Tailored immunotherapy approach with nivolumab with or without ipilimumab in patients with advanced transitional cell carcinoma after platinum-based chemotherapy (TITAN-TCC): a multicentre, single-arm, phase 2 trial.

BACKGROUND: Nivolumab is used after platinum-based chemotherapy in patients with metastatic urothelial carcinoma. Studies suggest improved outcomes for dual checkpoint inhibition with high ipilimumab doses. We aimed to examine the safety and activity of nivolumab induction and high-dose ipilimumab as an immunotherapeutic boost as a second-line treatment for patients with metastatic urothelial carcinoma. METHODS: TITAN-TCC is a multicentre, single-arm, phase 2 trial done at 19 hospitals and cancer centres in Germany and Austria. Adults aged 18 years or older with histologically confirmed metastatic or surgically unresectable urothelial cancer of the bladder, urethra, ureter, or renal pelvis were eligible. Patients had to have progression during or after first-line platinum-based chemotherapy and up to one more second-line or third-line treatment, a Karnofsky Performance Score of 70 or higher, and measurable disease as per Response Evaluation Criteria in Solid Tumors version 1.1. After four doses of intravenous nivolumab 240 mg induction monotherapy every 2 weeks, patients with a partial or complete response at week 8 continued maintenance nivolumab, whereas those with stable or progressive disease (non-responders) at week 8 received a boost of two or four doses of intravenous nivolumab 1 mg/kg plus ipilimumab 3 mg/kg every 3 weeks. Patients who subsequently had progressive disease during nivolumab maintenance also received a boost, using this schedule. The primary endpoint was the confirmed investigator-assessed objective response rate in the intention-to-treat population and had to exceed 20% for the null hypothesis to be rejected (based on the objective response rate with nivolumab monotherapy in the CheckMate-275 phase 2 trial). This study is registered with ClinicalTrials.gov, NCT03219775, and is ongoing. FINDINGS: Between April 8, 2019, and Feb 15, 2021, 83 patients with metastatic urothelial carcinoma were enrolled and all received nivolumab induction treatment (intention-to-treat population). The median age of enrolled patients was 68 years (IQR 61-76), and 57 (69%) were male and 26 (31%) were female. 50 (60%) patients received at least one boost dose. A confirmed investigator-assessed objective response was recorded in 27 (33%) of 83 patients in the intention-to-treat population, including six (7%) patients who had a complete response. This objective response rate was significantly higher than the prespecified threshold of 20% or less (33% [90% CI 24-42]; p=0·0049). The most common grade 3-4 treatment-related adverse events were immune-mediated enterocolitis (nine [11%] patients) and diarrhoea (five [6%] patients). Two (2%) treatment-related deaths were reported, both due to immune-mediated enterocolitis. INTERPRETATION: Treatment with nivolumab and nivolumab plus ipilimumab boosts in early non-responders and patients who progress late significantly improved objective response rate after previous platinum-based chemotherapy compared with the rate reported with nivolumab in the CheckMate-275 trial. Our study provides evidence for the added value of high-dose ipilimumab 3 mg/kg and suggests a potential role for the combination as a rescue strategy in platinum-pretreated patients with metastatic urothelial carcinoma. FUNDING: Bristol Myers Squibb.

Value of 68Ga-labeled bombesin antagonist (RM2) in the detection of primary prostate cancer comparing with [18F]fluoromethylcholine PET-CT and multiparametric MRI-a phase I/II study.

OBJECTIVES: The bombesin derivative RM2 is a GRPr antagonist with strong binding affinity to prostate cancer (PCa). In this study, the impact of [68Ga]Ga-RM2 positron emission tomography-computed tomography (PET-CT) for the detection of primary PCa was compared with that of [18F]FCH PET-CT and multiparametric magnetic resonance imaging (mpMRI). METHODS: This phase I/II study was conducted in 30 biopsy-positive PCa subjects. The patients were stratified into high (10 patients), intermediate (10 patients), and low risk (10 patients) for extraglandular metastases as defined by National Comprehensive Cancer Network (NCCN) criteria (NCCN Clinical Practice Guidelines in Oncology, 2016). The prostate gland was classified in 12 anatomic segments for data analysis of the imaging modalities as well as histopathologic findings. The segment with the highest radiotracer uptake was defined as the "index lesion." All cases were scheduled to undergo prostatectomy with pelvic lymph node (LN) dissection in intermediate- and high-risk patients. Intraprostatic and pelvic nodal [68Ga]Ga-RM2 and [18F]FCH PET-CT findings were correlated with mpMRI and histopathologic results. RESULTS: Of the 312 analyzed regions, 120 regions (4 to 8 lesions per patient) showed abnormal findings in the prostate gland. In a region-based analysis, overall sensitivity and specificity of [68Ga]Ga-RM2 PET-CT in the detection of primary tumor were 74% and 90%, respectively, while it was 60% and 80% for [18F]FCH PET-CT and 72% and 89% for mpMRI. Although the overall sensitivity of [68Ga]Ga-RM2 PET-CT was higher compared to that of [18F]FCH PET-CT and mpMRI, the statistical analysis showed only significant difference between [68Ga]Ga-RM2 PET-CT and [18F]FCH PET-CT in the intermediate-risk group (p = 0.01) and [68Ga]Ga-RM2 PET-CT and mpMRT in the high-risk group (p = 0.03). In the lesion-based analysis, there was no significant difference between SUVmax of [68Ga]Ga-RM2 and [18F]FCH PET-CT in the intraprostatic malignant lesions ([68Ga]Ga-RM2: mean SUVmax: 5.98 ± 4.13, median: 4.75; [18F]FCH: mean SUVmax: 6.08 ± 2.74, median: 5.5; p = 0.13). CONCLUSIONS: [68Ga]Ga-RM2 showed promising PET tracer for the detection of intraprostatic PCa in a cohort of patients with different risk stratifications. However, significant differences were only found between [68Ga]Ga-RM2 PET-CT and [18F]FCH PET-CT in the intermediate-risk group and [68Ga]Ga-RM2 PET-CT and mpMRT in the high-risk group. In addition, GRP-R-based imaging seems to play a complementary role to choline-based imaging for full characterization of PCa extent and biopsy guidance in low- and intermediate-metastatic-risk PCa patients and has the potential to discriminate them from those at higher risks. KEY POINTS: • [68Ga]Ga-RM2 is a promising PET tracer with a high detection rate for intraprostatic PCa especially in intermediate-risk prostate cancer patients. • GRPr-based imaging seems to play a complementary role to choline-based or PSMA-based PET/CT imaging in selected low- and intermediate-risk PCa patients for better characterization and eventually biopsy guidance of prostate cancer disease.

