Comparison of salvage radical prostatectomy vs. salvage ablation therapy for biopsy-proven radio-recurrent localized prostate cancer.

INTRODUCTION: Radiation therapy for prostate cancer is associated with a 15-20% five-year recurrence rate. Patients with recurrence in the prostate only are candidates for salvage local therapies; however, there is no consensus on modality. This study uses registries at Memorial Sloan Kettering Cancer Center (MSKCC) and University of Western Ontario (UWO) to compare the oncologic outcomes of salvage radical prostatectomy (SRP) and salvage ablation (SA). METHODS: A total of 444 patients were available for analysis. Due to intergroup differences, propensity score methodology was used and identified 378 patients with more comparable pre-salvage prostate-specific antigen (PSA), Gleason score, and primary radiation treatment. Patients underwent SRP at MSKCC and SA at UWO. RESULTS: Of the 378 patients, 48 died of disease, with a 6.0-year median (interquartile range [IQR] 3.0, 9.7) followup among survivors; 88 developed metastases, with a median 4.6-year (IQR 2.3, 7.9) followup among metastasis-free survivors. There was a non-significantly higher rate of cancer-specific (hazard ratio [HR ] 1.02, 95% confidence interval [CI] 0.51, 2.06, p=0.9) and improved metastasis-free survival (HR 0.71, 95% CI 0.44, 1.13, p=0.15) among patients undergoing SA compared to patients undergoing SRP. There were 143 patients who received hormonal therapy, with higher rates of androgen deprivation therapy (ADT) in SA (HR 1.42, 95% CI 0.97, 2.08, p=0.068), although this did not meet conventional levels of significance. CONCLUSIONS: This propensity score analysis of salvage therapy for radio-recurrent prostate cancer identified no statistically significant differences in oncologic outcome between SRP and SA; however, there was evidence of a lower risk of ADT in the cohort undergoing SRP. Given they are both potentially curative therapies, these treatments are viable options for men with clinically localized, radio-recurrent prostate cancer rather than ADT alone. Future research may further elucidate subpopulations that may be more amenable to either SRP or SA.

Long-Term Outcomes of Whole Gland Salvage Cryotherapy for Locally Recurrent Prostate Cancer following Radiation Therapy: A Combined Analysis of Two Centers.

PURPOSE: Radiation refractory prostate cancer (RRPCa) is common and salvage cryotherapy for RRPCa is emerging as a viable local treatment option. However, there is a paucity of long-term data. The purpose of this study is to determine long-term outcomes following salvage cryotherapy for RRPca. MATERIALS AND METHODS: Patients undergoing salvage cryotherapy for biopsy-proven, localized RRPCa from 1992 through 2004 were prospectively accrued at two centers. Preoperative characteristics, perioperative morbidity and postoperative data were reviewed from our database. The primary outcomes were overall survival (OS) and disease-specific survival (DSS). The secondary outcomes were freedom from castration-resistant prostate cancer (CRPC) and freedom from androgen deprivation therapy (ADT). RESULTS: A total of 268 patients were identified with a median followup of 10.3 years. A total of 223 complication events were recorded; of them, 168 were Clavien I-II events and 55 Clavien III events. At 10 years, 69% had freedom from ADT and 76% had freedom from CRPC. The 10-year DSS rate was 81%, and the 10-year OS rate was 77%. A pre-salvage prostate specific antigen level of >10 ng/ml was associated with an increased risk of developing CRPC and initiation of ADT but was not associated with DSS or OS. The use of neoadjuvant ADT was associated with improved OS and DSS but did not affect freedom from CRPC or adjuvant ADT. CONCLUSIONS: Salvage cryotherapy for RRPCa provides excellent long-term freedom from ADT, CRPC and DSS with acceptable morbidity. OS at 10 years was 77%. Prospective trials are required for validation.

A Randomized Controlled Trial of a Modified Cystoscopy Technique using the Peak-End Rule in order to Improve Pain and Anxiety.

