Morbidity and mortality after open radical cystectomy and ileal diversion - 10 years experience and a comprehensive assessment in a single tertiary center.

Open radical cystectomy (ORC) remains the gold standard for the treatment of muscle-invasive and high-risk non-muscle invasive bladder cancer unsuitable for bladder preservation techniques. Despite improvements in operative technique and perioperative care, it continues to be associated with significant complications. We analyzed our series of prospectively collected data of patients who underwent ORC at a tertiary referral academic center and evaluated early and late postoperative complications and mortality. The records of 391 ORCs with ileal diversion performed at our institution between January 2008 and July 2018 for non-metastatic transitional bladder carcinoma and other distinct pathological types were analyzed. Perioperative mortality was determined and 30-day and 90-day complications were reported according to the Martin Criteria and the European Association of Urology and graded according to the five-grade Clavien-Dindo classification. Univariate and multivariate analyses were used to evaluate predictors of complications and mortality. Gastrointestinal and infectious complications represented 41% and 43% of the total complications observed at 30 and 90 days after the surgery, respectively. The strongest predictor of infectious complications was the choice of ileal neobladder as the urinary diversion (p≤0.0001). Diabetes was a predictor of the overall, major and major infectious complications (p<0.05). The 30-day mortality rate was 1% while the 90-day mortality rate was 1.5%. Age ≥75 was the single predictor of mortality at both 30-days (p-value 0.003) and 90-days (p-value 0.01) in univariate and multivariate analyses. ORC is a morbid procedure, associated with a high mortality rate. Elderly patients should have proper counseling before the indication of this procedure. Gastrointestinal and infectious complications represent the most common and serious complications, and the study of their predictors is of the utmost importance.

Phase I/II trial of dendritic cell-based active cellular immunotherapy with DCVAC/PCa in patients with rising PSA after primary prostatectomy or salvage radiotherapy for the treatment of prostate cancer.

OBJECTIVE: Immunotherapy of cancer has the potential to be effective mostly in patients with a low tumour burden. Rising PSA (prostate-specific antigen) levels in patients with prostate cancer represents such a situation. We performed the present clinical study with dendritic cell (DC)-based immunotherapy in this patient population. MATERIALS AND METHODS: The single-arm phase I/II trial registered as EudraCT 2009-017259-91 involved 27 patients with rising PSA levels. The study medication consisted of autologous DCs pulsed with the killed LNCaP cell line (DCVAC/PCa). Twelve patients with a favourable PSA response continued with the second cycle of immunotherapy. The primary and secondary objectives of the study were to assess the safety and determine the PSA doubling time (PSADT), respectively. RESULTS: No significant side effects were recorded. The median PSADT in all treated patients increased from 5.67 months prior to immunotherapy to 18.85 months after 12 doses (p < 0.0018). Twelve patients who continued immunotherapy with the second cycle had a median PSADT of 58 months that remained stable after the second cycle. In the peripheral blood, specific PSA-reacting T lymphocytes were increased significantly already after the fourth dose, and a stable frequency was detected throughout the remainder of DCVAC/PCa treatment. Long-term immunotherapy of prostate cancer patients experiencing early signs of PSA recurrence using DCVAC/PCa was safe, induced an immune response and led to the significant prolongation of PSADT. Long-term follow-up may show whether the changes in PSADT might improve the clinical outcome in patients with biochemical recurrence of the prostate cancer.

Stratification model based on early postprostatectomy prostate-specific antigen kinetics may help to reduce the risk of overtreatment in candidates for adjuvant radiotherapy.

