Clinical presentation of bacille Calmette-Guérin (BCG) infections after BCG instillation therapy.

OBJECTIVES: To investigate the timing of the clinical presentation of various types of bacille Calmette-Guérin (BCG) infections in a Finnish population of patients with bladder cancer treated with BCG instillation therapy. PATIENTS AND METHODS: We identified patients with a history of post-instillation BCG infection from 1996 to 2016 using the Finnish Cancer Registry and the Finnish National Infectious Diseases Registry. We categorised infections as systemic if the infection was found in the non-urogenital system and genitourinary (GU) if the infection affected the urogenital tract. We calculated the time interval between the last BCG instillation and the presentation of the infection. The infection was considered late if the time interval was ≥1 year. RESULTS: A total of 100 patients with BCG infection were identified during the study period. In all, 39 (39%) infections presented as systemic and 61 (61%) were in the GU tract. The majority of the systemic infections presented rapidly after the last instillation, while five (13%) presented after a latency of ≥1 year. The presentation of GU infections was more heterogeneous, with 12 (20%) presenting as late infections. CONCLUSION: This study confirms the concept of early and late infection types, especially among systemic infections. However, late infections appeared to be rarer than previously described. Urologists should be aware of the possibility of late BCG infection if patients develop symptoms even several years after the BCG regimen.

Incidence of and mortality from Bacille Calmette-Guérin (BCG) infections after BCG instillation therapy.

OBJECTIVES: To investigate the incidence of and mortality associated with Bacille Calmette-Guérin (BCG) infections in a Finnish population of patients with bladder cancer treated with BCG instillations. MATERIALS AND METHODS: We conducted a nationwide register study and identified patients with BCG infections in Finland during 1996 to 2016 using the Finnish Cancer Registry and the Finnish National Infectious Diseases Register. We estimated the number of patients treated with BCG instillations based on data on national consumed BCG doses used to treat patients with bladder cancer, and calculated the annual incidence proportion of BCG infections. We further performed a detailed medical chart review to describe the clinical features and outcomes of the treated BCG infections. RESULTS: In total, 87 patients with BCG infection after BCG treatment of bladder cancer were identified. The incidence proportion increased gradually, yielding a cumulative incidence proportion of 2.5% during the latter half of the study period. BCG infections led to significant mortality, with 10% overall mortality and 17.5% mortality from systemic infections, which is notably higher than previously reported. CONCLUSION: The incidence proportion of BCG infections among bladder cancer patients treated with BCG has increased in Finland up to 2.5% at a nationwide level, with a notably higher mortality rate than previously reported.

Urine cytology is a feasible tool for assessing erythematous bladder lesions after bacille Calmette-Guérin (BCG) treatment.

OBJECTIVES: To investigate the need to biopsy erythematous lesions of the bladder after bacille Calmette-Guérin (BCG) treatment as well as the diagnostic value of voided urine cytology in the detection of recurrence. MATERIALS AND METHODS: Data on 206 consecutive patients with non-muscle-invasive bladder cancer treated with one or more BCG instillations in the period 2009-2015 at Satakunta Central Hospital and Turku University Hospital were reviewed. Biopsy histology was pooled according to lesion cystoscopy appearance regarding growth pattern and presence of erythema. Voided urine cytology grading before resection was reviewed. We correlated the cystoscopy findings with histology and calculated the sensitivity, specificity, and positive (PPV) and negative predictive value (NPV) for voided urine cytology. RESULTS: In total, 159 patients with a median follow-up of 35 months were included in the study. Altogether, 367 biopsies were analysed. In the case of papillary or flat tumours, 76% of biopsies showed malignant histology and the diagnostic value of cytology was very limited (sensitivity 33%, specificity 84%). Erythematous lesions constituted 57% of all biopsy targets, with the majority being either chronic non-specific inflammation or granulomatous inflammation; 10% of erythematous lesions were malignant at pathological examination. In contrast to papillary and flat tumours, cytology proved to be more accurate in the case of erythematous lesions with a sensitivity, specificity, PPV and NPV of 59%, 76%, 23% and 94%, respectively. CONCLUSION: Bladder lesions after BCG instillations pose a challenge during follow-up and the appropriate management strategy is not clear. Lesions should not be overlooked as being BCG-induced irritation because they may harbour significant malignancies. The presence of papillary or flat tumour always warrants a biopsy or resection. In the case of erythematous lesions, our results suggest that biopsy may be avoided if voided urine cytology is negative.