OBJECTIVE: To determine if a modified cystoscopy technique utilizing the peak-end rule cognitive bias decreases pain and anxiety during flexible cystoscopy in patients who undergo cystoscopy. METHODS: A total of 85 participants undergoing their first diagnostic cystoscopy were enrolled in a blinded single-center, prospective, randomized controlled trial. Patients with lower urinary tract abnormalities, prior radiation and chronic pelvic pain were excluded. Participants were randomized to a standard cystoscopy (arm A) or a modified cystoscopy (arm B) where a two-minute period at the end of the procedure was completed during which the cystoscope was left in the bladder without being manipulated. Following the cystoscopy, participants completed a standard pain and anxiety questionnaire. Differences in mean pain and anxiety score between arms were evaluated using a Mann-Whitney test with a two-sided alpha of 0.05. RESULTS: Eighty-five patients were randomized and underwent flexible cystoscopy. Three participants were ineligible, one required secondary procedures, and two did not complete the questionnaires. Among the 82 eligible patients, 45 were randomized to standard cystoscopy (arm A) and 37 to the modified cystoscopy (arm B) with mean pain scores of 23.20 and 11.97, respectively (P = .039). Mean anxiety scores were 2.09 and 0.88 for arm A and B, respectively (P = .013). CONCLUSION: This study demonstrated a clinically meaningful decrease in pain and anxiety for patients undergoing flexible cystoscopy when employing the modified cystoscopy technique versus the standard practice. This free and straightforward method to improve patient comfort and decrease stress during first time flexible cystoscopy should be considered by clinicians.

Long-term outcomes of two ablation techniques for treatment of radio-recurrent prostate cancer.

BACKGROUND: In men with recurrence of prostate cancer post radiation therapy, further treatment remains a challenge. The default salvage option of androgen-deprivation therapy (ADT) has adverse effects. Alternatively, selected men may be offered salvage therapy to the prostate. Herein, we present long-term oncological outcomes of two whole-gland ablation techniques, cryotherapy (sCT) and high-intensity-focused ultrasound (sHIFU). METHODS: Men undergoing sCT (1995-2004) and sHIFU (2006-2018) at Western University were identified. Oncological endpoints included biochemical recurrence (BCR), ADT initiation, metastases, castration resistance (CRPC), and prostate cancer-specific mortality (PCSM). Survival analysis with competing risks of mortality was performed. Multivariable analysis was performed using Fine and Gray regression. RESULTS: A total of 187 men underwent sCT and 113 sHIFU. Mean (SD) age of the entire cohort was 69.9 (5.9 years), median pre-radiation PSA 9.6 ng/ml (IQR 6.1-15.2), and pre-salvage PSA 4.5 ng/ml (IQR 2.8-7.0). Median total follow-up was 116 months (IQR 67.5-173.8). A total of 170 (57.6%) developed BCR, 68 (23.4%) metastases, 143 (49.3%) were started on ADT, 58 (20.1%) developed CRPC, and 162 (56%) patients died of which 59 (36.4%) were of prostate cancer. On multivariable analysis, sHIFU (HR 1.65, 95% CI 1.15-2.36, p = 0.006) and pre-salvage PSA (HR 1.09, 95% CI 1.06-1.13, p < 0.0001) were associated with a higher risk of BCR. Similarly, sHIFU patients had a higher risk of CRPC (HR 2.31, 95% CI 1.23-4.35, p = 0.009). The cumulative incidence (for both treatments) of PCSM was 16.5% (95% CI 12.2-21.4%) at 10 years and 28.4% (95% CI 22.1-34.9%) at 20 years, with no difference between treatment modalities. Pre-salvage PSA was a common predictor for the measured oncological outcomes. CONCLUSIONS: Although sHIFU had higher BCR and CRPC rates, there were no differences in PCSM when compared with sCT. The long-term oncological data on two ablation techniques highlighted that only 50% of patients started ADT after 10-year follow-up.

Magnetic resonance imaging-guided transurethral ultrasound ablation in patients with localised prostate cancer: 3-year outcomes of a prospective Phase I study.