OBJECTIVE: The aim of this study was to construct a stratification model based on early postoperative kinetics of prostate-specific antigen (PSA) to select the most suitable high-risk patients for early intervention after radical prostatectomy (RP). MATERIALS AND METHODS: The study evaluated 205 men who had undergone RP without any adjuvant treatment. All of the patients had positive surgical margins, extracapsular extension and/or seminal vesicle invasion. The patients underwent multiple ultrasensitive PSA measurements on days 14, 30, 60 and 90 after RP, and subsequently at 3 month intervals. The ability of particular PSA measurements to predict biochemical recurrence (BCR) was assessed using the area under the curve (AUC). A sequential mathematical decision procedure was constructed to create a stratification model. RESULTS: During the median follow-up of 45.9 months, 106 patients (51%) experienced BCR. Prediction of BCR in terms of the AUC for PSA measurements on days 14, 30, 60 and 90 after the surgery was 0.61, 0.70, 0.80 and 0.82, respectively. In the multivariate analysis, only PSA after RP remained as a predictor of progression-free survival (p < 0.001). The stratification model based on calculated cut-off values for PSA on day 30 (0.068 ng/ml) and PSA on day 60 (0.015 ng/ml) reduced the potential overtreatment rate by 37%. CONCLUSIONS: The results imply that ultrasensitive PSA values obtained very early after RP correlate with the presence of recurrent disease in high-risk patients. Incorporating these readily available variables into risk stratification models may help to individualize the administration of adjuvant radiotherapy and thus to minimize overtreatment.

Phase I/II clinical trial of dendritic-cell based immunotherapy (DCVAC/PCa) combined with chemotherapy in patients with metastatic, castration-resistant prostate cancer.

PURPOSE: We conducted an open-label, single-arm Phase I/II clinical trial in metastatic CRPC (mCRPC) patients eligible for docetaxel combined with treatment with autologous mature dendritic cells (DCs) pulsed with killed LNCaP prostate cancer cells (DCVAC/PCa). The primary and secondary endpoints were safety and immune responses, respectively. Overall survival (OS), followed as a part of the safety evaluation, was compared to the predicted OS according to the Halabi and MSKCC nomograms. EXPERIMENTAL DESIGN: Twenty-five patients with progressive mCRPC were enrolled. Treatment comprised of initial 7 days administration of metronomic cyclophosphamide 50 mg p.o. DCVAC/PCa treatment consisted of a median twelve doses of 1 × 107 dendritic cells per dose injected s.c. (Aldara creme was applied at the site of injection) during a one-year period. The initial 2 doses of DCVAC/PCa were administered at a 2-week interval, followed by the administration of docetaxel (75 mg/m2) and prednisone (5 mg twice daily) given every 3 weeks until toxicity or intolerance was observed. The DCVAC/PCa was then injected every 6 weeks up to the maximum number of doses manufactured from one leukapheresis. RESULTS: No serious DCVAC/PCa-related adverse events have been reported. The median OS was 19 months, whereas the predicted median OS was 11.8 months with the Halabi nomogram and 13 months with the MSKCC nomogram. Kaplan-Meier analyses showed that patients had a lower risk of death compared with both MSKCC (Hazard Ratio 0.26, 95% CI: 0.13-0.51) and Halabi (Hazard Ratio 0.33, 95% CI: 0.17-0.63) predictions. We observed a significant decrease in Tregs in the peripheral blood. The long-term administration of DCVAC/PCa led to the induction and maintenance of PSA specific T cells. We did not identify any immunological parameter that significantly correlated with better OS. CONCLUSIONS: In patients with mCRPC, the combined chemoimmunotherapy with DCVAC/PCa and docetaxel was safe and resulted in longer than expected survival. Concomitant chemotherapy did not preclude the induction of specific anti-tumor cytotoxic T cells.

The use of early postoperative prostate-specific antigen to stratify risk in patients with positive surgical margins after radical prostatectomy.