National trends of surgery for benign prostatic hyperplasia in Finland.

PURPOSE: To investigate national trends of surgical treatment for benign prostatic obstruction (BPO). METHODS: The Care Register for Healthcare in Finland was used to investigate the annual numbers and types of surgical procedures, operation incidence and duration of hospital stay between 2004 and 2018 in Finland. Procedures were classified using the Nordic Medico-Statistical Committee Classification of Surgical Procedures coding. Trends in incidence were analyzed with two-sided Cochran-Armitage test. Trends in duration of hospital stay and patient age were analyzed with linear regression. RESULTS: Transurethral resection of the prostate (TURP) was the most common operation type during the study period, covering over 70% of operations for BPO. Simultaneous with the implementation of photoselective vaporization of the prostate (PVP), the incidence of TURP, minimally invasive surgical therapies, transurethral vaporization of the prostate (TUVP) and open prostatectomies decreased (p < 0.05). The mean operation incidence rate in the population between 2004 and 2018 was 263 per 100,000. The duration of hospital stay shortened (p < 0.05), and the average age of operated patients increased by 2 years (p < 0.0001). CONCLUSION: The implementation of PVP did not challenge the dominating position of TURP in Finland, but it has probably influenced the overall use of other surgical therapies, excluding transurethral incision of the prostate.  The results might suggest that the conservative treatment is accentuated, patient selection is more thorough, and surgical intervention might be placed at a later stage of BPO.

Short- and long-term risks of photoselective laser vaporization of the prostate: a population-based comparison with transurethral resection of the prostate.

BACKGROUND: Transurethral resection of the prostate (TURP) is the standard surgical treatment for benign prostate enlargement (BPE). Photoselective vaporization of the prostate (PVP) is an alternative, but there is limited real-life evidence of PVP risks. OBJECTIVE: To compare short- and long-term risks of PVP to those of TURP in the treatment of BPE. MATERIALS AND METHODS: Consecutive patients who underwent elective PVP or TURP between 2006 and 2018 in 20 hospitals in Finland were retrospectively studied using a combination of national registries (n = 27,408; mean age 71 years). Short-term risks were postoperative mortality, major adverse cardiovascular events (MACE), and reoperations for bleeding. Long-term risks were reoperations for BPE or any urethral operations within 12 years. Differences between treatment groups were balanced by inverse probability of treatment weighting. Risks were analyzed using the Kaplan-Meier method and Cox regression. RESULTS: There were no differences in postoperative mortality or MACE between the study groups. Reoperations for bleeding were less frequent after PVP (0.9%, HR: 0.72, p = 0.042). Bleeding was more likely in patients with atrial fibrillation (number needed to treat [NNT] for PVP vs TURP: 61). Cumulative incidence for reoperation was higher after PVP (23.5%) than after TURP in long-term follow-up (17.8%; HR: 1.20, p < 0.0001, NNT: -31.7). CONCLUSIONS: PVP is associated with lower postoperative bleeding risk but higher long-term reoperation risk than TURP. Patients with high bleeding risk and a low likelihood of needing reoperation appear most suitable for laser vaporization.KEY MESSAGEPVP is associated with lower postoperative bleeding risk but higher long-term reoperation risk than TURP. PVP appears an attractive treatment option, especially for patients with high bleeding risk and a low likelihood of needing a reoperation.

Comparison of Bacillus Calmette-Guérin Maintenance Therapy with Monthly Instillations and the Southwest Oncology Group Protocol in the Treatment of Non-muscle-invasive Bladder Cancer.