Optimal time-point for 68Ga-PSMA-11 PET/CT imaging in assessment of prostate cancer: feasibility of sterile cold-kit tracer preparation?

PURPOSE: In this prospective study, we evaluated the optimal time-point for 68Ga-PSMA-11 PET/CT acquisition in the assessment of prostate cancer. We also examined, for the first time the feasibility of tracer production using a PSMA-11 sterile cold-kit in the clinical workflow of PET/CT centres. METHODS: Fifty prostate cancer patients (25 staging, 25 biochemical recurrence) were enrolled in this study. All patients received an intravenous dose of 2.0 MBq/kg body weight 68Ga-PSMA-11 prepared using a sterile cold kit (ANMI SA, Liege, Belgium), followed by an early (20 min after injection) semi-whole-body PET/CT scan and a standard-delay (100 min after injection) abdominopelvic PET/CT scan. The detection rates with 68Ga-PSMA-11 were compared between the two acquisitions. The pattern of physiological background activity and tumour to background ratio were also analysed. RESULTS: The total preparation time was reduced to 5 min using the PSMA-11 sterile cold kit, which improved the final radionuclide activity by about 30% per single 68Ge/68Ga generator elution. Overall, 158 pathological lesions were analysed in 45 patients (90%) suggestive of malignancy on both (early and standard-delay) 68Ga-PSMA PET/CT images. There was a significant (p < 0.001) increase in SUVmax on delayed images in suspicious prostates (11.6 ± 8.2 to 14.8 ± 1.0) and lymph nodes (LNs; 9.7 ± 5.9 to 12.3 ± 8.8), while bone lesions showed no significant increase (8.5 ± 5.6 to 9.2 ± 7.0, p = 0.188). However, the SUVmax of suspicious lesions on early images was adequate to support the criteria for correct interpretation (mean SUVmax 9.83 ± 6.7).In 26 of 157 lesions, but a decrease in SUV was seen, mostly in subcentimetre lesions in patients with multiple metastases. However, it did not affect the staging of the disease or patient management. The tumour to background ratio of primary prostate lesions and LNs showed a significant (p < 0.001) increase from the early to the standard-delay acquisition, but no significant increase was seen in bony lesions (p = 0.11). CONCLUSION: The PSMA-11 sterile cold kit seems to be feasible for use in routine clinical practice, and it has a shorter radionuclide preparation time and is less operator-dependent than the synthesizer-based production method. In addition, early 68Ga-PSMA-11 PET/CT imaging seems to provide a detection rate comparable with that of standard-delay imaging. Furthermore, the shorter preparation time using the 68Ga-PSMA-11 sterile cold kit and promising value of early PET/CT scanning could allow tailoring of imaging protocols which may reduce the costs and improve the time efficiency in PET/CT centres.

Neoadjuvant Chemotherapy with Gemcitabine plus Cisplatin in Patients with Locally Advanced Bladder Cancer.

BACKGROUND: Neoadjuvant chemotherapy with methotrexate-vinblastine-doxorubicin-cisplatin (MVAC) is the standard of care for muscle-invasive urothelial bladder cancer. Gemcitabine plus cisplatin (GC) shows similar efficacy with less toxicity in the metastatic setting and has therefore often been used interchangeably with MVAC. We report on the efficacy and safety of neoadjuvant GC in patients with locally advanced urothelial cancer. MATERIALS AND METHODS: We prospectively evaluated 87 patients in 2 centers. Their median age was 68 years. Treatment consisted of 3× GC prior to radical cystectomy. The primary endpoint was pathologic response. The secondary endpoints were safety, progression-free survival (PFS), and overall survival (OS). RESULTS: In all, 83 patients finished chemotherapy; 80 patients were evaluable for the primary endpoint. Pathologic complete response (pCR) was achieved in 22.5% and near pCR was seen in 33.7% of the patients. The 1-year PFS rate was 79.5% among those patients achieving ≤pT2 versus 100% among those patients achieving pCR or near pCR (p = 0.041). Five-year OS was 61.8% (95% CI 67.6 to NA). GC was well tolerated. Grade 3/4 toxicities occurred in 38% of the patients. There was no grade 3/4 renal toxicity, febrile neutropenia, or death. CONCLUSION: Neoadjuvant GC is a well-tolerated regimen. Although the pathologic response is lower than that reported with MVAC, our data support GC as a feasible option in the absence of a prospective randomized comparison, particularly for older patients, since its toxicity is lower than that of MVAC.

