Genomic analysis of primary epithelial neoplasms of the seminal vesicle identifies a subset of mucinous cystic tumours driven by KRAS mutations.

BACKGROUND: Carcinomas of the seminal vesicle are exceedingly rare, with a limited number of cases described in the literature. Reported cases span a relatively wide morphological spectrum, and their genomic features remain unexplored. DESIGN: In this study, we interrogated five primary epithelial neoplasms of the seminal vesicle using a targeted DNA sequencing platform (OncoPanel, 447 genes). RESULTS: The tumours included one adenocarcinoma with intestinal phenotype presenting after external beam radiation (for prostatic adenocarcinoma), one carcinoma with Müllerian-type clear cell phenotype, two mucinous tumours resembling low-grade mucinous neoplasms of the appendix (LAMN) and one mucinous cystadenoma. The post-radiation mucinous adenocarcinoma had genomic findings consistent with bi-allelic inactivation of TP53, as well as multiple copy-number changes with regional and chromosomal arm-level copy-number losses. The Müllerian-type clear cell carcinoma exhibited a complex copy-number profile with numerous regional and arm-level copy-number changes, as well as focal amplification events, including copy-number gain of 8q and amplification of a region within 20q13. Both low-grade mucinous tumours resembling LAMN harboured hot-spot gain-of-function KRAS variants (p.G12V and p.G13D) as the only genomic alteration. No genomic alterations were detected inthe lesion diagnosed as mucinous cystadenoma. CONCLUSION: Our results suggest that primary low-grade mucinous neoplasms of the seminal vesicle may represent a distinct entity equivalent to appendiceal counterparts, driven by gain-of-function variants of RAS GTPases. The remaining tumours showed genomic features that closely resembled those of neoplasms with comparable phenotypes and/or biological characteristics arising in other sites, suggesting that they could be managed similarly, with special considerations related to their anatomical location.

Intraoperative low tidal volume ventilation and the risk of ICD-10 coded delirium and the use for antipsychotic medications.

BACKGROUND: Low tidal volume (VT) ventilation and its associated increase in arterial carbon dioxide (PaCO2) may affect postoperative neurologic function. We aimed to test the hypothesis that intraoperative low VT ventilation affect the incidence of postoperative ICD-10 coded delirium and/or the need for antipsychotic medications. METHODS: This is a post-hoc analysis of a large randomized controlled trial evaluating low vs. conventional VT ventilation during major non-cardiothoracic, non-intracranial surgery. The primary outcome was the incidence of ICD-10 delirium and/or the use of antipsychotic medications during hospital stay, and the absolute difference with its 95% confidence interval (CI) was calculated. RESULTS: We studied 1206 patients (median age of 64 [55-72] years, 59.0% males, median ARISCAT of 26 [19-37], and 47.6% of ASA 3). ICD-10 coded delirium and /or antipsychotic medication use was diagnosed in 11.2% with similar incidence between low and conventional VT ventilation (11.1% vs. 11.3%; absolute difference, -0.24 [95%CI, -3.82 to 3.32]; p = 0.894). There was no interaction between allocation group and type of surgery. CONCLUSION: In adult patients undergoing major surgery, low VT ventilation was not associated with increased risk of ICD-10 delirium and/or the use of antipsychotic medications during hospital stay. TRIAL REGISTRATION: ANZCTR Identifier: ACTRN12614000790640 .

The effect of selection and referral biases for the treatment of localised prostate cancer with surgery or radiation.

