A Phase I Trial of Trametinib in Combination with Sorafenib in Patients with Advanced Hepatocellular Cancer

Lessons Learned

• The combination of trametinib and sorafenib has an acceptable safety profile, albeit at doses lower than approved for monotherapy.
• Maximum tolerated dose is trametinib 1.5 mg daily and sorafenib 200 mg twice daily.
• The limited anticancer activity observed in this unselected patient population does not support further exploration of trametinib plus sorafenib in patients with hepatocellular carcinoma.

BackgroundThe RAS/RAF/MEK/ERK signaling pathway is associated with proliferation and progression of hepatocellular carcinoma (HCC). Preclinical data suggest that paradoxical activation of the MAPK pathway may be one of the resistance mechanisms of sorafenib; therefore, we evaluated trametinib plus sorafenib in HCC.MethodsThis was a phase I study with a 3+3 design in patients with treatment‐naïve advanced HCC. The primary objective was safety and tolerability. The secondary objective was clinical efficacy.ResultsA total of 17 patients were treated with three different doses of trametinib and sorafenib. Two patients experienced dose‐limiting toxicity, including grade 4 hypertension and grade 3 elevation of aspartate aminotransferase (AST)/alanine aminotransferase (ALT)/bilirubin over 7 days. Maximum tolerated dose was trametinib 1.5 mg daily and sorafenib 200 mg twice a day. The most common grade 3/4 treatment‐related adverse events were elevated AST (37%) and hypertension (24%). Among 11 evaluable patients, 7 (63.6%) had stable disease with no objective response. The median progression‐free survival (PFS) and overall survival (OS) were 3.7 and 7.8 months, respectively. Phosphorylated‐ERK was evaluated as a pharmacodynamic marker, and sorafenib plus trametinib inhibited phosphorylated‐ERK up to 98.1% (median: 81.2%) in peripheral blood mononuclear cells.ConclusionTrametinib and sorafenib can be safely administered up to trametinib 1.5 mg daily and sorafenib 200 mg twice a day with limited anticancer activity in advanced HCC.     

Pathways in the association between sugar sweetened beverages and child asthma traits in the 2nd year of life: Findings from the BRISA cohort

Studies on the exposure of children to sugar-sweetened beverages (SSBs) at an early age may contribute to better understand the common causes and the temporal order of the relationships between obesity and asthma in early childhood. The objective of this study was to estimate the association between SSB and child asthma traits in the 2nd year of life, modeling direct and indirect pathways mediated by the highest BMI-z of the child and allergic inflammation. Data from the BRISA cohort, São Luís-MA, Brazil (n = 1140), were obtained from the baseline and from the follow-up performed at the 2nd year of life. The main explanatory variable was the calories from added sugars in SSBs as a percentage of the total daily energy intake. The outcome child asthma traits was a latent variable deduced from four indicators: medical diagnosis of asthma, wheezing, emergency visit due to intense wheezing, and medical diagnosis of rhinitis. A high percentage of daily calories from sugars added to SSBs was directly associated with higher values of child asthma traits (standardized coefficient (SC = 0.073; P = .030)). High levels of eosinophils were also directly associated with child asthma traits (SC = 0.118; P = .049). No mediation pathways were observed via greater BMI-z or eosinophil counts. Therefore, early exposure of children to SSB may contribute to increased risk of childhood asthma, preceding the link between sugar consumption and overweight/obesity, not yet evident in children in the first 2 years of life.     

A Novel Nomogram to Identify Candidates for Extended Pelvic Lymph Node Dissection Among Patients with Clinically Localized Prostate Cancer Diagnosed with Magnetic Resonance Imaging-targeted and Systematic Biopsies

Background

Available models for predicting lymph node invasion (LNI) in prostate cancer (PCa) patients undergoing radical prostatectomy (RP) might not be applicable to men diagnosed via magnetic resonance imaging (MRI)-targeted biopsies.

Pseudoathetosis: report of three patients.

We report on 3 patients with pseudoathetosis, which are involuntary, slow, writhing movements due to loss of proprioception.     

Primary hypothyroidism presenting as ovarian tumor and precocious puberty in a prepubertal girl.

We report a case of a prepubertal girl with juvenile primary hypothyroidism presenting as ovarian cysts and precocious puberty. The 7-year-old female was referred to our clinic because of a pelvic/abdominal mass and vaginal bleeding. Besides these findings, on physical examination we noticed the thyroid gland globally increased and the presence of secondary sexual characteristics. Based upon the clinical profile and investigations, the patient was diagnosed with juvenile primary hypothyroidism due to autoimmune thyroiditis. The cysts and precocious puberty resolved spontaneously after the simple replacement of thyroid hormone. It is important to bear in mind hypothyroidism in cases of girls presenting ovarian cysts and precocious puberty in order to avoid unnecessary surgery on the ovaries.     

Why do Italian people rate their health worse than French people do? An exploration of cross-country differentials of self-rated health

The prevalence of bad self-rated health (SRH) varies considerably across countries. Here we present the results of a cross-national comparative study based on the data of National Health Surveys conducted in France and Italy. According to these data, 11% of the Italian and 6% of the French adult population aged between 45 and 74 rate their health as bad or very bad. This gap may result from differences in population structure regarding the individual characteristics (sociodemographic characteristics, diseases and disabilities, lifestyle, and others) that impact on SRH i.e., a structural effect. It may also be that the link between these characteristics and SRH is “country-specific” i.e., a contextual effect. We use logistic regression models to assess the contribution of both explanations. We find that the structural effect plays a prominent role in the higher prevalence of bad SRH in Italy compared to France.     

Small-cell neuroendocrine carcinoma of the ampullary region. A clinicopathologic, immunohistochemical, and ultrastructural study of three cases.

We report the clinicopathologic, immunohistochemical, and ultrastructural features of three small-cell neuroendocrine carcinomas of the ampullary region of the duodenum. All patients were men; their ages were 51, 62, and 66 years. The therapy consisted of pancreatoduodenectomy. All patients died of the disease; median survival was 10 months from the diagnosis. The histological appearance was identical to pulmonary and extrapulmonary small-cell carcinoma. The neuroendocrine differentiation was demonstrated ultrastructurally by the presence of dense-core granules, and by the positive immunoreaction for neuron-specific enolase and Leu-7 in each case. One case expressed a focal positivity for chromogranin A (PHE-5) and argyrophilic granules. The same case showed the presence of neurofilaments on frozen material. Neurofilament proteins could not be demonstrated in any case in paraffin sections. Neoplastic cells exhibited cytoplasmic immunostaining for cytokeratins (CAM 5.2) in all cases. In one case, a large number of neoplastic cells (60-70%) exhibited nuclear Ki-67 positivity. We postulate that the disease's histogenesis was from epithelial stem cell expressing both epithelial and neuroendocrine characteristics. The clinical behavior of small-cell neuroendocrine carcinomas of the ampullary region appears to be extremely aggressive, with early metastases and fatal outcome.