Curcumin as Treatment for Bladder Cancer : A Preclinical Study of Cyclodextrin-Curcumin Complex and BCG as Intravesical Treatment in an Orthotopic Bladder Cancer Rat Model

Objective. To evaluate the antitumor effect of cyclodextrin-curcumin complex (CDC) on human and rat urothelial carcinoma cells in vitro and to evaluate the effect of intravesical instillations of CDC, BCG, and the combination in vivo in the AY-F344 orthotopic bladder cancer rat model. Curcumin has anticarcinogenic activity on urothelial carcinoma and is therefore under investigation for the treatment of non-muscle invasive bladder cancer. Curcumin and BCG share immunomodulating pathways against urothelial carcinoma. Methods. Curcumin was complexed with cyclodextrin to improve solubility. Four human urothelial carcinoma cell lines and the AY-27 rat cell line were exposed to various concentrations of CDC in vitro. For the in vivo experiment, the AY-27 orthotopic bladder cancer F344 rat model was used. Rats were treated with consecutive intravesical instillations of CDC, BCG, the combination of CDC+BCG, or NaCl as control. Results. CDC showed a dose-dependent antiproliferative effect on all human urothelial carcinoma cell lines tested and the rat AY-27 urothelial carcinoma cell line. Moreover, intravesical treatment with CDC and CDC+BCG results in a lower percentage of tumors (60% and 68%, respectively) compared to BCG (75%) or control (85%). This difference with placebo was not statistically significant (p=0.078 and 0.199, respectively). However, tumors present in the placebo and BCG-treated rats were generally of higher stage. Conclusions. Cyclodextrin-curcumin complex showed an antiproliferative effect on human and rat urothelial carcinoma cell lines in vitro. In the aggressive orthotopic bladder cancer rat model, we observed a promising effect of CDC treatment and CDC in combination with BCG.Peer reviewe

Bilateral testicular tumors resulting in recurrent Cushing's syndrome after bilateral adrenalectomy

Contains fulltext : 170123.pdf (publisher's version ) (Closed access)Context: Recurrence of hypercortisolism in patients after bilateral adrenalectomy for Cushing disease is extremely rare. Patient: We present a 27-year-old man who previously underwent bilateral adrenalectomy for Cushing disease with complete clinical resolution. Cushingoid features recurred 12 years later, with bilateral testicular enlargement. Hormonal tests confirmed adrenocorticotropic hormone (ACTH)-dependent Cushing disease. Surgical resection of the testicular tumors led to clinical and biochemical remission. Design and Results: Gene expression analysis of the tumor tissue by quantitative polymerase chain reaction showed high expression of all key steroidogenic enzymes. Adrenocortical-specific genes were 5.1 x 105 (CYP11B1), 1.8 x 102 (CYP11B2), and 6.3 x 104 (MC2R) times higher than nonsteroidogenic fibroblast control. This correlated with urine steroid metabolome profiling showing 2 fivefold increases in the excretion of the metabolites of 11-deoxycortisol, 21-deoxycortisol, and total glucocorticoids. Leydig-specific genes were 4.3 x 101 (LHCGR) and 9.3 x 100 (HSD17B3) times higher than control, and urinary steroid profiling showed twofold increased excretion of the major androgen metabolites androsterone and etiocholanolone. These distinctly increased steroid metabolites were suppressed by dexamethasone but unresponsive to human chorionic gonadotropin stimulation, supporting the role of ACTH, but not luteinizing hormone, in regulating tumor-specific steroid excess. Conclusion: We report bilateral testicular tumors occurring in a patient with recurrent Cushing disease 12 years after bilateral adrenalectomy. Using mRNA expression analysis and steroid metabolome profiling, the tumors demonstrated both adrenocortical and gonadal steroidogenic properties, similar to testicular adrenal rest tumors found in patients with congenital adrenal hyperplasia, suggesting the presence of pluripotent cells even in patients without congenital adrenal hyperplasia

