Extraperitoneal cystectomy with ureterocutaneostomy derivation in fragile patients - should it be performed more often?

INTRODUCTION AND OBJECTIVES: Radical cystectomy (RC) continues to be standard of care for muscle-invasive bladder cancer and recurrent or refractory nonmuscle invasive bladder cancer. Unfortunately, it has high rates of perioperative morbidity and mortality. One of the most important predictors of postoperative outcomes is frailty, while the majority of complications are diversion related. The aim of our study was to evaluate safety of extraperitoneal cystectomy with ureterocutaneostomy in patients considered as frail. MATERIALS AND METHODS: We retrospectively collected data of frail patients who underwent extraperitoneal cystectomy with ureterocutaneostomy from October 2018 to August 2020 in a single center. We evaluated frailty by assessing patients' age, body mass index (BMI), nutritional status by Malnutrition Universal Screening Tool, overall health by RAI (Risk Analysis Index) and ASA (American Society of Anaesthesiologists) score, and laboratory analyses. We observed intraoperative outcomes and rates of perioperative (within 30 days) and early postoperative (within 90 days) complications (Clavien-Dindo classification). We defined extraperitoneal cystectomy with ureterocutaneostomy as safe if patients did not develop Clavien Dindo IIIb, or worse, complication. RESULTS: A total of 34 patients, 3 female and 31 male, were analyzed. The median age was 77, BMI 26, RAI 28, ASA 3 and the majority had preexisting renal insufficiency. Blood analyses revealed presence of severe preoperative hypoalbuminemia and anemia in half of our cohort. Intraoperative median blood loss was 250 cc, whilst operative time 245 min. During perioperative period 60% of our cohort developed Clavien Dindo II complication and during early postoperative period 32% of patients required readmission. One death occurred during early postoperative period (2.9%). After 12 months of follow-up, we observed stability of the renal function for most patients. CONCLUSIONS: We believe that extraperitoneal cystectomy with ureterocutaneostomy could be considered as a treatment option for elderly and/or frail patients.

Age above 70 years and Charlson Comorbidity Index higher than 3 are associated with reduced survival probabilities after radical cystectomy for bladder cancer. Data from a contemporary series of 334 consecutive patients.

OBJECTIVE: To assess the joint effect of age and comorbidities on clinical outcomes of radical cystectomy (RC). METHODS: 334 consecutive patients undergoing open RC for bladder cancer (BC) during the years 2005-2015 were analyzed. Pre-, peri- and post-operative parameters, including age at RC (ARC) and Charlson Comorbidity Index (CCI), were evaluated. Overall and cancer-specific survivals (OS, CSS) were assessed by univariate and multivariate modelling. Furthermore, a three-knot restricted cubic spline (RCS) was fitted to survival data to detect dependency between death-rate ratio (HR) and ARC. RESULTS: Median follow-up time was 3.8 years (IQR = 1.3-7.5) while median OS was 5.9 years (95%CL = 3.8-9.1). Globally, 180 patients died in our cohort (53.8%), 112 of which (62.2%) from BC and 68 patients (37.8%) for unrelated causes. After adjusting for preoperative, pathological and perioperative parameters, patients with CCI > 3 showed significantly higher death rates (HR = 1.61; p = 0.022). The highest death rate was recorded in ARC = 71-76 years (HR = 2.25; p = 0.034). After fitting an RCS to both OS and CSS rates, two overlapping nonlinear trends, with common highest risk values included in ARC = 70-75 years, were observed. CONCLUSIONS: Age over 70 years and CCI > 3 were significant factors limiting the survival of RC and should both be considered when comparing current RC outcomes.

Dermal graft surgery for Peyronie's disease: Long term results at a 15 years follow-up.

OBJECTIVES: To evaluate long-term outcomes of patients subjected to corporoplasty, plaque incision and excision, and autologous dermal grafting, with at least 15 years of follow-up. METHODS: The charts of consecutive patients with a penile curvature and a minimum of 15 years follow up were retrospectively reviewed. The patients underwent corporoplasty and penile straightening with autologous dermal grafting, harvested at the level of the anterior-superior iliac spine. At the time of the follow-up, a postoperative IIEF - 5 questionnaire was administered by telephonic interview, and patients were also asked to complete an 8 items self-evaluation questionnaire. After signing informed consent, the patients were invited to undergo dynamic and basal penile sonography, as well as injection of 10 mcg of PGE1 for dynamic evaluation of the graft. RESULTS: A total of 16 patients were identified. Penile shortening of up to 1.5 cm was reported in about 40% of cases and residual bending was reported by 4 of 16 patients. However, there was no impairment in penetration. On physical examination of the suture site, a small indurated nodule was palpable in two patients. Data regarding the dynamic sonography is available for the 5 patients who accepted to undergo the test. No sign of a fibrotic reaction or calcification was detected in the static phase. After injection of 10 mcg PGE-1, in comparison to the basal measurement, the dermal grafts showed compliant length adaptation. CONCLUSIONS: Dermal graft substitution surgery for Peyronie's disease allows to obtain good functional results with durable satisfaction of the patients on long term follow up.