A European multicenter randomized noninferiority trial comparing 180 W GreenLight XPS laser vaporization and transurethral resection of the prostate for the treatment of benign prostatic obstruction: 12-month results of the GOLIATH study.

PURPOSE: We present the 1-year results of the GOLIATH prospective randomized controlled trial comparing transurethral resection of the prostate to GreenLight XPS for the treatment of men with nonneurogenic lower urinary tract symptoms due to prostate enlargement. The updated results at 1 year show that transurethral resection of the prostate and GreenLight XPS remain equivalent, and confirm the therapeutic durability of both procedures. We also report 1-year followup data from several functional questionnaires (OABq-SF, ICIQ-SF and IIEF-5) and objective assessments. MATERIALS AND METHODS: A total of 291 patients were enrolled at 29 sites in 9 European countries. Patients were randomized 1:1 to undergo GreenLight XPS or transurethral resection of the prostate. The trial was designed to evaluate the hypothesis that GreenLight XPS is noninferior to transurethral resection of the prostate on the International Prostate Symptom Score at 6 months. Several objective parameters were assessed, including maximum urinary flow rate, post-void residual urine volume, prostate volume and prostate specific antigen, in addition to functional questionnaires and adverse events at each followup. RESULTS: Of the 291 enrolled patients 281 were randomized and 269 received treatment. Noninferiority of GreenLight XPS was maintained at 12 months. Maximum urinary flow rate, post-void residual urine volume, prostate volume and prostate specific antigen were not statistically different between the treatment arms at 12 months. The complication-free rate at 1 year was 84.6% after GreenLight XPS vs 80.5% after transurethral resection of the prostate. At 12 months 4 patients treated with GreenLight XPS and 4 who underwent transurethral resection of the prostate had unresolved urinary incontinence. CONCLUSIONS: Followup at 1 year demonstrated that photoselective vaporization of the prostate produced efficacy outcomes similar to those of transurethral resection of the prostate. The complication-free rates and overall reintervention rates were comparable between the treatment groups.

Utilization of a novel valveless trocar system during robotic-assisted laparoscopic prostatectomy.

PURPOSE: To evaluate the effect of a novel valveless trocar system (VTS) on perioperative outcomes in patients undergoing robotic-assisted laparoscopic prostatectomy (RALP). METHODS: A single-institution retrospective review was performed of 792 patients undergoing RALP. Preoperative patient variables, tumor characteristics, and perioperative variables were collected and analyzed. The first 150 patients were excluded from analysis to account for the learning curve of robotic surgery. Univariate and multivariate linear regression models were used to assess factors affecting operative time (ORT). RESULTS: A total of 257 and 385 patients underwent RALP utilizing the VTS and conventional insufflation, respectively. There were no significant differences in American Society of Anesthesiologist score, body mass index (BMI), prostate volume, final Gleason score, estimated blood loss, and complications between the cohorts. The only difference noted was a significantly shorter mean ORT in the VTS cohort (149.5 vs. 170.1 min, p < 0.0001). In light of this finding, further analysis was performed to identify associations with ORT. Multivariable analysis demonstrated that VTS, BMI, final Gleason score, prostate volume, surgeon, and node dissection were significantly associated with ORT. The use of the VTS decreased mean ORT by 23.2 min when controlling for confounding factors (p < 0.001). The performance of a nerve sparing operation was found to decrease ORT by 15.9 min (p < 0.001), though more often performed for lower-risk disease. CONCLUSION: The use of a novel VTS demonstrated decreased ORT in patients undergoing RALP when controlling for confounding factors. Prospective randomized trials are needed to evaluate its ultimate benefit in various surgical cohorts.

Inhibition of smooth muscle force generation by focal adhesion kinase inhibitors in the hyperplastic human prostate.

Smooth muscle contraction may be critical for lower urinary tract symptoms (LUTS) in patients with benign prostate hyperplasia and requires stable anchorage of the cytoskeleton to the cell membrane. These connections are regulated by focal adhesion kinase (FAK). Here, we addressed the involvement of FAK in the regulation of smooth muscle contraction in hyperplastic human prostate tissues. Prostate tissues were obtained from radical prostatectomy. Expression of FAK and focal adhesion proteins was assessed by Western blot analysis and immunohistochemical stainings. Effects of the FAK inhibitors PF-573228 and Y-11 on contraction of prostate strips were examined in the organ bath. Expression of FAK and focal adhesion proteins (integrin-5α, paxilin, and c-Src) was detected by Western blot analysis in prostate samples. By double immunofluorescence staining with calponin and pan-cytokeratin, expression of FAK was observed in stromal and epithelial cells. Immunoreactivity for FAK colocalized with integrin-5α, paxilin, talin, and c-Src. Stimulation of prostate tissues with the α1-adrenergic agonist phenylephrine increased the phosphorylation state of FAK at Tyr³97 and Tyr9²5 with different kinetics, which was blocked by the α1-adrenoceptor antagonist tamsulosin. Norepinephrine and phenylephrine induced concentration-dependent contractions of prostate strips. Both FAK inhibitors PF-573228 and Y-11 significantly inhibited norepinephrine- and phenylephrine-induced contractions. Finally, PF-573228 and Y-11 inhibited contractions induced by electric field stimulation, which was significant at the highest frequency. In conclusion, α1-adrenergic smooth muscle contraction or its regulation involves FAK in the human prostate. Consequently, FAK may be involved in the pathophysiology of LUTS and in current or future LUTS therapies.