BACKGROUND: It is well recognized that the presence of positive surgical margins (PSM) after radical prostatectomy (RP) adversely affects cancer specific outcomes and recent evidence from randomized trials supports the use of adjuvant radiotherapy in these cases. However, not all of the patients with PSM develop disease recurrence and the policy of adjuvant radiation could result in considerable over-treatment. We investigated the ability of early postoperative prostate specific antigen (PSA) and PSA decline rates to stratify the risk of disease progression during the first weeks after the surgery thereby allowing adequate time for planning eventual adjuvant therapy. METHODS: We studied 116 consecutive patients with the finding of PSM after RP for localized prostate cancer between 2001 and 2012. No patients were treated with radiation or hormonal therapy. An intensive postoperative PSA monitoring using ultrasensitive assay started first at day 14 after the surgery, then at day 30, 60, 90 and 180, and subsequently in 3 monthly intervals. Biochemical recurrence (BCR) presented the failure of surgical treatment and it was defined as PSA ≥0.2 ng/ml. The ability of PSA decline parameters to predict BCR was assessed using Cox regression model and area under the curve (AUC) calculation. RESULTS: Overall 55 (47%) patients experienced BCR during median follow-up of 31.4 months (range 6-69). Preoperative PSA, pathologic Gleason sum and pathologic grade failed to reveal any association with observation of BCR. Postoperative PSA levels achieved significant predictive accuracy already on day 30 (AUC 0.74). PSA >0.073 ng/ml at day 30 increased significantly the risk of BCR (HR 4.35, p < 0.001). Predictive accuracy was significantly exceeded on day 60 (AUC 0.84; p < 0.001), while further enhancements on day 90 (AUC 0.84) and 180 (AUC 0.91) were not significant. CONCLUSIONS: The level of ultrasensitive PSA yields valuable information about the prostatectomy outcome already at the first month after the surgery and should aid risk stratification in patients with PSM. Patients not likely to experience subsequent disease progression may be spared the toxicity of immediate adjuvant radiotherapy.

Regulatory T cells, dendritic cells and neutrophils in patients with renal cell carcinoma.

We evaluated dendritic cells (DC), regulatory T lymphocytes (Treg) and neutrophils in 37 patients with newly diagnosed renal cell carcinoma (RCC) in the tumor and peripheral blood (PB) and correlated these parameters with tumor staging (early-T1, 2, late-T3, 4 and metastatic disease). The number of myeloid and plasmacytoid DC in blood of RCC patients was higher than in healthy controls. The percentage of myeloid dendritic cells (mDC) from CD45+ cells in tumors was higher in comparison with peripheral blood irrespective of disease stage. Higher percentage of these cells expressed a maturation marker in the periphery in the early stage (CD83 expressing cells). The number of plasmacytoid dendritic cells (pDC) in PB was similar in both early and late stage groups, but the early group displayed a significantly higher percentage of pDC in tumor cell suspension. Neutrophil counts in the peripheral blood of RCC patients were higher than in healthy controls, but the counts in both tumor stage groups were similar. The proportion of neutrophils from CD45+ cells was higher in late stage tumors. Higher percentage of Treg from CD4+ cells was detected in renal carcinoma tissue in comparison to PB with no difference between stages of the disease. Our results reflect the complex interplay between various cells of the immune system and the tumor microenvironment. Activation of dendritic cell subpopulations at early stages of the disease course is counterbalanced by the early appearance of T regulatory cells both in the periphery and tumor tissue. Later stages are characterized by the accumulation of neutrophils in the tumor. Appropriate timing of anticancer strategies, especially immunotherapy, should take these dynamics of the immune response in RCC patients into account.

Parameters derived from the postoperative decline in ultrasensitive PSA improve the prediction of radical prostatectomy outcome.

