Diagnostic evaluation for adrenal tumors - What does the urologist need to know about endocrine metabolic work up?

PURPOSE OF REVIEW: Adrenal lesions are commonly discovered on abdominal imaging studies, whereas some patients with adrenal tumors present with symptoms of homonal excess. They are categorized as either hormone active or inactive and either as benign or malignant. This review is focused on the endocrine work up in patients with adrenal tumors. Knowledge of the use and limitations of hormonal assessment is essential for propper interpretation of the obtained test results. This article reviews which diagnostics are necessary to identify adrenal masses requiring treatment. RECENT FINDINGS: Delayed hormonal assessment is not uncommon and associated with delayed treatment. The endocrine work up is guided by data from prospective and retrospective observational studies. Adrenal tumors include a wide spectrum of diseases and as a principle, most patients require biochemical testing to select the appropriate treatment. SUMMARY: The most important factor for the outcome in the management of adrenal masses is, beside the exclusion of malignancy, a structured evaluation of the patients endocrine status.

Treatment of adrenocortical carcinoma: oncological and endocrine outcomes.

PURPOSE OF REVIEW: Adrenocortical carcinoma (ACC) is a rare, aggressive disease with a paucity of data and great variability between published studies regarding its treatment. This review provides information on current clinical management and oncological and endocrine outcomes. RECENT FINDINGS: Complete surgical resection is the only potentially curative treatment for adrenocortical carcinoma (ACC). Adjuvant mitotane treatment is recommended in patients with favourable/intermediate prognosis. As part of the endocrine follow-up, steroid hormones and thyroid hormones may be decreased or increased and may need to be substituted or suppressed. Recurrences are common. If the disease-free interval is more than 12 months, surgery is a treatment if complete resection is feasible. In advanced/metastatic ACC patients, the prognosis is poor. Mitotane monotherapy is only appropriate for patients with low tumour burden and indolent disease. Patients with unfavourable prognosis should be treated with aggressive cytotoxic therapy. Patients requiring third-line treatment should be considered for clinical trials. Immunotherapy and targeted therapy are currently being investigated, but have so far yielded only unsatisfactory results. SUMMARY: There is scarce evidence for the treatment of ACC, which often complicates clinical decision-making. Patients who progress on EDP-M should be treated in clinical trials.

The prognostic impact of tumour NSD2 expression in advanced prostate cancer.

Purpose: To assess the prognostic significance of the nuclear receptor binding SET protein 2 (NSD2), a co-activator of the NFkB-pathway, on tumour progression in patients with advanced prostate cancer (PCa).Methods: We retrospectively assessed NSD2 expression in 53 patients with metastatic and castration-resistant PCa. Immunohistochemical staining for NSD2 was carried out on specimen obtained from palliative resection of the prostate. Univariable and multivariable analyses were performed to assess the association between NSD2 expression and PCa progression.Results: Of the 53 patients, 41 had castration-resistant PCa and 48 men had metastases at time of tissue acquisition. NSD2 expression was increased in tumour specimen from 42 patients (79.2%). In univariable Cox regression analyses, NSD2 expression was associated with PSA progression, progression on imaging and overall survival (p = 0.04, respectively). In multivariable analyses, NSD2 expression did not retain its association with these endpoints.Conclusions: NSD2 expression is abnormal in almost 80% of patients with advanced PCa. Expression levels of this epigenetic regulator are easily detected by immunohistochemistry while this biomarker exhibited prognostic value for PCa progression and death in univariable analysis. Further studies on NSD2 involvement in PCa proliferation, progression, metastasis and resistance mechanisms are needed.

Fibrin-Hyaluronic Acid Hydrogel (RegenoGel) with Fibroblast Growth Factor-18 for In Vitro 3D Culture of Human and Bovine Nucleus Pulposus Cells.