Association of diabetes mellitus and metformin use with biochemical recurrence in patients treated with radical prostatectomy for prostate cancer.

PURPOSE: The impact of diabetes mellitus (DM) and metformin use on biochemical recurrence (BCR) in patients treated with radical prostatectomy (RP) remains controversial. METHODS: We retrospectively evaluated 6,863 patients who underwent RP for clinically localized PC between 2000 and 2011. Univariable and multivariable Cox regression models addressed the association of DM and metformin use with BCR. RESULTS: Overall, 664 patients had a diagnosis of DM from which 287 (43 %) were on metformin and 377 (57 %) were on anti-diabetics other than metformin. DM and metformin were not associated with any clinicopathologic features (p values >0.05). Within a median follow-up of 25 months (interquartile range 35 months), 774 (11.3 %) patients experienced BCR. Actuarial 5-year biochemical-free survival was 83 % for non-diabetic, 79 % for diabetic patients without metformin use, and 85 % for diabetic patients with metformin use (log rank p = 0.17). In uni- and multivariable Cox regression analyses with the non-diabetic group as referent, DM without metformin use (HR = 0.99; 95 % CI 0.75-1.30, p = 0.65) and DM with metformin use (HR = 0.84, 95 % CI 0.58-1.22, p = 0.36) were not associated with BCR after RP. A subgroup analysis stratified by nodal status, surgical margins, tumor stage, and Gleason sum did not reveal any significant association between DM, use of metformin and risk of BCR. CONCLUSIONS: We found no association between DM or metformin use and cancer-specific features or BCR in patients treated with RP. The effect of DM and metformin on complications, wound healing and overall survival needs to be assessed in similar cohorts.

Nivolumab + Ipilimumab as Immunotherapeutic Boost in Metastatic Urothelial Carcinoma: A Nonrandomized Clinical Trial.

Importance: Studies with nivolumab, an approved therapy for metastatic urothelial carcinoma (mUC) after platinum-based chemotherapy, demonstrate improved outcomes with added high-dose ipilimumab. Objective: To assess efficacy and safety of a tailored approach using nivolumab + ipilimumab as an immunotherapeutic boost for mUC. Design, Setting, and Participants: In this phase 2 nonrandomized trial, patients with mUC composed 2 cohorts. Cohort 1 received first-line or second-/third-line nivolumab with escalating doses of ipilimumab, and cohort 2 received second-/third-line nivolumab with high-dose ipilimumab. Recruitment spanned 26 sites in Germany and Austria from August 8, 2017, to February 18, 2021. All patients had a 70% or higher Karnofsky Performance Score and measurable disease per Response Evaluation Criteria in Solid Tumours, version 1.1. Interventions: All patients initiated 4 doses of 240-mg nivolumab (1× every 2 wk). Week 8 nonresponders received nivolumab + ipilimumab (1× every 3 wk). Cohort 1 received 2 doses of 3-mg/kg nivolumab + 1-mg/kg ipilimumab followed by 2 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab if no response. Due to safety concerns, cohort 1 treatment was halted, and first-line cohort 2 treatment was not pursued. Cohort 2 received 2 to 4 doses of 1-mg/kg nivolumab + 3-mg/kg ipilimumab. Responders continued with nivolumab maintenance but could receive nivolumab + ipilimumab for later progression. Main Outcomes and Measures: The primary end point was objective response rate. Results: The study comprised 169 patients (118 [69.8%] men; median [range] age, 68 [37-84] years): 86 in cohort 1 (42 first-line; 44 second-/third-line) and 83 in cohort 2. The median (IQR) follow-up times were 10.4 (4.2-23.5) months (first-line cohort 1), 7.5 (3.1-23.8) months (second-/third-line cohort 1), and 6.2 (3.2-22.7) months (cohort 2). Response rates to nivolumab induction were 12/42 (29%, first-line cohort 1), 10/44 (23%, second-/third-line cohort 1), and 17/83 (20%, cohort 2). Response rates to a tailored approach were 20/42 (48% [90% CI, 34%-61%], first-line cohort 1), 12/44 (27% [90% CI, 17%-40%], second-/third-line cohort 1), and 27/83 (33% [90% CI, 23%-42%], cohort 2). Three-year overall survival rates for first-line cohort 1, second-/third-line cohort 1, and cohort 2 using the Kaplan-Meier method were 32% (95% CI, 17%-49%), 19% (95% CI, 8%-33%), and 34% (95% CI, 23%-44%), respectively. Conclusions and Relevance: In this nonrandomized trial, although first-line cohort 1 treatment improved objective response rates, considerable progression events urge caution with this as a first-line therapy. Second-/third-line cohort 1 treatment did not improve response rates compared with nivolumab monotherapy. However, added high-dose ipilimumab may improve tumor response and survival in patients with mUC. Trial Registration: ClinicalTrials.gov Identifier: NCT03219775.

