Increased association of the ERG oncoprotein expression in advanced stages of prostate cancer in Filipinos.

BACKGROUND: Filipinos with prostate cancer (CaP) are at increased risk of harboring advanced stages and lower survival rates compared to other Asians. This study aims to investigate prevalence of ETS-related gene (ERG) oncoprotein overexpression in Filipinos as surrogate of TMPRSS2-ERG gene fusions, using a highly specific monoclonal antibody (ERG-MAb), and conduct the first attempt to study the role of genetic alterations in the aggressive tumor biologic behaviour of CaP among Filipinos. METHODS: This case-matched, case-control retrospective study evaluated ERG expression in Filipino patients diagnosed with CaP and its effect on stage and Gleason grade of their disease. Men who underwent radical prostatectomy for organ-confined disease at the University of the Philippines-Philippine General Hospital (UP-PGH) comprised the organ-confined cohort. Age-matched adults who had trans-rectal ultrasound-guided prostate (TRUSP) biopsy or trans-urethral resection of the prostate (TURP) with bilateral orchiectomy for T4 or stage IV CaP composed the advanced disease cohort. RESULTS: Overall ERG expression frequency of 23.08% (N = 104) was demonstrated, with a higher rate observed in the advanced disease cohort (32.69%) compared to the organ-confined group (13.46%). Furthermore, ERG overexpression was only detected among intermediate and high-risk tumors. A high-specificity (98.08%) of the ERG-MAb for malignant prostatic cells was likewise demonstrated. CONCLUSIONS: In contrast to higher ERG frequency in Western countries, it is much lower in Filipino CaP, which is similar to lower rates noted from other Asian countries. The 98.08% specificity of ERG oncoprotein for prostate tumor cells combined with its increased association in advanced disease, suggests for prognostic potential of ERG that may aid clinicians in treatment decisions for Filipino CaP patients.

Safety and Efficacy of Upadacitinib for Atopic Dermatitis in Japan: Analysis of the 3-Year Phase 3 Rising Up Study.

INTRODUCTION: Upadacitinib is an oral Janus kinase inhibitor approved in multiple countries for moderate-to-severe atopic dermatitis (AD). Here we present long-term data for up to 3 years of continuous upadacitinib treatment in Japanese patients with AD. METHODS: Rising Up was a phase 3, randomized, multicenter study in Japan investigating the safety and efficacy of upadacitinib in patients with moderate-to-severe AD. Patients aged 12-75 years (weight ≥ 40 kg if < 18 years) were randomized 1:1:1 to receive upadacitinib 15 mg, upadacitinib 30 mg, or placebo through week 16 (all in combination with topical corticosteroids). At week 16, patients who received placebo were rerandomized 1:1 to upadacitinib 15 mg or 30 mg; topical corticosteroids were optional per investigator discretion from weeks 16-160. Safety was assessed by monitoring adverse events (AEs). Efficacy assessments included patients who achieved ≥ 75%/≥ 90% improvement from baseline in Eczema Area and Severity Index (EASI 75/90), clear/almost clear on the validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD 0/1), or a ≥ 4-point improvement from baseline in Worst Pruritus Numerical Rating Scale (WP-NRS). RESULTS: Of 272 patients enrolled, 230 completed the study. Through week 160, the long-term incidence rate of overall AEs was numerically higher with upadacitinib 30 mg than 15 mg; rates of serious AEs, AEs considered possibly related to study drug, AEs leading to discontinuation, and AEs of special interest were generally low and similar between dose groups. EASI 75, EASI 90, vIGA-AD 0/1, and WP-NRS response rates were generally greater with upadacitinib 30 mg than 15 mg and maintained through week 160 with either dose. CONCLUSION: For up to 3 years of continuous treatment, upadacitinib was well tolerated in Japanese patients, with a similar safety profile to that of short-term studies and durable long-term response rates for skin clearance and itch improvement. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03661138.

More Time Spent with Clear Skin and No Itch with Upadacitinib versus Dupilumab for Atopic Dermatitis.