OBJECTIVES: To report the 3-year follow-up of a Phase I study of magnetic resonance imaging (MRI)-guided transurethral ultrasound ablation (TULSA) in 30 men with localised prostate cancer. Favourable 12-month safety and ablation precision were previously described. PATIENTS AND METHODS: As a mandated safety criterion, TULSA was delivered as near whole-gland ablation, applying 3-mm margins sparing 10% of peripheral prostate tissue in 30 men. After 12-month biopsy and MRI, biannual follow-up included prostate-specific antigen (PSA), adverse events (AEs), and functional quality-of-life assessment, with repeat systematic biopsy at 3 years. RESULTS: A 3-year follow-up was completed by 22 patients. Between 1 and 3 years, there were no new serious or severe AEs. Urinary and bowel function remained stable. Erectile function recovered by 1 year and was stable at 3 years. The PSA level decreased 95% to a median (interquartile range) nadir of 0.33 (0.1-0.4) ng/mL, stable to 0.8 (0.4-1.6) ng/mL at 3 years. Serial biopsies identified clinically significant disease in 10/29 men (34%) and any cancer in 17/29 (59%). By 3 years, seven men had recurrence (four histological, three biochemical) and had undergone salvage therapy without complications (including six prostatectomies). At 3 years, three of 22 men refused biopsy, and two of the 22 (9%) had clinically significant disease (one new, one persistent). Predictors of salvage therapy requirement included less extensive ablation coverage and higher PSA nadir. CONCLUSION: With 3-year Phase I follow-up, TULSA demonstrates safe and precise ablation for men with localised prostate cancer, providing predictable PSA and biopsy outcomes, without affecting functional abilities or precluding salvage therapy.

Prostatic dystrophic calcification following salvage cryotherapy for prostate cancer - an under-reported entity?

BACKGROUND: Salvage cryoablation (SCA) is an accepted treatment for radio-recurrent prostate cancer with well-established oncological and functional outcomes. Based on one of the longest reported prospective follow-ups in the literature (median 12 years) on 187 patients, this study reports what appears to be an under-appreciated finding in eight patients with dystrophic calcifications (DC) of the prostate following SCA, causing severe bladder outlet obstruction. MATERIALS AND METHODS: Between 1995 and 2004, 187 patients underwent SCA, with a median follow-up of 12 years. This database was reviewed for functional and oncological outcomes and DC were evaluated. RESULTS: Functional data was available in 85 patients, amongst whom eight patients were found to develop DC (9.4%) proven when the patients presented with urinary difficulties and attempted transurethral resection was undertaken for bladder outlet obstruction. Mean time for emergence of significant symptoms of bladder outlet obstruction was 8.6 years from SCA (standard deviation (SD) = 6 years). All eightpatients required permanent drainage (seven suprapubic catheters, one nephrostomy). All patients with DC experienced biochemical recurrence (BCR), compared to 57.1% of the patients with no DC (p = 0.01). CONCLUSION: DC following SCA appears to be an under-reported late adverse effect which may only become evident with long follow-up, and should be included in preoperative counselling.

Abiraterone acetate preferentially enriches for the gut commensal Akkermansia muciniphila in castrate-resistant prostate cancer patients.

Abiraterone acetate (AA) is an inhibitor of androgen biosynthesis, though this cannot fully explain its efficacy against androgen-independent prostate cancer. Here, we demonstrate that androgen deprivation therapy depletes androgen-utilizing Corynebacterium spp. in prostate cancer patients and that oral AA further enriches for the health-associated commensal, Akkermansia muciniphila. Functional inferencing elucidates a coinciding increase in bacterial biosynthesis of vitamin K2 (an inhibitor of androgen dependent and independent tumor growth). These results are highly reproducible in a host-free gut model, excluding the possibility of immune involvement. Further investigation reveals that AA is metabolized by bacteria in vitro and that breakdown components selectively impact growth. We conclude that A. muciniphila is a key regulator of AA-mediated restructuring of microbial communities, and that this species may affect treatment response in castrate-resistant cohorts. Ongoing initiatives aimed at modulating the colonic microbiota of cancer patients may consider targeted delivery of poorly absorbed selective bacterial growth agents.

Anatomical characterization of the inguinal lymph nodes using microcomputed tomography to inform radical inguinal lymph node dissections in penile cancer.

