MCL1 inhibition: a promising approach to augment the efficacy of sorafenib in NSCLC through ferroptosis induction.

Ferroptosis, an iron-dependent form of regulated cell death, plays a crucial role in modulating the therapeutic response in non-small cell lung cancer (NSCLC) patients. Studies have identified the signal transducer and activator of transcription 3 (STAT3) and myeloid cell leukemia-1 (MCL1) as potential targets for sorafenib, which exhibits activities in inducing ferroptosis. However, the role of STAT3-MCL1 axis in sorafenib-induced ferroptosis in NSCLC is still unclear. This study provided evidence that ferroptosis is a critical driver of sorafenib-induced cell death in NSCLC, supported by the accumulation of lipid peroxidation products, indicative of oxidative stress-induced cell death. Additionally, both in vitro and in vivo experiments showed that ferroptosis contributed to a significant portion of the anti-cancer effects elicited by sorafenib in NSCLC. The noticeable accumulation of lipid peroxidation products in sorafenib-treated mice underscored the significance of ferroptosis as a contributing factor to the therapeutic response of sorafenib in NSCLC. Furthermore, we identified the involvement of the STAT3/MCL1 axis in sorafenib-induced antitumor activity in NSCLC. Mechanistically, sorafenib inhibited endogenous STAT3 activation and downregulated MCL1 protein expression, consequently unleashing the ferroptosis driver BECN1 from the BECN1-MCL1 complex. Conversely, there is an augmented association of BECN1 with the catalytic subunit of system Xc-, SLC7A11, whose activity to import cystine and alleviate lipid peroxidation is hindered upon its binding with BECN1. Notably, we found that MCL1 upregulation correlated with ferroptosis resistance in NSCLC upon sorafenib treatment. Our findings highlight the importance of sorafenib-triggered ferroptosis in NSCLC and offer a novel strategy to treat advanced NSCLC patients: by downregulating MCL1 and, in turn, predispose NSCLC cells to ferroptosis.

Treatment Outcomes of Patients with Ependymoma Receiving Radiotherapy: A Single Institution Experience.

INTRODUCTION: The study explored the failure pattern and clinical outcomes in patients with ependymoma undergoing radiotherapy. METHODS: Between January 2004 and June 2022, we included 32 patients with ependymoma who underwent radiotherapy as part of the multimodality treatment at our institution. Of these, 27 (84.4%) underwent adjuvant radiotherapy, four received radiotherapy after local recurrence, and one received definitive CyberKnife radiotherapy (21 Gy in three fractions). The median prescribed dose was 54 Gy in patients who received conventional radiotherapy. We analyzed the local progression-free survival (LPFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), overall survival (OS), and potential prognostic factors. RESULTS: The median age was 29.8 years. Approximately 28.1% were pediatric patients. Fifteen tumors (46.9%) were World Health Organization (WHO) grade II, 10 (31.3%) were WHO grade III, and seven (22.8%) were WHO grade I. Among them, 15 patients (46.9%) had posterior fossa tumors, 10 (31.3%) had supratentorial tumors, and seven (22.8%) had spinal tumors. Of the 31 patients who underwent upfront surgical resection, 19 (61.3%) underwent gross total resection or near total resection. Seventeen of 19 patients with first failures (89.5%) had isolated local recurrences. Of the 19 patients with disease progression, 11 (57.9%) were disease-free or had stable disease after salvage therapy, and five (26.3%) had disease-related mortality. Most of the first local recurrences after radiotherapy occurred in the infield (13 of 16, 81.3%). The 5-year LPFS, DMFS, PFS, and OS rates were 48.5%, 89.6%, 45.1%, and 88.4%, respectively, at a median follow-up of 6.25 years. Subtotal resection was associated with poorer LPFS and PFS in patients with intracranial ependymoma (hazard ratio = 3.69, p = 0.018 for LPFS; hazard ratio = 3.20, p = 0.029 for PFS). CONCLUSION: Incorporating radiotherapy into multimodal treatment has led to favorable outcomes in patients with ependymoma, and the extent of resection is a prognostic factor for the local control of intracranial ependymoma.