INTRODUCTION: Atopic dermatitis (AD), with its hallmark symptoms of pruritus and skin lesions, often impairs patients' quality of life. We assessed time spent with clear/almost clear skin and no/minimal itch during upadacitinib treatment versus placebo or dupilumab among patients with moderate-to-severe AD. METHODS: This analysis consisted of a post hoc analysis of Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), and Heads Up (NCT03738397). Measure Up 1 and 2 were replicate, randomized, double-blind, placebo-controlled phase 3 studies with patients randomized (1:1:1) to once-daily oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo for 16 weeks. Heads Up was a head-to-head, randomized, double-blind, double-dummy, phase 3b study with patients randomized (1:1) to upadacitinib 30 mg or subcutaneous dupilumab 300 mg for 24 weeks. Skin clearance was assessed with the Eczema Area and Severity Index (EASI) at baseline, weeks 1, 2, and 4, and every 4 weeks thereafter. Itch was assessed using the Worst Pruritus Numerical Rating Scale (WP-NRS) daily over 16 weeks and every 2 weeks thereafter to week 24 in Heads Up. RESULTS: This analysis included 1683 patients in Measure Up 1 and 2 and 673 patients in Heads Up. Through 16 weeks in Measure Up 1 and 2, patients receiving upadacitinib spent 9.8-13.4 times as many days with an EASI 90 response and 7.0-10.3 times as many days with a WP-NRS 0/1 response versus placebo. In Heads Up, patients receiving upadacitinib spent 2.0 and 1.7 times as many days through 16 and 24 weeks, respectively, with an EASI 90 response versus dupilumab. Through 16 and 24 weeks, patients receiving upadacitinib spent 3.0 and 2.6 times as many days, respectively, with a WP-NRS 0/1 response versus dupilumab. CONCLUSIONS: Patients with moderate-to-severe AD spent more time with clear/almost clear skin and no/minimal itch with upadacitinib versus placebo or dupilumab. TRIAL REGISTRATION: ClinicalTrials.gov identifier, Measure Up 1 (NCT03569293), Measure Up 2 (NCT03607422), Heads Up (NCT03738397).

Pharmacokinetics, Safety, Tolerability, and Exploratory Efficacy of Upadacitinib in Children with Severe Atopic Dermatitis.

PURPOSE: This study aims to characterize the pharmacokinetics, safety, tolerability, and exploratory efficacy of upadacitinib, an oral Janus kinase inhibitor approved for treating moderate to severe atopic dermatitis (AD) in adults and adolescents, in children with severe AD. METHODS: In an open-label, multiple-dose, Phase 1 study, pediatric patients with severe AD from two age groups (2 to <6 years and 6 to <12 years) received bodyweight-based dosing regimens of upadacitinib using either twice-daily immediate-release (IR) oral solution or once-daily extended-release (ER) tablets. A pharmacokinetic assessment was conducted on Day 7 of the study, which was followed by a long-term safety and exploratory efficacy evaluation for up to 108 weeks. The results reported here are based on an interim analysis when the study had completed enrollment and pharmacokinetic assessment. FINDINGS: A total of 35 patients were enrolled and received upadacitinib. The maximum upadacitinib plasma concentration was attained within a median time of 0.5 to 2 hours and 2 to 2.5 hours for the IR oral solution and ER tablet formulations, respectively. Upadacitinib functional half-life was generally shorter with IR oral solution relative to ER tablets. Upadacitinib apparent oral clearance decreased with decreasing body weight in the pediatric patients enrolled in this study. Upadacitinib was generally safe and well tolerated. The most common (≥3 patients) adverse events were upper respiratory tract infection, COVID-19 infection, headache, abdominal discomfort, vomiting, asthma, and cough. No new safety risks were identified compared to the known safety profile for upadacitinib in adults and adolescents. In the 30 patients with available exploratory efficacy data at Week 12, 36.7% achieved validated Investigator's Global Assessment scale for AD score of 0 or 1 (Validated Investigator Global Assessment for AD 0/1), and 70.0% had Eczema Area and Severity Index (EASI) improvement of at least 75% (EASI 75). IMPLICATIONS: The characterized pharmacokinetic profiles in this study, together with the observed safety and exploratory efficacy results, support further investigation of the current upadacitinib dosing regimen in future confirmatory Phase 3 clinical trials in children with AD. CLINICAL TRIAL NUMBER: NCT03646604, registered 2018-08-23.

Acne Among Japanese Patients with Atopic Dermatitis Receiving Upadacitinib in the Phase 3 Rising Up Study.