BACKGROUND & OBJECTIVES: Radical inguinal lymph node dissections (rILND) for penile cancer risk significant postoperative lymphocele and lymphedema. However, reducing the risk of lymphatic complications is limited by our understanding of lymphatic anatomy. Therefore, this study aims to elucidate the lymphatic anatomy within the current surgical borders of a rILND. METHODS: To visualize the position of the lymph nodes, tissue packets excised from the inguinal region of five fresh, male cadavers were imaged using microcomputed tomography (µCT). To standardize the position, rotation and size between specimens, each lymph node packet was aligned using a Generalized Procrustes analysis. RESULTS: There was a median of 13.5 lymph nodes (range = 8-18) per packet, with the majority (99%) clustered within a 6 cm radius of the saphenofemoral junction; a region 39%-41% smaller than current surgical borders. No difference existed between the number of nodes between sides, or distribution around the saphenofemoral junction. CONCLUSIONS: This study provides the first 3D, in situ, standardized characterization of lymph node anatomy in the inguinal region using µCT. By using knowledge of the normal lymphatic anatomy, this study can help inform the reduction in borders of rILND to limit disruption and ensure a complete lymphadenectomy.

The history of cryosurgery in Canada: A tale of two cities.

Although not commonly available in Canada, cryosurgery (cryoablation) for prostate cancer has been practiced in many countries. The field of cryoablation has evolved significantly over the past 30 years. Two prostate cryoablation programs were started in Canada in the early 1990s, in London, ON and Calgary, AB, focusing, respectively, on salvage therapy following radiation failure and primary local treatment. This article chronicles the development of the two programs and outlines the scientific and clinical contributions by investigators at the two centers.

Microcomputed Tomography Is a Precise Method That Allows for Topographical Characterization of Lymph Nodes and Lymphatic Vessels.

Background: Surgical excision and/or radiation targeting of regional lymph nodes are an essential component in the clinical management of cancer. Importantly, a more accurate understanding of lymphatic anatomy could enable refinement of present treatment strategies. Given the spatial resolution limitations of contemporary imaging methods, our group sought to utilize noncontrast-enhanced microcomputed tomography (µCT) imaging to clarify regional lymphatic anatomy. Methods and Results: This study was conducted with embalmed en bloc lymphatic tissue packets from six donors (three females and three males: medianage of death = 78 years). All specimens were investigated with noncontrast-enhanced µCT imaging using a conebeam-CT imaging system. Adipose and lymphatic tissues were segmented by radiodensity based on sampling regions of interest. To confirm the observations from µCT, lymph nodes from each packet were exposed to hematoxylin and eosin staining and anti-D240 immunostaining. Following µCT imaging, mean peak radiodensities of -203.14 ± 19.35 Hounsfield units (HU) and 37.25 ± 31.95 HU were revealed for adipose and lymphatic tissues, respectively (p < 0.01). By analyzing histograms of the radiodensity distributions, we determined a threshold of -82.42 HU to differentiate adipose and lymphatic tissue, to generate three-dimensional renderings, and to calculate quantitative metrics. On average, adipose tissue comprised 9.62 ± 3.60 cm3 (73.6%) of the total packet volume, whereas lymphatic tissue comprised 3.47 ± 2.71 cm3 (26.4%). Moreover, each en bloc packet contained four small lymph nodes (1-5 mm) and three to four large lymph nodes (>5 mm). Histology corroborated the observations from µCT. Conclusions: Altogether, a precise understanding of regional lymphatic anatomy elucidated by the present imaging modality may help refine clinical cancer treatment strategies.

Aspiration and sclerotherapy of hydroceles and spermatoceles/epididymal cysts with 100% alcohol.