OBJETIVOS: Evaluar los resultados a largo plazo de los pacientes sometidos a corporoplastia, incisión y escisión de la placa, e injerto dérmico autólogo, con al menos 15 años de seguimiento. MÉTODOS: Revisamos retrospectivamente las historias clínicas de los pacientes con incurvación peneana y un mínimo de 15 años de seguimiento. Los pacientes fueron sometidos consecutivamente a corporoplastia y corrección de la curvatura con injerto dérmico autólogo, obtenido a nivel de la espina iliaca antero-superior. En el seguimiento, se pasó el cuestionario IIEF-5 postoperatorio mediante entrevista telefónica, y también se pidió a los pacientes completar un cuestionario de autoevaluación de 8 preguntas. Después de firmar un consentimiento informado, los pacientes fueron invitados a realizar ecografía peneana dinámica y basal, así como inyección de 10 mcg de PGE1, para la evaluación dinámica del injerto. RESULTADOS: Fueron identificados un total de 16 pacientes. Cerca del 40% de los casos comunicaban un acortamiento del pene de hasta 1,5 cm y 4 de 16 pacientes referían incurvación residual. Sin embargo, no había empeoramiento de la penetración. En la exploración física del sitio de la sutura, en dos pacientes era palpable un pequeño nódulo indurado. Los datos referentes a la ecografía estaban disponibles en los 5 pacientes que aceptaron realizar la prueba. En la fase estática no se detectaron signos de reacción fibrótica o calcificación. Después de la Inyeccion de 10 mcg de PGE-1, los injertos dérmicos mostraron una adaptación longitudinal adecuada en comparación con la medición basal. CONCLUSIONES: En la enfermedad de La Peyronie, la cirugía de substitución con injerto dérmico permite obtener buenos resultados funcionales con satisfacción de los pacientes perdurable en el seguimiento a largo plazo.

Dermal graft surgery for peyronie’s disease: long term results at a 15 years follow-up / Cirugía con injerto dérmico en la enfermedad de Peyronie: resultados a largo plazo a los 15 años de seguimiento

Objectives: To evaluate long-term outcomes of patients subjected to corporoplasty, plaque incision and excision, and autologous dermal grafting, with at least 15 years of follow-up. Metethos: The charts of consecutive patients with a penile curvature and a minimum of 15 years follow up were retrospectively reviewed. The patients underwent corporoplasty and penile straightening with autologous dermal grafting, harvested at the level of the anterior-superior iliac spine. At the time of the follow-up, a postoperative IIEF - 5 questionnaire was administered by telephonic interview, and patients were also asked to complete an 8 items self-evaluation questionnaire. After signing informed consent, the patients were invited to undergo dynamic and basal penile sonography, as well as injection of 10 mcg of PGE1 for dynamic evaluation of the graft. Results: A total of 16 patients were identified. Penile shortening of up to 1.5 cm was reported in about 40% of cases and residual bending was reported by 4 of 16 patients. However, there was no impairment in penetration. On physical examination of the suture site, a small indurated nodule was palpable in two patients. Data regarding the dynamic sonography is available for the 5 patients who accepted to undergo the test. No sign of a fibrotic reaction or calcification was detected in the static phase. After injection of 10 mcg PGE-1, in comparison to the basal measurement, the dermal grafts showed compliant length adaptation. Conclusions: Dermal graft substitution surgery for Peyronie's disease allows to obtain good functional results with durable satisfaction of the patients on long term follow up