INTRODUCTION: Upadacitinib, an oral selective Janus kinase (JAK) inhibitor, is used to treat moderate-to-severe atopic dermatitis (AD). Acne is the most common treatment-emergent adverse event in patients with AD treated with upadacitinib. In this post hoc analysis, we describe the acne events in Japanese patients with AD who received upadacitinib during the Rising Up study. METHODS: In this phase 3, double-blind, 3-year trial evaluating the safety and efficacy of upadacitinib 15 mg or 30 mg in Japanese patients with moderate-to-severe AD, patients were randomized 1:1:1 to receive upadacitinib 15 mg, 30 mg, or placebo for up to 16 weeks. At week 16, placebo-treated patients were re-randomized 1:1 to receive upadacitinib 15 mg or 30 mg. The incidence, characteristics, and management of treatment-emergent acne events up to the 52-week cutoff date were summarized. RESULTS: Among 272 patients in this analysis, the incidence of acne was higher in patients receiving upadacitinib compared with patients who received placebo. The rate of acne was higher in patients receiving upadacitinib 30 mg (32.4%) compared with those taking upadacitinib 15 mg (17.3%) during the long-term treatment period. All cases of acne were mild or moderate; no cases led to study drug discontinuation. The mean (range) of acne onset was 135.4 (7-465) days after starting study drug. Most acne occurred on the face; inflammatory papules were the most common morphology. Risk factors for acne included relevant concomitant medications (e.g., corticosteroids) started before acne onset and family and personal history of acne. Acne was generally managed with topical treatments. CONCLUSION: Mild or moderate acne reported in Japanese patients with AD receiving upadacitinib occurred in a dose-dependent manner and had a variable onset time. Acne was readily managed with topical treatments. Patients and clinicians should be aware of the risk of acne associated with upadacitinib treatment for AD. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03661138.

Safety and Efficacy of Upadacitinib for Atopic Dermatitis in Japan: 2-Year Interim Results from the Phase 3 Rising Up Study.

INTRODUCTION: Upadacitinib, an oral, selective Janus kinase inhibitor, is approved in Japan for the treatment of moderate-to-severe atopic dermatitis (AD), a chronic inflammatory skin disease characterized by eczematous morphology and intense itch. METHODS: Rising Up is an ongoing phase 3, randomized, multicenter study evaluating the long-term safety and efficacy of upadacitinib in Japan. Patients with moderate-to-severe AD were randomized 1:1:1 to topical corticosteroids plus upadacitinib 15 mg (UPA15), upadacitinib 30 mg (UPA30), or placebo at baseline; at week 16, placebo patients were rerandomized 1:1 to UPA15 or UPA30 (plus topical corticosteroids per investigator discretion). This 2-year interim analysis evaluated safety and efficacy through 112 weeks (data cutoff date: 11 August 2021). Adverse events (AEs), AEs of special interest (AESIs), and laboratory data were assessed. Efficacy assessments included ≥ 75% and ≥ 90% improvement from baseline in Eczema Area and Severity Index (EASI 75/90), achievement of clear or almost clear on the validated Investigator Global Assessment for Atopic Dermatitis (vIGA-AD 0/1), and ≥ 4-point improvement in the Worst Pruritus Numerical Rating Scale (WP-NRS). RESULTS: A total of 272 patients were enrolled and 242 were ongoing at data cutoff (UPA15, n = 120; UPA30, n = 122). After 112 weeks of treatment, serious AEs, AEs leading to discontinuation, and most AESIs were generally infrequent, and rates were similar between the two upadacitinib groups. One event each of rectal cancer and cerebellar hemorrhage was reported in the UPA15 group; no thrombosis events were observed. The most common AEs included acne, nasopharyngitis, and herpes zoster. EASI 75, EASI 90, vIGA-AD 0/1, and WP-NRS response rates were maintained through week 112. CONCLUSION: UPA15 and UPA30 were well tolerated through 112 weeks of treatment with similar safety profiles to short-term studies and demonstrated durable long-term efficacy for the treatment of moderate-to-severe AD in adults and adolescents. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT03661138.

Efficacy and Safety of Upadacitinib Treatment in Adolescents With Moderate-to-Severe Atopic Dermatitis: Analysis of the Measure Up 1, Measure Up 2, and AD Up Randomized Clinical Trials.