OBJECTIVE: To evaluate the efficacy of aspiration and sclerotherapy with 100% alcohol for the primary treatment of benign scrotal cysts. METHODS: From March 2014 to March 2018, 114 patients were identified who underwent their first aspiration and sclerotherapy procedure (80 hydroceles and 34 spermatoceles/epididymal cysts). The procedure was carried out in the outpatient clinic with local anaesthesia. A 16-gauge IV catheter is used to puncture the sac under aseptic conditions. The volume of alcohol instilled was 10% of the aspirated volume (maximum of 50 mL). Patients were then observed in the waiting room and completed a questionnaire. Urology clinic follow up was scheduled at 6 weeks. RESULTS: At follow up, 54 patients (67.5%) with hydroceles and 25 patients (73.5%) with spermatoceles/epididymal cysts had resolution after a single procedure. A second procedure was offered if fluid collection persisted, of which 71% of patients with hydroceles and 100% of patients with spermatoceles/epididymal cysts had a successful outcome. At a median of 31 months post-initial procedure, the overall success rate, after at most two procedures, was 80% for hydroceles and 85% for spermatoceles/epididymal cysts. The complication rate was low (6%). Almost all patients were happy to undergo the procedure again, if needed. Persistence following aspiration and sclerotherapy were more likely to occur in younger patients (45.4 versus 61.2 years, P = 0.001). Persistence was not related to the volume of fluid aspirated. CONCLUSION: Aspiration and sclerotherapy with alcohol is a reliable, safe and effective technique for treatment of benign scrotal cysts.

Primary Mediastinal Germ Cell Tumors-The University of Western Ontario Experience.

Extragonadal germ cell tumors account for 2-5.7% of germ cell tumors (GCTs). Of these, primary mediastinal GCTs (PMGCTs) are responsible for 16-36% of cases. Given the rarity of these tumors, specific treatment strategies have not been well defined. We report our experience in treating these complex patients. In total, 318 men treated at our institution with chemotherapy for GCTs between 1980 and 2016 were reviewed. PMGCT was defined as clinically diagnosed mediastinal GCT with no evidence of testicular GCT (physical exam/ultrasound). We identified nine patients diagnosed with PMGCT. All patients presented with an anterior mediastinal mass and no gonadal lesion; four patients also had metastatic disease. Median age at diagnosis was 30 years (range, 14-56) and median mass size at diagnosis was 9 cm (range, 3.4-19). Eight patients had non-seminoma and one had pure seminoma. All patients received cisplatin-based chemotherapy initially. Surgical resection was performed in four patients; three patients had a complete resection and one patient was found to have an unresectable tumor. At a median follow-up of 2 years (range, 3 months-28 years) six patients had progressed. Progression-free survival was short with a median of 4.1 months from diagnosis (range 1.5-122.2 months). Five patients died at a median of 4.4 months from diagnosis. One and 5-year overall survivals were 50% and 38%, respectively. PMGCT are rare and aggressive. Our real-life Canadian experience is consistent with current literature suggesting that non-seminoma PMGCT has a poor prognosis despite prompt cisplatin-based chemotherapy followed by aggressive thoracic surgery.

Long-term Testis Cancer Survivors in Canada-Mortality Risks in a Large Population-based Cohort.

BACKGROUND: Testis cancer (TC) patients are young with excellent cancer prognosis. Hence, the risk of late-onset treatment-related morbidity and mortality is of concern due to longer survival after treatment. OBJECTIVE: We set to characterize long-term survival of TC patients through a Canadian population dataset. DESIGN SETTING AND PARTICIPANTS: We used a population-based dataset, the Canadian Census Health and Environment Cohort (CanCHEC), to identify individuals diagnosed with TC between 1991 and 2010. We compared them with all other male individuals without TC. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary outcome was mortality due to cardiovascular disease (CVD) or nontesticular malignancy. Mann-Whitney or chi-square test was used where applicable. Data were analyzed using a Cox proportional hazard model with and without matching. RESULTS AND LIMITATIONS: We identified 1950 individuals with TC. We compared them with 1 300 295 men with no TC. There were 335 deaths in the study group during the study period (17.2%) with a mean follow-up of 19.6 yr. TC patients were at increased risk of death from secondary malignancies (hazard ratio [HR] 1.63, 95% confidence interval [CI] 1.39-1.91; p < 0.0001) with specific risks for hematologic neoplasms (HR 3.86, 95% CI 2.78-5.37; p < 0.001) and other malignancies (HR 2.41, 95% CI 1.76-3.29; p < 0.001). Gastrointestinal, hematologic, and respiratory toxicities were the most common secondary malignancies leading to death. When stratified according to histology, nonseminoma (NS) patients were at significantly increased risk of death from CVD (HR 2.03, 95% CI 1.27-3.25; p = 0.0032). Individuals with seminoma were at increased risk of death from other nontestis neoplasms (HR 1.46, 95% CI 1.17-1.82; p = 0.0007), specifically hematologic neoplasms (HR 2.09, 95% CI 1.18-3.72; p = 0.0118). CONCLUSIONS: NS patients are at increased risk of CVD-related death, whereas seminoma patients are at increased risk of death from non-testis-related malignancies. PATIENT SUMMARY: We report long-term mortality following diagnosis of testis cancer. Nonseminoma patients have an increased risk of death from cardiovascular disease, while seminoma patients have an increased risk of death from secondary malignancies.