BACKGROUND: Bacillus Calmette-Guérin (BCG) therapy using the Southwest Oncology Group (SWOG) maintenance protocol is the standard in non-muscle-invasive bladder cancer (NMIBC). Maintenance with monthly instillations is also widely used, but evidence comparing the two maintenance protocols is scarce. OBJECTIVE: To compare monthly and SWOG instillation schedules in maintenance BCG therapy. DESIGN, SETTING, AND PARTICIPANTS: We retrospectively identified patients with NMIBC treated with maintenance BCG according to either the monthly or the SWOG instillation regimen in two tertiary care centers in Finland between 2009 and 2019. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We compared discontinuation rates of the monthly and SWOG maintenance protocols due to toxicity, and recurrence and progression rates by protocols. Baseline characteristics were compared with the Wilcoxon rank sum test, chi-square test, and Fisher's exact test. The Kaplan-Meier method and Cox proportional hazards model were used to evaluate the discontinuation of BCG due to toxicity and oncological efficacy. RESULTS AND LIMITATIONS: We identified 723 patients, of whom 545 (75%) and 178 (25%) received maintenance according to the monthly and SWOG protocols, respectively. The median follow-up time was 66 (interquartile range: 45-99) mo. In the monthly and SWOG groups, 131 (24%) and 50 (28%) patients, respectively, discontinued BCG due to toxicity, with no difference in a univariate or multivariate analysis (hazard ratio 1.01, 95% confidence interval [CI]: 0.73-1.40, p = 0.940). The 5-yr recurrence-free survival rates in the monthly and SWOG groups were 65% (95% CI: 61-69%) and 71% (95% CI: 64-79%, p = 0.370), respectively. The 5-yr progression-free survival rates were 89% (95% CI: 86-92%) and 91% (95% CI: 86-96%, p = 0.240), respectively. CONCLUSIONS: Monthly maintenance is a comparable alternative to the SWOG protocol. PATIENT SUMMARY: In this study, we compared two schedules of intravesical bacillus Calmette-Guérin (BCG) treatment used in the treatment of non-muscle-invasive bladder cancer. We found that there were no significant differences between the two instillation schedules in terms of tolerability or efficacy.

Methyl-beta-cyclodextrin suppresses hyaluronan synthesis by down-regulation of hyaluronan synthase 2 through inhibition of Akt.

Hyaluronan synthases (HAS1-3) are integral plasma membrane proteins that synthesize hyaluronan, a cell surface and extracellular matrix polysaccharide necessary for many biological processes. It has been shown that HAS is partly localized in cholesterol-rich lipid rafts of MCF-7 cells, and cholesterol depletion with methyl-beta-cyclodextrin (MbetaCD) suppresses hyaluronan secretion in smooth muscle cells. However, the mechanism by which cholesterol depletion inhibits hyaluronan production has remained unknown. We found that cholesterol depletion from MCF-7 cells by MbetaCD inhibits synthesis but does not decrease the molecular mass of hyaluronan, suggesting no major influence on HAS stability in the membrane. The inhibition of hyaluronan synthesis was not due to the availability of HAS substrates UDP-GlcUA and UDP-GlcNAc. Instead, MbetaCD specifically down-regulated the expression of HAS2 but not HAS1 or HAS3. Screening of signaling proteins after MbetaCD treatment revealed that phosphorylation of Akt and its downstream target p70S6 kinase, both members of phosphoinositide 3-kinase-Akt pathway, were inhibited. Inhibitors of this pathway suppressed hyaluronan synthesis and HAS2 expression in MCF-7 cells, suggesting that the reduced hyaluronan synthesis by MbetaCD is due to down-regulation of HAS2, mediated by the phosphoinositide 3-kinase-Akt-mTOR-p70S6K pathway.

Palliative MRI-guided transurethral ultrasound ablation for symptomatic locally advanced prostate cancer.

