Circulating inflammatory cytokine expression in men with prostate cancer undergoing androgen deprivation therapy

Prostate cancer (PCa) is one of the most common cancers in men. Androgen deprivation therapy (ADT) is employed in the treatment of patients with metastatic or recurrent PCa, resulting in castrate levels of testosterone. Recent studies have shown that male hypogonadism is associated with increased levels of proinflammatory and diminished concentrations of anti-inflammatory cytokines, which normalize upon testosterone treatment. Furthermore, an inflammatory state is associated with osteoporosis, sarcopenia and metabolic abnormalities. We examined 3 groups of men: 1) 20 men with PCa undergoing ADT for at least 12 months prior to the onset of the study (ADT group); 2) 18 age-matched men with non-metastatic PCa who had undergone local surgery and/or radiotherapy and had not yet received ADT and were eugonadal (non-ADT group); and 3) 20 age-matched healthy eugonadal men (control group). None of the subjects were suffering from any acute or chronic inflammatory conditions. Mean age was similar in the 3 groups (P = .41). Men in the ADT and non-ADT groups had higher BMI compared to the control group (P = .0005 and P = .01, respectively). Men in the ADT group had significantly lower mean serum total (P < .0001) and free (P < .0001) testosterone and estradiol (P < .0001) levels compared to the other 2 groups. No significant differences in serum levels of pro-inflammatory or anti-inflammatory cytokines were observed between the 3 groups. These data suggest that men with PCa undergoing long-term ADT do not have elevated levels of pro-inflammatory cytokines compared to age and disease matched controls. Prospective studies are needed to evaluate for any acute changes in these inflammatory markers that might occur after the initiation of ADT.     

Decursinol angelate inhibits PGE2-induced survival of the human leukemia HL-60 cell line via regulation of the EP2 receptor and NFκB pathway

Decursinol angelate (DA), an active pyranocoumarin compound from the roots of Angelica gigas, has been reported to possess anti-inflammatory and anti-cancer activities. In a previous study, we demonstrated that prostaglandin E₂ (PGE₂) plays a survival role in HL-60 cells by protecting them from the induction of apoptosis via oxidative stress. Flow cytometry and Hoechst staining revealed that PGE₂ suppresses menadione-induced apoptosis, cell shrinkage, and chromatin condensation, by blocking the generation of reactive oxygen species. Treatment of DA was found to reverse the survival effect of PGE₂ as well as restoring the menadione-mediated cleavage of caspase-3, lamin B, and PARP. DA blocked PGE₂-induced activation of the EP2 receptor signaling pathway, including the activation of PKA and the phosphorylation of CREB. DA also inhibited PGE₂-induced expression of cyclooxygenase-2 and the activation of the Ras/Raf/ Erk pathway, which activates downstream targets for cell survival. Finally, DA greatly reduced the PGE₂-induced activation of NF-κB p50 and p65 subunits. These results elucidate a novel mechanism for the regulation of cell survival and apoptosis, and open a gateway for further development and combinatory treatments that can inhibit PGE₂ in cancer cells.     

A Physician’s Attempt to Self-Medicate Bipolar Depression with N,N-Dimethyltryptamine (DMT)

N,N-dimethyltryptamine (DMT) is a psychoactive substance that has been gaining popularity in therapeutic and recreational use. This is a case of a physician who chronically took DMT augmented with phenelzine in an attempt to self-medicate refractory bipolar depression. His presentation of altered mental status, mania, and psychosis is examined in regards to his DMT use. This case discusses DMT, the possible uses of DMT, and the theorized mechanism of DMT in psychosis and treatment of depression, particularly involving its agonist activity at 5-HT1A, 5-HT2A, and 5-HT2C. It is also important to recognize the dangers of self-medication, particularly amongst physicians.     

Social preference weights for treatments in Fabry disease in the UK: a discrete choice experiment

Objective: Fabry disease is a rare inherited lysosomal storage disorder caused by deficiency of α-galactosidase A. Effective enzyme replacement therapies are available that are administered intravenously. However, a new oral treatment is being developed as an alternative option for patients with amenable mutations. This study was designed to understand the value that people place on the different features of treatments for Fabry disease.

Research design and methods: A discrete choice experiment (DCE) was designed to assess the importance of different aspects of treatments for Fabry disease. The attributes included overall survival, mode of administration, treatment related reactions, treatment related headaches and risk of antibody formation. Attributes were combined using a published orthogonal array into choice sets. A research panel was used to survey the UK general public. The mixed logit model was used to estimate strength of preference for the attributes and marginal rates of substitution (MRSs). Disutilities were estimated from the DCE data for changes in each attribute.

Results: The sample (n?=?506) was broadly representative of UK demographics. The logit model revealed that all attributes were significant predictors of choice. Participants were significantly more likely to choose a treatment which meant an increase in their life expectancy by 1 year (odds ratio = 1.574; 95% CI = 1.504–1.647) and significantly less likely to choose self-administered intravenous (IV) treatment compared to an every other day tablet (OR = 0.426 95% CI = 0.384–0.474). Estimated disutilities were ?0.0543 (self-administered infusion), treatment related headaches 12 times a year (?0.0361) and infusion reactions six times a year (?0.0202).

Conclusions: The survey revealed a significant preference for oral treatment compared with IV even in the context of a treatment that can extend overall survival. MRSs were used as a basis for estimating disutilities associated with changes in attribute levels which could be used to weight QALYs. It is possible that other important treatment attributes are missing from this research which may have provided further insights. It would also be useful to extend this research to include Fabry disease patients so their preferences can be assessed against the societal perspective.     

Detection of BRAF mutation on fine needle aspiration biopsy specimens: a new diagnostic tool for papillary thyroid cancer

Numerous biomolecular markers have been studied to improve the accuracy of fine needle aspiration biopsy (FNAB) in the diagnostic and prognostic evaluation of thyroid tumors, but none of them has yet become clinically useful. The recently discovered BRAF mutation, which occurs specifically in papillary thyroid cancers (PTC) with a high prevalence and is associated with poor clinicopathological outcomes, has the potential to be a useful diagnostic and prognostic marker for PTC. In the present study, we investigated whether detection of BRAF mutation on FNAB specimens was technically possible and could be used as an adjunct diagnostic tool with routine FNAB. Evaluation of a new colorimetric mutation detection method demonstrated 100% sensitivity and 100% specificity in comparison with conventional DNA sequencing as the "gold standard" in a large pool of DNA samples from various primary thyroid tumor specimens and cell lines. We found this novel technique even more sensitive in detecting BRAF mutation on FNAB specimens than conventional sequencing. In a series of 48 patients undergoing thyroidectomy, mostly for thyroid cancer or for suspicion of cancer, we performed preoperative FNAB and, using the colorimetric mutation detection method, identified BRAF mutation on the cytological specimens. Prospective analysis showed that 50% of the nodules that proved to be PTC on surgical histopathology were correctly diagnosed by BRAF mutation analysis on FNAB specimens; there were no false positive findings. Thus, we have demonstrated the usefulness of BRAF mutation detection on FNAB specimens that can help diagnose and identify those PTC patients who may need more aggressive surgical treatment and vigilant clinical monitoring.