Identifying the role of MTHFD1L in prostate cancer progression from genetic analysis and experimental validation.

One-carbon metabolism plays a crucial role in tumorigenesis as it supplies the one-carbon units necessary for nucleotide synthesis, epigenetic regulation, and redox metabolism, ensuring the rapid proliferation of cancer cells. However, their roles in prostate cancer progression remain poorly understood. In this study, we investigated the association between genetic variants in the one-carbon metabolism pathway and clinical outcomes in patients receiving androgen deprivation therapy for prostate cancer. The associations of 130 single-nucleotide polymorphisms located within 14 genes involved in the one-carbon metabolism pathway with cancer-specific survival (CSS), overall survival, and progression-free survival were assessed using Cox regression in 630 patients with prostate cancer. Subsequently, functional studies were performed using prostate cancer cell lines. After adjusting for covariates and multiple testing, MTHFD1L rs2073190 was found to be significantly associated with CSS (P = 0.000184). Further pooled analysis of multiple datasets demonstrated that MTHFD1L was upregulated in prostate cancer and increased MTHFD1L expression was positively correlated with tumor aggressiveness and poor patient prognosis. Functionally, MTHFD1L knockdown suppressed prostate cancer cell proliferation and colony formation. RNA sequencing and pathway analysis revealed that differentially expressed genes were predominantly enriched in the cell cycle pathway. In conclusion, genetic variants in MTHFD1L of one-carbon metabolism may serve as promising predictors, and our findings offer valuable insights into the underlying genetic mechanisms of prostate cancer progression.

Prognostic factors of intravesical recurrence after radical nephroureterectomy for upper tract urothelial carcinoma.

PURPOSE: To evaluate predictive factors of increasing intravesical recurrence (IVR) rate in patients with upper tract urothelial carcinoma (UTUC) after receiving radical nephroureterectomy (RNUx) with bladder cuff excision (BCE). MATERIALS AND METHODS: A total of 2114 patients were included from the updated data of the Taiwan UTUC Collaboration Group. It was divided into two groups: IVR-free and IVR after RNUx, with 1527 and 587 patients, respectively. To determine the factors affecting IVR, TNM stage, the usage of pre-operative ureteroscopy, and pathological outcomes were evaluated. The Kaplan-Meier estimator was used to estimate the rates of prognostic outcomes in overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and bladder recurrence-free survival (BRFS), and the survival curves were compared using the stratified log-rank test. RESULTS: Based on our research, ureter tumor, female, smoking history, age (< 70 years old), multifocal tumor, history of bladder cancer were determined to increase the risk of IVR after univariate analysis. The multivariable analysis revealed that female (BRFS for male: HR 0.566, 95% CI 0.469-0.681, p < 0.001), ureter tumor (BRFS: HR 1.359, 95% CI 1.133-1.631, p = 0.001), multifocal (BRFS: HR 1.200, 95% CI 1.001-1.439, p = 0.049), history of bladder cancer (BRFS: HR 1.480, 95% CI 1.118-1.959, p = 0.006) were the prognostic factors for IVR. Patients who ever received ureterorenoscopy (URS) did not increase the risk of IVR. CONCLUSION: Patients with ureter tumor and previous bladder UC history are important factors to increase the risk of IVR after RNUx. Pre-operative URS manipulation is not associated with higher risk of IVR and diagnostic URS is feasible especially for insufficient information of image study. More frequent surveillance regimen may be needed for these patients.

C-C chemokine receptor 4 (CCR4)-positive regulatory T cells interact with tumor-associated macrophages to facilitate metastatic potential after radiation.

