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The optimal use of many biotherapeutics is restricted by Anti-drug antibodies (ADAs) and hypersensitivity responses which can affect potency and ability to administer a treatment. Here we demonstrate that Re-surfacing can be utilized as a generalizable approach to engineer proteins with extensive surface residue modifications in order to avoid binding by pre-existing ADAs. This technique was applied to E. coli Asparaginase (ASN) to produce functional mutants with up to 58 substitutions resulting in direct modification of 35% of surface residues. Re-surfaced ASNs exhibited significantly reduced binding to murine, rabbit and human polyclonal ADAs, with a negative correlation observed between binding and mutational distance from the native protein. Reductions in ADA binding correlated with diminished hypersensitivity responses in an in vivo mouse model. By using computational design approaches to traverse extended distances in mutational space while maintaining function, protein Re-surfacing may provide a means to generate novel or second line therapies for life-saving drugs with limited therapeutic alternatives.

Purpose: To assess the safety and efficacy of gemcitabine and cisplatin as neoadjuvant chemotherapy followed by selective bladder preservation chemoradiotherapy in muscle-invasive bladder cancer (MIBC). Materials and Methods: Patients with clinical T2-T4aN0M0 MIBC eligible for radical cystectomy and cisplatin-based chemotherapy were treated with gemcitabine 1,000 mg/m2 on days 1, 8 and 15, and cisplatin 70 mg/m2 on day 1 every 28 days for 3 cycles. After clinical re-staging with computed tomography scans and cystoscopy, patients with clinical complete response (CR) were eligible to proceed without cystectomy and receive bladder preservation chemoradiotherapy involving weekly cisplatin 10 mg/m2 and up to 70.2 Gy of radiation. The primary endpoint of the present prospective phase II study was metastasis-free survival (MFS). Results: Between Oct 2017 and Nov 2019, a total of 138 MIBC patients were enrolled and treated with neoadjuvant gemcitabine/cisplatin. Neoadjuvant chemotherapy was well-tolerated, with fatigue, nausea, and pruritus being the most commonly observed adverse events. After completion of planned neoadjuvant chemotherapy, 54 patients with a clinical CR and 10 patients who did not have CR but refused surgery received bladder preservation chemoradiotherapy. With a median follow-up duration of 34 months (95% confidence interval [CI], 32%–36%), the 3-year MFS rate in 64 chemoradiotherapy patients was calculated to be 70% (95% CI, 58%–82%). Conclusions: Neoadjuvant chemotherapy followed by selective bladder preservation chemoradiotherapy based on the clinical CR was feasible and efficacious in the treatment of MIBC.

This study aimed to assess the prognostic role of body mass index (BMI) in patients with metastatic renal cell carcinoma (mRCC) treated with first-line immune checkpoint inhibitor (ICI)-based therapy. We searched for relevant studies in the MEDLINE, Embase, and Cochrane Library databases. The initial search yielded 599 records, of which seven articles (2,517 patients) were selected for analysis. Patients with a high BMI had a favorable overall survival (OS) based on hazard ratio (HR) (crude HR 0.69, 95% confidence interval [CI] 0.57-0.83, p<0.0001; adjusted (a)HR 0.75, 95% CI 0.59-0.95, p=0.02), but not relative risk (RR 0.88, 95% CI 0.67-1.16, p=0.37). In the subgroup analysis, patients with a high BMI had better OS in the ICI with tyrosine kinase inhibitor (TKI) subgroup (aHR 0.71, 95% CI 0.55-0.92, p=0.01), while no significant difference was found in the ICI-only subgroup (aHR 1.02, 95% CI 0.56-1.87, p=0.95). Adjusted statistics for progression-free survival (PFS) were assessable in predominantly ICI-only studies and demonstrated a favorable outcome for patients with a low BMI (aHR 1.67, 95% CI 1.14-2.45, p=0.01). In conclusion, the impact of high BMI varies depending on the treatment type, exhibiting a favorable correlation with OS within ICI with TKI subgroup, but indicating an adverse association with PFS in the ICI-only subgroup. Further research is needed to clarify the influence of BMI by stratifying patients into ICI-only and ICI with TKI treatment to provide more insights. [ABSTRACT FROM AUTHOR]