BACKGROUND: Consultation with radiation oncologists, in addition to urologists, is advocated for patients diagnosed with prostate cancer. Treatment patterns for patients receiving consultation from radiation oncologists in addition to urologists have not previously been described. METHODS: We conducted a matched cohort study of men with newly diagnosed non-metastatic prostate cancer in Ontario, Canada. Patients who underwent consultation with a radiation oncologist prior to treatment were matched 1:1 with patients managed by a urologist alone based on tumour and patient characteristics. We examined rates of active treatment (surgery or radiotherapy) within one year following diagnosis. RESULTS: Among 5708 matched pairs (11,416 patients), those who received radiation oncology consultation were more likely to undergo active treatments whether they had intermediate or high-risk disease (88.6% vs. 65.9%, p < 0.0001; adjusted odds ratio 4.0, 95% CI: 3.6-4.4) or low-risk disease (56.1% vs. 13.3%, p < 0.0001; adjusted odds ratio 8.4, 95% CI: 6.7-10.6). This effect persisted after considering age, comorbidity, tumour volume and year of diagnosis. CONCLUSIONS: Patients newly diagnosed with prostate cancer who receive radiation oncology consultation are associated with a higher rate of active treatment, compared to patients managed by urologists only. Selection and referral biases, and unmeasured confounding such as patient preference must be considered as important factors attributing this association.

Establishment of primary patient-derived xenografts of palliative TURP specimens to study castrate-resistant prostate cancer.

BACKGROUND: Fresh patient specimens of castrate-resistant prostate cancer (CRPC) are invaluable for studying tumor heterogeneity and responses to current treatments. They can be used for primary patient-derived xenografts (PDXs) or serially transplantable PDXs, but only a small proportion of samples grow successfully. To improve the efficiency and quality of PDXs, we investigated the factors that determine the initial engraftment of patient tissues derived from TURP specimens. METHODS: Fresh tissue was collected from castrate patients who required a TURP for urinary symptoms. Tissue was grafted under the renal capsule of immune-compromised mice for up to 14 weeks. The abundance of cancer in ungrafted and grafted specimens was compared using histopathology. Mice were castrated or implanted with testosterone pellets to determine the androgen-responsiveness of CRPC PDXs from TURP tissue. RESULTS: Primary PDXs were successfully established from 7 of 10 patients that underwent grafting. Of the 112 grafts generated from these 10 patients, 21% contained cancer at harvest. Grafts were most successful when the original patient specimens contained high amounts of viable cancer, defined as samples with (i) at least 50% cancer cells, (ii) no physical damage, and (iii) detectable Ki67 expression. PDX grafts survived in castrated hosts and proliferated in response to testosterone, confirming that they were castrate resistant but androgen-responsive. CONCLUSIONS: Primary PDXs of CRPC can be established from TURP specimens with modest success. The take rate can be increased if the original tissues contain sufficient numbers of actively proliferating cancer cells. Selecting specimens with abundant viable cancer will maximize the rate of engraftment and increase the efficiency of establishing PDXs that can be serially transplanted.

Patients with medical risk factors for chronic kidney disease are at increased risk of renal impairment despite the use of nephron-sparing surgery.

OBJECTIVE: To determine whether patients with normal preoperative renal function, but who possess medical risk factors for chronic kidney disease (CKD), experience poorer renal function after partial nephrectomy (PN) for renal cell carcinoma (RCC) compared with those without risk factors. PATIENTS AND METHODS: The effects of age, hypertension (HTN) and diabetes mellitus (DM) on estimated glomerular filtration rate (eGFR) were investigated in 488 consecutive operations for RCC performed during 2005-2012 at six Australian tertiary referral centres; 156 patients underwent PN and 332 patients underwent radical nephrectomy (RN). We used chi-squared test and binary logistic regression to analyse new-onset CKD, and multiple linear regression to investigate determinants of postoperative eGFR. RESULTS: The development of new-onset eGFR of <60 mL/min was related to undergoing RN rather than PN (risk ratio [RR] 2.7, P < 0.001), older age (RR 1.6, P < 0.001) and the presence of HTN (RR 1.6, P = 0.001) and DM (RR 1.5, P = 0.003). Patients undergoing PN were still at risk of new-onset CKD if medical risk factors were present. Whereas 7% of patients undergoing PN without CKD risk factors developed new-onset eGFR <60 mL/min, this figure increased to 24%, 30% and 42% for older age, HTN and DM, respectively. Patients with eGFR of 45-59 mL/min were more likely to progress to more severe forms of CKD and end-stage renal failure than those with eGFR of ≥60 mL/min. On multivariate analysis, RN, rather than PN, age and the presence of DM (but not HTN), predicted both the development of new-onset eGFR of <60 mL/min (R(2) = 0.37) and new-onset eGFR <45 mL/min (R(2) = 0.42). CONCLUSION: Patients with medical risk factors for CKD are at increased risk of progressive renal impairment despite the use of PN. Where feasible, nephron-sparing surgery should be considered for these patients.

