Identification of potential molecular targets for the treatment of cluster 1 human pheochromocytoma and paraganglioma via comprehensive proteomic characterization.

BACKGROUND: Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors. New drug targets and proteins that would assist sensitive PPGL imagining could improve therapy and quality of life of patients with PPGL, namely those with recurrent or metastatic disease. Using a combined proteomic strategy, we looked for such clinically relevant targets among integral membrane proteins (IMPs) upregulated on the surface of tumor cells and non-membrane druggable enzymes in PPGL. METHODS: We conducted a detailed proteomic analysis of 22 well-characterized human PPGL samples and normal chromaffin tissue from adrenal medulla. A standard quantitative proteomic analysis of tumor lysate, which provides information largely on non-membrane proteins, was accompanied by specific membrane proteome-aimed methods, namely glycopeptide enrichment using lectin-affinity, glycopeptide capture by hydrazide chemistry, and enrichment of membrane-embedded hydrophobic transmembrane segments. RESULTS: The study identified 67 cell surface integral membrane proteins strongly upregulated in PPGL compared to control chromaffin tissue. We prioritized the proteins based on their already documented direct role in cancer cell growth or progression. Increased expression of the seven most promising drug targets (CD146, CD171, ANO1, CD39, ATP8A1, ACE and SLC7A1) were confirmed using specific antibodies. Our experimental strategy also provided expression data for soluble proteins. Among the druggable non-membrane enzymes upregulated in PPGL, we identified three potential drug targets (SHMT2, ARG2 and autotaxin) and verified their upregulated expression. CONCLUSIONS: Application of a combined proteomic strategy recently presented as "Pitchfork" enabled quantitative analysis of both, membrane and non-membrane proteome, and resulted in identification of 10 potential drug targets in human PPGL. Seven membrane proteins localized on the cell surface and three non-membrane druggable enzymes proteins were identified and verified as significantly upregulated in PPGL. All the proteins have been previously shown to be upregulated in several human cancers, and play direct role in cancer progression. Marked upregulation of these proteins along with their localization and established direct roles in tumor progression make these molecules promising candidates as drug targets or proteins for sensitive PPGL imaging.

Deep Membrane Proteome Profiling Reveals Overexpression of Prostate-Specific Membrane Antigen (PSMA) in High-Risk Human Paraganglioma and Pheochromocytoma, Suggesting New Theranostic Opportunity.

Pheochromocytomas and paragangliomas (PPGLs) are rare neuroendocrine tumors arising from chromaffin cells of adrenal medulla or sympathetic or parasympathetic paraganglia, respectively. To identify new therapeutic targets, we performed a detailed membrane-focused proteomic analysis of five human paraganglioma (PGL) samples. Using the Pitchfork strategy, which combines specific enrichments of glycopeptides, hydrophobic transmembrane segments, and non-glycosylated extra-membrane peptides, we identified over 1800 integral membrane proteins (IMPs). We found 45 "tumor enriched" proteins, i.e., proteins identified in all five PGLs but not found in control chromaffin tissue. Among them, 18 IMPs were predicted to be localized on the cell surface, a preferred drug targeting site, including prostate-specific membrane antigen (PSMA), a well-established target for nuclear imaging and therapy of advanced prostate cancer. Using specific antibodies, we verified PSMA expression in 22 well-characterized human PPGL samples. Compared to control chromaffin tissue, PSMA was markedly overexpressed in high-risk PPGLs belonging to the established Cluster 1, which is characterized by worse clinical outcomes, pseudohypoxia, multiplicity, recurrence, and metastasis, specifically including SDHB, VHL, and EPAS1 mutations. Using immunohistochemistry, we localized PSMA expression to tumor vasculature. Our study provides the first direct evidence of PSMA overexpression in PPGLs which could translate to therapeutic and diagnostic applications of anti-PSMA radio-conjugates in high-risk PPGLs.

Diagnostic Value of Unenhanced CT Attenuation and CT Histogram Analysis in Differential Diagnosis of Adrenal Tumors.