PURPOSE: Our previous study revealed that elevated C-C motif chemokine ligand 2 (CCL2) secretion by irradiated cancer cells recruited C-C motif chemokine receptor 2 (CCR2)-positive myeloid cells and polarized M2-type tumor-associated macrophages (TAMs), promoting lung metastasis in an established mouse model. This study investigated the impact of CCL2 and TAMs on adaptive immunity. METHODS: We assessed the influence of CCL2 and TAMs on adaptive immunity through two ectopic allograft mouse models constructed with MB49 bladder cancer cells and Lewis lung carcinoma cells. Both models exhibited delayed primary tumor growth following radiation therapy (RT), but RT promoted the development of pulmonary metastases in C57BL/6 mice. Additionally, we employed a direct coculture system to investigate the interaction between macrophages and target cells in the context of adaptive immunity. RESULTS: C-C motif chemokine receptor 4 (CCR4)-positive regulatory T cells (Tregs) were recruited to the postirradiated tumor microenvironment (TME). Utilizing a CCR4 antagonist to inhibit CCL2-CCR4 activation reversed the infiltration of CCR4 + Tregs and reduced the incidence of pulmonary metastases. In addition, a positive feedback loop between M2-type TAMs and Tregs was observed. The combined blockade of the CCL2-CCR4 and CCL2-CCR2 signaling pathways further decreased the risk of RT-promoted lung metastasis. CONCLUSION: The recruitment of CCR4 + Tregs to the postirradiated TME increases the metastatic potential of tumor cells through increased interactions with M2-type TAMs. A significant reduction in post-RT lung metastases in ectopic mouse models was achieved by disrupting the recruitment of both CCR4 + Tregs and CCR2 + myeloid cells, which are TAM precursors.

Integrated analysis identifies GABRB3 as a biomarker in prostate cancer.

BACKGROUND: Treatment failure following androgen deprivation therapy (ADT) presents a significant challenge in the management of advanced prostate cancer. Thus, understanding the genetic factors influencing this process could facilitate the development of personalized treatments and innovative therapeutic strategies. The phosphoinositide 3-kinase (PI3K)/AKT signaling pathway plays a pivotal role in controlling cell growth and tumorigenesis. We hypothesized that genetic variants within this pathway may affect the clinical outcomes of patients undergoing ADT for prostate cancer. METHODS: We genotyped 399 single-nucleotide polymorphisms (SNPs) across 28 core PI3K/AKT pathway genes in a cohort of 630 patients with prostate cancer undergoing ADT. We assessed the potential association of the SNPs with patient survival. Functional analyses of the implicated genes were also performed to evaluate their effects on prostate cancer. RESULTS: After multivariate Cox regression analysis and multiple testing correction, GABRB3 rs12591845 exhibited the most significant association with both overall and cancer-specific survivals (P < 0.003). A comprehensive pooled analysis of 16 independent gene expression datasets revealed elevated expression of GABRB3 in prostate cancer tissues compared to that in normal tissues (P < 0.001). Furthermore, gene set enrichment analysis unveiled differential enrichment of pathways such as myogenesis, interferon γ and α responses, and the MYC proto-oncogene pathway in tumors with elevated GABRB3 expression, implying a role for GABRB3 in prostate cancer. CONCLUSION: Our results suggest that rs12591845 could potentially serve as a valuable prognostic indicator for patients undergoing ADT. The potential role of GABRB3 in promoting prostate tumorigenesis is also highlighted.

EGFR-mediated hyperacetylation of tubulin induced docetaxel resistance by downregulation of HDAC6 and upregulation of MCAK and PLK1 in prostate cancer cells.

