Immune Contexture Changes Following Blue Light Cystoscopy with Hexaminolevulinate in Bladder Cancer.

Background: Transurethral resection of bladder tumor (TURBT) is a central component in the diagnosis of non-muscle-invasive bladder cancer (NMIBC) and can be guided by several optical imaging techniques for better visualization of lesions. Objective: To investigate if a change in tumor microenvironment (TME) composition could be observed as an effect of hexaminolevulinate (HAL)-assisted blue light cystoscopy (BLC) in TURBT samples from patients with bladder cancer. Design setting and participants: This was a retrospective study of 40 patients with bladder cancer who underwent either BLC-guided TURBT (n = 20) or white light cystoscopy (WLC)-guided TURBT (n = 20) before radical cystectomy (RC). Tissue samples (n = 80) were collected from paired TURBT and RC specimens for all 40 patients. Tumor tissue was stained using multiplex immunofluorescence and immunohistochemistry. Outcome measurements and statistical analysis: Immune cell infiltration was assessed according to the proportions of each immune cell or immune evasion marker and the relative change from TURBT as baseline was calculated. Statistical comparisons between groups were performed using the Wilcoxon rank-sum test or the paired-sample Wilcoxon test. Results and limitations: Comparison of relative changes in the TME revealed a significant decrease in stromal infiltration of cytotoxic T cells (p = 0.024), B cells (p = 0.041), and stromal cells expressing PD-1 (p = 0.011) in patients treated with BLC-guided TURBT compared to WLC-guided TURBT. Conclusions: Our pilot study showed that HAL-BLC during TURBT in bladder cancer may influence the immune cell composition and TME. Patient summary: We investigated the potential therapeutic effect of blue light versus white light for guidance in removing bladder tumors via the urethra in patients with bladder cancer. For blue light guidance, a compound called hexaminolevulinate is used to visualize tumor tissue. We found changes in immune cell composition that may have been influenced by the blue light guidance.

Chronic Urticaria: A Swedish Registry-based Cohort Study on Population, Comorbidities and Treatment Characteristics.

Swedish databases present unique opportunities to research population data on diseases and treatments. The current study is, to our knowledge, the most comprehensive registry-based study on a chronic urticaria population in Sweden to date. The aim of this study was to describe the chronic urticaria population in Stockholm County regarding epidemiology, demographics, comorbidity, healthcare usage and treatment patterns in relation to current international guidelines. Real-world data were extracted between 2013 and 2019, yielding 10,642 adult patients. Study period prevalence of chronic urticaria was 0.53%, the mean annual incidence was approximately 0.08%, and 68% of patients were female. Regarding diagnosis, 58% were first diagnosed in primary care, approximately 50% were diagnosed before the age of 40 years. Regarding type of urticaria, 89% had chronic spontaneous urticaria, 11% had chronic inducible urticaria, and 5% of patients with chronic urticaria had coexisting angioedema. Common coexisting diagnoses were, for example, asthma, allergy, psychiatric and behavioural disorders and cardiometabolic disorders. Treatment patterns generally followed guidelines, yet data indicated that guidelines were not fully implemented, especially in primary care.

Factors Predicting the Off-treatment Duration in Patients with Prostate Cancer Receiving Degarelix as Intermittent Androgen Deprivation Therapy.