Detection of Recurrence through microRNA-371a-3p Serum Levels in a Follow-up of Stage I Testicular Germ Cell Tumors in the DRKS-00019223 Study.

PURPOSE: Surveillance of clinical stage I (CSI) testicular germ cell tumors (GCT) is hampered by low sensitivity and specificity of current biomarkers for detecting relapses. This study evaluated if serum levels of microRNA371a-3p (M371 test) can: (i) Accurately detect relapses, (ii) detect relapses earlier than conventional technology, and (iii) if elevated postoperative M371 levels may predict relapse. EXPERIMENTAL DESIGN: In a multicentric setting, 258 patients with testicular CSI GCT were prospectively followed by surveillance for a median time of 18 months with serial measurements of serum M371 levels, in addition to standard diagnostic techniques. Diagnostic characteristics of M371 for detecting relapses were calculated using ROC curve analysis. RESULTS: Thirty-nine patients recurred (15.1%), all with elevated M371 levels; eight without relapse had elevations, too. The test revealed the following characteristics: area under the ROC curve of 0.993, sensitivity 100%, specificity 96.3%, positive predictive value 83%, negative predictive value 100%. Earlier relapse detection with the test was found in 28%, with non-significant median time gain to diagnosis. Postoperative M371 levels did not predict future relapse. CONCLUSIONS: The sensitivity and specificity of the M371 test for detecting relapses in CSI GCTs are much superior to those of conventional diagnostics. However, post-orchiectomy M371 levels are not predictive of relapse, and there is no significant earlier relapse detection with the test. In all, there is clear evidence for the utility of the M371 test for relapse detection suggesting it may soon be ready for implementation into routine follow-up schedules for patients with testicular GCT.

Real-World Evidence of Triplet Therapy in Metastatic Hormone-Sensitive Prostate Cancer: An Austrian Multicenter Study.

INTRODUCTION: Two randomized trials demonstrated a survival benefit of triplet therapy (androgen deprivation therapy [ADT]) plus androgen receptor pathway inhibitor [ARPI] plus docetaxel) over doublet therapy (ADT plus docetaxel), thus changing treatment strategies in metastatic hormonesensitive prostate cancer (mHSPC). PATIENTS AND METHODS: We conducted the first real-world analysis comprising 97 mHSPC patients from 16 Austrian medical centers, among them 79.4% of patients received abiraterone and 17.5% darolutamide treatment. Baseline characteristics and clinical parameters during triplet therapy were documented. Mann-Whitney U test for continuous or X²-test for categorical variables was used. Variables on progression were tested using logistic regression analysis and tabulated as hazard ratios (HR), 95% confidence interval (CI). RESULTS: Of 83.5% patients with synchronous and 16.5% with metachronous disease were included. 83.5% had high-volume disease diagnosed by conventional imaging (48.9%) or PSMA PET-CT (51.1%). While docetaxel and ARPI were administered consistent with pivotal trials, prednisolone, prophylactic gCSF and osteoprotective agents were not applied guideline conform in 32.5%, 37%, and 24.3% of patients, respectively. Importantly, a nonsimultaneous onset of chemotherapy and ARPI, performed in 44.3% of patients, was associated with significantly worse treatment response (P = .015, HR 0.245). Starting ARPI before chemotherapy was associated with significantly higher probability for progression (P = .023, HR 15.781) than vice versa. Strikingly, 15.6% (abiraterone) and 25.5% (darolutamide) low-volume patients as well as 14.4% (abiraterone) and 17.6% (darolutamide) metachronous patients received triplet therapy. Adverse events (AE) occurred in 61.9% with grade 3 to 5 in 15% of patient without age-related differences. All patients achieved a PSA decline of 99% and imaging response was confirmed in 88% of abiraterone and 75% of darolutamide patients. CONCLUSIONS: Triplet therapy arrived in clinical practice primarily for synchronous high-volume mHSPC. Regardless of selected therapy regimen, treatment is highly effective and tolerable. Preferably therapy should be administered simultaneously, however if not possible, chemotherapy should be started first.

Quantitative measurement of the androgen receptor in prepuces of boys with and without hypospadias.