Background and Objectives: Our aim was to verify the optimal cut-off value for unenhanced CT attenuation and the percentage of negative voxels in the volume CT histogram analysis of adrenal masses. Materials and Methods: We retrospectively analyzed the CT data of patients who underwent an adrenalectomy in the period 2002-2019. In total, 413 adrenalectomies were performed. Out of these, 233 histologically verified masses (123 adenomas, 58 pheochromocytomas, 18 carcinomas, and 34 metastases) fulfilled the inclusion criteria and were selected for analysis. The mean unenhanced attenuation in Hounsfield units (HU) and the percentage of voxels with attenuation less than 0 HU (negative voxels) were measured in each mass. Results: The mean unenhanced attenuation with a cut-off value of 10 HU reached a sensitivity of 59.4% and a specificity of 99.1% for benign adenomas. The mean unenhanced attenuation with a cut-off value of 15 HU reached a sensitivity of 69.1% and a specificity of 98.2%. For the histogram analysis, a cut-off value of 10% of negative pixels reached a sensitivity of 82.9% and a specificity of 98.2%, whereas a cut-off value of 5% of negative pixels reached a sensitivity of 87.8% and a specificity of 75.5%. The percentage of negative voxels reached a slightly better area under the curve (0.919) than unenhanced attenuation (0.908). Conclusion: Mean unenhanced attenuation with a cut-off value of 10 HU represents a simple tool, and the most specific one, to distinguish adrenal adenomas from non-adenomas. CT histogram analysis with cut-off values of 10% of negative voxels improves sensitivity without any loss of specificity.

Interfraction variation in prostate cancer - analysis of 11726 cone-beam CT.

PURPOSE: To investigate the setup margins in prostate cancer treatment without using daily online repositioning methods. METHODS: We analysed the data from patients treated with curative-intend radiotherapy. Each patient underwent a series of pretreatment online localizations during daily setup using conebeam CT. The skin-prostate shifts and bone-prostate shifts were recorded in anteroposterior (AP), craniocaudal (CC), and laterolateral (LL)direction. The safety margins based on van Herk equation (2.5Σ+0.7σ) were calculated and the correlations between margins and various patient characteristics and prostate locations were investigated. RESULTS: A total of 307 patients were included, representing 11,726 localisations resulting in 70,356 shifts. The man skin-prostate setup inaccuracy was 0.8 ± 5.4mm in AP, 1.3 ± 4.8mm for CC, and 0.1 ± 5.6mm in LL direction. The man bone-prostate setup inaccuracy was 0.4 ± 3.3mm in AP, 0.1 ± 2.5mm for CC, and 0.1 ± 1.4mm in LL direction. According to van Herk equation, clinical target volume (CTV)-planning target volume (PTV) margins of 11.4, 10.6, and 11.8 mm (AP, CC, and LL, respectively) would be required for setup using skin markers and margins of 7.0, 4.7, and 2.1mm would be necessary for setup using bone structures. The average rectal area < 11cm(2) and volume of bladder > 300 cm(3) were associated with smaller CTV-PTV margins for setup using bone structures. The largest margins (15.8 mm in LL direction) were needed in patients with body mass index (BMI) > 35 using skin markers. CONCLUSIONS: Our results confirm that the commonly used CTV-PTV margins are inadequate.

Robotic assisted living donor nephrectomy - the first in the Czech Republic.