We investigated the effects of a fibrin-hyaluronic acid hydrogel (FBG-HA) and fibroblast growth factor 18 (FGF-18) for nucleus pulposus (NP) regeneration. Healthy bovine (n = 4) and human degenerated NP cells (n = 4) were cultured for 14 days in FBG-HA hydrogel with FGF-18 (∆51-mutant or wild-type) in the culture medium. Gene expression, DNA content, and glycosaminoglycan (GAG) synthesis were evaluated on day 7 and 14. Additionally, histology was performed. Human NP cells cultured in FBG-HA hydrogel showed an increase in collagen type II (COL2) and carbonic anhydrase XII (CA12) gene expression after 14 or 7 days of culture, respectively. GAG release into the conditioned medium increased over 14 days. Healthy bovine NP cells showed increased gene expression of ACAN from day 7 to day 14. Wild type FGF-18 up-regulated CA12 gene expression of human NP cells. Histology revealed an increase of proteoglycan deposition upon FGF-18 stimulation in bovine but not in human NP cells. The FBG-HA hydrogel had a positive modulatory effect on human degenerated NP cells. Under the tested conditions, no significant effect of FGF-18 was observed on cell proliferation or GAG synthesis in human NP cells.

The evolving role of percutaneous biopsy in renal masses.

PURPOSE OF REVIEW: To review the current literature concerning the role of biopsy for renal masses. RECENT FINDINGS: Improvements in biopsy techniques lead to a redefinition of the role of renal mass biopsy (RMB).Additionally, several studies highlighted the safety, high diagnostic accuracy, and very low rate of clinically relevant complications of RMB. As the knowledge about the nature of renal masses has expanded, and management options for small renal masses are increasing, the current indications for RMB and its role for the management of small renal masses are also expanding. SUMMARY: The future role of RMB will be influenced by the combination of pathological, molecular, and genetic information that will, heighten and improve our knowledge about these lesions and set the stage for risk-adapted personalized medicine.

Risk factors for acute kidney injury following TA-TAVI or minimally invasive aortic valve replacement: which procedure is less kidney damaging in elderly patients?

BACKGROUND: Acute kidney injury (AKI) represents a major complication following aortic valve replacement in elderly patients. The aim of this study was to determine possible risk factors for AKI and to find the ideal strategy, minimally invasive valve replacement (MIS-AVR) or transapical valve implantation (TA-TAVI), regarding the postoperative renal outcome. METHODS: A total of 133 patients (age ≥ 75 years, 67 male) with severe aortic stenosis were included over 2 years: 42% were treated with MIS-AVR, 58% underwent TA-TAVI procedure. AKI was considered as a postprocedural 1.5× increase in creatinine or an increase of > 0.3 mg/dL/48 hours. Group differences were tested with chi-square or t-test. AKI risk assumption was analyzed in multiple multivariate logistic regression models. RESULTS: EuroSCORE II-related risk assumption was 8.7 ± 6.9 for TA-TAVI and 4.5 ± 5.7 for MIS-AVR (p < 0.001). The overall 30-day survival rate was 93%. Fifty-eight patients developed a risk for AKI and 13 developed a manifest renal injury/failure. Logistic regression analysis revealed a higher AKI risk for TA-TAVI (odds ratio, OR = 2.58; 95% confidence interval, CI = 1.18, 5.63; p = 0.017). EuroSCORE II (OR = 0.98; 95% CI = 0.92, 1.04; p = 0.433); preoperative creatinine (OR = 1.78; 95% CI = 0.67, 4.77; p = 0.249) and estimated glomerular filtration rate (OR = 1.00; 95% CI = 0.97, 1.02; p = 0.655) had no impact on AKI. A regression model adjusting for the variables age, gender, body mass index (BMI), diabetes, and procedure type revealed a higher AKI rate for male gender (OR = 2.41; 95% CI = 1.13, 5.11; p = 0.022). Operation time and radio-contrast media volume had no influence on the AKI-occurrence. There was no correlation between AKI and early mortality. CONCLUSION: A higher risk for AKI after TA-TAVI should be considered in the therapy decision, especially in elderly male patients because MIS-AVR still yields excellent results.

The SMARCD Family of SWI/SNF Accessory Proteins Is Involved in the Transcriptional Regulation of Androgen Receptor-Driven Genes and Plays a Role in Various Essential Processes of Prostate Cancer.