Abstract We aimed to evaluate the detection rates of prostate cancer (PCa) and clinically significant PCa (csPCa) using magnetic resonance imaging-targeted biopsy (MRI-TBx) in men with low prostate-specific antigen (PSA) levels (2.5–4.0 ng/mL). Clinicopathologic data of 5502 men with PSA levels of 2.5–10.0 ng/mL who underwent transrectal ultrasound-guided biopsy (TRUS-Bx) or MRI-TBx were reviewed. Participants were divided into four groups: LP-T [low PSA (2.5–4.0 ng/mL) and TRUS-Bx, n = 2018], LP-M (low PSA and MRI-TBx, n = 186), HP-T [high PSA (4.0–10.0 ng/mL) and TRUS-Bx, n = 2953], and HP-M (high PSA and MRI-TBx, n = 345). The detection rates of PCa and csPCa between groups were compared, and association of biopsy modality with detection of PCa and csPCa in men with low PSA levels were analyzed. The detection rates of PCa (20.0% vs. 38.2%; P

Abstract This study aims to compare oncologic and functional outcomes after radical nephroureterectomy (RNU) and segmental ureterectomy (SU) in patients with upper urinary tract urothelial carcinoma (UTUC). We retrospectively collected data on patients who underwent either RNU or SU of UTUC. Propensity score matching was performed among 394 cases to yield a final cohort of 40 RNU and 40 SU cases. Kaplan–Meier analysis and the log-rank test were used to compare overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), and intravesical recurrence-free survival (IVRFS) between the groups. We also compared the change in postoperative estimated glomerular filtration rate (eGFR). There was no significant difference in terms of CSS, PFS, and IVRFS between the RNU and SU groups, but the RNU group had a better OS than the SU group (p = 0.032). Postoperative eGFR was better preserved in the SU group than in the RNU group (p

Abstract We evaluated the predictive role of circulating tumor DNA (ctDNA) detection by targeted deep sequencing in patients with metastatic renal cell carcinoma (mRCC) treated with immune checkpoint blockades (ICB). To determine the feasibility of ctDNA detection in our panel encompassing 40 genes, we collected 10 ml of blood from 20 patients at the time of radical nephrectomy. We analyzed somatic mutations in primary tumors and ctDNA samples from these patients. We finally collected 10 ml of blood before and after 1 month of treatment, respectively, from four patients with mRCC who received first-line ICB treatment. Variants were detected in primary tumors of 15 patients (75%) and ctDNA was detected in the plasma of 9 patients (45%). We examined the predictive role of ctDNA in four patients who received first-line ICB therapy. In two patients showing partial response, ctDNA levels decreased after 1 month of ICB treatment. However, in one patient who showed disease progression, ctDNA levels increased after 1 month of ICB treatment. Taken together, ctDNA detection in plasma by targeted deep sequencing was feasible in patients with RCC. Moreover, the levels of ctDNA could be an early predictor of treatment response in patients with mRCC who receive ICB therapy.

Purpose: We investigated the relationship between body mass index (BMI), radiological body composition, and survival outcomes in patients with metastatic renal cell carcinoma (mRCC) underwent first-line immune checkpoint inhibitor (ICI)-based therapy. Methods: Analyzing data from 102 patients treated between November 2019 and March 2023, pre-treatment computed tomography (CT) scans assessed fat and muscle areas. BMI and body composition indices were examined, including skeletal muscle index, subcutaneous fat index (SFI), visceral fat index, and total fat index. Kaplan–Meier curves and Log rank tests compared progression-free survival (PFS) and overall survival (OS), while multivariable Cox proportional regression analysis was performed to identify the variables significantly associated with survival outcomes. Results: 54 patients (52.9%) experienced disease progression, and 26 (25.5%) died during a median follow-up of 17.4 months. High SFI was significantly associated with improved OS (p = 0.018) but not PFS (p = 0.090). Multivariable analysis confirmed the positive impact of high SFI on OS (adjusted HR: 0.37, p = 0.029) and suggested a trend towards improved PFS (adjusted HR: 0.61, p = 0.088). Notably, in the ipilimumab + nivolumab subgroup, high SFI significantly correlated with both PFS and OS (p = 0.047 and p = 0.012, respectively). Conclusion: High SFI predicts favorable OS in patients with mRCC receiving first-line ICI-based therapy, especially patients treated with ipilimumab + nivolumab displayed a significant association between high SFI and favorable PFS and OS. [ABSTRACT FROM AUTHOR]