INTRODUCTION: A kidney transplant is the best method for treating terminal kidney failure. Long-term results of kidney transplants from living donors are significantly better than transplants from dead donors. Living kidney donors are healthy people who undergo a major operation in order to improve the health of another person. Therefore, major emphasis is on safety, low level of invasiveness and a desirable cosmetic effect of the donor nephrectomy. Since 2012, the Department of Urology at the University Hospital in Olomouc has performed 12 kidney harvestings from living donors. The kidney harvesting was conducted using various techniques. CASE REPORT: The first robotic assisted kidney harvesting in the Czech Republic was performed in June 2022. The donor was a 57-year-old man who donated his kidney to his 32-year-old daughter. The left kidney was evaluated as suitable for kidney harvesting. The operation took 174 min. The kidney's warm ischemia was 145 s. Based on the Clavien Dindo classification, no 2nd degree or high post-operative complications were recorded. The donor's pre-operative glomerular filtration was 1.63 mL/s. Six months post-operation, it went down to 1.19 mL/s. This represents a 27% decrease. The kidney recipient did not require early dialysis. Six months post-operation, the recipient's glomerular filtration was 2.03 mL/s. CONCLUSION: In the hands of experienced professionals and transplantation centres, robotic assisted donor nephrectomy is a feasible and safe option for this operation. It not only provides all the advantages of a laparoscopic operation but it also adds other technical improvements and minimizes intraoperative stress on the surgeon. Currently, the global trend is moving towards increasing the ratio of robotic assisted donor nephrectomies.

Bacillus Calmette-Guérin pneumonitis after intravesical instillation: Report of two cases and a review of the literature.

OBJECTIVE: Intravesical administration of bacillus Calmette-Guérin is standard adjuvant treatment of non-muscle invasive bladder cancer. In spite of the fact that this immunotherapy is locoregional, there are still risk of some complications. METHODS: We describe two cases of systemic BCG infection after intravesical administration of BCG vaccine in patients with early stage of bladder cancer. RESULTS: Both patients suffered from systemic BCG infection manifesting as BCG pneumonitis. After standard therapy with antituberculotic agents, both of them fully recovered. CONCLUSION: BCG infection can occur as a rare but potentially serious complication of this treatment procedure. Gravity of this side effect and its specific therapy require prompt and right diagnosis.

Iodinated Contrast Medium Affects Urine Cytology Assessment: A Prospective, Single-Blind Study and Its Impact on Urological Practice.

During endoscopic procedures for suspected urothelial tumors of the upper urinary tract, radiographic imaging using an iodinated contrast medium is often required. However, following ureteropyelography, we detected changes in cytology characteristics not correlating with real cytology findings in naive urine. The aim of our study was to assess cytology changes between naive and postcontrast urine according to The Paris System of cytology classification. Methods: We prospectively assessed urine samples from 89 patients (23 patients with histologically proven urothelial cancer and 66 healthy volunteers). The absence of malignancy was demonstrated by CT urography and/or ureteroscopy. The study was single blind (expert cytopathologist) and naïve Paris system for urine cytology assessment was used. Furthermore, additional cytological parameters were analyzed (e.g., specimen cellularity, degree of cytolysis, cytoplasm and nucleus color, chromatin and nucleo-cytoplasmic ratio). Results: Our study showed statistically significant differences when comparing naïve and postcontrast urine in healthy volunteers (only 51 % concordance, p = 0.001) versus malignant urine specimens (82 % concordance). The most important differences were in the shift from The Paris System category 2 (negative) to 1 (non-diagnostic) and from category 2 (negative) to 3 (atypia). Other significant changes were found in the assessment of specimen cellularity (p = 0.0003), degree of cytolysis (p = 0.001), cytoplasm color (p = 0.003), hyperchromasia (p = 0.001), course chromatin (p = 0.002), nucleo-cytoplasmatic ratio (p = 0.001) and nuclear borders' irregularity (p = 0.01). Conclusion: Our unique study found crucial changes in the cytological assessment of naive and postcontrast urine and we confirm that postcontrast urine is more often assessed as abnormal, suspect or non-diagnostic. Therefore, before urine collection for cytology, the clinician should avoid administration of iodinated contrast into the urinary tract.

Hypertension outcomes of adrenalectomy for unilateral primary aldosteronism.