BACKGROUND: Intermittent androgen deprivation therapy (IAD) is commonly used in prostate cancer because of the benefits of the off-treatment period (OTP). The off-treatment time for patients depends on cancer progression, often measured as a rise in prostate-specific antigen (PSA). OBJECTIVE: To evaluate if certain factors can predict OTP duration following 7-mo degarelix therapy. DESIGN, SETTING, AND PARTICIPANTS: This multivariable analysis included 191 prostate cancer patients with baseline PSA 4-50 ng/ml or PSA doubling time <24 mo entering the first OTP with PSA ≤4 ng/ml and testosterone <0.5 ng/ml. OTP continued until disease progression, measured as PSA >4 ng/ml. Despite a study-defined OTP maximum of 24 mo, a 50% failure rate was not observed within certain strata. A Weibull distribution was used to estimate median time to PSA >4 ng/ml adjusted for the following variables: age; baseline (or end of induction period [EOI]) PSA; baseline testosterone; cancer stage/previous curative treatment; and Gleason score. According to the results and the utility of these factors in clinical practice, the model was reduced in a stepwise manner. Time to testosterone recovery (testosterone >0.5 and >2.2 ng/ml) was estimated in a similar manner. RESULTS: The full five-factor model showed that baseline PSA (p<0.0001), age (p=0.004), prostate cancer stage/previous therapy (p=0.023), and baseline testosterone (p=0.039) influenced OTP. A reduced two-factor model (baseline PSA, age) showed that only baseline PSA influenced OTP (p<0.0001), and patients with baseline PSA ≤4 ng/ml had the longest OTP. In addition, EOI PSA (p<0.0001) and age (p=0.050) significantly influenced OTP. The times to testosterone >0.5 and >2.2 ng/ml were longer for older patients and those with lower baseline testosterone levels. CONCLUSION: Patients with lower baseline and EOI PSA, and older patients can stay off therapy longer and therefore may benefit more from degarelix IAD. These factors may help in proposing an algorithm to predict the OTP and optimise visit frequency. PATIENT SUMMARY: We describe extended analysis results for a trial in which patients with prostate cancer received intermittent androgen deprivation treatment. Prostate-specific antigen levels at baseline and at the end of the induction period, as well as older age, predicted the duration of the off-treatment period. Testosterone recovery was slower in older patients and in patients who had lower pretreatment testosterone levels. These factors may help in deciding whether to choose continuous or intermittent treatment as a strategy. TRIAL REGISTRATION: Clinicaltrials.gov NCT00801242.

Degarelix Versus Goserelin Plus Bicalutamide in the Short-Term Relief of Lower Urinary Tract Symptoms in Prostate Cancer Patients: Results of a Pooled Analysis.

OBJECTIVE: In patients with prostate cancer (PCa), prostate enlargement may give rise to lower urinary tract symptoms (LUTS); many patients suffer from moderate-to-severe symptoms. We compare the efficacy of degarelix and goserelin plus bicalutamide in improving LUTS in PCa patients. METHODS: Data were pooled from three Phase 3, randomized clinical trials of once-monthly treatment for 12 weeks with degarelix (240/80 mg; n = 289) or goserelin (3.6 mg) plus bicalutamide (50 mg; n = 174) for initial flare protection. LUTS at weeks 4, 8, and 12 were compared to baseline. Clinically relevant LUTS relief was a ≥3-point International Prostate Symptom Score (IPSS) decrease. Adverse events were assessed throughout the trials. RESULTS: Patients receiving degarelix had significantly greater decreases in IPSS vs. goserelin at week 12 (adjusted difference: -1.24; 95% CI -2.33 to -0.14, P = 0.03). Clinically relevant LUTS relief with degarelix was especially pronounced in patients with moderate-to-severe LUTS (baseline IPSS ≥13) (odds ratio; OR 2.31; 95% CI 1.19-4.47, P = 0.01) and advanced PCa (OR 2.36; 95% CI 1.10-5.04, P = 0.03). A twofold higher OR for early (week 4) LUTS relief was seen with degarelix vs. goserelin (OR 2.03; 95% CI 1.14-3.60, P = 0.02). No difference in total prostate volume or urinary tract infection-related adverse events (2%) was seen between treatment groups. CONCLUSION: An early, significant and clinically more pronounced improvement of LUTS, especially in patients with moderate-to-severe LUTS or advanced PCa, was seen with degarelix vs. goserelin plus bicalutamide.

EFFICACY AND SAFETY OF A NEW TOPICAL TESTOSTERONE REPLACEMENT GEL THERAPY FOR THE TREATMENT OF MALE HYPOGONADISM.