Purpose: Bladder preservation chemoradiotherapy (CRT) in patients with a clinical complete response (cCR) following cisplatin-based neoadjuvant chemotherapy (NAC) is a promising treatment strategy for muscle-invasive bladder urothelial carcinoma (MIBC). A combined analysis of raw data from two prospective phase II studies was performed to better evaluate the feasibility of selective bladder preservation CRT. Materials and Methods: The analysis was based on primary efficacy data from two independent studies, including 76 MIBC patients receiving NAC followed by bladder preservation CRT. The efficacy data included metastasis-free survival (MFS) and disease-free survival (DFS). For the present analysis, starting point of survival was defined as the date of commencing CRT. Results: Among 76 patients, 66 had a cCR following NAC. Sixty-four patients received gemcitabine and cisplatin (GC) combination chemotherapy in neoadjuvant setting, and 12 received nivolumab plus GC. Bladder preservation CRT following NAC was generally well-tolerated, with low urinary tract symptoms being the most common late complication. With a median follow-up of 64 months, recurrence was recorded in 43 patients (57%): intravesical only (n=20), metastatic only (n=16), and both (n=7). In 27 patients with intravesical recurrence, transurethral resection, and Bacillus Calmette-Guerin treatment was given to 17 patients. Salvage cystectomy was performed in 10 patients. Median DFS was 46.3 (95% confidence interval [CI], 25.1 to 67.5) months, and the median MFS was not reached. Neither DFS nor MFS appeared to be affected by any of the baseline characteristics. However, DFS was significantly longer in patients with a cCR than in those without (hazard ratio, 0.465; 95% CI, 0.222 to 0.976). Conclusion The strategy of NAC followed by selective bladder preservation CRT based on the cCR is feasible in the treatment of MIBC. A standardized definition of cCR is needed to better assess disease status post-NAC. [ABSTRACT FROM AUTHOR]

Purpose: The aim of this retrospective study was to evaluate the efficacy of adjuvant cisplatin-based chemotherapy in patients with locally advanced upper tract urothelial carcinoma (UTUC), administered following radical nephroureterectomy. Materials and Methods: Patients with UTUC, arising from renal pelvis or ureter, staged pT3/T4 or N+ were treated with adjuvant chemotherapy following surgery. The chemotherapy consisted of gemcitabine 1,000 mg/m2 on days 1 and 8, cisplatin 70 mg/m2 on day 1. Treatment was repeated every 3 weeks for up to 4 cycles. Endpoints included disease-free survival (DFS), metastasis-free survival (MFS), and safety. Results: Among 89 eligible patients, 85 (95.5%) completed at least 3 cycles of adjuvant chemotherapy. Chemotherapy was well tolerated, the main toxicities being mild-to-moderate gastrointestinal toxic effects and pruritus. With a median follow-up of 37 months, median DFS was 30 months (95% confidence interval, 22 to 39), and the median MFS was not reached. The 3-year DFS and MFS were 44% and 56%, respectively. Multivariate analyses revealed that the main factor associated with DFS and MFS was the lymph node involvement, whereas age, T category, grade, or the primary site of UTUC were not significantly associated with DFS or MFS. Conclusion Adjuvant cisplatin-based chemotherapy after radical surgery of pT3/T4 or N+ UTUC was feasible and may demonstrate benefits in DFS and MFS. Whether novel agents added to the chemotherapy regimen, as a concurrent combination or maintenance, impacts on survival or reduces the development of metastases remains to be studied. [ABSTRACT FROM AUTHOR]