PURPOSE: To evaluate laboratory and clinical results after unilateral adrenalectomy in patients with primary aldosteronism (PHA). METHODS: A cross-sectional analysis was performed using data from patients who underwent transperitoneal laparoscopic adrenalectomy for PHA, between January 2008 and December 2019. Surgical indications were based on adrenal venous sampling without ACTH stimulation. Analyses included patient demographics; preoperative clinical, pharmacological, laboratory, and radiological data; and postoperative results assessed after a median of 4 months. Antihypertensive drug use was quantified by estimating the daily defined dose (DDD) of antihypertensive medication, thus enabling standardized comparison of dosage between the drug classes. Statistical assessments included univariable and multivariable logistic regression analysis. RESULTS: This study enrolled 87 patients. The patients were taking 5.4 DDD of antihypertensive medication before surgery, and 3.0 DDD after surgery. Complete biochemical success of surgery was reached 67 patients (77%), 19 patients (22%) had partial biochemical success. Complete clinical success with normalization of blood pressure and withdrawal of all antihypertensive drugs was achieved in 19 patients (22%). 57 patients (65%) exhibited a reduction of DDD after surgery and/or improvement of blood pressure-partial clinical success. Thus, in 76 (87%) of all enrolled patients, surgery had an overall positive effect on hypertension control. Multivariable logistic regression showed that complete clinical success was independently associated with female gender and baseline sum of antihypertensive drugs DDD < 4. CONCLUSION: A majority of patients undergoing unilateral adrenalectomy for PHA achieved markedly improved hypertension control, despite almost halving their antihypertensive medication. Almost a quarter of patients were cured and able to cease using all antihypertensive drugs.

Germline SUCLG2 Variants in Patients With Pheochromocytoma and Paraganglioma.

BACKGROUND: Pheochromocytoma and paraganglioma (PPGL) are neuroendocrine tumors with frequent mutations in genes linked to the tricarboxylic acid cycle. However, no pathogenic variant has been found to date in succinyl-CoA ligase (SUCL), an enzyme that provides substrate for succinate dehydrogenase (SDH; mitochondrial complex II [CII]), a known tumor suppressor in PPGL. METHODS: A cohort of 352 patients with apparently sporadic PPGL underwent genetic testing using a panel of 54 genes developed at the National Institutes of Health, including the SUCLG2 subunit of SUCL. Gene deletion, succinate levels, and protein levels were assessed in tumors where possible. To confirm the possible mechanism, we used a progenitor cell line, hPheo1, derived from a human pheochromocytoma, and ablated and re-expressed SUCLG2. RESULTS: We describe 8 germline variants in the guanosine triphosphate-binding domain of SUCLG2 in 15 patients (15 of 352, 4.3%) with apparently sporadic PPGL. Analysis of SUCLG2-mutated tumors and SUCLG2-deficient hPheo1 cells revealed absence of SUCLG2 protein, decrease in the level of the SDHB subunit of SDH, and faulty assembly of the complex II, resulting in aberrant respiration and elevated succinate accumulation. CONCLUSIONS: Our study suggests SUCLG2 as a novel candidate gene in the genetic landscape of PPGL. Large-scale sequencing may uncover additional cases harboring SUCLG2 variants and provide more detailed information about their prevalence and penetrance.

Spleno-adrenal fusion mimicking an adrenal metastasis of a renal cell carcinoma: A case report and embryological background.

Foci of splenic tissue separated from the spleen can occur as a congenital anomaly. Isolated nodules of splenic tissue are called accessory spleens or spleniculli. However, nodules of splenic tissue can merge with other organs during embryonic development, in which case we speak of spleno-visceral fusions: most often, they merge with the tail of the pancreas (thus forming spleno-pancreatic fusion or an intrapancreatic accessory spleen), with the reproductive gland (i.e., spleno-gonadal fusion), or with the kidney (i.e., spleno-renal fusion). Our case report describes the fusion of heterotopic splenic tissue with the right adrenal gland, which was misinterpreted as a metastasis of a renal cell carcinoma. To the best of our knowledge, this is the first reported case of spleno-adrenal fusion. Spleno-visceral fusions usually represent asymptomatic conditions; their main clinical significance lies in the confusion they cause and its misinterpretation as tumors of other organs. We believe that the cause of retroperitoneal spleno-visceral fusions is the anomalous migration of splenic cells along the dorsal mesentery to the urogenital ridge, together with primitive germ cells, at the end of the fifth week and during the sixth week of embryonic age. This theory explains the possible origin of spleno-visceral fusions, their different frequency of occurrence, and the predominance of findings on the left side.

