Hartwig Büttner

HER2 overexpression in muscle‐invasive urothelial carcinoma of the bladder: Prognostic implications

The HER2 (c‐erbB‐2) receptor is overexpressed in a variety of human malignant tumors and, in breast carcinoma, has been identified as a target for anti‐HER2–directed therapy with the monoclonal antibody (MAb) trastuzumab. The aim of this retrospective study was to evaluate immunohistochemic HER2 expression in a large cohort of muscle‐invasive urothelial cell carcinomas of the urinary bladder and to compare the results to pathologic characteristics and survival. Paraffin‐embedded tumor specimens from 138 patients undergoing radical cystectomy for muscle‐invasive bladder carcinoma were studied immunohistochemically with the Food and Drug Administration (FDA)‐approved HercepTest (Dako, Glostrup, Denmark). HER2 overexpression was observed in 57 of 138 tumors (41%) and occurred more frequently in high‐grade carcinomas than in low‐grade carcinomas (p = 0.036). No significant relationship with HER2 overexpression was registered for tumor staging and lymph node status. Kaplan‐Meier curves showed a significantly worse disease‐related survival (p = 0.034) in patients with HER2‐overexpressing tumors compared to those without HER2 overexpression. In addition to lymph node status (p = 0.0001; relative risk [RR] = 2.93), HER2 status (p = 0.020; RR = 2.22) was identified as an independent predictor for disease‐related survival in a multivariate analysis. These results suggest that HER2 expression might provide additional prognostic information in patients with muscle‐invasive bladder carcinomas. Because many of these patients harbor HER2‐overexpressing tumors, clinical trials evaluating the efficacy of trastuzumab in bladder carcinoma are warranted.

Effects of Tadalafil Treatment on Erectile Function Recovery Following Bilateral Nerve-sparing Radical Prostatectomy: A Randomised Placebo-controlled Study (REACTT)

BACKGROUND The potential rehabilitative and protective effect of phosphodiesterase type 5 inhibitors (PDE5-Is) on penile function after nerve-sparing radical prostatectomy (NSRP) remains unclear. OBJECTIVE The primary objective was to compare the efficacy of tadalafil 5mg once daily and tadalafil 20mg on demand versus placebo taken over 9 mo in improving unassisted erectile function (EF) following NSRP, as measured by the proportion of patients achieving an International Index of Erectile Function-Erectile Function domain (IIEF-EF) score ≥ 22 after 6-wk drug-free washout (DFW). Secondary measures included IIEF-EF, Sexual Encounter Profile question 3 (SEP-3), and penile length. DESIGN, SETTING, AND PARTICIPANTS Randomised, double-blind, double-dummy, placebo-controlled trial in men ≤ 68 yr of age with adenocarcinoma of the prostate (Gleason ≤ 7) and normal preoperative EF who underwent NSRP at 50 centres from nine European countries and Canada. INTERVENTIONS 1:1:1 randomisation to 9 mo of treatment with tadalafil 5mg once daily, tadalafil 20mg on demand, or placebo followed by a 6-wk DFW and 3-mo open-label tadalafil once daily (all patients). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Logistic regression, mixed-effects model for repeated measures, and analysis of covariance, adjusting for treatment, age, and country, were applied to IIEF-EF scores ≥ 22, SEP-3, and penile length. RESULTS AND LIMITATIONS Four hundred twenty-three patients were randomised to tadalafil once daily (n=139), on demand (n=143), and placebo (n=141). The mean age was 57.9 yr of age (standard deviation: 5.58 yr); 20.9%, 16.9%, and 19.1% of patients in the tadalafil once daily, on demand, and placebo groups, respectively, achieved IIEF EF scores ≥ 22 after DFW; odds ratios for tadalafil once daily and on demand versus placebo were 1.1 (95% confidence interval [CI], 0.6-2.1; p=0.675) and 0.9 (95% CI, 0.5-1.7; p=0.704). At the end of double-blind treatment (EDT), least squares (LS) mean IIEF-EF score improvement significantly exceeded the minimally clinically important difference (MCID: ΔIIEF-EF ≥ 4) in both tadalafil groups; for SEP-3 (MCID ≥ 23%), this was the case for tadalafil once daily only. Treatment effects versus placebo were significant for tadalafil once daily only (IIEF-EF: p=0.016; SEP-3: p=0.019). In all groups, IIEF-EF and SEP-3 decreased during DFW but continued to improve during open-label treatment. At month 9 (EDT), penile length loss was significantly reduced versus placebo in the tadalafil once daily group only (LS mean difference 4.1mm; 95% CI, 0.4-7.8; p=0.032). CONCLUSIONS Tadalafil once daily was most effective on drug-assisted EF in men with erectile dysfunction following NSRP, and data suggest a potential role for tadalafil once daily provided early after surgery in contributing to the recovery of EF after prostatectomy and possibly protecting from penile structural changes. Unassisted EF was not improved after cessation of active therapy for 9 mo. TRIAL REGISTRATION ClinicalTrials.gov identifier NCT01026818.