Purpose: We aimed to assess the effectiveness of early single intravesical administration of epirubicin in preventing intravesical recurrence after radical nephroureterectomy for upper tract urothelial carcinoma. Materials and Methods: Patients with upper tract urothelial carcinoma who underwent radical nephroureterectomy between November 2018 and May 2022 were retrospectively reviewed. Intravesical epirubicin was administered within 48 hours if no evidence of leakage was observed. Epirubicin (50 mg) in 50 mL normal saline solution was introduced into the bladder via a catheter and maintained for 60 minutes. The severity of adverse events was graded using the Clavien-Dindo classification. We compared intravesical recurrence rate between the two groups. Multivariate analyses were performed to identify the independent predictors of bladder recurrence following radical nephroureterectomy. Results: Epirubicin (n=55) and control (n=116) groups were included in the analysis. No grade 1 or higher bladder symptoms have been reported. A statistically significant difference in the intravesical recurrence rate was observed between the two groups (11.8% at 1 year in the epirubicin group vs. 28.4% at 1 year in the control group; log-rank p=0.039). In multivariate analysis, epirubicin instillation (hazard ratio [HR], 0.43; 95% confidence interval [CI], 0.20 to 0.93; p=0.033) and adjuvant chemotherapy (HR, 0.29; 95% CI, 0.13 to 0.65; p=0.003) were independently predictive of a reduced incidence of bladder recurrence. Conclusion This retrospective review revealed that a single immediate intravesical instillation of epirubicin is safe and can reduce the incidence of intravesical recurrence after radical nephroureterectomy. However, further prospective trials are required to confirm these findings. [ABSTRACT FROM AUTHOR]

Purpose: This study aimed to analyze the treatment outcomes of combined definitive radiation therapy (RT) and androgen deprivation therapy (ADT) for clinically node-positive prostate cancer. Materials and Methods: Medical records of 60 patients with clinically suspected metastatic lymph nodes on radiological examination were retrospectively analyzed. Eight patients (13.3%) were suspected to have metastatic common iliac or para-aortic lymph nodes. All patients underwent definitive RT with a dose fractionation of 70 Gy in 28 fractions. ADT was initiated 2-3 months before RT and continued for at least 2 years. Biochemical failure rate (BFR), clinical failure rate (CFR), overall survival (OS), and prostate cancer-specific survival (PCSS) were calculated, and genitourinary and gastrointestinal adverse events were recorded. Results: The median follow-up period was 5.47 years. The 5-year BFR, CFR, OS, and PCSS rates were 19.1%, 11.3%, 89.0%, and 98.2%, respectively. The median duration of ADT was 2.30 years. BFR and CFR increased after 3 years, and 11 out of 14 biochemical failures occurred after the cessation of ADT. Grade 2 and beyond late genitourinary and gastrointestinal toxicity rates were 5.0% and 13.3%, respectively. However, only two grade 3 adverse events were reported, and no grade 4-5 adverse events were reported. Patients with non-regional lymph node metastases did not have worse BFR, CFR, or adverse event rates. Conclusion: This study reported the efficacy and tolerable toxicity of hypofractionated definitive RT combined with ADT for clinically node-positive prostate cancer. Additionally, selected patients with adjacent non-regional lymph node metastases might be able to undergo definitive RT combined with ADT. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse large B-cell lymphoma (DLBCL) is an aggressive blood cancer and the most common non-Hodgkin lymphoma. DLBCL has a 40% relapse rate with current therapies, warranting investigations into potential vulnerabilities leading to new treatment avenues. Many DLBCLs increase the levels of a protein called BCL2 that blocks lymphoma cell death and contributes to treatment resistance and relapse. A drug was developed to target BCL2 (venetoclax/ABT-199) to induce DLBCL cell death. However, it was ineffective as a single agent, revealing that DLBCL relies on more than BCL2 for survival. Our study of intrinsic venetoclax resistance and developed venetoclax resistance in DLBCL identifies new targetable vulnerabilities in DLBCL by exposing dependencies on critical cellular processes. Our findings have the potential to lead to new treatments for DLBCL and possibly other B-cell lymphomas. Clinical trials with single-agent venetoclax/ABT-199 (anti-apoptotic BCL2 inhibitor) revealed that diffuse large B-cell lymphoma (DLBCL) is not solely dependent on BCL2 for survival. Gaining insight into pathways/proteins that increase venetoclax sensitivity or unique vulnerabilities in venetoclax-resistant DLBCL would provide new potential treatment avenues. Therefore, we generated acquired venetoclax-resistant DLBCL cells and evaluated these together with intrinsically venetoclax-resistant and -sensitive DLBCL lines. We identified resistance mechanisms, including alterations in BCL2 family members that differed between intrinsic and acquired venetoclax resistance and increased dependencies on specific pathways. Although combination treatments with BCL2 family member inhibitors may overcome venetoclax resistance, RNA-sequencing and drug/compound screens revealed that venetoclax-resistant DLBCL cells, including those with TP53 mutation, had a preferential dependency on oxidative phosphorylation. Mitochondrial electron transport chain complex I inhibition induced venetoclax-resistant, but not venetoclax-sensitive, DLBCL cell death. Inhibition of IDH2 (mitochondrial redox regulator) synergistically overcame venetoclax resistance. Additionally, both acquired and intrinsic venetoclax-resistant DLBCL cells were similarly sensitive to inhibitors of transcription, B-cell receptor signaling, and class I histone deacetylases. These approaches were also effective in DLBCL, follicular, and marginal zone lymphoma patient samples. Our results reveal there are multiple ways to circumvent or overcome the diverse venetoclax resistance mechanisms in DLBCL and other B-cell lymphomas and identify critical targetable pathways for future clinical investigations. [ABSTRACT FROM AUTHOR]