Objetivos: Evaluar los resultados a largo plazo de los pacientes sometidos a corporoplastia, incisión y escisión de la placa, e injerto dérmico autólogo, con al menos 15 años de seguimiento. Métodos: Revisamos retrospectivamente las historias clínicas de los pacientes con incurvación peneana y un mínimo de 15 años de seguimiento. Los pacientes fueron sometidos consecutivamente a corporoplastia y corrección de la curvatura con injerto dérmico autólogo, obtenido a nivel de la espina iliaca antero-superior. En el seguimiento, se pasó el cuestionario IIEF-5 postoperatorio mediante entrevista telefónica, y también se pidió a los pacientes completar un cuestionario de autoevaluación de 8 preguntas. Después de firmar un consentimiento informado, los pacientes fueron invitados a realizar ecografía peneana dinámica y basal, así como inyección de 10 mcg de PGE1, para la evaluación dinámica del injerto. Resultados: Fueron identificados un total de 16 pacientes. Cerca del 40% de los casos comunicaban un acortamiento del pene de hasta 1,5 cm y 4 de 16 pacientes referían incurvación residual. Sin embargo, no había empeoramiento de la penetración. En la exploración física del sitio de la sutura, en dos pacientes era palpable un pequeño nódulo indurado. Los datos referentes a la ecografía estaban disponibles en los 5 pacientes que aceptaron realizar la prueba. En la fase estática no se detectaron signos de reacción fibrótica o calcificación. Después de la Inyeccion de 10 mcg de PGE-1, los injertos dérmicos mostraron una adaptación longitudinal adecuada en comparación con la medición basal. Conclusiones: En la enfermedad de La Peyronie, la cirugía de substitución con injerto dérmico permite obtener buenos resultados funcionales con satisfacción de los pacientes perdurable en el seguimiento a largo plazo

Developing a five-step training model for transperineal prostate biopsies in a naïve residents' group: a prospective observational randomised study of two different techniques.

PURPOSE: To evaluate a five-step training model for transperineal prostate biopsies (TPPB) and the differences in terms of the detection rate (DR) and the ease of execution when using either the "fan technique" (FT) or the use of a Free Hand technique (FH). METHODS: A prospective observational randomised study was conducted from September 2015 to November 2017. Six naïve residents, who underwent the same five-steps training model, were randomly subdivided into two different groups of three residents based on the selected TPPB technique: A (FT) and B (FH). Patient characteristics (age, PSA, prostatic volume, DRE, MRI), intraoperative (operative time, number of samples) and postoperative parameters (histologic, pain) were evaluated in the 2 groups. The overall and stratified DR for PSA ranges and prostate volume (PV), operative time and complications were compared. RESULTS: The overall detection rate was very high in both groups (FT 58.2% vs FH 59.6%) and not statistically different between the two techniques. There were no differences in terms of complication rates and pain. The FH showed a better detection rate in prostates smaller than 40 cc (p = 0.023) and a faster operative time (p = 0.025) compared to FT. CONCLUSIONS: Within the TPPB, FH is associated with a higher detection rate in patients with prostate < 40 cc compared to an FT when performed by inexperienced trainees. Standardised training organised in consecutive steps seems to contribute to the achievement of overall high detection rates with both methods.

The pathologist's role in the detection of rare variants of bladder cancer and analysis of the impact on incidence and type detection.

BACKGROUND: Histology is one of the most important factors determining the prognosis of bladder cancers and rare variants are generally associated with decreased disease specific survival compared to pure transitional cell carcinomas. We believe that rare bladder cancer variants are likely underdiagnosed in the absence of a dedicated uro-pathologist in many centers. The objective of this study is to evaluate the contribution of a dedicated uro-pathologist on the identification of rare bladder cancer variants. METHODS: We retrospectively analyzed the clinical and histological records of all patients which underwent a radical cystectomy and lymph node dissection between January 2000 and September 2015. The sample was divided in two groups: Group A, consists of patients who underwent radical cystectomy in the absence of a dedicated uro-pathologist at our institution, whereas the Group B consists of patients who underwent surgery when a dedicated uro-pathology service was available. We then evaluated the impact of a dedicated uro-pathologist on rare variants detection. RESULTS: One hundred thirty-seven out of 551 (24.9%) of patients who underwent RC had at least one rare variant. In Group A 38/238 (16%) of patients showed a rare variant, while 99/313 (31.6%; P<0.001) in group B. Furthermore, the diagnosis of sarcomatoid variant was statistically significantly less common in group A (P=0.0026). The concordance between final radical cystectomy histology and previous transurethral resection of bladder tumor (TURBT) histology was poor in both groups (overall 50.4%). CONCLUSIONS: The presence of a dedicated urological anatomical pathologist is of paramount importance and significantly increases the detection rate of non-transitional cell carcinoma bladder cancer types, but it does not increase the concordance rate between histological diagnoses in TURBT and radical cystectomy specimens.

Large bladder diverticula: a comparison between laparoscopic excision and endoscopic fulguration.

