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.

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.

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 .

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.

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.

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.

Inflammatory Myofibroblastic Tumor of the Urinary Bladder: A Case Report.

Inflammatory myofibroblastic tumor is a rare but benign clinical entity. Its ability to mimic malignancy poses a diagnostic challenge. Here, we report the first case in Australia, of inflammatory myofibroblastic tumor in the bladder in a 40-year-old male, removed via transurethral resection.

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.

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.

Rare synchronous metastases of renal cell carcinoma.

Renal cell carcinoma can metastasize to any region of the body. We review a patient who presents fourteen years after initial resection of the primary tumor with distant metastatic disease. This included spread to the bladder and penis that manifested as frank haematuria and malignant priapism respectively. We discuss the mechanism of spread and the management options available.

Holmium Laser Enucleation of the Prostate: Comparison of Immediate Postoperative Outcomes in Patients with and without Antithrombotic Therapy.

OBJECTIVE: To compare the immediate postoperative outcomes of patients with benign prostatic hyperplasia undergoing Holmium laser enucleation of the prostate (HOLEP) with and without full anticoagulation or antiplatelet therapy at the time of surgery. MATERIALS AND METHODS: A retrospective review was performed on a series of consecutive patients undergoing HOLEP at our institution by a single surgeon from February 2004 to September 2010. Demographic, surgical, pathological and outcome data were collected. Two cohorts were identified on the basis of antithrombotic therapy at the time of surgery. Patients who continued on aspirin, aspirin/dipyridamole, clopidogrel and warfarin throughout the surgery were included in the antithrombotic cohort. Univariate analysis was performed to determine differences in outcomes between the 2 cohorts. RESULTS: Total 125 consecutive patients underwent HOLEP with 52 patients on antithrombotic therapy at the time of surgery and 73 patients were not on antithrombotic therapy during surgery. Patients in the antithrombotic group were older (75.1 ±7.5 vs. 71.7 ± 8.3 years; p = 0.02) and had a higher median ASA physical status (3 (3-3) vs. 2 (2-3), p < 0.0001). The mean operating time and median specimen volume were not significantly different between the 2 cohorts. The median length of stay (2 (1-3) vs. 1 (1-2) d, p = 0.014) was longer in the antithrombotic cohort. The transfusion rate (7.7 vs. 0%, p = 0.028) was predictably higher in the antithrombotic cohort. No patients required re-operation for bleeding. CONCLUSIONS: The use of HOLEP in patients on antithrombotic therapy is safe despite the higher surgical risk profile of that particular patient population and the potential increased risk for significant bleeding.

Helping doctors utilize the prostate-specific antigen effectively: an online randomized controlled trial (The DUPE trial).

OBJECTIVES: The objectives of this study were to evaluate the effectiveness of an information aid (IA) on doctor's knowledge about the strengths and limitations of prostate-specific antigen/digital rectal examination (PSA/DRE) testing, and to help doctors make better and more informed decisions about prostate cancer screening. METHODS: An online randomized trial among 45 doctors in Victoria's public health-care network that fulfilled CONSORT requirements was conducted. Participants were randomized to either immediate or delayed access to an online IA, and knowledge was compared across both groups at the conclusion of the trial. RESULTS: Doctors spent a mean time of 4:04 (95% confidence interval: 0.53-7:52) reading and completing the IA. Those who read IA were more knowledgeable (mean score out of 9, 7.45 versus 5.75, P < 0.0001). Potential harms and current literature findings were better recognized, as well as having a better understanding of what is meant by the term screening. Eighty-two per cent found that IA helped them understand prostate cancer screening, and 73% found it easy to understand. CONCLUSION: The IA increased knowledge, took minimal time to complete and was found to be helpful in understanding prostate cancer screening. PRACTICAL IMPLICATIONS: The IA is an easy-to-access resource that improves knowledge regarding the strengths and limitations of the PSA/DRE test for prostate cancer screening. Doctors who are unsure how to summarize the latest evidence should be directed towards the IA.