Germline BRCA2 mutations drive prostate cancers with distinct evolutionary trajectories.

Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations (BRCA2-mutant PCa). We show that BRCA2-mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2-mutant PCa shows genomic and epigenomic dysregulation of the MED12L/MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2-mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2-mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.

Acute urinary retention and the difficult catheterization: current emergency management.

Acute urinary retention (AUR) is a common presentation to emergency departments. This article updates the reader on the appropriate management, investigations and guidelines for AUR. It looks at the mechanism of normal micturition and describes the theories of AUR. It outlines urethral catheterization techniques for difficult cases, reviews suprapubic catheterization procedures and describes the management of AUR in polytrauma. Although emergency management is by bladder drainage, key points in the history and examination may expose significant, latent pathologies.

Patient-derived xenografts reveal that intraductal carcinoma of the prostate is a prominent pathology in BRCA2 mutation carriers with prostate cancer and correlates with poor prognosis.

BACKGROUND: Intraductal carcinoma of the prostate (IDC-P) is a distinct clinicopathologic entity associated with aggressive prostate cancer (PCa). PCa patients carrying a breast cancer 2, early onset (BRCA2) germline mutation exhibit highly aggressive tumours with poor prognosis. OBJECTIVE: To investigate the presence and implications of IDC-P in men with a strong family history of PCa who either carry a BRCA2 pathogenic mutation or do not carry the mutation (BRCAX). DESIGN, SETTING, AND PARTICIPANTS: Patient-derived xenografts (PDXs) were generated from three germline BRCA2 mutation carriers and one BRCAX patient. Specimens were examined for histologic evidence of IDC-P. Whole-genome copy number analysis (WG-CNA) was performed on IDC-P from a primary and a matched PDX specimen. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The incidence of IDC-P and association with overall survival for BRCA2 and BRCAX patients were determined using Kaplan-Meier analysis. RESULTS AND LIMITATIONS: PDXs from BRCA2 tumours showed increased incidence of IDC-P compared with sporadic PCa (p=0.015). WG-CNA confirmed that the genetic profile of IDC-P from a matched (primary and PDX) BRCA2 tumour was similar. The incidence of IDC-P was significantly increased in BRCA2 carriers (42%, n=33, p=0.004) but not in BRCAX patients (25.8%, n=62, p=0.102) when both groups were compared with sporadic cases (9%, n=32). BRCA2 carriers and BRCAX patients with IDC-P had significantly worse overall and PCa-specific survival compared with BRCA2 carriers and BRCAX patients without IDC-P (hazard ratio [HR]: 16.9, p=0.0064 and HR: 3.57, p=0.0086, respectively). CONCLUSIONS: PDXs revealed IDC-P in patients with germline BRCA2 mutations or BRCAX classification, identifying aggressive tumours with poor survival even when the stage and grade of cancer at diagnosis were similar. Further studies of the prognostic significance of IDC-P in sporadic PCa are warranted. PATIENT SUMMARY: Intraductal carcinoma of the prostate is common in patients with familial prostate cancer and is associated with poor outcomes. This finding affects genetic counselling and identifies patients in whom earlier multimodality treatment may be required.

Altered significance of D'Amico risk classification in patients with prostate cancer linked to a familial breast cancer (kConFab) cohort.

OBJECTIVE: To ascertain whether D'Amico risk classification is an accurate discriminator of prostate cancer mortality risk in BRCA2 pathogenic mutation carriers and non-carriers from a familial breast cancer cohort. PATIENTS AND METHODS: From family cancer pedigrees of patients evaluated through a familial breast cancer cohort all related men with a diagnosis of prostate cancer were identified. Genotyping of each patient or of the dominant familial BRCA2 mutation was undertaken in each instance. Prostate cancers were analysed by BRCA2 carrier vs non-carrier status for their clinical progression and survival according to their D'Amico risk groups. RESULTS: For patients who were BRCA2-mutation positive, there was no significant difference in cancer-specific survival (CSS) between those patients who were graded as having D'Amico high- or intermediate-risk disease. For patients who were BRCA2-mutation negative, but were identified via a family cancer pedigree, there was no statistically significant difference in CSS between D'Amico high- and intermediate-risk prostate cancers. Patients with D'Amico high-risk disease who were BRCA2-mutation carriers had substantially increased disease-specific mortality compared with high-risk non-carriers (hazard ratio 2.94, P = 0.004). CONCLUSION: D'Amico risk classification has limitations in predicting variations in prostate cancer-specific mortality for this group of patients.

Fournier's gangrene - delayed pedicle flap based upon the anterior abdominal wall.