OBJECTIVE: The treatment of bladder diverticula consists of diverticulectomy, mainly by a laparoscopic approach or transurethral resection of the diverticular neck and fulguration of the mucosa. The endoscopic approach is generally dedicated to small diverticula. The aim of this study was to compare laparoscopic diverticulectomy versus endoscopic fulguration for bladder diverticula larger than 4 cm. MATERIALS AND METHODS: A retrospective review of the medical records of consecutive patients undergoing endoscopic or laparoscopic treatment for bladder diverticula larger than 4 cm at two tertiary hospitals was performed. Therapeutic success was defined as either complete resolution or a decrease of at least 80% in the size of the diverticulum. Complications were recorded and graded according to the Clavien-Dindo classification. RESULTS: All patients were treated with transurethral resection of the prostate in the same operative session. The endoscopic group included a cohort of 20 male patients. The median age, diverticular diameter and operative time were 65 years, 7 cm and 62.5 min, respectively. No early postoperative complications were observed. Therapeutic success was achieved in 15 cases (75%). The laparoscopic group included a cohort of 13 male patients with a median age of 63 years and median diverticular diameter of 7.0 cm. The median operative time was 185 min (p < 0.0001). Two grade III postoperative complications were observed (15.3%). Therapeutic success was achieved in all patients (100%). CONCLUSIONS: Acquired bladder diverticula larger than 4 cm can be effectively managed either by a laparoscopic approach or by endoscopic fulguration.

Eleven-year management of prostate cancer patients on active surveillance: what have we learned?

PURPOSE: To evaluate the outcomes of active surveillance (AS) on patients with low-risk prostate cancer (PCa) and to identify predictors of disease reclassification. METHODS: In 2005, we defined an institutional AS protocol (Sorveglianza Attiva Istituto Nazionale Tumori [SAINT]), and we joined the Prostate Cancer Research International: Active Surveillance (PRIAS) study in 2007. Eligibility criteria included clinical stage ≤T2a, initial prostate-specific antigen (PSA) <10 ng/mL, and Gleason Pattern Score (GPS) ≤3 + 3 (both protocols); ≤25% positive cores with a maximum core length containing cancer ≤50% (SAINT); and ≤2 positive cores and PSA density <0.2 ng/mL/cm3 (PRIAS). Switching to active treatment was advised for a worsening of GPS, increased positive cores, or PSA doubling time <3 years. Active treatment-free survival (ATFS) was assessed using the Kaplan-Meier method. Factors associated with ATFS were evaluated with a multivariate Cox proportional hazards model. RESULTS: A total of 818 patients were included: 200 in SAINT, 530 in PRIAS, and 88 in personalized AS monitoring. Active treatment-free survival was 50% after a median follow-up of 60 months. A total of 404/818 patients (49.4%) discontinued AS: 274 for biopsy-related reclassification, 121/404 (30%) for off-protocol reasons, 9/404 (2.2%) because of anxiety. Biopsy reclassification was associated with PSA density (hazard ratio [HR] 1.8), maximum percentage of core involvement (HR 1.5), positive cores at diagnostic biopsy (HR 1.6), older age (HR 1.5), and prostate volume (HR 0.6) (all p<0.01). Patients from SAINT were significantly more likely to discontinue AS than were the patients from PRIAS (HR 1.65, p<0.0001). CONCLUSIONS: Five years after diagnosis, 50% of patients with early PCa were spared from active treatment. Wide inclusion criteria are associated with lower ATFS. However, at preliminary analysis, this does not seem to affect the probability of unfavorable pathology.

"What if ": decisional regret in patients who discontinued active surveillance.

PURPOSE: To investigate the presence of regret in patients about having followed an active surveillance (AS) protocol. The secondary aim was to identify variables that influence regret. METHODS: From February 2006 to May 2014, 204 patients discontinued the AS protocols and were invited to enter the study. Sociodemographic variables were collected at AS enrollment, together with health-related quality of life (Functional Assessment of Cancer Therapy-Prostate version [FACT-P]) and coping (Mini-Mental Adjustment to Cancer). Patients were asked to complete a Treatment Regret Scale as well as the FACT-P questionnaire. Clinical data were gathered, as well as time of stay within the AS protocol, reason for discontinuing AS, kind of post-AS treatment, and time elapsed since AS discontinuation. Questionnaires were completed by 105 patients (51.5% of those who had been invited to enter the study). RESULTS: Most of the patients had a low or null degree of regret on the Treatment Regret Scale from 0 to 100 (82/105 patients [78.1%] obtained a score <30, and about 30% of the sample had a score equal to zero). Only 5 patients (4.7%) scored 60 or more, indicating some degree of regret. None of the statistical tests between regret scores and a number of analyzed variables reached significance. CONCLUSIONS: These results show that the degree of regret about following an AS protocol and after its discontinuation because of entering active treatment was very low. The regret after AS was not related to sociodemographic or clinical factors.