Dose escalation in prostate radiotherapy up to 82 Gy using simultaneous integrated boost: direct comparison of acute and late toxicity with 3D-CRT 74 Gy and IMRT 78 Gy.

PURPOSE: To compare acute and late toxicity after three-dimensional conformal radiotherapy to the prostate to 74 Gy (3D-CRT) with intensity-modulated radiotherapy to 78 Gy (IMRT 78) and IMRT using simultaneous integrated boost to 82 Gy (IMRT/SIB 82). PATIENTS AND METHODS: 94 patients treated with 3D-CRT to the prostate and base of seminal vesicles to 74 Gy represented the first group. The second group consisted of 138 patients subjected to IMRT covering the prostate and base of seminal vesicles to 78 Gy. The last group was treated with IMRT using SIB. The prescribed doses were 82 Gy and 73.8 Gy in 42 fractions to the prostate and seminal vesicles. Late toxicity was prospectively scored according to the RTOG/FC-LENT scale. RESULTS: Acute gastrointestinal toxicity >or= grade 2 occurred in 35.1% of patients treated with 3D-CRT, in 16% subjected to IMRT 78, and in 7.7% receiving IMRT/SIB 82. Acute genitourinary toxicity >or= grade 2 was observed in 26.6% (3D-CRT), 33% (IMRT 78), and 30.7% (IMRT/SIB 82). At 3 years, the estimated cumulative incidence of grade 3 late gastrointestinal toxicity was 14% for 3D-CRT, 5% for IMRT 78, and 2% for IMRT/SIB 82. The difference became significant (log rank p = 0.02). The estimated cumulative incidence of grade 3 late genitourinary toxicity was 9% (3D-CRT), 7% (IMRT 78), and 6% (IMRT/SIB 82) without statistical differences (log rank p = 0.32) CONCLUSION: SIB enables dose escalation up to 82 Gy with a lower rate of gastrointestinal toxicity grade 3 in comparison with 3D-CRT up to 74 Gy.

Audio-visual navigation reduces treatment time in deep-inspiration breath hold radiotherapy.

AIMS: The purpose of this study was to compare the treatment times for deep-inspiration breath hold with and without audio-visual (A-V) navigation. METHODS: We measured the real treatment time in 60 patients with breast cancer undergoing postoperative radiotherapy. Thirty consecutive patients were treated without deep-inspiration breath hold (DIBH) and another 30 patients using deep-inspiration breath hold (10 patients with DIBH only, 10 patients with DIBH using visual feedback and 10 patients with DIBH using visual feedback following breath training). The treatment time was relativized to number of fields and 100 monitor units (MU). The independent t-test was used to analyse differences between cohorts. RESULTS: The mean treatment time for patients without DIBH was 46.5 seconds per field and 90.9 seconds per 100 MU, for DIBH only 92.3 and 170.2 seconds, for DIBH with audio-visual navigation 68.1 and 133.8 seconds, and for DIBH with A-V feedback including breath training 66.1 and 132.5 seconds. The treatment times for patients treated using DIBH with visual navigation were significantly shorter in comparison with patients without visual feedback. We were not able to prove any significant benefit for breath training in terms of reducing the treatment time. CONCLUSION: Audio-visual navigation enables to significantly reduce the treatment time in comparison with DIBH without A-V feedback.

Prolonged treatment planning can increase real rectal dose in 3D brachytherapy for cervical cancer.