Previous studies have demonstrated an involvement of chromatin-remodelling SWI/SNF complexes in the development of prostate cancer, suggesting both tumor suppressor and oncogenic activities. SMARCD1/BAF60A, SMARCD2/BAF60B, and SMARCD3/BAF60C are mutually exclusive accessory subunits that confer functional specificity and are components of all known SWI/SNF subtypes. To assess the role of SWI/SNF in prostate tumorigenesis, we studied the functions and functional relations of the SMARCD family members. Performing RNA-seq in LnCAP cells grown in the presence or absence of dihydrotestosterone, we found that the SMARCD proteins are involved in the regulation of numerous hormone-dependent AR-driven genes. Moreover, we demonstrated that all SMARCD proteins can regulate AR-downstream targets in androgen-depleted cells, suggesting an involvement in the progression to castration-resistance. However, our approach also revealed a regulatory role for SMARCD proteins through antagonization of AR-signalling. We further demonstrated that the SMARCD proteins are involved in several important cellular processes such as the maintenance of cellular morphology and cytokinesis. Taken together, our findings suggest that the SMARCD proteins play an important, yet paradoxical, role in prostate carcinogenesis. Our approach also unmasked the complex interplay of paralogue SWI/SNF proteins that must be considered for the development of safe and efficient therapies targeting SWI/SNF.

Vesical Imaging Reporting and Data System (VI-RADS): Are the individual MRI sequences equivalent in diagnostic performance of high grade NMIBC and MIBC?

PURPOSE: To investigate the diagnostic performance of the overall Vesical Imaging Reporting and Data System (VI-RADS) score and its individual magnetic resonance imaging (MRI) parameters in assessing grade and muscle invasiveness of bladder cancer (BC). METHODS: This IRB-approved retrospective, single-center, cross-sectional study included patients with BC wo underwent 3 Tesla preoperative multiparametric (mp)-MRI including T2-weighted (T2w), diffusion weighted imaging (DWI) and dynamic contrast enhanced (DCE) sequences. An independent evaluation according to VI-RADS was performed by two radiologists in separate sessions, blinded to histological findings. RESULTS: The mean age of 59 included patients was 68.2 (±13.6 standard deviation) years. Among bladder cancer patients, 26 (51%) were identified as high grade and 14 (27.5%) as muscle invasive urothelial carcinomas in histological sections. The area under the curve (AUC) for the overall VI-RADS score to predict muscle invasion was 0.986 (R1) and 0.992 (R2). The AUC to diagnose high grade bladder cancer was 0.908 (R1) and 0.905 (R2). There was no significance difference between the AUC of single parameters (T2w, DWI and DCE) compared to the total VI-RADS score (P > 0.05, respectively). Upon multivariate logistic regression, only the T2w VI-RADS score contributed independently to the diagnosis of high grade and muscle invasive bladder cancer (P = 0.001 (R1) and P = 0.0022 (R2) for high grade cancer; P = 0.0007 (R1) and P = 0.0019 (R2) for muscle invasiveness). CONCLUSION: VI-RADS provides high diagnostic accuracy to diagnose high grade and muscle invasive BC. Our results suggest, that mp-MRI parameters provide overlapping information and for sake of clinical simplicity, a biparametric, contrast free image acquisition may be approached without sacrificing diagnostic accuracy.

A Microdosing Study with 99mTc-PHC-102 for the SPECT/CT Imaging of Primary and Metastatic Lesions in Renal Cell Carcinoma Patients.

99mTc-PHC-102 is a 99mTc-labeled derivative of acetazolamide, a high-affinity small organic ligand of carbonic anhydrase IX (CAIX). 99mTc-PHC-102 has previously shown favorable in vivo biodistribution properties in mouse models of CAIX-positive clear cell renal cell carcinoma (ccRCC) and colorectal cancer. In this study, we aimed to explore the targeting performance of 99mTc-PHC-102 in SPECT in patients with renal cell carcinoma while also assessing the safety and tolerability of the radiotracer. Methods: We studied 5 patients with localized or metastatic ccRCC in a microdosing regimen, after the administration of a 50-µg total of CAIX ligand and 600-800 MBq of 99mTc-PHC-102. Tissue distribution and residence time in normal organs and tumors were analyzed by serial SPECT/CT scans at 3 time points (30 min, 2 h, and 6 h) after intravenous administration. Results: In the 5 patients studied, 99mTc-PHC-102 was well tolerated and no study drug-related adverse events were recorded. In the stomach, kidneys, and gallbladder, the radiotracer showed a rapid initial uptake, which cleared over time. Localization of the study drug in primary tumors of 5 patients was observed, with favorable tumor-to-background ratios. 99mTc-PHC-102 SPECT/CT allowed the identification of 4 previously unknown lung and lymph node metastases in 2 patients. Conclusion:99mTc-PHC-102 is a promising SPECT tracer for the imaging of patients with ccRCC. This tracer has the potential to identify primary and metastatic lesions in different anatomic locations. 99mTc-PHC-102 might also serve as a companion diagnostic agent for future CAIX-targeting therapeutics.