INTRODUCTION: Fournier's gangrene is a poly-microbial necrotizing fasciitis that involves the perineum and/or external genitalia. Urgent surgical debridement is well recognized as essential acute treatment yet unique challenges arise for plastic surgical reconstruction to obtain a complete functional recovery. This case describes a successful delayed pedicle flap repair based upon the anterior abdominal wall. CASE DESCRIPTION: A 24 year old man was admitted to ICU ten days after elective circumcision with Fournier's gangrene. He underwent a number of surgical debridements, and was referred for plastic surgical management. He had penile reconstruction using a random pattern abdominal flap, which was performed as a three stage procedure including flap vascular delay technique. DISCUSSION: Perineal and penile skin loss can be significant and is difficult to repair. Various techniques have been used to reconstruct lost tissue: skin grafts, transposition of the testes and spermatic cords to the thigh, flaps, and other types of pediculated myocutaneous flaps. Muscle flap reconstruction provides an environment that allows for complete regeneration of the urethral epithelium but is bulky and unsightly. Skin grafts contract and may produce painful and dysfunctional reconstructions. This novel technique produces a functional, and aesthetic reconstruction. CONCLUSION: Penile skin recovery following Fournier's gangrene recovery is problematic. This case demonstrates the functionality of a delayed flap repair using the anterior abdominal wall.

Fournier?s gangrene - delayed pedicle flap based upon the anterior abdominal wall

Introduction Fournier’s gangrene is a poly-microbial necrotizing fasciitis that involves the perineum and/or external genitalia. Urgent surgical debridement is well recognized as essential acute treatment yet unique challenges arise for plastic surgical reconstruction to obtain a complete functional recovery. This case describes a successful delayed pedicle flap repair based upon the anterior abdominal wall. Case description A 24 year old man was admitted to ICU ten days after elective circumcision with Fournier’s gangrene. He underwent a number of surgical debridements, and was referred for plastic surgical management. He had penile reconstruction using a random pattern abdominal flap, which was performed as a three stage procedure including flap vascular delay technique. Discussion Perineal and penile skin loss can be significant and is difficult to repair. Various techniques have been used to reconstruct lost tissue: skin grafts, transposition of the testes and spermatic cords to the thigh, flaps, and other types of pediculated myocutaneous flaps. Muscle flap reconstruction provides an environment that allows for complete regeneration of the urethral epithelium but is bulky and unsightly. Skin grafts contract and may produce painful and dysfunctional reconstructions. This novel technique produces a functional, and aesthetic reconstruction. Conclusion Penile skin recovery following Fournier’s gangrene recovery is problematic. This case demonstrates the functionality of a delayed flap repair using the anterior abdominal wall. .

The dilemma of distance: patients with kidney cancer from regional Australia present at a more advanced stage.

OBJECTIVE: To determine whether patients from regional areas undergoing surgery for kidney cancer present with more advanced disease as a result of geographic isolation. PATIENTS AND METHODS: Retrospective analysis of 221 patients undergoing surgery for renal cell carcinoma (RCC) from January 2004 to June 2012, from both a metropolitan centre and a large inner regional hospital. Data was collected on age, gender, presentation (incidental or symptomatic), clinical stage and pathological features. The Australian Standard Geographical Classification-Remoteness Area (ASGC-RA) is a system developed to allow quantitative comparisons between metropolitan and rural Australia. A score was assigned to each patient based on their location of residence at the time of surgery: metropolitan, RA1; inner regional, RA2; outer regional, RA3. Statistical significance was specified as P < 0.05 on Pearson's chi-square tests. RESULTS: Patients in each ASGC-RA group did not differ significantly in age, sex or mode of presentation. Pathological T stage on presentation increased with increasing ASGC-RA and thus distance from tertiary centres (P = 0.004). The proportion of patients with ≥T3 disease rose from 30% of RA1 to 73% of RA3 patients (P = 0.016) treated at our tertiary centre. Similarly, our regional centre had a larger proportion of patients presenting with ≥T3 disease from RA3 (31% vs 5%, P = 0.003). When the 221 patients with RCC were analysed as a group, clinical T stage was significantly associated with ASGC-RA (P < 0.001), symptomatic presentation (P < 0.001), N stage (P < 0.001), M stage (P < 0.001) and Fuhrman grade (P < 0.001). CONCLUSIONS: Our data quantifies the detrimental effect of physical distance on the health outcomes of regional Australians with kidney cancer. Australia's unique geography and rural culture may preclude any attempts to centralise cancer care to specialised metropolitan units, as has occurred in other countries.

Advances in ureteroscopy.

Ureteroscopy (URS) is a procedure which has been constantly evolving since the development of first generation devices 40 years ago. Progress towards smaller and more sophisticated equipment has been particularly rapid in the last decade. We review the significant steps that have been made toward improving outcomes and limiting morbidity with this procedure which is central to the management of urolithiasis and other upper urinary tract pathology.