PURPOSE: The purpose of this study was to evaluate the influence of 3D brachytherapy planning time on the real dose distribution. MATERIAL AND METHODS: 10 patients with cervical cancer were evaluated using 2 computed tomography (CT) scans brachytherapy. The first scan was performed after the insertion of UVAG applicators, and the second was done after creating the treatment plan, just before the irradiation of first and third fraction. Both plans were compared in terms of changes of volumes and differences in the dose for high-risk organs using GEC-ESTRO Working Group parameters. RESULTS: The median planning time was 54 minutes (36-64 minutes). The absolute median change of volume for bladder, rectum, and sigmoid was 32.1 cm3 (1.6-108.6 cm3), 5.6 cm3 (0.4-61.8 cm3), and 8.4 cm3 (0.2-74.1 cm3), respectively. This difference led to an increased dose for bladder and sigmoid for D0.1cc by 46.7 cGy and 25.7 cGy, for D1cc by 59.2 cGy and 11.8 cGy, and for D2cc by 44.7 cGy and 10 cGy, respectively, per each fraction. Measured volume change in case of rectum led to a decreased dose per each fraction for D0.1cc with 7.1 cGy, for D1cc with 3.5 cGy, and for D2cc with 4.8 cGy. We observed that statistically significant dependency between the planning time and the dose was proved for rectum. The longer time for planning, the higher dose for rectum. The correlation coefficient for D0.1cc was 0.6715 (p = 0.0061), for D1cc was 0.6404 (p = 0.011), and for D2cc was 0.5891 (p = 0.0197). CONCLUSIONS: Extended treatment planning time for brachytherapy due to the changes in topography of small pelvis can lead to different dose in high-risk organs than previously planned. It seems that the most significant changes are related to rectum.

Influence of slice thickness on result of CT histogram analysis in indeterminate adrenal masses.

PURPOSE: The aim was to determine the optimal slice thickness of CT images and the optimal threshold of negative voxels for CT histogram analysis to distinguish adrenal adenomas from non-adenomas with a mean attenuation more than 10 Hounsfield units (HU). METHODS: Volume CT histogram analysis of 83 lipid-poor adenomas and 80 non-adenomas was performed retrospectively. The volume of interest was extracted from each adrenal lesion, and the mean attenuation, standard deviation (SD), and percentage of voxels with a negative CT value were recorded using reconstructions with different slice thicknesses (5 mm, 2.5 mm, 1.25 mm). The percentage of negative voxels was correlated with SD as a measure of image noise and with the reference splenic tissue values. The sensitivity, specificity, and positive predictive value (PPV) for the identification of adenomas were calculated using reconstructions with different slice thicknesses and three different thresholds of negative voxels (1%, 5%, 10%). RESULTS: The percentage of negative voxels increased with a thinner slice thickness and correlated with increasing CT image noise in adenomas, non-adenomas, and spleen. Using a threshold of 10% negative voxels and a slice thickness of 5 mm, we reached a sensitivity of 53.0%, specificity of 98.8% and the highest PPV, and thus we propose this combination for clinical use. Other combinations achieved a clearly lower specificity and PPV as a result of the increasing noise in CT images. CONCLUSION: The CT slice thickness significantly affects the result and diagnostic value of histogram analysis. Thin CT slice reconstructions are inappropriate for histogram analysis.

Characteristic CT features of pheochromocytomas - probability model calculation tool based on a multicentric study.

OBJECTIVES: The aim of the study was to evaluate the CT features of adrenal tumors in an effort to identify features specific to pheochromocytomas and second, to define a feasible probability calculation model. METHODS: This multicentric retrospective study included patients from the period 2003 to 2017 with an appropriate CT examination and a histological diagnosis of an adrenal adenoma, pheochromocytoma, adrenocortical carcinoma, or metastasis. In total, 346 patients were suitable for the CT image analysis, which included evaluation of the largest diameter, the shape of the lesion, the presence of central necrosis and its margins, and the presence of an enhancing peripheral rim ("ring sign"). RESULTS: Pheochromocytomas have a significantly more spherical shape (P<0.001), whereas an elliptical shape significantly reduces the probability of a pheochromocytoma (odds ratio = 0.015), as does another shape (odds ratio = 0.006). A "ring sign" is also more frequent in pheochromocytomas compared to other adrenal tumors (P=0.001, odds ratio = 6.49). A sharp necrosis also increases the probability of a pheochromocytoma more than unsharp necrosis (odds ratio 231.6 vs. 20.2). The probability calculation model created on the basis of the results confirms a high sensitivity and specificity (80% and 95%). CONCLUSION: This study confirms the value of anatomical features in the assessment of adrenal masses with the ability to significantly improve the identification of pheochromocytomas. Advanced assessment of the tumor shape was defined and a original comprehensive calculating tool of the pheochromocytoma probability was created on the basis of the results presented here and could be used in clinical routine.