Acute management of priapism in men.

UNLABELLED: What's known on the subject? and What does the study add? Priapism is a rare event. However, various medications and medical conditions may increase the risk. Priapism can be ischaemic, non-ischaemic or stuttering. It is paramount to distinguish the type of priapism, as misdiagnosis may lead to significant morbidity. Ischaemic priapism represents a compartment syndrome of the penis and is therefore a medical emergency. A delay in management may significantly affect future erectile function. Stuttering priapism represents recurrent subacute episodes of ischaemic priapism, which may lead to erectile dysfunction. Thus episodes must be minimised. Non-ischaemic priapism is not a medical emergency. However, misdiagnosis and injection with sympathomimetic agents can result in system absorption and toxicity. This review article provides a summary of the evaluation and management of priapism. Furthermore, a step by step flow chart is provided to guide the clinician through the assessment and management of this complex issue. OBJECTIVES: To review the literature regarding ischaemic, non-ischaemic and stuttering priapism. To provide management recommendations. PATIENTS AND METHODS: A Medline search was carried out to identify all relevant papers with management guidelines for priapism. RESULTS: Ischaemic priapism represents a compartment syndrome of the penis and urgent intervention is required to decrease the risk of erectile dysfunction. Non-ischaemic priapism is not a medical emergency; however, it can result in erectile dysfunction. The treatment objective for stuttering priapism is to reduce future episodes with systemic treatments, whilst treating each ischaemic episode as an emergency. CONCLUSIONS: Priapism is a complex condition that requires expert care to prevent complications and irreversible erectile dysfunction.

Novel extraction technique to remove a penile constriction device.

INTRODUCTION: Penile strangulation can be a challenging clinical situation and usually requires prompt treatment. The clinician should be aware of the various techniques to remove such devices. AIM: The aim of this article was to describe a new noninvasive technique, the "pseudo-pulley" method, to remove a penile constriction device. METHODS: During an episode of medication-induced hypersexuality, a 63-year-old man presented to the emergency department with a cast iron locking nut of a vehicle towbar lodged at the base of the patient's penis. RESULTS: The utilization of the "pseudo-pulley" method to remove the constriction device negated the need for more invasive measures. We outline a step-by-step description on this new technique. The patient's recovery was complete and uneventful. CONCLUSION: The current case report describes a noninvasive technique for removing a penile constriction device that does not rely on specialized equipment and industrial drills that can cause iatrogenic injury.

Dose-escalated radiotherapy to 82 Gy for prostate cancer following insertion of a peri-rectal hydrogel spacer: 3-year outcomes from a phase II trial.