Importance: Atopic dermatitis onset usually occurs in childhood. Persistence of disease into adolescence and adulthood is common. It is important to evaluate new treatment options in adolescents because of the high unmet need in this population. Objective: To assess the efficacy and safety of upadacitinib to treat moderate-to-severe atopic dermatitis in adolescents. Design, Setting, and Participants: Prespecified analysis of adolescents enrolled in 3 randomized, double-blind, placebo-controlled phase 3 clinical trials in more than 20 countries across Europe, North and South America, Oceania, the Middle East, and the Asia-Pacific region from July 2018 through December 2020. Participants were adolescents aged 12 to 17 years with moderate-to-severe atopic dermatitis. Data analysis was performed from April to August 2021. Interventions: Patients were randomized (1:1:1) to once-daily oral upadacitinib 15 mg, upadacitinib 30 mg, or placebo alone (Measure Up 1 and Measure Up 2) or with topical corticosteroids (AD Up). Main Outcomes and Measures: Safety and efficacy, including at least a 75% improvement in the Eczema Area and Severity Index from baseline and validated Investigator Global Assessment for Atopic Dermatitis score of 0 (clear) or 1 (almost clear) at week 16 (coprimary end points). Results: A total of 552 adolescents (290 female; 262 male) were randomized. Mean (SD) age was 15.4 (1.8), 15.5 (1.7), and 15.3 (1.8) years for adolescents in Measure Up 1, Measure Up 2, and AD Up, respectively. In Measure Up 1, Measure Up 2, and AD Up, respectively, a greater proportion of adolescents (% [95% CI]) achieved at least 75% improvement in the Eczema Area and Severity Index at week 16 with upadacitinib 15 mg (73% [63%-84%], 69% [57%-81%], 63% [51%-76%]), and upadacitinib 30 mg (78% [68%-88%], 73% [62%-85%], 84% [75%-94%]), than with placebo (12% [4%-20%], 13% [5%-22%], 30% [19%-42%]; nominal P < .001 for all comparisons vs placebo). Similarly, a greater proportion of adolescents treated with upadacitinib achieved a validated Investigator Global Assessment for Atopic Dermatitis score of 0 or 1 at week 16 and improvements in quality of life with upadacitinib than with placebo. Upadacitinib was generally well tolerated in adolescents. Acne was the most common adverse event, and all acne events were mild or moderate. Conclusions and Relevance: In this analysis of 3 randomized clinical trials, upadacitinib was an effective treatment for adolescents with moderate-to-severe atopic dermatitis, with an acceptable safety profile. Trial Registration: ClinicalTrials.gov Identifiers: NCT03569293 (Measure Up 1), NCT03607422 (Measure Up 2), and NCT03568318 (AD Up).

Prostate cancer in Asian Americans: incidence, management and outcomes in an equal access healthcare system.

UNLABELLED: Study Type--Therapy (outcomes research) Level of Evidence 2c. What's known on the subject? and What does the study add? While epidemiological studies have shown a significantly lower incidence of adenocarcinoma of the prostate in Asia than the United States, several studies have demonstrated that Asian Americans present with more advanced stages, higher tumour grades, and worse mortality-incidence ratios than Caucasian Americans. This study, conducted in an equal access military healthcare system, reveals improved pathological and survival outcomes in Asian Americans compared to other races. This may indicate that worsened outcomes previously reported among Asian Americans diagnosed with adenocarcinoma of the prostate may be related to access to care, language barriers, socioeconomic status, or cultural factors. OBJECTIVE: • To characterize the incidence, management and clinicopathological characteristics of prostate cancer (CaP) in a population of Asian Americans undergoing mandatory annual screening in an equal access healthcare system. PATIENTS AND METHODS: • Men registered into the military-based Center for Prostate Disease Research multi-institutional database from 1989-2007 with biopsy-proven CaP and categorized as Asian American, Caucasian or African American were included. • Demographic information, treatment modality, clinicopathological characteristics and outcomes were compared. RESULTS: • In total, there were 10,964 patients; 583 (5.3%) were Asian Americans. Asian Americans had lower clinical stage (P < 0.001) but worse biopsy grade (P < 0.001) than other groups. They were more likely to choose radical prostatectomy (RP) (P < 0.001) and showed a higher percentage of organ-confined disease (P < 0.001). • Asian Americans had improved biochemical recurrence free (P < 0.01) and overall survival (P < 0.001) rates compared to African Americans or Caucasians treated with RP or external radiation therapy. CONCLUSIONS: • Asian Americans with CaP treated in an equal access healthcare system have improved pathological outcomes and survival characteristics compared to other races. • Asian ethnicity's negative impact on survival noted by others appears to be the result of factors other than the tumour's intrinsic behaviour, such as language barriers, socioeconomic status and cultural norms.

Factors affecting patient radiation exposure during percutaneous nephrolithotomy.

