The application of natural compounds in uveal melanoma drug discovery.

OBJECTIVES: Uveal melanoma (UM) is the most common primary intraocular tumour in adults. UM has a poor overall prognosis and ~50% of patients progress to metastatic disease that has a median survival of 5.2 months. There are currently no proven pharmacological treatments for primary or metastatic UM. Research efforts continue to seek new agents. Many natural compounds have shown promising anti-UM activity in in-vitro and/or in-vivo studies. This review summarises the current findings for natural compounds that may be potentially useful in treating UM. KEY FINDINGS: Literature suggests that natural compounds, such as pristimerin, picropodophyllin, oridonin, zeaxanthin, withaferin and FR-900359, may be promising candidate compounds to treat UM. Most of these compounds have demonstrated satisfactory efficacy in inhibiting in-vitro UM cell growth. SUMMARY: The evidence regarding the anti-UM effects of natural compounds is mainly limited to in-vitro studies; to date, only a small number of these agents have been evaluated in vivo. The molecular mechanisms underpinning the anti-UM properties of these compounds remain largely undefined. Further studies are required to evaluate the in-vivo anticancer activity, appropriate dosage regimen and safety of natural compounds that could be developed for use in UM.

The unfolded protein response and the biology of uveal melanoma.

Uveal melanoma (UM) is a highly metastatic ocular cancer that arises from the melanocytes of the uveal tract (the choroid, ciliary body and iris). Despite a growing understanding of UM biology, effective systemic treatments are currently lacking and the cancer has an extremely poor prognosis. Therefore, identifying novel agents that act by new tumorigenic mechanisms in UM is essential to address this unmet clinical need. Endoplasmic reticulum (ER) stress occurs when misfolded proteins accumulate in the organelle, and the unfolded protein response (UPR) is the cellular mechanism that is activated so that cells may adapt to the situation. Dysregulated UPR signalling has been detected in UM tumors and has been associated with an increase in immune evasion and metastatic activity. A number of established and novel oncology drugs act in part by modulating ER stress and the UPR. The induction of protein-folding stress and the UPR could be a novel approach for the development of new therapeutics in UM. Further studies are now warranted to understand the mechanisms and consequences of UPR signalling in UM.

The Role of Growth Hormone in Depression: A Human Model.

BACKGROUND: Although the relationship between acromegaly and depression has been ascribed to the effects of chronic disease, the role of growth hormone (GH), and insulin like growth factor-1 (IGF-1) is not clear. OBJECTIVE: To determine whether related hormones levels in acromegalics are correlated with depressive symptoms and whether these symptoms are ameliorated following surgery. MATERIALS AND METHODS: A prospective cohort study was conducted on patients diagnosed with acromegaly (n = 15) or non-functioning pituitary adenomas (NFPA; n = 20, as controls) and undergoing first-time surgery, who completed the Center for Epidemiological Studies Depression (CES-D) questionnaire both pre-surgery and post-surgery. The primary outcome was the patient's severity of depression symptomatology using the CES-D score; GH, IGF-1 levels, and tumor characteristics were also measured. RESULTS: Hormone levels (GH and IGF-1) and depression scores in acromegaly patients showed significant reductions following surgery (p < 0.05). The average change in CES-D score was 5.73 ± 2.58 (mean ± SE). A moderate correlation was found between GH levels and CES-D scores (r = 0.52, p < 0.01). The depressed affect subscale accounted for the most improvement in CES-D scores postoperatively and correlated most highly with GH levels. We did not find similar declines in the matched cohort of NFPA patients. CONCLUSION AND RELEVANCE: Surgical resection of the pituitary tumor in acromegaly patients leads to reduction in GH levels that is correlated with reduction in CES-D scores. The results suggest a role for GH in depression and provide a stronger foundation on which to build the hypothesis that GH impacts affect. The study also suggests that hormones should be factored into the matrix that entails the neuro-biological underpinnings of depressive disorders. Future work could explore the mechanisms involved, further brain and neuropeptide interactions, and, novel potential therapeutic targets in depressive and other mental health disorders.

Recovery Room Cortisol Predicts Long-Term Glucocorticoid Need After Transsphenoidal Surgery for Pituitary Tumors.

BACKGROUND: Accurate assessment of the need for glucocorticoid therapy is essential after transsphenoidal surgery (TSS) for pituitary tumors. Agreement on the best test to use in the early postoperative setting is lacking. OBJECTIVE: To examine recovery room (RR) cortisol as a predictor of long-term need for glucocorticoids. METHODS: We conducted a retrospective cohort study of 149 patients who underwent TSS for pituitary tumors between January 2007 and December 2014. Pathological tumor diagnoses were confirmed. Endocrinologists assessed the need for glucocorticoid supplementation within 6 to 8 wk after TSS. We extracted data on preoperative, RR, and day 1 to 3 post-TSS morning serum cortisol (MSC). We reported areas under the receiver operating characteristic curve (AUC) and diagnostic measures for different cortisol measures. We also conducted a logistic regression to identify the most predictive variables. RESULTS: Eighteen patients required glucocorticoid supplementation at follow-up. RR cortisol was the most accurate measurement in the early postoperative period (AUC [95% confidence interval (CI)], .92 [.85-.99]; P < .001), followed by day 1, 2, and 3 post-TSS MSC, respectively. A threshold RR cortisol of 744.0 nmol/L (26.97 µg/dL) had 90.9% sensitivity and 73.7% specificity for detecting patients in the hypocortisolism group, while 757.5 nmol/L (27.46 µg/dL) had 100% and 70.0%, respectively. The logistic regression identified RR cortisol as the sole significant predictor (odds ratio [CI], .36[.18-.71] for every 100 nmol/L increase; P = .0033). CONCLUSION: The RR cortisol is accurate in predicting long-term glucocorticoid supplementation and may be the best early postoperative measure. Future larger studies should validate these findings and derive optimal RR cortisol threshold values.

Endoscopic versus microscopic approach for surgical treatment of acromegaly.

Transsphenoidal surgery in the setting of acromegaly is quite challenging due to increased soft tissue mass, bony overgrowth, and bleeding. There is a debate on the endoscopic versus microscopic approach for these patients. The purpose of our study is to compare the outcomes for acromegaly after transsphenoidal surgery using both techniques. Retrospective review of 65 acromegalic patients who underwent transsphenoidal surgery in our department. Clinical remission was defined as resolution of typical acromegalic symptoms. Radiological resection was defined by volumetric criteria, and biochemical remission was defined as by the 2010 consensus on the criteria for remission of acromegaly. There was no significant difference in age, preoperative endocrine status, percent of macro adenomas, suprasellar, or infrasellar extension between both groups. Patients were assigned to both groups based on our existing referral pattern. Endoscopic approach was performed in 42 patients, while the microscopic approach was performed in 23 patients. No significant difference in remission rates was found between both groups (45.2 vs. 34.7 %, p = 0.40). The endoscopic group, however, had a significantly higher rate of gross total resections (61 vs. 42 %, p = 0.05). There was also a trend towards higher rates of gross total resections when cavernous sinus was present (48 vs. 14.2 %, p = 0.09). Postoperative diabetes insipidus occurred more in microscopic patients (34.7 vs. 17 %, p = 0.05), otherwise there was no significant difference in rates of complications. The median follow-up period was 56.6 months (range 6-156, mean 66.1). There is no significant difference in the rates of biochemical remission between the endoscopic and microscopic techniques. The endoscope technique, however, seems to be superior in achieving gross total resection especially with tumors invading the cavernous sinus.