Here we discuss the current treatment landscape of metastatic prostate cancer, clinical challenges, and the emerging role of molecular biomarkers for targeting biologic subsets of advanced disease and co-targeting heterogenous resistance patterns.In recent years, tumor metabolism has become a prevalent research topic for scientists and pharmaceutical companies. As research in the field has progressed, the metabolism-based therapy of tumors has ushered in new opportunities. Most tumors emerge and evolve under selective pressure from their microenvironment, which promotes the diversification of both neoplastic and non-neoplastic compartments of the tumor microenvironment (TME), and finally reaches a certain degree of intratumoral heterogeneity. As a result of the tumor intratumoral heterogeneity, tumor cells often possess a complex energy metabolism phenotype. During tumor progression, the metabolism for both tumor parenchyma and stroma is reprogrammed. The tumor stroma mainly consists of the extracellular matrix, fibroblasts, and immune cells. Interestingly, tumor-infiltrating immune cells utilize different metabolites based on their subtype and function, and these immunometabolic pathways can be modified in the TME. In particular, interleukins play a vital role in the activation and differentiation of immune cells and have exhibited multiple effects on tumor cell neoplasia, invasion, and metastasis. In this review, we summarize the common mechanisms of interleukins affecting the tumor and tumor-infiltrating immune cells metabolically and discuss how these mechanisms may lead to novel therapeutic opportunities. This review might contribute to the novel development of cancer immunotherapy.Despite HER2-targeted cancer treatments have provided considerable clinical benefits, resistance to HER2-targeted agents will inevitably develop. Targeting non-oncogene vulnerabilities including endoplasmic reticulum (EnR) stress has emerged as an attractive alternative approach to improve the efficacy of existing targeted cancer therapies. In the current study, we find that Melatonin sensitizes HER2-positive breast cancer cells to the dual tyrosine kinase inhibitor Lapatinib in vitro. Mechanistically, Melatonin enhances the cytotoxic effects of Lapatinib through promoting excessive EnR stress-induced unfolded protein response (UPR) and ROS overaccumulation. Consistently, the antioxidant N-acetylcysteine remarkably reverses the effects of the drug combination on ROS production, DNA damage and cytotoxicity. Furthermore, Melatonin significantly enhances the anti-tumor effect of Lapatinib in an HCC1954 xenograft model. Meanwhile, Lapatinib resistant HER2-positive breast cancer cells (LapR) display lower basal expression levels of UPR genes and enhanced tolerance to EnR stress with attenuated response to Brefeldin A and Tunicamycin. Importantly, Melatonin also increases the sensitivity of HCC1954 LapR cells to Lapatinib. Together, our findings highlight the potential utility of Melatonin as an adjuvant in the treatment of primary or therapy resistant HER2-positive breast cancer via EnR stress-mediated mechanisms.Bilirubin is a tetrapyrrolic compound originating from heme catabolism. QX77 manufacturer Although originally considered only a potentially dangerous waste product, it has become increasingly evident that this molecule represents an important modulator of various biological functions in the human body. Bilirubin appears to have versatile functions, from cell signaling (behaving almost like a “real” hormonal substance), modulation of metabolism, to immune regulation, affecting biological activities with apparent clinical and even therapeutic consequences. These activities may be the reason for the lower incidence of diseases of civilisation (cardiovascular diseases, arterial hypertension, diabetes, obesity, metabolic syndrome, certain cancers, autoimmune, and neurodegenerative diseases) observed in individuals with a chronic mild unconjugated hyperbilirubinemia, a typical sign of Gilbert’s syndrome. While higher serum concentrations of unconjugated bilirubin may serve as an important protective factor against these diseases, low levels of bilirubin are associated with the opposite effect.

Subungual melanoma (SUM) has a poor prognosis because of delayed diagnosis. Its progression, consensus on surgical treatment, and correlation with clinical outcomes remain unclear.

We aimed to identify the pattern of dermal invasion in different locations of the nail apparatus and its relationship with prognosis.

In this retrospective review of surgically treated SUM patients between January 2011 and April 2019, the nail apparatus was divided into 5 anatomic subunits the dorsal roof of proximal nail fold, ventral floor of proximal nail fold, germinal matrix, nail bed, and hyponychium. Invasions in the subunits were categorized using 3 criteria no tumor, in situ tumor, or invasion.

Among 44 cases of SUM, dermal invasion occurred mostly in the distal areas, with 11, 30, 18, 7, and 4 in the hyponychium, nail bed, germinal matrix, ventral floor of proximal nail fold, and dorsal roof of proximal nail fold, respectively. The patients with hyponychial invasion showed a significantly greater Breslow depth (P=.009), a higher rate of lymph node metastasis (P=.019), distant metastasis (P=.036), and shorter disease-free survival (P=.001).

Hyponychial invasion is an important prognostic predictor of SUM, given its strong association with invasion depth, metastatic progression, and disease-free survival. Patients with invasion in the hyponychium should undergo more strict workup, treatment, and surveillance.

Hyponychial invasion is an important prognostic predictor of SUM, given its strong association with invasion depth, metastatic progression, and disease-free survival. Patients with invasion in the hyponychium should undergo more strict workup, treatment, and surveillance.The purpose was to evaluate late-onset AEs in melanoma patients treated with anti-PD1 administered at least 2 years in a real-life setting. Patients were screened from MelBase (NCT02828202), a French multicentric biobank dedicated to the prospective follow-up of unresectable stage III or IV melanoma. 119 patients who received anti-PD1 during at least 2 years from January 2013 to November 2019 were included. Median follow-up was 41.7 months (25.2-57.5). Patients received nivolumab (n=53) or pembrolizumab (n=66). AEs occurred in 99 patients (83%) with a median time of 13.3 months (0-53.9), including severe AEs (grade 3 or 4) in 30 patients (30%). Late-onset AEs, mostly grade 1-2, occurred in 51 (43%) patients and led to 5 (4%) hospitalizations of which 4 were severe. Factors associated with late-onset AEs in multivariate analysis were early-onset AEs (within the first two years of treatment) and treatment duration (p=0,02 and p=0,03 respectively). Our data demonstrate the possibility of late-onset AEs occurring after 2 years of anti-PD1 therapy.