UNLABELLED: WHAT'S KNOWN ON THE SUBJECT? AND WHAT DOES THE STUDY ADD?: Despite diverse anatomical and histological trials in humans and animal models, the aetiology of hypospadias remains unknown and currently there is no clear molecular explanation about the emergence of this disease; however, genetic, endocrine and environmental mechanisms have been suggested. The aim of the present study was to quantify and compare the androgen receptor (AR; mRNA and protein) levels in 40 prepuces of boys with and without hypospadias using quantitative real-time polymerase chain reaction, Western Blot and standardised, automated immunohistochemistry. AR mRNA (P = 0.013) and AR protein (P = 0.014) was significantly elevated in the prepuces of boys with hypospadias compared with boys without hypospadias. Altogether our data indicate that elevated AR mRNA and protein levels can be considered as a biochemical response of an AR signalling defect as an identified cause in boys with hypospadias. Additionally, nuclear staining intensity for AR-protein in specimens of boys with hypospadias was higher than in boys with phimosis. OBJECTIVE: To address the role of the androgen receptor (AR) on mRNA and protein levels in prepuces of boys with and without hypospadias. PATIENTS AND METHODS: Data from 40 foreskin specimens of consecutive circumcised boys (20 with vs 20 without hypospadias) were enrolled in this prospective study. After surgery, samples were fixed in formaldehyde and frozen in liquid nitrogen. Total RNA was isolated from frozen tissue and transcribed to complementary DNA. The amount of AR mRNA was measured by quantitative real-time polymerase chain reaction and Western Blot and standardised, automated immunohistochemistry were used to assess AR protein levels. RESULTS: The mean age at time of surgery was 61.8 and 30.9 months in boys without and with hypospadias, respectively. There was penile, coronal and sine hypospadias in seven (35%), nine (45%), and four (20%) boys, respectively. AR mRNA was significantly elevated in the prepuces of boys with hypospadias compared with boys without hypospadias, at a mean (sd) of 28.33 (5.39) vs 15.31 (1.85) (P = 0.013). Furthermore, the amount of AR protein was higher in boys with, compared with boys without hypospadias, at a mean (sd) of 133.25 (6.17) vs 100 (4.45) (P = 0.014). CONCLUSIONS: Different AR mRNA expression and protein levels seem to be an indication of an AR signalling defect as a cause in boys with hypospadias. Decreased AR DNA binding and functional capability may result in a compensatory up-regulation of both AR mRNA and protein. Further studies are necessary to perform structural analysis of the AR and to corroborate these preliminary findings.

Prevalence of the human papillomavirus (HPV) expression of the inner prepuce in asymptomatic boys and men.

OBJECTIVE: To investigate the prevalence of high-risk (HR) and low-risk (LR) human papillomavirus (HPV) in prepuces of boys and men without any HPV related lesions. PATIENTS AND METHODS: Between 2009 and 2011, a total collective of 250 boys and men were investigated in this prospective study. The samples were subdivided into 3 groups regarding their age, consisting of 125 (50%) children (0-10 years), 38 (15.2%) adolescents (11-20 years) and 87 (34.8%) adults (>20 years). In situ hybridization (ISH) was performed to detect HR and LR virus types within the epithelium, followed by microscopic interpretation and determination between episomal and integrative signal pattern. RESULTS: Our results revealed high levels of HPV concentration (HR and LR) in all age groups: HR versus LR positivity was seen in 45.5 versus 35% (children), 60.6 versus 63.6% (adolescents) and 58.3 versus 48.6% (adults). The topmost rate of HR (59.8%)- and LR (50.6%)-positive probes was found in the group with high estimated sexual activity (>14 years). CONCLUSION: Concerning the high prevalence of male HPV infection even in children, indicating non-sexual transmission pathways, inclusion of boys in the vaccination program seems to be required reducing their burden of HPV related disease.

Characterization and root cause analysis of immunogenicity to pasotuxizumab (AMG 212), a prostate-specific membrane antigen-targeting bispecific T-cell engager therapy.

Introduction: In oncology, anti-drug antibody (ADA) development that significantly curtails response durability has not historically risen to a level of concern. The relevance and attention ascribed to ADAs in oncology clinical studies have therefore been limited, and the extant literature on this subject scarce. In recent years, T cell engagers have gained preeminence within the prolific field of cancer immunotherapy. These drugs whose mode of action is expected to potently stimulate anti-tumor immunity, may potentially induce ADAs as an unintended corollary due to an overall augmentation of the immune response. ADA formation is therefore emerging as an important determinant in the successful clinical development of such biologics. Methods: Here we describe the immunogenicity and its impact observed to pasotuxizumab (AMG 212), a prostate-specific membrane antigen (PSMA)-targeting bispecific T cell engager (BiTE®) molecule in NCT01723475, a first-in-human (FIH), multicenter, dose-escalation study in patients with metastatic castration-resistant prostate cancer (mCRPC). To explain the disparity in ADA incidence observed between the SC and CIV arms of the study, we interrogated other patient and product-specific factors that may have explained the difference beyond the route of administration. Results: Treatment-emergent ADAs (TE-ADA) developed in all subjects treated with at least 1 cycle of AMG 212 in the subcutaneous (SC) arm. These ADAs were neutralizing and resulted in profound exposure loss that was associated with contemporaneous reversal of initial Prostate Surface Antigen (PSA) responses, curtailing durability of PSA response in patients. Pivoting from SC to a continuous intravenous (CIV) administration route remarkably yielded no subjects developing ADA to AMG 212. Through a series of stepwise functional assays, our investigation revealed that alongside a more historically immunogenic route of administration, non-tolerant T cell epitopes within the AMG 212 amino acid sequence were likely driving the high-titer, sustained ADA response observed in the SC arm. Discussion: These mechanistic insights into the AMG 212 ADA response underscore the importance of performing preclinical immunogenicity risk evaluation as well as advocate for continuous iteration to better our biologics.

Randomized Phase II Cabazitaxel Dose Individualization and Neutropenia Prevention Trial in Patients with Metastatic Castration-Resistant Prostate Cancer.