PURPOSE: Contemporary tools estimating increased risk of prostate cancer (PCa) relapse after radical prostatectomy (RP) are far from perfect and there has been an intensive search for additional predictive variables. We aimed to explore whether the parameters of postoperative ultrasensitive prostate-specific antigen (PSA) decline provide additional information for predicting PCa progression. METHODS: A total of 319 consecutive men, with at least 2 years of follow-up after RP for clinically localized PCa were subjected to this study. Intensive postoperative measurements of ultrasensitive PSA resulted in total of 4028 PSA values available for statistical evaluation. Biochemical recurrence (BCR) was defined as PSA ≥0.2 ng/ml. The accuracy of predictive models was quantified with the area under the curve. RESULTS: Over a median follow-up of 43 months (24-99 months), 107 patients (34%) experienced BCR after RP. In patients with BCR, significantly higher values of PSA nadir (p < 0.001) and a decreased time interval from surgery to reach PSA nadir (p < 0.001) were observed. A multivariable Cox regression model confirmed that PSA nadir >0.01 ng/ml (HR 6.01, 95% CI: 3.89-9.52) and time to PSA nadir <3 months (HR 2.86, 95% CI: 1.74-5.01) were independent predictors of BCR. The inclusion of PSA nadir and the time to PSA nadir into the model resulted in improvement of predictive accuracy by 16% over the model designed on the basis of established parameters. CONCLUSIONS: Our results demonstrate that the level of PSA nadir and the time to PSA nadir determined by ultrasensitive assay significantly improve the identification of patients who are at high risk of disease recurrence after RP.

Gender reassignment surgery in male-to-female transsexualism: A retrospective 3-month follow-up study with anatomical remarks.

INTRODUCTION: Greater acceptance of sexual minorities has enabled people with transsexualism access to adequate treatment and social integration. Gender reassignment surgery is a complex phase in the care of transsexual patients. In response to a greater volume of patients, surgical techniques have evolved and the outcome in patients with male-to-female transsexualism is now a very accurate imitation of female genitalia, enabling sexual intercourse with orgasm. AIM: To evaluate the results of surgical reassignment of genitalia in male-to-female transsexuals. METHODS: A retrospective 3-month follow-up study of patients' opinions following gender reassignment surgery in 129 patients having a primary procedure (eight of whom had later sigmoideocolpoplasty) and five patients undergoing reoperation following an initial unsuccessful procedure at other units. All patients were male transsexuals. The surgical techniques are described in detail. MAIN OUTCOME MEASURES: Sexual functions and complications 3 months after surgery. RESULTS: All patients were satisfied with the first phase operation. Thirteen patients (9.7%) underwent successful sigmoideocolpoplasty. Main complications were as follows: rectal lesions developing during preparation of the vaginal canal (1.5%); bleeding from the stump of the shortened urethra in the first 48 hours postoperatively requiring secondary suturing (4.5%); temporary urinary retention requiring repeated insertion of urinary catheters for up to 6 days (5.2%); and healing of the suture between the perineum and the posterior aspect of the vaginal introitus healing by secondary intention (5.2%). The neoclitoris had erogenous sensitivity in 93.9% of patients and 65.3% reached orgasm in the first 3 months. CONCLUSIONS: Surgical conversion of the genitalia is a safe and important phase of the treatment of male-to-female transsexuals.

Influence of tumour-associated symptoms on the prognosis of patients with renal cell carcinoma.