Evaluation of tongue squamous cell carcinoma resection margins using ex-vivo MR

Contains fulltext : 174271.pdf (publisher's version ) (Open Access)PURPOSE: Purpose of this feasibility study was (1) to evaluate whether application of ex-vivo 7T MR of the resected tongue specimen containing squamous cell carcinoma may provide information on the resection margin status and (2) to evaluate the research and developmental issues that have to be solved for this technique to have the beneficial impact on clinical outcome that we expect: better oncologic and functional outcomes, better quality of life, and lower costs. METHODS: We performed a non-blinded validation of ex-vivo 7T MR to detect the tongue squamous cell carcinoma and resection margin in 10 fresh tongue specimens using histopathology as gold standard. RESULTS: In six of seven specimens with a histopathologically determined invasion depth of the tumor of [Formula: see text] mm, the tumor could be recognized on MR, with a resection margin within a 2 mm range as compared to histopathology. In three specimens with an invasion depth of [Formula: see text] mm, the tumor was not visible on MR. Technical limitations mainly included scan time, image resolution, and the fact that we used a less available small-bore 7T MR machine. CONCLUSION: Ex-vivo 7T probably will have a low negative predictive value but a high positive predictive value, meaning that in tumors thicker than a few millimeters we expect to be able to predict whether the resection margin is too small. A randomized controlled trial needs to be performed to show our hypothesis: better oncologic and functional outcomes, better quality of life, and lower costs

Head-to-head Comparison of Transrectal Ultrasound-guided Prostate Biopsy Versus Multiparametric Prostate Resonance Imaging with Subsequent Magnetic Resonance-guided Biopsy in Biopsy-naive Men with Elevated Prostate-specific Antigen: A Large Prospective Multicenter Clinical Study

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Risk of urothelial bladder cancer in Lynch syndrome is increased, in particular among MSH2 mutation carriers

Contains fulltext : 89346.pdf (publisher's version ) (Open Access)BACKGROUND: Colorectal, endometrial and upper urinary tract tumours are characteristic for Lynch syndrome (hereditary non-polyposis colon carcinoma, HNPCC). The aim of the present study was to establish whether carriers of mutations in mismatch repair genes MLH1, MSH2 or MSH6 are at increased risk of urinary bladder cancer. METHODS: Carriers and first degree relatives of 95 families with a germline mutation in the MLH1 (n=26), MSH2 (n=43), or MSH6 (n=26) gene were systematically questioned about the occurrence of carcinoma. The cumulative risk of cancer occurring before the age of 70 years (CR70) was compared to the CR70 of the general Dutch population. Microsatellite instability (MSI) testing and/or immunohistochemistry (IHC) for mismatch repair proteins was performed on bladder tumour tissue. RESULTS: Bladder cancer was diagnosed in 21 patients (90% men) from 19 Lynch syndrome families (2 MLH1, 15 MSH2, and 4 MSH6). CR70 for bladder cancer was 7.5% (95% CI 3.1% to 11.9%) for men and 1.0% (95% CI 0% to 2.4%) for women, resulting in relative risks for mutation carriers and first degree relatives of 4.2 (95% CI 2.2 to 7.2) for men and 2.2 (95% CI 0.3 to 8.0) for women. Men carrying an MSH2 mutation and their first degree relatives were at highest risks: CR70 for bladder and upper urinary tract cancer being 12.3% (95% CI 4.3% to 20.3%) and 5.9% (95% CI 0.7% to 11.1%). Bladder cancer tissue was MSI positive in 6/7 tumours and loss of IHC staining was found in 14/17 tumours, indicating Lynch syndrome aetiology. CONCLUSION: Patients with Lynch syndrome carrying an MSH2 mutation are at increased risk of urinary tract cancer including bladder cancer. In these cases surveillance should be considered.01 juli 201

Guideline on urothelial carcinoma of the bladder

Urothelial carcinoma of the bladder is diagnosed predominantly in people over 60 years of age. The most common symptom is haematuria. Smoking is an important risk factor (relative risk 2.5 to 3). Cystoscopy is performed whenever bladder carcinoma is suspected. The recurrence rate of a non-muscle invasive urothelial carcinoma is high (31-78% within 5 years). A single intravesical instillation with a chemotherapeutic agent within 24 hours of transurethral resection (TUR) reduces the risk of recurrence. Carcinoma in situ (CIS) should be treated as high-grade urothelial carcinoma. Standard treatment for patients with non-metastasized muscle-invasive urothelial carcinoma is cystectomy in combination with extensive lymph node dissection. There are several possibilities for urinary diversion following cystectomy, none of which are any better than the others. Bladder-sparing brachytherapy may be used in patients with solitary T1 - T2 urothelial carcinoma &lt; 5 cm. Neoadjuvant cisplatin-containing chemotherapy prior to cystectomy in muscle-invasive carcinoma only slightly improves survival. Cisplatin-containing combination chemotherapy is the standard treatment for metastasized urothelial carcinoma.</p