BACKGROUND: Dose-escalation to above 80 Gy during external beam radiotherapy for localised prostate cancer leads to improved oncological outcomes but also substantially increased rectal toxicity. The aim of this study was to demonstrate the safety and efficacy of escalating the dose to 82 Gy following insertion of a peri-rectal hydrogel spacer (HS) prior to radiotherapy. METHODS: This was a single arm, open-label, prospective study of men with localised prostate cancer who were prescribed a course of intensity modulated radiotherapy escalated to 82 Gy in 2 Gy fractions following insertion of the SpaceOAR™ HS (Boston Scientific, Marlborough, MA). Patients were prescribed a standard course of 78 Gy in 2 Gy fractions where rectal dose constraints could not be met for the 82 Gy plan. The co-primary endpoints were the rate of grade 3 gastrointestinal (GI) and genitourinary (GU) adverse events (CTCAE, v4), and patient-reported quality of life (QoL) (EORTC QLQ-C30 and PR25 modules), up to 37.5 months post-treatment. RESULTS: Seventy patients received treatment on the study, with 64 (91.4%) receiving an 82 Gy treatment course. The median follow-up time post-treatment was 37.4 months. The rate of radiotherapy-related grade 3 GI and GU adverse events was 0% and 2.9%, respectively. There were 2 (2.9%) grade 3 adverse events related to insertion of the HS. Only small and transient declines in QoL were observed; there was no clinically or statistically significant decline in QoL beyond 13.5 months and up to 37.5 months post-treatment, compared to baseline. No late RTOG-defined grade ≥ 2 GI toxicity was observed, with no GI toxicity observed in any patient at 37.5 months post-treatment. Nine (12.9%) patients met criteria for biochemical failure within the follow-up period. CONCLUSIONS: Dose-escalation to 82 Gy, facilitated by use of a hydrogel spacer, is safe and feasible, with minimal toxicity up to 37.5 months post-treatment when compared to rates of rectal toxicity in previous dose-escalation trials up to 80 Gy. Trials with longer follow-up of oncological and functional outcomes are required to robustly demonstrate a sustained widening of the therapeutic window. Trial registration Australian New Zealand Clinical Trials Registry, ACTRN12621000056897 , 22/01/2021. Retrospectively registered.

68 Ga-prostate-specific membrane antigen (PSMA) PET/CT as a clinical decision-making tool in biochemically recurrent prostate cancer.

OBJECTIVE: PSMA PET/CT has demonstrated superior sensitivity over conventional imaging in the detection of local and distant recurrence in biochemically relapsed (BCR) prostate cancer. We prospectively investigated the management impact of 68 Ga-PSMA PET/CT imaging in men with BCR, with the aim of identifying baseline clinicopathological predictors for management change. PATIENTS AND METHODS: Men with BCR who met eligibility criteria underwent 68 Ga-PSMA-11 PET/CT at Monash Health (Melbourne, Australia). Intended management plans were prospectively documented before and after 68 Ga-PSMA PET/CT imaging. Binary logistic regression analysis was performed to identify potential clinicopathological predictors of management change. Descriptive statistics were used to characterize the nature of these changes. RESULTS: Seventy men underwent 68 Ga-PSMA-11 PET/CT imaging. Median age was 67 years (IQR 63-72) and median PSA was 0.48 ng/ml (IQR 0.21-1.9). PSMA-avid disease was observed in 56% (39/70) of patients. Pre-scan management plan was altered following scanning in 43% (30/70) of patients. Management changes were significantly more common in patients with higher baseline PSA levels (PSA≥2 ng/ml, p = 0.01). 18/36 (50%) of the patients initially planned for watchful waiting had their management changed, including the use of salvage pelvic radiotherapy (n = 7) and stereotactic ablative body radiotherapy to oligometastatic disease (n = 6). CONCLUSION: Management change after 68 Ga-PSMA PET/CT for BCR is common and typically resulted in treatment intensification strategies in those planned for a watchful waiting approach. This study adds to the growing pool of evidence supporting the clinical utility of PSMA PET/CT imaging in the care of patients with BCR after definitive therapy.

Age-related properties of the tumour vasculature in renal cell carcinoma.