Single Postoperative Instillation of Gemcitabine in Patients with Non-muscle-invasive Transitional Cell Carcinoma of the Bladder: A Randomised, Double-blind, Placebo-controlled Phase III Multicentre Study

BACKGROUND Recurrence prophylaxis with intravesical gemcitabine (GEM) was effective and safe in patients with non-muscle-invasive bladder cancer (NMIBC); efficacy as single-shot instillation remains to be proved. OBJECTIVE To compare the efficacy of a single GEM instillation versus placebo (PBO) immediately after transurethral resection (TUR) of tumour in patients with histologically confirmed NMIBC (pTa/pT1,G1-3). DESIGN, SETTING, AND PARTICIPANTS This was a double-blind, randomised, PBO-controlled study in patients with clinical evidence of primary or recurrent NMIBC (Ta/T1,G1-3). Of 355 patients randomised at 24 urologic centres, 328 underwent TUR and received instillation (92.4%; GEM/PBO: 166/162). In case of nonmalignancy, carcinoma in situ (CIS), > or = pT2 disease, or intraoperative complications, patients were discontinued. INTERVENTION We used a single, postoperative 30-40-min instillation of GEM (2000 mg/100 ml of saline) or PBO (100 ml of saline) followed by continuous bladder irrigation for > or = 20 h. A second TUR (no instillation) and adjuvant bacillus Calmette-Guérin (BCG) instillations were allowed. MEASUREMENTS Primary outcome was recurrence-free survival (RFS). Secondary outcomes included type of recurrence and adverse events. To detect a difference in RFS, 191 recurrences were required (80% power, log-rank-test, alpha = 0.050). RESULTS AND LIMITATIONS Two hundred forty-eight patients (69.9%, GEM, PBO: 124, 124) had histologically confirmed pTa/pT1 G1-3 Gx tumour and were eligible for efficacy (GEM: 76.6% male; median age: 65 yr; PBO: 83.1% male; median age: 67 yr). Treatment groups were balanced (pTa: 75.0%, 71.0%; G1-G2: 85.5%, 87.9%; recurrent tumour: 24.2%, 21.0%; BCG: 10.5%, 16.9%). After a median follow-up of 24 mo, there were only 94 recurrences and 11 deaths. The study was terminated early based on predefined decision criteria. RFS was high in both groups (12-mo RFS [95% confidence interval (CI)]: GEM: 77.7% [68.8-84.3]; PBO: 75.3% [66.3-82.3]). There was no significant group difference (hazard ratio [HR]: 0.946 [0.64-1.39], log-rank test, p=0.777). CONCLUSIONS In this study of NMIBC, the immediate single instillation of GEM 2000 mg/100 ml of saline after TUR was not superior to PBO in terms of RFS. Rigid continuous irrigation and improved TUR/cystoscopy techniques may have contributed to the high RFS in both groups.

Leiomyo-adenomatoid Tumor of the Epididymis

Primary tumors of the epididymis are rare. Adenomatoid tumors are the most frequently diagnosed benign tumors of the epididymis and are well known, while leiomyomas are uncommon. We report a case of combined leiomyo-adenomatoid tumor of the right epididymis, which was difficult to diagnose. CASE REPORT A 44-year-old white man presented with a painful right scrotal mass 2 months in duration. History was unremarkable and no other symptoms were reported. Physical examination revealed a 2 3 3 cm. mass at the lower pole of the right testicle. Ultrasound showed a 3 2 cm. combined hypodense and hyperdense mass of the right epididymal tail, which was not clearly separable from the testicle. The right testicle and contralateral scrotal contents were normal. Doppler ultrasound demonstrated enhanced signals of the right rete testis when compared to the contralateral testis. Blood studies, including the tumor markers -fetoprotein, human chorionic gonadotropin, placental alkaline phosphatase and lactate dehydrogenase, revealed normal parameters. Primarily, the patient was thought to have epididymitis and conservative treatment was started. After an initial decrease in symptoms, the patient was referred to our department with recurrent pain and unchanged clinical and sonographic findings 1 month later. Subsequently, right inguinal exploration was performed, during which a firm solid mass arising from the tail of the epididymis was found. Although the mass was firmly adherent to the testicle, epididymectomy was easy to perform. Fresh frozen sections of the tumor were interpreted as leiomyoma of the epididymis. Biopsies of the adjacent testicle were normal. Due to the histological findings, radical orchiectomy was not performed. However, after epididymectomy, routinely processed histological sections of different tumor sites showed a leiomyo-adenomatoid tumor of the epididymis. At 8-month followup the patient was well and without evidence of disease. DISCUSSION

