) were treated. Results: Median OS differed significantly between patients with segmental and lobar or main PVT (p = 0.031), but was 17 months in both those with patent vessels and segmental PVT. Median OS did not differ for infiltrative and nodular HCC. Median OS was prolonged in patients with a treatment response at 3 months (p = 0.023). Prior TACE was also a significant predictor of improved OS. Conclusion: A further indication for radioembolization might be infiltrative HCC, since OS was similar to nodular types