Results of a Randomised Controlled Trial Comparing Intravesical Chemohyperthermia with Mitomycin C Versus Bacillus Calmette-Guérin for Adjuvant Treatment of Patients with Intermediate- and High-risk Non-Muscle-invasive Bladder Cancer.

BACKGROUND: Despite adjuvant intravesical therapy, recurrences in non-muscle-invasive bladder cancer (NMIBC) are still high; therefore, new treatment options are needed. The use of chemohyperthermia (CHT) as an alternative treatment is expanding in Europe. To date, however, there has been a lack of prospective randomised data. OBJECTIVE: To compare CHT using mitomycin C (MMC) with bacillus Calmette-Guérin (BCG) as adjuvant treatment for intermediate- and high-risk NMIBC. DESIGN, SETTING, AND PARTICIPANTS: Between 2002 and 2012, 190 NMIBC patients were randomised in this controlled, open-label, multicentre trial for 1-yr CHT (six weekly treatments and six maintenance treatments) and 1-yr BCG immunotherapy (six weekly treatments and three weekly maintenance treatments at months 3, 6, and 12). Patients and physicians giving the interventions were aware of assignment. This study is registered with ClinicalTrials.gov (NCT00384891). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was 24-mo recurrence-free survival (RFS) in the intention-to-treat (ITT) and per-protocol (PP) analyses in all papillary NMIBC patients (n=147). Analyses were done with the log-rank test and Fisher exact test. All tests were two-sided. RESULTS AND LIMITATIONS: The 24-mo ITT RFS was 78.1% in the CHT group compared with 64.8% in the BCG group (p=0.08). The 24-mo RFS in the PP analysis was 81.8% in the CHT group compared with 64.8% in the BCG group (p=0.02). Progression rates were <2% in both groups. Regarding the side-effects, no new safety concerns were identified. A concern is that this study closed prematurely and thus is underpowered. Furthermore, blinding of treatment for patients and physicians was impossible; this may have resulted in unavoidable bias. CONCLUSIONS: CHT is a safe and effective treatment option in patients with intermediate- and high-risk papillary NMIBC. A significantly higher 24-mo RFS in the CHT group was seen in the PP analysis. Based on the results above, CHT is an option for BCG therapy as adjuvant treatment for intermediate- and high-risk papillary NMIBC. PATIENT SUMMARY: Recurrences in non-muscle-invasive bladder cancer are common, despite adjuvant therapies. We compared 24-mo recurrence-free survival (RFS) with chemohyperthermia (CHT) versus bacillus Calmette-Guérin (BCG) therapy. According to these data, CHT therapy appears to be safe and has higher 24-mo RFS than BCG therapy.

Integrated gene and miRNA expression analysis of prostate cancer associated fibroblasts supports a prominent role for interleukin-6 in fibroblast activation.

Tumor microenvironment coevolves with and simultaneously sustains cancer progression. In prostate carcinoma (PCa), cancer associated fibroblasts (CAF) have been shown to fuel tumor development and metastasis by mutually interacting with tumor cells. Molecular mechanisms leading to activation of CAFs from tissue-resident fibroblasts, circulating bone marrow-derived fibroblast progenitors or mesenchymal stem cells are largely unknown. Through integrated gene and microRNA expression profiling, we showed that PCa-derived CAF transcriptome strictly resembles that of normal fibroblasts stimulated in vitro with interleukin-6 (IL6), thus proving evidence, for the first time, that the cytokine is able per se to induce most of the transcriptional changes characteristic of patient-derived CAFs. Comparison with publicly available datasets, however, suggested that prostate CAFs may be alternatively characterized by IL6 and TGFß-related signatures, indicating that either signal, depending on the context, may concur to fibroblast activation. Our analyses also highlighted novel pathways potentially relevant for induction of a reactive stroma. In addition, we revealed a role for muscle-specific miR-133b as a soluble factor secreted by activated fibroblasts to support paracrine activation of non-activated fibroblasts or promote tumor progression.Overall, we provided insights into the molecular mechanisms driving fibroblast activation in PCa, thus contributing to identify novel hits for the development of therapeutic strategies targeting the crucial interplay between tumor cells and their microenvironment.

Prognostic reclassification of patients with intermediate-risk metastatic germ cell tumors: Implications for clinical practice, trial design, and molecular interrogation.