Value of Acute–Phase Proteins in the Differential Diagnosis of Acute Scrotum

Objectives: The evaluation of patients with an acute scrotum is primarily based on physical examination, imaging studies, as well as blood and urine tests. However, the differential diagnosis may be difficult in some cases. In a retrospective study, we investigated the value of acutephase proteins in serum and plasma from patients with an acute scrotum. Methods: A total of 104 patients (epididymitis n=52, testicular tumor n=17, testicular torsion n = 11, other conditions n = 24) with an acute scrotum were included in this study. In all patients the acute–phase proteins C–reactive protein (CRP), haptoglobin, α1–acid glycoprotein and transferrin in serum as well as fibrinogen in plasma were determined by turbidimetric analysis. The results were compared to the clinical findings, routine blood and urine tests and ultrasound. Results: Patients with an epididymitis showed at least a 4–fold elevation of CRP except for 2 cases (median 63.2 mg/l). In these patients, the sensitivity of CRP was 96.2%, the specificity 94.2%, the negative predictive value 94.2% and the positive predictive value 94.3%. Patients with a testicular tumor had no significant elevation of CRP (median 9 mg/l) as well as those with a testicular torsion (median 5 mg/l) except for 1 patient. The difference between patients with epididymitis and those with noninflammatory conditions was statistically significant (p<0.001, Kruskal–Wallis test and Tukey–Kramer test). The remaining parameters (haptoglobin, fibrinogen, a1–acid glycoprotein, transferrin, white blood count, body temperature and ultrasound) were less sensitive and specific. Conclusions: Acute–phase proteins (especially C–reactive protein) are helpful in differentiating epididymitis from noninflammatory conditions like testicular torsion or tumor. Turbidimetric analysis of these proteins is rapid, easy and inexpensive.

Effect of surgical approach on erectile function recovery following bilateral nerve-sparing radical prostatectomy: an evaluation utilising data from a randomised, double-blind, double-dummy multicentre trial of tadalafil vs placebo

To report pre‐specified and exploratory results on the effect of different surgical approaches on erectile function (EF) after nerve‐sparing radical prostatectomy (nsRP) obtained from the multicentre, randomised, double‐blind, double‐dummy REACTT trial of tadalafil (once a day [OaD] or on‐demand [pro‐re‐nata, PRN]) vs placebo.

PRIMARY TREATMENT OF CONDYLOMATA ACUMINATA WITH VIABLE BACILLUS CALMETTE-GUERIN

PURPOSE Condylomata acuminata or genital warts are caused by human papillomavirus. Prevalence data show that infection rates are increasing. To our knowledge we report the first successful primary treatment of genital warts with topical bacillus Calmette-Guerin (BCG) and provide long-term followup in a group of adjuvant treated patients with recurrent condylomata acuminata. MATERIALS AND METHODS In 10 consecutive men viable BCG was directly applied to the condylomata acuminata lesions once weekly for 6 weeks. In nonresponding patients another course of 9 applications was administered for 3 weeks. RESULTS A complete response was achieved in 6 of the 10 men after 1 or 2 treatment cycles. All responding patients are disease-free at a median followup of 9.2 months (range 4 to 12). One patient achieved partial regression of the lesions and in 3 the condylomata did not disappear. Side effects were rare and mild. Long-term followup in 6 adjuvant treated patients with rapidly recurrent condylomata acuminata showed no further recurrence after topical BCG in 5 at a median of 30.8 months (range 29 to 50). CONCLUSIONS Topical application of viable BCG has therapeutic activity as adjuvant and primary treatment for penile condylomata acuminata with negligible side effects. Long-term followup implies the prevention of recurrent disease.

Fatal Basilar Artery Thrombosis after Chemotherapy for Testicular Cancer

We report a 31-year-old patient with a pT3N2M1 seminoma who received cisplatin-based chemotherapy. During the second course of chemotherapy, the patient suffered a thrombosis of the basilar artery. He died 14 h after hospital admission. Cerebrovascular events related to cisplatin-based chemotherapy are rare, however, these potentially fatal events should be kept in mind when treating patients with testicular cancer.

[Chronic PDE-5 inhibition in patients with erectile dysfunction: new treatment approach using once daily Tadalafil].