PURPOSE: There is ongoing controversy about the recommended dose of cabazitaxel in patients with metastatic castration-resistant prostate cancer (mCRPC). PATIENTS AND METHODS: This multicenter phase II open-label, randomized, parallel-group study compared 3-weekly cabazitaxel at 25 mg/m2 (conventional arm A) with cabazitaxel therapeutic drug monitoring (experimental arm B) in mCRPC. The primary objective was to improve the clinical feasibility rate (CFR), defined as the absence of grade 4 neutropenia or thrombocytopenia, any thrombocytopenia with bleeding, febrile neutropenia, severe nonhematologic toxicity, withdrawal for cabazitaxel-related toxicity, or death. A total of 60 patients had to be randomized to detect a difference in CFR of 35% (power 80%, two-sided alpha 10%). RESULTS: A total of 40 patients were randomized to arm A and 33 patients to arm B. CFR was 69.4% in arm A and 64.3% in arm B (P = 0.79). Week-12 PSA response was 38.5% in both arms. A radiological response by RECIST v.1.1 was seen in 3 (9.7%) patients in arm A versus 6 (23.1%) patients in arm B (P = 0.28), disease progression was higher in arm A compared with arm B (61.3% vs. 30.8%, P = 0.05). Median progression-free survival was longer in arm B compared with arm A (9.5 vs. 4.4 months; HR = 0.46; P = 0.005). Median overall survival was higher in arm B compared with arm A (16.2 vs. 7.3 months; HR = 0.33; P < 0.0001). CONCLUSIONS: Pharmacokinetic-guided dosing of cabazitaxel in patients with mCRPC is feasible and improves clinical outcome due to individual dose escalations in 55% of patients.

Nivolumab Switch Maintenance Therapy After Tyrosine Kinase Inhibitor Induction in Metastatic Renal Cell Carcinoma: A Randomized Clinical Trial by the Interdisciplinary Working Group on Renal Tumors of the German Cancer Society (NIVOSWITCH; AIO-NZK-0116ass).

BACKGROUND: The role of immune checkpoint inhibitor (ICI) maintenance therapy in metastatic renal cell carcinoma (mRCC) is undefined. OBJECTIVE: To determine whether switch maintenance therapy with nivolumab improves clinical outcomes in patients with mRCC with tyrosine kinase inhibitor (TKI) sensitivity. DESIGN, SETTING, AND PARTICIPANTS: This open-label phase 2 trial randomized patients with a partial response or stable disease after 10-12-wk TKI induction therapy to either TKI or nivolumab maintenance. Key inclusion criteria were measurable disease, clear cell histology, Eastern Cooperative Oncology Group performance status (ECOG PS) 0-2, and adequate organ function. INTERVENTION: Intravenous nivolumab 8 × 240 mg every 2 wk, followed by 480 mg every 4 wk or sunitinib 50 mg (4-2 regimen) or pazopanib 800 mg once daily orally. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSES: The primary endpoint was overall survival (OS). Secondary endpoints were the objective response rate (ORR; Response Evaluation Criteria in Solid Tumors v1.1), progression-free survival (PFS), safety (Common Terminology Criteria for Adverse Events v4.03), and patient-reported outcomes (Functional Assessment of Cancer Therapy Kidney Symptom Index). The Kaplan-Meier method, two-sided log-rank tests, and Cox regression models were used for statistical analysis. RESULTS AND LIMITATIONS: Maintenance therapy was nivolumab for 25 patients (51.0%) and TKI for 24 (48.9%). The median age was 65 yr (range 35-79). Nine patients (18.4%) were female, 31 (63.3%) had ECOG PS of 0, and 15 (30.6%) had favorable risk. OS data are immature (17 deaths, 34.7%). The ORR was 20.0% (n = 5) for nivolumab and 52.2% (n = 12) for TKI. PFS was worse with nivolumab (hazard ratio 2.57, 95% confidence interval 1.36-4.89; p = 0.003). Grade ≥3 adverse events occurred in 14 patients (56.0%) with nivolumab and 17 (70.8%) with TKI. A major limitation is early termination of our study. CONCLUSIONS: TKI treatment achieved superior ORR and PFS in comparison to nivolumab maintenance therapy. Our data do not indicate a role for nivolumab switch maintenance in mRCC. PATIENT SUMMARY: Patients with metastatic kidney cancer who experienced a tumor response or disease stabilization after a short period of targeted treatment with a tyrosine kinase inhibitor did not benefit from a switch to the immunotherapy drug nivolumab. Patients who continued their original treatment achieved better responses and a longer time without disease progression. This trial is registered on EudraCT as 2016-002170-13 and on ClinicalTrials.gov as NCT02959554.

Impact of smoking on outcomes of patients with a history of recurrent nonmuscle invasive bladder cancer.

PURPOSE: We investigated the effects of cigarette smoking status, cumulative exposure and time from cessation on disease recurrence and progression in patients with a history of recurrent nonmuscle invasive bladder cancer. MATERIALS AND METHODS: A total of 390 patients with recurrent nonmuscle invasive bladder cancer were treated with transurethral resection of the bladder, of whom 159 (41%) received instillation therapy immediately postoperatively and 73 (19%) received adjuvant intravesical immunotherapy or chemotherapy. Smoking history included smoking status, number of cigarettes per day, smoking duration in years and years since smoking cessation. Cumulative smoking exposure was categorized as light short-term--19 or fewer cigarettes per day and 19.9 years or less, moderate--all combinations except light short-term and heavy long-term, and heavy long-term--20 or greater cigarettes per day and 20 years or greater. RESULTS: A total of 91 (23%), 192 (49%) and 107 patients (28%) were never, former and current smokers, respectively. Of ever smokers 56 (19%), 156 (52%) and 87 (29%) were light short-term, moderate and heavy long-term smokers, respectively. There was no difference in the risk of disease recurrence and progression among current, former and never smokers. On univariable analyses in ever smokers the risk of disease recurrence and progression increased with augmented smoking intensity (p ≤ 0.015), duration (p <0.001) and cumulative exposure (p <0.001). On multivariable analyses cumulative smoking exposure was an independent risk factor for disease recurrence and progression (p ≤ 0.003). Smoking cessation greater than 10 years before treatment was independently associated with decreased disease recurrence compared to current smoking (HR 0.4, p <0.001). In addition, current smokers had worse survival than former smokers, who in turn had worse survival than never smokers (p >0.05). CONCLUSIONS: There is a dose-response relationship of smoking exposure and smoking cessation with disease recurrence and progression in ever smokers with a history of recurrent nonmuscle invasive bladder cancer. These findings support counseling on smoking cessation benefits.