Purpose: To determine the clinical significance and correlation between the Prostate Health Index (PHI) and Gleason score in patients with a prostate-specific antigen (PSA) value of 2.5–10 ng/mL. Materials and Methods: This retrospective analysis included 114 patients who underwent biopsy after completion of the PHI from November 2018 to July 2019. Various parameters such as PSA, PHI, PSA density, free PSA, p2PSA, and %free PSA were collected, and correlations with biopsy Gleason score and cancer detection rates were investigated. Results: Baseline characteristics were comparable between PHI groups (0–26.9 [n=11], 27.0–35.9 [n=17], 36.0–54.9 [n=50], and ≥55.0 [n=36]). A total of 37 patients (32.5%) were diagnosed with prostate cancer, and 28 (24.6%) were diagnosed with clinically significant prostate cancer (CSPC, Gleason score ≥7) after prostate biopsy. The cancer detection rate gradually increased with a corresponding increase in the PHI (18%, 24%, 30%, and 44%, respectively). The same pattern was observed with detecting CSPC (0%, 18%, 26%, and 33%, respectively). There was no CSPC in the groups with PHI

Background: Few studies report on indications for prostate biopsy using Prostate Imaging–Reporting and Data System (PI-RADS) score and prostate-specific antigen density (PSAD). No study to date has included biopsy-naïve and prior biopsy-negative patients. Therefore, we evaluated the predictive values of the PI-RADS, version 2 (v2) score combined with PSAD to decrease unnecessary biopsies in biopsy-naïve and prior biopsy-negative patients. Materials and methods: A total of 1,098 patients who underwent multiparametric magnetic resonance imaging at our hospital before a prostate biopsy and who underwent their second prostate biopsy with an initial benign negative prostatic biopsy were included. We found factors associated with clinically significant prostate cancer (csPca). We assessed negative predictive values by stratifying biopsy outcomes by prior biopsy history and PI-RADS score combined with PSAD. Results: The median age was 65 years (interquartile range: 59-70), and the median PSA was 5.1 ng/mL (interquartile range: 3.8-7.1). Multivariate logistic regression analysis revealed that age, prostate volume, PSAD, and PI-RADS score were independent predictors of csPca. In a biopsy-naïve group, 4% with PI-RADS score 1 or 2 had csPca; in a prior biopsy-negative group, 3% with PI-RADS score 1 or 2 had csPca. The csPca detection rate was 2.0% for PSA density