OBJECTIVE: To assess whether ageing processes influence angiogenesis in renal cell carcinoma (RCC) we carried out a pilot study of vascular properties in a series of archival primary kidney tumours in patients of different ages. PATIENTS AND METHODS: A cohort of patients with RCC was identified restrospectively, with an age range of 35-84 years. Paraffin-embedded, formalin-fixed sections of surgical tumour specimens were stained for endothelial (CD31, von Willebrand factor [vWF]), pericyte (alpha smooth muscle actin [SMA]) and leucocytic (CD45) markers, as well as for proliferative (Ki67) and angiogenic activity (tumour endothelial markers [TEMs], delta-like 4 [Dll4], Dll1, endothelial nitric oxide synthase [eNOS]). Vascular properties were compared between patients above and below 65 years of age. RESULTS: Microvascular density (MVD) within capillary hot spots was generally higher in patients with non-metastatic clear-cell RCC (ccRCC; n = 21) than in those with metastatic RCC (mRCC; n= 9). Patients with ccRCC who were more than 65 years old showed significantly higher MVD than their younger (< 65 years) counterparts. There were dividing (Ki67-positive) endothelial and mural cells in both small (< 20 µm) capillary and large (> 20 µm), pre-capillary vessels, suggesting the involvement of both angiogenic and remodelling/arteriogenic processes. Tumour endothelial markers (TEM1, TEM7, TEM8), Notch ligands (Dll1, Dll4), and other molecular characteristics (eNOS) were analysed. Age-related differences were observed in the frequency of pre-capillary vessels expressing Dll1, which was significantly higher in tumours of younger patients (< 65 years), while eNOS was more prevalent among capillaries associated with ccRCC in older patients (>6 5 years). CONCLUSIONS: The results of the present study suggest that age influences the structural and molecular properties of the tumour vasculature in ccRCC. We postulate that vascular ageing could also be relevant in the context of anti-angiogenic therapy.

Improving interpretation of biopsies during microsurgical testicular sperm exploration in azospermic patients: use of Davidson's fluid.

Histological interpretation of testicular biopsies in the investigation of infertility in men with azoospermia requires adequate tissue fixation to preserve the nuclear and cytoplasmic detail, as well as the architectural organisation of germ cells in different phases of maturation within seminiferous tubules. The aim of the study was to assess the histomorphological quality of testicular biopsies using Davidson's fluid (DF) as fixative and compare it to standard 10% neutral buffered formalin. Concurrent testicular biopsies from the same testis from patients undergoing microsurgical testicular sperm exploration (m-TESE) were separately fixed in DF and formalin and processed for histological examination. Histological parameters including sloughing of cells, cytoplasmic shrinkage of seminiferous tubular cells, nuclear chromatin detail, cytoplasmic graininess and overall clarity of morphological detail were graded on a scale of 0-4 (0, none; 1, minimal; 2, slight; 3, moderate; 4, marked). The effect of DF on biopsy diagnoses was assessed by comparison with corresponding formalin fixed biopsy diagnoses. Eighty-seven testicular biopsies from 27 patients were examined. DF fixation resulted in significantly less luminal sloughing of cells (1.59±1.34 vs 3.44±0.83, p≤0.00001), less cytoplasmic shrinkage of seminiferous tubular cells (1.58±1.11 vs 3.11±1.07, p≤0.00001), better nuclear chromatin detail (3.06±0.91 vs 1.92±0.48, p≤0.00001), less cytoplasmic graininess (2.11±0.96 vs 2.86±0.87, p=0.0014) and better overall clarity of morphological detail than formalin fixation (3.14±0.69 vs 2.14±0.58, p≤0.00001). The diagnostic concordance between DF fixed and formalin fixed biopsies was 90.8%. This study supports the use of DF as a superior alternative fixative to formalin for histological assessment of testicular biopsies.

Recovery of erectile function after unilateral and bilateral cavernous nerve interposition grafting during radical pelvic surgery.