OBJECTIVE: Testosterone replacement therapy is indicated for male hypogonadism. This study aimed to evaluate the efficacy and safety of testosterone gel 2% (Tgel) over 90 days. METHODS: This phase 3, open-label, noncomparator study was conducted in adult hypogonadal men (2 consecutive fasting serum testosterone values <300 ng/dL and >86% subjects with symptoms consistent with testosterone deficiency). Subjects applied Tgel 23 mg/day (single pump-actuation using a hands-free cap applicator). The dose was uptitrated to 46 mg/day after 2 weeks if the 4-hour serum total testosterone level was <500 ng/dL. The dose could be further up- or downtitrated to 23, 46, and 69 mg on Days 21, 42, and 63. The primary endpoint included the percentage of subjects with average testosterone concentration (Cave (0-24)) between 300 and 1,050 ng/dL on Day 90. Safety endpoints were adverse events (AEs), laboratory parameters, and vital signs. RESULTS: Of the 159 who enrolled, 139 men completed the study. Approximately three-quarters (76.1%) of subjects met Cave criteria on Day 90. Most AEs were mild to moderate. There were 5 serious AEs, and 1 (myocardial infarction) was judged as possibly related to Tgel. Confirmed excessive increases in prostate-specific antigen or hematocrit levels were rare. Tgel had a favorable local skin tolerability profile. CONCLUSION: Overall, 76% of subjects achieved Cave between 300 and 1,050 ng/dL with Tgel. Symptoms of testosterone deficiency improved with few safety concerns. ABBREVIATIONS: AE = adverse event Cave(0-24) = average testosterone concentration CI = confidence interval Cmax = maximum concentration IIEF = International Index of Erectile Function MAF = Multidimensional Assessment of Fatigue PK = pharmacokinetic PSA = prostate-specific antigen SAE = serious adverse event SF-12 = Short Form 12 Health Survey Tgel = testosterone gel 2% Tmax = time to achieve maximum concentration TRT = testosterone replacement therapy.

Degarelix as an intermittent androgen deprivation therapy for one or more treatment cycles in patients with prostate cancer.

BACKGROUND: Guidelines for prostate cancer treatment suggest that intermittent androgen deprivation (IAD) can be considered for certain patients. OBJECTIVE: To evaluate the efficacy and safety of degarelix as IAD for one or more treatment cycle(s) in prostate cancer patients requiring androgen deprivation. DESIGN, SETTING, AND PARTICIPANTS: This open-label uncontrolled multicenter study included patients with prostate-specific antigen (PSA) >4 to 50 ng/ml or PSA doubling time <24 mo. Induction included 7-mo treatment. Off-treatment period started when PSA was ≤4 ng/ml and lasted up to 24 mo based on PSA and testosterone levels. Treatment was reinitiated when PSA was >4 ng/ml. INTERVENTION: Each induction period included a starting dose of degarelix 240mg, and thereafter 80mg once a month for 6 mo, followed by off-treatment periods. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: The primary end point was time to PSA >4 ng/ml. Secondary end points were subgroup analysis of the primary end point, time to testosterone >0.5 and >2.2 ng/ml, quality of life (QoL), and sexual function during the first off-treatment period. RESULTS AND LIMITATIONS: Of 213 patients in the first induction period, 191 entered the first off-treatment period, 35 patients entered the second induction, and 30 entered the second off-treatment period. Only two patients entered the third cycle. Median time to PSA >4 ng/ml and duration of first off-treatment period was 392 d each. Significant differences in time to PSA >4 ng/ml were observed between subgroups stratified by prognostic factors (previous curative treatment, cancer stage, PSA levels, and Gleason scores). Time to testosterone >0.5 and >2.2 ng/ml was 112 and 168 d, respectively. Change in QoL remained nonsignificant, and sexual function gradually improved during the off-treatment period. Adverse events were fewer during the off-treatment period and subsequent treatment cycles. CONCLUSIONS: IAD with degarelix resulted in an improvement in sexual function commensurate with increased testosterone levels while PSA remained suppressed. The treatment for one treatment cycle or more was well tolerated. PATIENT SUMMARY: Guidelines for prostate cancer treatment suggest that intermittent androgen deprivation (IAD) can be considered for certain patients. IAD with degarelix resulted in improved sexual function commensurate with increased testosterone levels while prostate-specific antigen remained suppressed. The treatment for one treatment cycle or more was well tolerated. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00801242.