OBJECTIVE: To evaluate the prognostic significance of symptoms related to renal cell carcinoma (RCC) in comparison with incidentally detected tumours in a group of long-term observed patients. MATERIAL AND METHODS: The study included 396 patients operated for RCC between 1982 and 2001. The patients were classified according to age, gender, detection mode, pathological stage and grade, tumour size, nodal involvement and Eastern Cooperative Oncology Group (ECOG) performance status. Special attention was given to the analysis of duration and quality of symptoms. The endpoint of the study was overall survival, which was assessed with univariate and multivariate analyses using the Kaplan-Meier method, log-rank test and Cox proportional hazards model. RESULTS: Of the 396 patients, 135 (34%) and 261 (66%) presented with incidental and symptomatic RCC, respectively. Compared with incidental cases, symptomatic tumours had significantly larger size (p < 0.0001), and higher pathological stage (p < 0.0001) and grade (p < 0.02). Five-year survival in patients with incidental and symptomatic tumours was 88.1% and 59.4% (p < 0.0001), respectively. In relation to the quality of symptoms, the 5-year survival in patients with local and systemic symptoms was 75.4% and 44.4% (p < 0.0001), respectively. In the group of patients with a history of tumour-related symptoms shorter and longer than 3 months, the 5-year survival was 62.2% and 55.6% (p < 0.0001), respectively. Multivariate analysis found tumour size [hazard ratio (HR) 1.22, p = 0.05] tumour grade (HR 1.44, p = 0.002), tumour stage (HR 1.35, p = 0.001), presence of symptoms (HR 1.36, p = 0.004) and ECOG (HR 1.25, p = 0.005) to be independent prognostic variables. CONCLUSION: Preoperative somatic symptoms and performance status in patients with RCC provide readily available prognostic information in addition to tumour size, stage and grade.

Clinical implications of a close vicinity of nervus dorsalis penis/clitoridis and os pubis.

INTRODUCTION: Close relation of nervus dorsalis penis/clitoris and os pubis has a major impact in surgical disciplines. AIM: To summarize a current knowledge about this region, represented by the course of sulcus nervi dorsalis penis/clitoridis. METHODS: Literature search of years 1970-2007. MAIN OUTCOME MEASURES: In male, it accommodates nervus dorsalis penis whereas in female nervus et arteria dorsalis clitoridis. Lateral border of sulcus nervi dorsalis penis corresponds to vertical ridge and lateral border of sulcus nervi dorsalis clitoridis to ventral arc-two parameters, which are parts of the Phenice's method for sexing of isolated os pubis. RESULTS: Exact preparation of nervus dorsalis penis is crucial in correct performance of conversion of genitalia in patients with transsexualism, in reconstruction of posterior urethra, in hypospadia, during performance of penile blockade during circumcision and in revascularization surgery of erectile dysfunction. Possible role of the sulcus nervi dorsalis penis in the Alcock's syndrome is discussed. Similarly, it is advisable to take care of nervus dorsalis clitoridis during reduction clitoridoplasty in patients with adrenogenital syndrome and during the insertion of transobturator vaginal tape. Injury of nervus dorsalis penis/clitoridis leads to hypesthesia or anesthesia of glans penis/clitoridis. The injury to arteria dorsalis clitoridis leads to bleeding and/or hematoma. CONCLUSIONS: Clinical anatomy of sulci is important in several situations in urologic surgery. It is possible to use sulcus nervi dorsalis penis/clitoridis for sexing of isolated pubis for anthropological or forensic purposes.

Sulcus nervi dorsalis penis/clitoridis: anatomic structure and clinical significance.

OBJECTIVES: The aim of this study was to correlate the anatomic and clinical significance of the prepubic course of dorsal nerve of penis and its groove on the pubic bone from the perspective of the surgeon. METHODS: The course of the dorsal nerve of the penis/clitoris was studied in six male and six female formalin-fixed cadavers. Several parameters of the pubis were quantified and analysed in 286 isolated pelvises. RESULTS: The course of the dorsal nerve of the penis is described in detail. This pubic sulcus was present in a majority of the pelvises examined. The dorsal nerve of the penis filled this groove, which we term the "sulcus nervi dorsalis penis/clitoridis." In contrast, the dorsal nerve and artery of the clitoris coursed in this groove in women. CONCLUSIONS: The course of dorsal nerve of the penis is described in detail including a previously unreported pubic structure-"sulcus nervi dorsalis penis/clitoridis." In the majority of individuals, the dorsal nerve of the penis/clitoris courses through the sulcus in the pubis. Based on the anatomy of the pelvic region, compression of the dorsal nerve is more apt to occur at the inferior border of the pubis or in the pubic sulcus than in the pudendal canal.