PURPOSE: The use of cavernous nerve interposition grafting to preserve erectile function in men who require neurovascular bundle resection for cancer control is controversial. We report outcomes and predictors of cavernous nerve interposition grafting in men undergoing unilateral grafting during radical prostatectomy or bilateral grafting during radical cystectomy and prostatectomy with autologous nerve grafts. MATERIALS AND METHODS: We retrospectively reviewed the electronic records of 36 patients who underwent cavernous nerve interposition grafting between 2003 and 2006. Postoperatively erectile function was assessed with the International Index of Erectile Function 15-item questionnaire. Predictors of potency, including age at surgery, time since surgery and prostate specific antigen at surgery, were assessed by univariate analysis. RESULTS: A total of 33 patients (92% response rate) were followed for a median of 32, 25 and 11 months after bilateral grafting during radical cystectomy (10), unilateral grafting during radical prostatectomy (20), and bilateral grafting during radical cystectomy and prostatectomy (3), respectively. The rate of potency, defined as the ability to attain and maintain erection sufficient for penetration at least 50% of the time with or without phosphodiesterase-5 inhibitors, was 31% (5 of 13 men) for unilateral grafts, 38% (5 of 16) for bilateral grafts and 30% (3 of 10) for bilateral grafts during radical cystectomy. Age at surgery was the only significant determinant of potency and it showed an inverse relationship in the bilateral nerve graft group (p = 0.02). CONCLUSIONS: Cavernous nerve interposition grafting appears to have a role in the recovery of erectile function. To our knowledge this study represents the largest series of cavernous nerve interposition grafting during cystectomy and it suggests that this should be considered during bilateral neurovascular bundle resection.

Analysis of the spatial and temporal accuracy of heating in the prostate gland using transurethral ultrasound therapy and active MR temperature feedback.

A new MRI-guided therapy is being developed as a minimally invasive treatment for localized prostate cancer utilizing high-intensity ultrasound energy to generate a precise region of thermal coagulation within the prostate gland. The purpose of this study was to evaluate in vivo the capability to produce a spatial heating pattern in the prostate that accurately matched the shape of a target region using transurethral ultrasound heating and active MR temperature feedback. Experiments were performed in a canine model (n = 9) in a 1.5 T MR imager using a prototype device comprising a single planar transducer operated under rotational control. The spatial temperature distribution, measured every 5 s with MR thermometry, was used to adjust the acoustic power and rotation rate in order to achieve a temperature of 55 degrees C along the outer boundary of the target region. The results demonstrated the capability to produce accurate spatial heating patterns within the prostate gland. An average temperature of 56.2 +/- 0.6 degrees C was measured along the outer boundary of the target region across all experiments in this study. The average spatial error between the target boundary and the 55 degrees C isotherm was 0.8 +/- 0.7 mm (-0.2 to 3.2 mm), and the overall treatment time was < or =20 min for all experiments. Excellent spatial agreement was observed between the temperature information acquired with MRI and the pattern of thermal damage measured on H&E-stained tissue sections. This study demonstrates the benefit of adaptive energy delivery using active MR temperature feedback, and an excellent capability to treat precise regions within the prostate gland with this technology.

Peripheral primitive neuroectodermal tumor arising from the seminal vesicle.

In the genitourinary tract, masses in the seminal vesicles, particularly primary tumors, are an unusual event. One must consider all diagnoses including Ewing's sarcoma or its variant, peripheral primitive neuroectodermal tumor (PPNET). In this case report we describe a case of PPNET arising from the seminal vesicle. The prognosis of such tumors is generally poor and requires aggressive multimodal management if it is to be successful. It is essential that unusual tumors are considered when confronted by a seminal vesicle mass and that appropriate investigation and management are initiated.

Incidental Finding of a Rare Urachal Pathology: Urachal Mucinous Cystic Tumour of Low Malignant Potential.

Urachal mucinous cystic tumours are rare pathological findings with only 23 previously reported cases in the literature. We present the case of a 54-year-old man with an incidentally found urachal mucinous cystic tumour laparoscopically excised. With its known potential to cause pseudomyxoma peritonei, complete surgical excision is important. Long-term cystoscopic and radiological surveillance is also required.