Current diagnostic imaging of pheochromocytomas and implications for therapeutic strategy.

The topic of pheochromocytomas is becoming increasingly popular as a result of major advances in different medical fields, including laboratory diagnosis, genetics, therapy, and particularly in novel advances in imaging techniques. The present review article discusses current clinical, biochemical, genetic and histopathological aspects of the diagnosis of pheochromocytomas and planning of pre-surgical preparation and subsequent surgical treatment options. The main part of the paper is focused on the role of morphological imaging methods (primarily computed tomography and magnetic resonance imaging) and functional imaging (scintigraphy and positron emission tomography) in the diagnosis and staging of pheochromocytomas.

Targeting NAD+/PARP DNA Repair Pathway as a Novel Therapeutic Approach to SDHB-Mutated Cluster I Pheochromocytoma and Paraganglioma.

Purpose: Cluster I pheochromocytomas and paragangliomas (PCPGs) tend to develop malignant transformation, tumor recurrence, and multiplicity. Transcriptomic profiling suggests that cluster I PCPGs and other related tumors exhibit distinctive changes in the tricarboxylic acid (TCA) cycle, the hypoxia signaling pathway, mitochondrial electron transport chain, and methylation status, suggesting that therapeutic regimen might be optimized by targeting these signature molecular pathways.Experimental Design: In the present study, we investigated the molecular signatures in clinical specimens from cluster I PCPGs in comparison with cluster II PCPGs that are related to kinase signaling and often present as benign tumors.Results: We found that cluster I PCPGs develop a dependency to mitochondrial complex I, evidenced by the upregulation of complex I components and enhanced NADH dehydrogenation. Alteration in mitochondrial function resulted in strengthened NAD+ metabolism, here considered as a key mechanism of chemoresistance, particularly, of succinate dehydrogenase subunit B (SDHB)-mutated cluster I PCPGs via the PARP1/BER DNA repair pathway. Combining a PARP inhibitor with temozolomide, a conventional chemotherapeutic agent, not only improved cytotoxicity but also reduced metastatic lesions, with prolonged overall survival of mice with SDHB knockdown PCPG allograft.Conclusions: In summary, our findings provide novel insights into an effective strategy for targeting cluster I PCPGs, especially those with SDHB mutations. Clin Cancer Res; 24(14); 3423-32. ©2018 AACR.

Advanced Reconstruction of Vesicourethral Support (ARVUS) during Robot-assisted Radical Prostatectomy: One-year Functional Outcomes in a Two-group Randomised Controlled Trial.