OBJECTIVES: Approximately one-third of the metastatic germ cell tumors (GCT) in patients are classified as intermediate-risk metastatic GCT, and available guidelines recommend the same treatment of poor-risk cases. Yet the prognosis of these patients is heterogeneous, and consequently refining the intensity of treatment is warranted. We aimed to address the heterogeneity of this category by providing a proof of principle for reclassification attempt. PATIENTS AND METHODS: Data on consecutive patients with intermediate-risk metastatic GCT and who received treatment at Fondazione INT Milano in the time frame between February 1980 and March 2014 were collected. Cox regression analyses were done, evaluating potential prognostic factors for overall survival (OS, primary end point) to first-line therapy. Each factor was evaluated in a multivariable model. Recursive partitioning was performed to define prognostic risk groups. RESULTS: A total of 224 patients were suitable for the present analysis. Median age was 26 years (interquartile range: 22-31), 11 patients (4.9%) had a retroperitoneal primary tumor, 6 yielded seminomatous histology, 85 (37.9%) had lung metastases, and 58 (25.9%) had bulky (i.e.,≥ 10 cm) retroperitoneal lymph nodes. Patients received cisplatin, bleomycin, and etoposide (PEB, n = 199) or vinblastine (PVB, n = 23); however, 2 patients received other treatments. Median follow-up was 135 months (interquartile range: 81-223). Globally, 5-year progression-free survival and OS rates were 72.8% (95% CI: 67.1-79.0) and 86.2% (81.7-91.0), respectively. In the multivariable model for OS, elevated alfa fetoprotein (AFP) level was the only significant prognostic factor (hazard ratio = 1.48, 95% CI: 1.12-1.96). The 2 separate prognostic groups with differential OS outcomes were identified based on the cutoff level of 6,200 IU/ml. The 10-year OS rate was 55.6% (95% CI: 36.6-84.3), and it was 86.7% (95% CI: 82.0-91.7) for those with AFP levels more than (n = 19, 8.5%) and less than (n = 205, 91.5%) the cutoff, respectively. CONCLUSIONS: A small fraction of patients with highly elevated AFP levels have an OS approximating the poor prognostic category, whereas most of them are close to good-risk cases. This might have implications to select outlier patients for clinical trials and molecular characterization.

Clinical Outcomes of Metastatic Poor Prognosis Germ Cell Tumors: Current Perspective From a Referral Center.

BACKGROUND: Survival estimates with first-line treatment for patients with metastatic poor prognosis germ cell tumors (GCT) are still suboptimal in the literature. We conducted a retrospective study to evaluate the outcome of patients referred to our tertiary cancer center. PATIENTS AND METHODS: A retrospective analysis was conducted on patients who received at least first-line chemotherapy at our center. Distribution of clinical characteristics was evaluated in the periods < 1997, 1997 to 2001, 2001 to 2006, and 2007 to 2013. The Kaplan-Meier method was used to estimate progression-free (PFS) and overall survival (OS). Univariable and multivariable Cox models with prespecified clinical variables were undertaken for PFS and OS. All tests and confidence intervals were 2-sided and set at a P = .05 level of significance. RESULTS: Between 1982 and 2013, 168 patients were identified. The median age was 27 years (interquartile range [IQR], 22-34). The presence of liver, bone, or brain metastases trended to greater incidence from 1997 onward (27.5% < 1997 to 55.6% in 2007-2013; χ(2)P = .054). Median follow-up was 102 (IQR, 63-166) months. Global 5-year PFS was 48.5% (95% confidence interval [CI], 41.5-56.8) and OS was 63.2% (95% CI, 56.0-71.2). In multivariable analysis, treatment period was not significantly associated with either PFS (overall P = .229) or OS (overall P = .216). CONCLUSION: In this single-center series of consecutive poor prognosis GCT we could observe greater PFS and OS than the historical estimates. This observation was independent from the period of treatment. Based on the present results, studies focused on improving the outcome in the sole poor-risk cohort should be discouraged. Results were biased by their retrospective quality.

Clinical outcome in testicular sex cord stromal tumors: testis sparing vs. radical orchiectomy and management of advanced disease.