PURPOSE: We identified patient and stone characteristics that may contribute to increased radiation exposure during percutaneous nephrolithotomy and offer technique modifications to limit the radiation dose. MATERIAL AND METHODS: We reviewed the records of 96 patients who underwent percutaneous nephrolithotomy in the last 2 years. The effective radiation dose was calculated using accepted conversion tables. We performed multivariate linear regression to determine the association of the effective radiation dose with specific patient, stone and procedural characteristics. RESULTS: Mean±SD patient age was 51.5±13.4 years and 62.5% of the patients were female. Median body mass index was 32.0±9.7 kg/m2 (range 16.2 to 59.6) and the median stone burden was 4 cm2. Increased body mass index (p<0.001), higher stone burden (p=0.013), stone nonbranched configuration (p=0.002) and a greater number of percutaneous access tracts (p=0.040) were significantly associated with an increased effective radiation dose. Specifically obese patients with a body mass index of 30 to 39.9 kg/m2 had a more than 2-fold increase in the mean adjusted effective radiation dose and morbidly obese patients with a body mass index of 40 kg/m2 or greater had a greater than 3-fold increase vs that in normal weight patients with a body mass index of less than 25 kg/m2 (6.49 and 9.13 mSv, respectively, vs 2.66, p<0.001). Other stone specific parameters, including site and composition, percutaneous access site and estimated blood loss were not associated with the effective radiation dose. CONCLUSIONS: Patients with higher body mass index, greater stone burden, nonbranched stones and multiple nephrostomy access tracts are at risk for increased radiation exposure during percutaneous nephrolithotomy. Urologists must seek alternative strategies to minimize radiation exposure, such as tighter collimation to the region of interest, judicious use of magnification and the acquisition of as few images as possible during stone removal.

Third prize: the role of endoscopic nephron-sparing surgery in the management of upper tract urothelial carcinoma.

INTRODUCTION: Upper tract urothelial carcinoma (UT-UC) is an uncommon disease with pronounced difference in 5-year survival for noninvasive (96%) versus invasive (17%) disease. High survival rate of early disease questioned the accepted norm of using radical nephroureterectomy (RNU) for all stages. This review assesses effectiveness of endoscopic management for UT-UC. METHODS: A review of 131 UT-UC patients seen between January 1999 and October 2009 was performed. Demographic, clinicopathologic, and outcomes data were collected and compared between patients initially managed with RNU versus those initially managed with nephron-sparing surgery (NSS). The chi-square or Fisher's exact tests for categorical variables and the Wilcoxon-Mann-Whitney test for continuous variables were used. Clinical and pathologic stages of RNU patients were evaluated with chi-square testing, whereas difference in length of stay was detected using linear regression. Recurrence rates were compared using multivariate Cox regression. RESULTS: The two arms had similar distributions of age, sex, frequency of medical comorbidities, American Society of Anesthesiologists (ASA), and Charlson scores. Mean-adjusted length of stay was 2.1 (95% confidence interval [1.6, 2.5]) and 5.5 days (95% confidence interval [5.3, 6.4]) for the NSS and RNU groups, respectively (p < 0.001). Comparison of clinical and pathologic stages of RNU patients showed a difference (p < 0.001), with under-staging noted in 32%. Men (Hazards Ratio = 2.9 [1.5-5.5], p = 0.001) and NSS patients (hazards ratio [HR] = 3.5 [1.7-7.3], p < 0.001) had threefold increased recurrence risk. CONCLUSION: NSS offered shorter hospital stay but had increased risk of recurrence. Therefore, extreme care should be made to rule out occult invasive tumors preoperatively. Patients being managed endoscopically must be informed of the necessity for close follow-up.

A feedback loop between the androgen receptor and a NEDD4-binding protein, PMEPA1, in prostate cancer cells.

PMEPA1 was identified originally as a highly androgen-inducible gene with prostate-abundant expression that was restricted to prostatic epithelial cells. PMEPA1 protein is a NEDD4 (ubiquitin-protein isopeptide ligase)-binding protein, which negatively regulates prostate cancer cell growth. In this study we establish that PMEPA1 is a direct transcriptional target of the androgen receptor (AR). We also demonstrate that PMEPA1 negatively regulates AR protein levels in different cell culture models. Transient expression of PMEPA1 down-regulates AR protein levels and AR transcriptional targets in prostate cancer cells. Conversely, knockdown of PMEPA1 leads to elevated levels of AR protein, AR transcriptional targets (prostate-specific antigen), and increased cell cycle S phase. We define that the PMEPA1-dependent down-regulation of AR is because of AR ubiquitination and proteasome-mediated degradation. The mutant PMEPA1 (PY1/2 motif mutation) that is impaired in NEDD4 recruitment shows attenuated AR ubiquitination and AR protein down-regulation. These data support the hypothesis that PMEPA1 negatively regulates the stability of AR protein by enhancing AR ubiquitination and proteasome-mediated degradation through NEDD4. The effect of PMEPA1 on AR ubiquitination and degradation appears to be MDM2-independent. Thus, the PMEPA1-AR degradation pathway may represent a new androgen-dependent mechanism for regulating AR levels in prostate epithelial cells. These findings underscore that the decreased PMEPA1 expression frequently noted in prostate cancers may lead to increased AR functions and strengthen the biological role of PMEPA1 in prostate cancers.