PURPOSE: Locally advanced prostate cancer can cause bladder outlet obstruction, gross hematuria and frequent hospitalization. While these complications are commonly treated by palliative transurethral resection of the prostate, the improvement is often insufficient. The purpose of this study was to evaluate the safety and feasibility of MRI-guided transurethral ultrasound ablation as an alternative palliative treatment option (pTULSA) for men suffering from symptomatic locally advanced prostate cancer. METHODS: This prospective, phase one study included 10 men in need of palliative surgical intervention due to urinary retention and gross hematuria caused by locally advanced prostate cancer. Patients were followed for 1 year at 3-month intervals. Time without catheter, time without hematuria, reduction in hospitalization time, and adverse events were measured. RESULTS: Ten patients with locally advanced prostate cancer were enrolled, all having continuous catheterization due to urinary retention and nine had gross hematuria before treatment. At 1 week post-pTULSA five patients were catheter-free. At last follow-up catheter-free and gross hematuria-free rates were 70% and 100%, respectively. Average hospitalization time from local complications reduced from 7.3 to 1.4 days in the 6 months before and after pTULSA. No > Grade 2 treatment related adverse events were reported, with all five being urinary tract infections. CONCLUSIONS: pTULSA appears safe and feasible for palliative ablation of locally advanced prostate cancer. The therapy seems to accomplish long-term hematuria control, can relieve bladder outlet obstruction in selected patients, and seems to reduce the burden of hospitalization due to local complications. Trial Registration Number: NCT03350529.

Salvage Magnetic Resonance Imaging-guided Transurethral Ultrasound Ablation for Localized Radiorecurrent Prostate Cancer: 12-Month Functional and Oncological Results.

BACKGROUND: Up to half of all men who undergo primary radiotherapy for localized prostate cancer (PCa) experience local recurrence. OBJECTIVE: To evaluate the safety and early functional and oncological outcomes of salvage magnetic resonance imaging-guided transurethral ultrasound ablation (sTULSA) for men with localized radiorecurrent PCa. DESIGN SETTING AND PARTICIPANTS: This prospective, single-center phase 1 study (NCT03350529) enrolled men with biopsy-proven localized PCa recurrence after radiotherapy. Multiparametric magnetic resonance imaging (mpMRI) and 18F prostate-specific membrane antigen-1007 (18F PSMA-1007) positron emission tomography (PET)-computed tomography (CT) were used to confirm organ-confined disease localization. Patients underwent either whole-gland or partial sTULSA, depending on their individual tumor characteristics. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Patients were followed at 3-mo intervals. Adverse events (AEs, Clavien-Dindo scale), functional status questionnaires (Expanded Prostate Cancer Index [EPIC]-26, International Prostate Symptom Score, International Index of Erectile Function-5), uroflowmetry, and prostate-specific antigen (PSA) were assessed at every visit. Disease control was assessed at 1 yr using mpMRI and 18F-PSMA-1007 PET-CT, followed by prostate biopsies. RESULTS AND LIMITATIONS: Eleven patients (median age 69 yr, interquartile range [IQR] 68-74) underwent sTULSA (3 whole-gland, 8 partial sTULSA) and have completed 12-mo follow-up. Median PSA was 7.6 ng/ml (IQR 4.9-10) and the median time from initial PCa diagnosis to sTULSA was 11 yr (IQR 9.5-13). One grade 3 and three grade 2 AEs were reported, related to urinary retention and infection. Patients reported a modest degradation in functional status, most significantly a 20% decline in the EPIC-26 irritative/obstructive domain at 12 mo. A decline in maximum flow rate (24%) was also observed. At 1 yr, 10/11 patients were free of any PCa in the targeted ablation zone, with two out-of-field recurrences. Limitations include the nonrandomized design, limited sample size, and short-term oncological outcomes. CONCLUSIONS: sTULSA appears to be safe and feasible for ablation of radiorecurrent PCa, offering encouraging preliminary oncological control. PATIENT SUMMARY: We present safety and 1-yr functional and oncological outcomes of magnetic resonance imaging-guided transurethral ultrasound ablation (TULSA) as a salvage treatment for local prostate cancer recurrence after primary radiation. Salvage TULSA is safe and shows the ability to effectively ablate prostate cancer recurrence, with acceptable toxicity.