OBJECTIVE: To assess the clinical outcome of testicular sex cord stromal tumors (TSCST) according to management and stage. PATIENTS AND METHODS: Clinical and pathologic features, stage, and treatment of patients with TSCST were retrieved from our database. The Kaplan-Meier method estimated the relapse-free survival and cancer-specific survival. RESULTS: We identified 67 patients between December 1982 and January 2013: 55 patients (82.1%) had a Leydig cell tumor and 11 patients (16.4%) had a Sertoli cell tumor. Four patients (5.9%) presented with gynecomastia. Forty-eight patients (71.6%) had no pathologic risk factor, and patients 3 had ≥3 risk factors. Testis-sparing surgery was performed in 31 patients (46.3%) and orchiectomy in 36 patients (53.7%). The median tumor diameter was 0.7 cm (interquartile range, 0.6-1.3) and 1.5 cm (interquartile range, 0.9-2.6) in the 2 groups, respectively (P, .007 at Mann-Whitney rank-sum test). The 5-year relapse-free survival was 89.4% (95% confidence interval, 75.9%-95.5%) and cancer-specific survival was 90.3% (95% confidence interval, 72.7%-96.7%), respectively. Metastases were documented in 8 patients (11.9%), 5 relapsing after a median follow-up of 37.4 months. All 3 patients with ≥3 risk factors had metastatic disease. Four of 5 patients with retroperitoneal metastases only were cured by retroperitoneal lymph node dissection (3 patients at presentation and 1 during follow-up); 4 patients undergoing chemotherapy progressed and ultimately died of disease. CONCLUSION: Most of the patients with TSCST had a favorable prognosis. Testis-sparing surgery may be feasible and effective in case of small tumors. Few patients had metastatic spread, but only those with nodal metastases may benefit from an early retroperitoneal lymph node dissection. Risk factors associate with disease behavior, but indications to prophylactic intervention remain controversial.

A prognostic model including pre- and postsurgical variables to enhance risk stratification of primary mediastinal nonseminomatous germ cell tumors: the 27-year experience of a referral center.

BACKGROUND: Primary mediastinal germ cell tumors (PMGCTs) poorly benefit from chemotherapy and half of patients die because of disease progression. Enhancing the risk stratification might result in tailoring a more personalized treatment strategy from the time of diagnosis. PATIENTS AND METHODS: Between the years 1985 and 2012, 86 patients with PMGCT were treated at our center. Cox proportional hazards regression analysis was conducted in the population of nonseminomas to examine the prognostic effect of candidate factors on progression-free and OS. OS curves were compared using the Kaplan-Meier method and the log-rank test. RESULTS: Mean age was 29.8 years (range, 15-63 years). Twenty-five patients (29.1%) had lung and 8 (9.3%) liver, bone, or brain metastases. Twelve patients (13.9%) received upfront high-dose chemotherapy and 45 patients (52.3%) underwent surgery after chemotherapy. Cox analyses included 61 evaluable primary mediastinal nonseminomatous germ cell tumors (PMNSGCTs). The final model of factors indicating a poor prognosis included the combination of surgery and histological response (overall P = .011) and lung metastases (hazard ratio, 3.03; 95% confidence interval, 1.12-8.15; P = .028). The model showed a bootstrap-corrected Harrel c-statistic for OS of 0.66. A risk stratification model based on the combination of these factors and accounting for a 50% 5-year survival cutoff identified 2 groups (poor prognosis, n = 33 vs. good prognosis, n = 28) with distinct OS curves (P < .001). Preoperative serum tumor marker level was not associated with the final histology (P = .853, χ(2) test). Results were limited by small numbers. CONCLUSION: Patients with PMNSGCT included 2 subpopulations with distinct prognosis, and therapeutic improvements are needed for patients with poor-risk features.

Immunohistochemistry to enhance prognostic allocation and guide decision-making of patients with advanced urothelial cancer receiving first-line chemotherapy.

BACKGROUND: Knowledge of the expression of molecular drivers and potentially druggable targets might enhance prognostic classification of M UC. MATERIALS AND METHODS: We analyzed archival tissue from patients with UC who underwent first-line chemotherapy for locally advanced (LA) and M disease between the years 2000 and 2013. The following biomarkers were evaluated using IHC: excision repair cross complementation (ERCC) group 1 (ERCC1), epidermal growth factor receptor (EGFR), HER2, VEGFR-3, PDGFRα, p53, and p63. Expression of ERCC1, EGFR, and HER2 was dichotomized as positive (2+, 3+) or negative (≤ 1+). Cox regression models were used to evaluate the association of biomarker expression with progression-free (PFS) and overall survival (OS), after controlling for known prognostic factors. RESULTS: Since June of 2009, tissues of 88 cases (27 LA, 61 M) were stained. Rates of positive IHC/number evaluable were as follows: ERCC1: 30 of 66 (45%); HER2: 24 of 52 (46%); EGFR: 31 of 54 (57%); VEGFR-3: 50 of 66 (76%); PDGFRα: 10 of 63 (16%); p53: 25 of 56 (45%); and p63: 46 of 53 (87%). In the multivariable model, PDGFRα was significantly prognostic for poorer PFS (hazard ratio [HR], 2.53; 95% confidence interval [CI], 1.01-6.37; P = .047) and trended to significance for poorer OS (HR, 2.66; 95% CI, 0.96-7.42; P = .060) and VEGFR-3 was significantly prognostic for better PFS (HR, 0.33; 95% CI, 0.15-0.74; P = .007) and OS (HR, 0.36; 95% CI, 0.15-0.85; P = .019). The c-index of the model was 0.67 and 0.68 for the 2 end points, respectively. CONCLUSION: Tumor VEGFR-3 and PDGFRα expression appeared to confer a divergent prognostic effect. These data underscore the hurdles in defining the role of angiogenesis as a molecular driver and therapeutic target, and the controversial role of IHC to guide therapeutic decision-making.