Erectile dysfunction (ED) is often associated with increased cardiovascular risk. There is increasing evidence suggesting that dysfunction of the vascular endothelium with reduced bioavailability of nitric oxide (NO) may be the pathogenetic link between ED and cardiovascular disease. The crucial importance of the NO-guanylatecyclase-cGMP-phosphodiesterase pathway for penile erection is mirrored by the efficacy of phosphodiesterase-5 (PDE5) inhibitors in the treatment of ED. In contrast to other currently available PDE5 inhibitors with a half-life time of about 4 h Tadalafil has a half-life time of about 17.5 h resulting in erectile responsiveness for up to 36 h after 1 single dose. Most clinical experience has been reported with on-demand use of PDE-5 inhibitors, but meanwhile several studies were able to demonstrate that Tadalafil given daily in low (2.5 and 5 mg) doses is both highly effective and well-tolerated. In three randomized, double-blind, placebo-controlled multi-center trials, various validated measures of erectile function indicated that once daily Tadalafil at doses of 2.5, 5, and 10 mg was significantly superior to placebo.In another mono-center trial, once daily Tadalafil has shown significant efficacy even after failure of on-demand treatment. In a controlled cross-over study of on-demand versus daily Tadalafil treatment, 72% of the patients preferred once daily administration, mainly because of superior and longer efficacy allowing a more spontaneous sexual life. Interestingly in a pilot study of on-demand versus chronic administration of Tadalafil for 4 weeks, only regular dosing improved several markers of endothelial function.

Exploratory Decision-Tree Modeling of Data from the Randomized REACTT Trial of Tadalafil Versus Placebo to Predict Recovery of Erectile Function After Bilateral Nerve-Sparing Radical Prostatectomy

BACKGROUND Understanding predictors for the recovery of erectile function (EF) after nerve-sparing radical prostatectomy (nsRP) might help clinicians and patients in preoperative counseling and expectation management of EF rehabilitation strategies. OBJECTIVE To describe the effect of potential predictors on EF recovery after nsRP by post hoc decision-tree modeling of data from A Study of Tadalafil After Radical Prostatectomy (REACTT). DESIGN, SETTING, AND PARTICIPANTS Randomized double-blind double-dummy placebo-controlled trial in 423 men aged <68 yr with adenocarcinoma of the prostate (Gleason ≤7, normal preoperative EF) who underwent nsRP at 50 centers from nine European countries and Canada. INTERVENTION Postsurgery 1:1:1 randomization to 9-mo double-blind treatment with tadalafil 5mg once a day (OaD), tadalafil 20mg on demand, or placebo, followed by a 6-wk drug-free-washout, and a 3-mo open-label tadalafil OaD treatment. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS Three decision-tree models, using the International Index of Erectile Function-Erectile Function (IIEF-EF) domain score at the end of double-blind treatment, washout, and open-label treatment as response variable. Each model evaluated the association between potential predictors: presurgery IIEF domain and IIEF single-item scores, surgical approach, nerve-sparing score (NSS), and postsurgery randomized treatment group. RESULTS AND LIMITATIONS The first decision-tree model (n=422, intention-to-treat population) identified high presurgery sexual desire (IIEF item 12: ≥3.5 and <3.5) as the key predictor for IIEF-EF at the end of double-blind treatment (mean IIEF-EF: 14.9 and 11.1), followed by high confidence to get and maintain an erection (IIEF item 15: ≥3.5 and <3.5; IIEF-EF: 15.4 and 7.1). For patients meeting these criteria, additional non-IIEF-related predictors included robot-assisted laparoscopic surgery (yes or no; IIEF-EF: 19.3 and 12.6), quality of nerve sparing (NSS: <2.5 and ≥2.5; IIEF-EF: 14.3 and 10.5), and treatment with tadalafil OaD (yes and no; IIEF-EF: 17.6 and 14.3). Additional analyses after washout and open-label treatment identified high presurgery intercourse satisfaction as the key predictor. CONCLUSIONS Exploratory decision-tree analyses identified high presurgery sexual desire, confidence, and intercourse satisfaction as key predictors for EF recovery. Patients meeting these criteria might benefit the most from conserving surgery and early postsurgery EF rehabilitation. Strategies for improving EF after surgery should be discussed preoperatively with all patients; this information may support expectation management for functional recovery on an individual patient level. PATIENT SUMMARY Understanding how patient characteristics and different treatment options affect the recovery of erectile function (EF) after radical surgery for prostate cancer might help physicians select the optimal treatment for their patients. This analysis of data from a clinical trial suggested that high presurgery sexual desire, sexual confidence, and intercourse satisfaction are key factors predicting EF recovery. Patients meeting these criteria might benefit the most from conserving surgery (robot-assisted surgery, perfect nerve sparing) and postsurgery medical rehabilitation of EF. TRIAL REGISTRATION ClinicalTrials.gov, NCT01026818.