Purpose: To determine the number of cases required to achieve a specified recurrence-free rate (>80%) among urethroplasty types. Materials and Methods: A retrospective analysis of consecutive patients, who underwent urethroplasty performed by a single surgeon between April 2013 and January 2019, was conducted. Urethroplasty subtypes were divided according to stricture location: penile, bulbar, and posterior. If there was no recurrence for >6 months after surgery, the surgery was considered to be a success. The average success rates among quintile groups were compared to determine the learning curve for each type. Results: Of 150 patients who underwent urethroplasty, 112 were included in this study. The overall success rate was 89.7% in penile, 97.8% in bulbar, and 74.1% in posterior urethroplasty. Bulbar urethroplasty reached the target success rate in the first quintile group (1–9 cases). Penile urethroplasty also achieved the target success rate in the first quintile group (1–8 cases), and the success rate gradually increased until the fifth quintile group (32–39 cases). In posterior urethroplasty, the target success rate was achieved in the fifth quintile group (20–27 cases). Conclusions: Bulbar urethroplasty had the fastest learning curve, and posterior urethroplasty the slowest.

Purpose The aim of this study was to evaluate the efficacy and safety of naftopidil compared with tamsulosin in patients with neurogenic lower urinary tract dysfunction (LUTD). Methods This study was conducted as an 8-week, active-controlled, stratified-randomized, double-blind, double-dummy, parallel group, noninferiority, and multicenter clinical trial. After 2 weeks of screening, eligible subjects were randomly assigned to receive naftopidil (25 mg for 1 week followed by 75 mg for 7 weeks) or tamsulosin (0.2 mg for 8 weeks). Primary endpoint was a change of International Prostatic Symptom Score (IPSS) total score after 8 weeks of treatment. Results One hundred ninety-four subjects with neurogenic LUTD were included into this trial. There were no differences between the 2 groups in baseline characteristics, including urodynamic study results, subtype of LUTD, pretreatment and concomitant medication, and causes of neurogenic bladder. The medication compliance rate was 94.0% (naftopidil, 93.6%; tamsulosin, 94.4%). There was a statistically significant decrease of IPSS total score at 8 weeks versus baseline in both the naftopidil (-5.64±0.66) and tamsulosin (-6.53±0.65) groups (P

BackgroundMagnetic resonance imaging (MRI) and transrectal ultrasound (TRUS)-guided cognitive or image fusion biopsy is performed to target a prostate imaging reporting and data system (PI-RADS) 3–5 lesion. Biopsy Gleason score (GS) is frequently underestimated compared to prostatectomy GS. However, it is still unclear about how many cores on target are necessary to reduce undergrading and if additional cores around the target may improve grade prediction on surgical specimen.PurposeTo determine the number of target cores and targeting strategy to reduce GS underestimation.Materials and MethodsBetween May 2017 and April 2020, a total of 385 patients undergoing target cognitive or image fusion biopsy of PI-RADS 3–5 index lesions and radical prostatectomies (RP) were 2:1 matched with propensity score using multiple variables and divided into the 1–4 core (n = 242) and 5–6 core (n = 143) groups, which were obtained with multiple logistic regression with restricted cubic spline curve. Target cores of 1–3 and 4–6 were sampled from central and peripheral areas, respectively. Pathologic outcomes and target cores were retrospectively assessed to analyze the GS difference or changes between biopsy and RP with Wilcoxon signed-rank test.ResultsThe median of target cores was 3 and 6 in the 1–4 core and 5–6 core groups, respectively (p < 0.001). Restricted cubic spline curve showed that GS upgrade was significantly reduced from the 5th core and there was no difference between 5th and 6th cores. Among the matched patients, 35.4% (136/385; 95% confidence interval, 0.305–0.403) had a GS upgrade after RP. The GS upgrades in the 1–4 core and 5–6 core groups were observed in 40.6% (98/242, 0.343–0.470) and 26.6% (38/143, 0.195–0.346), respectively (p = 0.023). Although there was no statistical difference between the matched groups in terms of RP GS (p = 0.092), the 5–6 core group had significantly higher biopsy GS (p = 0.006) and lower GS change from biopsy to RP (p = 0.027).ConclusionFive or more target cores sampling from both periphery and center of an index tumor contribute to reduce GS upgrade.