Histomorphological analysis of false positive PI-RADS 4 and 5 lesions.

INTRODUCTION: Multiparametric magnetic resonance imaging (mpMRI)/ultrasound fusion-guided biopsy, in short "targeted biopsy (TB)", is becoming more attractive as it improves the detection of clinically significant prostate cancer (CaP). The accuracy of fusion-guided biopsies is limited due to false positive radiological findings as well as to histological evidence for cancer in radiologically inconspicuous regions of the prostate. We aimed to analyze histomorphological findings on mpMRI lesions highly suspicious for CaP classified as PI-RADS 4 or PI-RADS 5 (Prostate Imaging - Recording and Data System) but cancer-negative in the biopsy of this region of interest (ROI), and to compare them with findings in radiologically inconspicuous regions. MATERIALS AND METHODS: We re-evaluated prostate biopsies from 57 patients who underwent TB in combination with systematic standard biopsy (SB) from June 2017 to July 2018 at the University Hospital Schleswig Holstein Campus Luebeck. Out of 143 ROIs, 34 PI-RADS 4/5 cancer-negative lesions were identified and subjected to comprehensive histomorphological reevaluation. Contralateral cancer-negative SBs were used as control. Chi-square test was used for statistical analysis. RESULTS: The frequency of histomorphological alterations including stromal, glandular, vascular, and inflammatory alterations were 97% and 79.2% in prostatic tissues from cancer-negative TBs and SBs, respectively. Stromal, glandular, and inflammatory alterations were present in the majority of biopsies from both TBs and SBs. Statistical analysis revealed no significant difference between TBs and SBs with regard to stromal, glandular, and inflammatory alterations. However, vascular abnormalities were exclusively detected in TBs (18.2%). CONCLUSION: The frequency of histomorphological alterations is slightly higher in prostate tissues from TBs compared to SB. Only vascular alterations seem to be distinct for TBs. However, it has to be assumed that additional factors influence the false-negative rate of mpMRI/ultrasound fusion-guided TB.

Prevalence and Prognostic Value of the Polymorphic Variant 1245A>C of HSD3B1 in Castration-resistant Prostate Cancer.

INTRODUCTION: The purpose of this study was to investigate the prevalence and prognostic value of the polymorphic variant (1245A>C), a single nucleotide polymorphism (SNP) of the HSD3B1 gene, in the tumors of patients with castration-resistant prostate cancer (CRPC). MATERIALS AND METHODS: We retrospectively evaluated 44 patients with CRPC who underwent palliative transurethral resection of the prostate. Genomic DNA was extracted from formalin-fixed and paraffin-embedded material, and 1245A>C SNP of the HSD3B1 gene was analyzed via Sanger sequencing. Cox regression analysis was used to assess the prognostic value of the respective SNP with time to progression as well as cancer-specific and overall survival in the subgroup of patients receiving second systemic treatment. RESULTS: The SNP was present in 20 patients (51.2%) who received second line systemic treatment additionally to androgen deprivation, of which 16 (80%) patients were heterozygous and 4 (20%) were homozygous. Correlation analysis revealed no association of the SNP with any clinical characteristics at initiation of second-line systemic treatment. Moreover, the presence of the variant (1245A>C) of HSD3B1 was not associated with any survival endpoint. CONCLUSIONS: The variant allele 1245C of the HSD3B1 gene is present in approximately one-half of patients with CRPC; however, it is not associated with oncologic outcomes. These findings, however, need to be interpreted with caution as the sample size is small. Further research on biomarkers is needed to help tailor clinical decision making in prostate cancer, especially in the increasingly complex therapeutic landscape of CRPC.