[Importance of genetic testing in prostate cancer]. / Stellenwert der genetischen Testung beim Prostatakarzinom.

Due to the increasing accessibility, molecular diagnostics are becoming more important in urology. There are validated predictive and prognostic biomarkers available for prostate cancer. This has clinical implications for screening diagnosis and personalized treatment options. The best known examples are mutations in the DNA damage repair genes breast cancer 1 (BRCA1) and BRCA2 for which the poly (ADP-ribose) polymerase (PARP) inhibitor olaparib has been approved in 2020. This continuous progress enables a more tumor-specific and personalized treatment for prostate cancer. In order to provide this precision medicine, it is necessary to know the most important basic principles, have a close-knit interdisciplinary cooperation and access to a molecular tumor board due to the increased complexity.

Tailored Immunotherapy Approach With Nivolumab in Advanced Transitional Cell Carcinoma.

PURPOSE: Several anti-programmed cell death (ligand)-1 (PD-[L]1) immune checkpoint inhibitors are approved in advanced/metastatic urothelial carcinoma (mUC). Recently, improved activity of an anti-PD-1/anticytotoxic T-cell lymphocyte-4 (CTLA-4) combination versus anti-PD-1 monotherapy has been reported. We report a response-based approach starting treatment with nivolumab monotherapy with nivolumab/ipilimumab as immunotherapeutic boost. METHODS: After four doses of nivolumab induction, responders continued with nivolumab maintenance therapy. Patients with stable/progressive disease received nivolumab 3 mg/kg plus ipilimumab 1 mg/kg once every 3 weeks for 2 doses followed by nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 2 doses, if not responding to the initial boost. Responders to boosts continued with nivolumab maintenance. Between July 2017 and April 2019, 86 patients were enrolled. The median follow-up is 7.7 months. The primary end point is objective response rate (ORR) per RECIST1.1. Secondary end points include efficacy of nivolumab induction, remission rate with nivolumab/ipilimumab boosts, overall survival, and safety. RESULTS: Of all patients, 42, 39, and five were first- (1L), second- (2L), and third-line (3L), respectively. The median age was 68 years. The ORR with nivolumab monotherapy (assessed at week 8) was 29% in 1L and 23% in 2/3L, respectively. Forty-one patients received early (week 8) and 11 received later nivolumab/ipilimumab boosts. ORRs with nivolumab with or without nivolumab/ipilimumab (best overall response) were 45% and 27% in 1L and 2/3L, respectively. In 1L, 7 of 17 patients receiving boosts at week 8 improved, compared with 2 of 24 in 2/3L. CONCLUSION: The tailored approach of TITAN-TCC shows meaningful clinical activity supporting dual checkpoint inhibition in 1L mUC. However, starting therapy with nivolumab exclusively appears inadequate given the aggressive nature of mUC. In 2/3L, nivolumab/ipilimumab boosts with escalating ipilimumab dose did not improve efficacy outcomes versus nivolumab monotherapy. An independent 2L cohort of TITAN-TCC receiving nivolumab 1 mg/kg plus ipilimumab 3 mg/kg once every 3 weeks for 4 doses is ongoing.

Seasonal Variations in the Diagnosis of Testicular Germ Cell Tumors: A National Cancer Registry Study in Austria.

We conducted a retrospective National Cancer Registry study in Austria to assess a possible seasonal variation in the clinical diagnosis of testicular germ cell tumors (TGCT). In total, 3615 testicular cancer diagnoses were identified during an 11-year period from 2008 to 2018. Rate ratios for the monthly number of TGCT diagnoses, as well as of seasons and half-years, were assessed using a quasi-Poisson model. We identified, for the first time, a statistically significant seasonal trend (p < 0.001) in the frequency of monthly newly diagnosed cases of TGCT. In detail, clear seasonal variations with a reduction in the tumor incidence during the summer months (Apr-Sep) and an increase during the winter months (Oct-Mar) were observed (p < 0.001). Focusing on seasonality, the incidence during the months of Oct-Dec (p = 0.008) and Jan-Mar (p < 0.001) was significantly higher compared to the months of Jul-Sep, respectively. Regarding histopathological features, there is a predominating incidence in the winter months compared to summer months, mainly concerning pure seminomas (p < 0.001), but not the non-seminoma or mixed TGCT groups. In conclusion, the incidence of TGCT diagnoses in Austria has a strong seasonal pattern, with the highest rate during the winter months. These findings may be explained by a delay of self-referral during the summer months. However, the hypothetical influence of vitamin D3 in testicular carcinogenesis underlying seasonal changes in TGCT diagnosis should be the focus of further research.