BACKGROUND: The advent of robotics has facilitated new surgical techniques for radical prostatectomy. These allow adjustment of pelvic anatomical and functional relationships after removal of the prostate to ameliorate postprostatectomy incontinence (PPI) and reduce the time to complete continence. OBJECTIVES: To describe the results of a new surgical technique for reconstruction of vesicourethral anastomosis using the levator ani muscle for support during robot-assisted radical prostatectomy (RARP). DESIGN, SETTING, AND PARTICIPANTS: A prospective, randomised, single-blind study among 66 consecutive patients with localised prostate cancer (cT1-2N0M0) undergoing RARP from June to September 2014, 32 using the new technique and 34 using the standard posterior reconstruction according to Rocco. SURGICAL PROCEDURE: In the advanced reconstruction of vesicourethral support (ARVUS) intervention group, the fibres of the levator ani muscle, Denonvilliers fascia, retrotrigonal layer, and median dorsal raphe were used to form the dorsal support for the urethrovesical anastomosis. Suture of the arcus tendineus to the bladder neck served as the anterior fixation. MEASUREMENTS: We compared demographic data and preoperative and postoperative functional and oncologic results for the two groups. The primary endpoint was continence evaluated at different time points (24h, 2, 4, and 8 wk, and 6 and 12 mo). The secondary endpoints were perioperative and postoperative complications and erectile function. RESULTS AND LIMITATIONS: Using a continence definition of 0 pads/d, the continence rates for the ARVUS versus the control group were 21.9% versus 5.9% at 24h (p=0.079), 43.8% versus 11.8% at 2 wk (p=0.005), 62.5% versus 14.7% at 4 wk (p<0.001), 68.8% versus 20.6% at 8 wk (p<0.001), 75.0% versus 44.1% at 6 mo (p=0.013), and 86.66% versus 61.29% at 12 mo (p=0.04). International Index of Erectile Function questionnaire results at 6 and 12 mo after surgery showed similar potency rates for the control group (40.0% and 73.33%) and the ARVUS group (38.8% and 72.22%). There were four postoperative complications (2 in each group): three haematomas requiring transfusion and one lymphocele that needed drainage. No urinary retention, anastomosis leak, or perineal pain was observed. Limitations include the small sample size and the single-institution design. CONCLUSIONS: The ARVUS technique yielded better urinary continence results than standard posterior reconstruction, with no negative impact on erectile function, complication rate, or oncologic outcome. External validation is warranted before clear recommendations can be made. PATIENT SUMMARY: We showed that postprostatectomy incontinence can be assuaged using a new technique for vesicourethral anastomosis reconstruction during robot-assisted radical prostatectomy (RARP). This could significantly improve the quality of life of patients after RARP. More studies are needed to support our results.

Can renal ultrasonography and DMSA scintigraphy be used for the prediction of irreversible histological lesions of the upper pole in duplex system with ureteroceles or ectopic ureters?

AIM: To assess of the role of renal ultrasonography (US) and DMSA renal scintigraphy in the prediction of irreversible histological lesions of the upper pole in duplex system. METHODS: A prospective cohort study based on data collected between 2005 and 2012 at our institution. The cohort consisted of 23 patients with ureteroceles and 28 patients with ectopic ureters who underwent upper pole nephrectomy. Preoperative recordings from ultrasound and nuclear renal scans were compared with the histological findings. Histological irreversible lesions were defined as the presence of dysplasia and/or severe chronic interstitial nephritis (CIN) in ≥ 90% of the specimen. ROC (Receiver Operating Characteristic) curves were used to investigate thresholds in order to identify irreversible lesions using various differential functions. The histology was correlated with the results of imaging. RESULTS: Pathological findings were found in all histological samples. Histological lesions were irreversible in 20/23 patients (87.0%) with ureteroceles and in 14/28 patients (50.0%) with ectopic ureters. The model is able to predict irreversible lesions if an upper pole differential function is ≤ 3% in patients with ureteroceles, and ≤ 2% in the presence of ectopic ureters. Weak association between parenchymal thinning on ultrasonography and irreversible lesions was found in patients with ectopic ureters. CONCLUSION: DMSA renal scintigraphy provides a useful tool for the prediction of irreversible lesions in the upper pole. Low differential function (≤ 3% and ≤ 2%, respectively) indicates irreversible lesions, favoring heminephrectomy. Higher differential function indicates greater remaining biological potential of the parenchyma, favoring reconstruction of the upper pole.

Secondary hypertension and hirsutism as a clinical manifestation of tumor duplicity.

BACKGROUND: The differential diagnosis of the pathogenetic causes of hirsutism in combination with hypertension is a challenge for clinicians. METHODS AND RESULTS: This case report demonstrates a patient suffering from two hormonally active tumors - an adrenal adenoma with primary aldosteronism and a Leydig cell ovarian tumor with hyperandrogenism. The task of the authors was easier due to the perimenopausal age of the proband. Adrenal selective venous sampling was very helpful in the diagnosis of these active endocrine tumors. Both were resolved by a single laparoscopic surgery. CONCLUSION: The combination of the two described tumors is a unique clinical finding. The resolution using laparoscopy in a single procedure provided an elegant and efficient therapeutic approach.