Postchemotherapy lymphadenectomy in patients with metastatic urothelial carcinoma: long-term efficacy and implications for trial design.

BACKGROUND: The contribution of postchemotherapy pelvic (PLND) or retroperitoneal lymphadenectomy (RPLND) on survival in patients with advanced and metastatic UC is still unclear. PATIENTS AND METHODS: Between September 1986 and May 2012, 157 patients with locally advanced or metastatic UC received first-line chemotherapy consisting of mMVAC (modified methotrexate, vinblastine, doxorubicin, and cisplatin), according to our policy. Patients with subdiaphragmatic nodal disease and/or local recurrence only and who experienced at least stable disease (SD) were selected. Fifty-nine patients were identified, 28 of whom underwent surgery, 31 started consolidation chemotherapy with or without radiotherapy or observation. The prognostic effect of candidate factors on survival was evaluated using Cox proportional hazard regression models. RESULTS: A total of 14 PLND and 14 RPLND patients were identified after they had achieved a complete response (CR; n = 7) or a partial response (PR) and SD (n = 21). Median follow-up was 88 months (interquartile range, 24-211 months). Median PFS was 18 (95% confidence interval [CI], 11-not estimated) and 11 (95% CI, 5-19) months, respectively, in favor of the surgical cohort and curves were statistically different (log-rank test, P = .009). In multivariate analysis, postchemotherapy surgery was significantly prognostic for PFS and OS and response to chemotherapy (PR and SD vs. CR) was prognostic for PFS and trended to significance for OS. A model including these 2 factors showed bootstrap-corrected Harrel C statistics for PFS and OS of 0.65 and 0.68, respectively. CONCLUSION: In well selected patients with UC like those who achieved a clinical benefit with chemotherapy and had nodal metastatic disease, there was a survival advantage in removal of disease residuals.

Recurrence and progression in patients with non-muscle invasive bladder cancer: prognostic models including multicolor fluorescence in situ hybridization molecular grading.

OBJECTIVE: To test the prognostic value of multicolor fluorescence in situ hybridization analyses of tumor cells in urine for prediction of the recurrence and progression of tumor in patients with intermediate risk non-muscle invasive bladder cancer. METHODS: A total of 168 patients with non-muscle invasive bladder cancer were included in the study. Fluorescence in situ hybridization was carried out on the bladder wash urine collected before resection. Tumors were classified as low molecular grading if they had a diploid chromosomal pattern or only a loss of p16 or ch3 aneuploidy, and as high molecular grading if they showed aneuploidy of ch7 or 17. Cox regression models assessed the added prognostic value of fluorescence in situ hybridization for primary tumor recurrence or progression, respectively. RESULTS: Median follow up was 67 months. A total of 57% of tumors were classified as low molecular grading. The 2- and 5-year recurrence-free survival was 68% and 49% for low molecular grading, and 47% and 30% for high molecular grading, respectively. The 2- and 5-year progression-free survival was 95% and 84% for low molecular grading, and 79% and 58% for high molecular grading tumor patients, respectively. Molecular grading (hazard ratio 1.60; P = 0.03) was associated with recurrence, when also accounting for histopathology and a patient's characteristics. Both cancer severity score (hazard ratio 1.51; P < 0.01) and molecular grading (hazard ratio 2.53; P < 0.01) independently and positively predicted progression in multivariable models. The C-index for predicting recurrence increased from 0.58 to 0.61 when molecular grading fluorescence in situ hybridization was included in the model, and from 0.68 to 0.72 when predicting progression. CONCLUSIONS: Fluorescence in situ hybridization-based molecular grading increases the accuracy of a prognostic model, predicting both recurrence and progression in patients with intermediate risk non-muscle invasive bladder cancer.