Examining Mannitol Use in Kidney Cancer Surgery: A Cautionary Tale of Extrapolated Surgical Data.

Mannitol for renal protection during partial nephrectomy is common but unsupported by evidence from clinical trials. The impact of mannitol on renal physiology includes both beneficial and harmful effects. Current understanding of renal ischemia reperfusion injury suggests potentially targetable processes that have a lower potential risk.

Accessory right spermatic ganglion: possible embryological basis and clinical significance.

The spermatic ganglia are collections of sympathetic neuron cell bodies located within the cords of the infrarenal aortic plexus, positioned at the origin of the testicular arteries in males. During routine dissection of the aortic plexus at our institution, one specimen exhibited a second (accessory) testicular artery on the right side that coursed retrocaval. Histology was used to confirm the presence of an accessory right spermatic ganglion at the base of the accessory retrocaval testicular artery. Interestingly, the accessory spermatic ganglion was also supplied by its own right lumbar splanchnic nerve. This is the first case to describe the anatomy of an accessory spermatic ganglion in a specimen that exhibits an accessory testicular artery on the right side. This neurovascular variation is of interest to surgeons who aim to perform nerve-sparing retroperitoneal lymph node dissections for malignancy.

Melatonin treatment following stroke induction modulates L-arginine metabolism.

The efficacy of melatonin treatment in experimental stroke has been established. Some of the neuroprotective properties have been attributed to its anti-oxidant and anti-inflammatory effects. Nitric oxide synthases (NOS) and cyclooxygenases (COX) are considered to have a significant role in the inflammatory milieu occurring in acute stroke. While previous reports have shown that pretreatment with melatonin in a stroke model can modulate NOS isoforms, the effect of post-treatment with melatonin on l-arginine metabolism has not been investigated. This study initially examined the effect of melatonin (1 nm-1 mm) on l-arginine metabolism pathways in human fibrosarcoma fibroblasts (HT-1080) fibroblasts. Evidence of neuroprotection with melatonin was evaluated in rats subjected to middle cerebral artery occlusion (MCAO). Animals were treated with three daily doses of 5 mg/kg i.p., starting 1 hr after the onset of ischemia. Constitutive NOS activity but not expression was significantly increased by in vitro exposure (72 hr) to melatonin. In addition, melatonin treatment increased arginase activity by increasing arginase II expression. In vivo studies showed that melatonin treatment after MCAO significantly inhibited inducible NOS activity and attenuated expression of the inducible isoform, resulting in decreased total NOS activity and tissue nitrite levels. COX activity was significantly reduced with melatonin treatment. The neuroprotective anti-inflammatory effects of melatonin were consistent with the substantial reduction in infarct volume throughout the cortex and striatum and recovery of mitochondrial enzyme activities. The evidence presented here suggests that modulation of l-arginine metabolism by melatonin make it a valuable neuroprotective therapy for stroke.

Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoid CB2 receptor in the brain.

Until recently the cannabinoid CB2 receptor was believed to be absent from the central nervous system. In this study we have identified CB2 expressing cells that appear in the rat brain following stroke and hypoxic-ischemia. At 3 days following surgery CB2-positive macrophages, deriving from resident microglia and/or invading monocytes appear on the lesioned side of the brain. By day 7, a mixed population of CB2-positive cells is present. Microglia-derived macrophages are the key cells in the first stages of brain inflammation, and a pivotal step in the neurodegeneration that follows the acute stage of injury. Thus, CB2 may be important in the brain during injury, and in inflammatory neurodegenerative disorders. The presence of CB2-positive cells in the brain following stroke may provide a novel strategy for cannabinoid-mediated intervention into stroke induced neurodegeneration without the psychoactive effects of CB1 receptor stimulation.