Docetaxel-based chemotherapy has generally been considered as one of the effective treatments for castration-resistant prostate cancer (PCa). However, clinical treatment with docetaxel often encounters a number of undesirable effects, including drug resistance. Tubulin isoforms have been previously examined for their resistance to docetaxel in many cancers, but their real mechanisms remained unclear. In this study, a series of docetaxel-resistant PC/DX cell sublines were established by chronically exposing PC3 to progressively increased concentrations of docetaxel. Western blotting results showed significantly higher expression of acetyl-tubulin, α-tubulin, ß-tubulin, γ-tubulin, and ßIII-tubulin in PC/DX25 than in parental PC3 cells. PC/DX25 with greater resistance to docetaxel had higher levels of acetyl-tubulin and mitotic centromere-associated kinesin (MCAK) than PC3 cells. This study found that docetaxel induced the expression of acetyl-tubulin and MCAK in PC3 cells at a dose- and time-dependent manner. Both mRNA and protein levels of histone deacetylase 6 (HDAC6) were significantly decreased in PC/DX25 compared with PC3 cells. PC3 increased the resistance to docetaxel by HDAC6 knockdown and Tubastatin A (HDAC6 inhibitor). Conversely, PC/DX25 reversed the sensitivity to docetaxel by MCAK knockdown. Notably, flow cytometry analysis revealed that MCAK knockdown induced significantly sub G1 fraction in PC/DX cells. Overexpression of polo-like kinase-1 increased the cell survival rate and resistance to docetaxel in PC3 cells. Moreover, epidermal growth factor receptor (EGFR) activation induced the upregulation of acetyl-tubulin in docetaxel-resistant PCa cells. These findings demonstrated that the EGFR-mediated upregulated expression of acetyl-tubulin played an important role in docetaxel-resistant PCa.

Comparison of senhance and da vinci robotic radical prostatectomy: short-term outcomes, learning curve, and cost analysis.

BACKGROUND: The Senhance® Robotic System is a new laparoscopy-based platform that has been increasingly used in radical prostatectomy (RP) procedures. The purpose of this study is to compare the outcome of Senhance RP (SRP) with da Vinci RP (DRP) cases. METHODS: From August 2019 to April 2022, we prospectively recruited 63 cases of SRP. We compared the perioperative data, postoperative complication rates, short-term surgical outcomes (3-month postoperative undetectable prostate-specific antigen (PSA) and incontinence rates), learning curves, and cost analysis with data from 63 matched da Vinci Xi RP cases. RESULTS: There was no difference in BL (180 versus 180 ml, p = 0.86) and postoperative surgical complication rate (Clavient -Dindo grade I-IV, 25.3 versus 22.2%, p = 0.21) between the SRP cases and the DRP. Regarding the oncologic and continence function, there was no difference between positive margin rate (36.5% versus 41.3%, p = 0.58), rate of undetectable PSA level at postoperative 3 months (68.3 versus 66.7%, p = 0.85), and incontinence rate (14.3 versus 15.9%, p = 1.0) at postoperative 3 months between the two cohorts. The learning curve showed a quick downward slope for laparoscopic experienced surgeons. The median pocket cost for SRP patients in our hospital was $4170, which was lower than $7675 for the DRP patients. CONCLUSIONS: Safety and short-term outcomes are comparable between SRP and DRP. For experienced LRP surgeons, using the Senhance system to perform RP is straightforward. With a more affordable price as its biggest advantage, the Senhance system may serve as a safe and effective alternative for robotic RP.

Prognostic nutritional index and neutrophil-lymphocyte ratio predict toxicities and prognosis in patients with cervical cancer treated with curative radiochemotherapy.

BACKGROUND: This study aimed to investigate the influence of immunonutritional factors on treatment-related toxicities and survival outcomes in patients with cervical cancer undergoing definitive radiochemotherapy. METHODS: Patients with cervical cancer who received curative radiochemotherapy between 2016 and 2021 were retrospectively investigated. Pretreatment prognostic nutritional index (PNI), neutrophil-lymphocyte ratio (NLR), monocyte-lymphocyte ratio (MLR), and platelet-lymphocyte ratio (PLR) were measured. Survival outcomes, acute and late toxicities were evaluated. RESULTS: Among the 138 patients, those with larger tumor diameters had significantly lower pre-treatment PNI (p = 0.005). Pre-treatment immunonutritional factors were predictive of clinical survival, whereas post-treatment factors did not correlate with prognosis. Patients with low pre-treatment PNI (<49.5) or high NLR (>2.4) had shorter progression-free survival (PFS, HR: 1.86, p = 0.045 for PNI; HR: 3.15, p = 0.002 for NLR) and overall survival (OS, HR: 1.80, p = 0.048 for PNI; HR: 3.83, p = 0.015 for NLR). High pre-treatment NLR was associated with an increased risk of acute diarrhea (p = 0.049) and late severe toxicities (p = 0.046). Combined analysis revealed that pre-treatment good nutritional status and low systemic inflammation were linked to longer PFS (p = 0.007) and OS (p = 0.002), and poor nutritional status and substantial systemic inflammation were associated with higher rates of late severe toxicities (p = 0.036), with higher prognostic value in advanced stage patients. CONCLUSIONS: Pretreatment immunonutritional measures serve as quantitative biomarkers for predicting survivals and treatment toxicities in patients with cervical cancer treated with definitive radiochemotherapy.