Pharmacokinetics and bioavailability of a new testosterone gel formulation in comparison to Testogel® in healthy men.

This randomized, open-label, multiple-dose three-way cross-over study compared the pharmacokinetics of a new testosterone gel formulation in two strengths, testosterone gel 1% and testosterone gel 2% (FE 999303), with Testogel® in 11 testosterone-suppressed healthy men. Subjects received one of six treatment sequences; 50 mg of testosterone was administered once daily for 7 consecutive days, with different treatments separated by washout-periods of 6-9 days. Testosterone gel 1% and testosterone gel 2% displayed greater relative bioavailability (2.6- and 1.6-fold, respectively) than Testogel on Day 1, which persisted, to a smaller extent, on Day 7. Initial absorption was highest and most rapid for testosterone gel 1% and 2%, showing apparent first-order absorption kinetics. Maximum serum concentrations (Cmax ) were 6.25 and 2.97 ng/mL, respectively, occurring ∼5-6 hours post-application on Day 1 versus Cmax of 1.71 ng/mL after ∼24 hours with Testogel, showing apparent zero-order absorption kinetics. Similar differences were observed on Day 7. All treatments appeared to reach approximately the same steady-state level within the first 24 hours. No application-site skin reactions occurred with any preparation. In conclusion, the new testosterone formulation showed higher bioavailability, and the ability to deliver more testosterone in a smaller volume.

Continuation of quetiapine versus switching to placebo or lithium for maintenance treatment of bipolar I disorder (Trial 144: a randomized controlled study).

OBJECTIVE: Quetiapine, combined with lithium or divalproex, demonstrates efficacy in the maintenance treatment of bipolar I disorder. This study investigated the efficacy and safety of quetiapine monotherapy as maintenance treatment in bipolar I disorder compared with switching to placebo or lithium. METHOD: Patients aged ≥ 18 years with DSM-IV-diagnosed bipolar I disorder and a current or recent manic, depressive, or mixed episode received open-label quetiapine (300-800 mg/d) for 4-24 weeks. Patients achieving stabilization were randomized to continue quetiapine or to switch to placebo or lithium (0.6-1.2 mEq/L) for up to 104 weeks in a double-blind trial. Outcome measures included times to recurrence of any mood event (primary outcome measure), manic event, or depressive event. Safety assessments included adverse events and laboratory values. The study was terminated early after planned interim analysis provided positive results. The study was conducted between March 2005 and July 2007. RESULTS: Of 2,438 patients starting open-label quetiapine, 1,226 (50.3%) were randomized to double-blind treatment, including 1,172 (95.6%) in the intent-to-treat population. Time to recurrence of any mood event was significantly longer for quetiapine versus placebo (hazard ratio [HR] = 0.29; 95% CI, 0.23-0.38; P < .0001) and for lithium versus placebo (HR = 0.46; 95% CI, 0.36-0.59; P < .0001). Quetiapine and lithium significantly increased time to recurrence of both manic events (quetiapine: HR = 0.29; 95% CI, 0.21-0.40; P < .0001; lithium: HR = 0.37; 95% CI, 0.27-0.53; P < .0001) and depressive events (quetiapine: HR = 0.30; 95% CI, 0.20-0.44; P < .0001; lithium: HR = 0.59; 95% CI, 0.42-0.84; P < .004) compared with placebo. Overall rates of adverse events were generally similar between treatment groups, and safety findings for quetiapine were consistent with its known profile. CONCLUSIONS: In patients stabilized during acute quetiapine treatment, continuation of quetiapine significantly increased time to recurrence of any mood, manic, or depressive event compared with switching to placebo. Switching to lithium was also more effective than placebo for the prevention of manic and depressive events. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00314184.