Active Surveillance for Taiwanese Men with Localized Prostate Cancer: Intermediate-Term Outcomes and Predictive Factors.

PURPOSE: Active surveillance (AS) is one of the management options for patients with low-risk and select intermediate-risk prostate cancer (PC). However, factors predicting disease reclassification and conversion to active treatment from a large population of pure Asian cohorts regarding AS are less evaluated. This study investigated the intermediate-term outcomes of patients with localized PC undergoing AS. MATERIALS AND METHODS: This cohort study enrolled consecutive men with localized non-high-risk PC diagnosed in Taiwan between June 2012 and Jan 2023. The study endpoints were disease reclassification (either pathological or radiographic progression) and conversion to active treatment. The factors predicting endpoints were evaluated using the Cox proportional hazards model. RESULTS: A total of 405 patients (median age: 67.2 years) were consecutively enrolled and followed up with a median of 64.6 months. Based on the National Comprehensive Cancer Network (NCCN) risk grouping, 70 (17.3%), 164 (40.5%), 140 (34.6%), and 31 (7.7%) patients were classified as very low-risk, low-risk, favorable-intermediate risk, and unfavorable intermediate-risk PC, respectively. The 5-year reclassification rates were 24.8%, 27.0%, 18.6%, and 25.3%, respectively. The 5-year conversion rates were 20.4%, 28.8%, 43.6%, and 37.8%, respectively. A prostate-specific antigen density (PSAD) of ≥0.15 ng/mL² predicted reclassification (hazard ratio [HR] 1.84, 95% confidence interval [CI] 1.17-2.88) and conversion (HR 1.56, 95% CI 1.05-2.31). A maximal percentage of cancer in positive cores (MPCPC) of ≥15% predicted conversion (15% to <50%: HR 1.41, 95% CI 0.91-2.18; ≥50%: HR 1.97, 95% CI 1.1453-3.40) compared with that of <15%. A Gleason grade group (GGG) of 3 tumor also predicted conversion (HR 2.69, 95% CI 1.06-6.79; GGG 3 vs 1). One patient developed metastasis, but none died of PC during the study period (2,141 person-years). CONCLUSIONS: AS is a viable option for Taiwanese men with non-high-risk PC, in terms of reclassification and conversion. High PSAD predicted reclassification, whereas high PSAD, MPCPC, and GGG predicted conversion.

Health-Related Quality of Life Assessment in Prostate Cancer Patient Undergoing Androgen Deprivation Therapy: Real-World Experience in the READT Study.

PURPOSE: To investigate the effect of androgen deprivation therapy (ADT) on health-related quality of life (HRQOL) in Asian men with all stages of prostate cancer. MATERIALS AND METHODS: READT (real-life evaluation of the effect of ADT in prostate cancer patients in Asia) was a multi-center, prospective observational study involving six sites across four Asian populations. We enrolled eligible prostate cancer patients, who opted for ADT alone or in combination without prior neoadjuvant or adjuvant ADT within 12 months. The EuroQoL-5 dimensions, 5 level scale (EQ-5D-5L) utility index scores and visual analog scale (VAS) were evaluated at baseline, month 6 and month 12. RESULTS: A total of 504 patients were recruited into READT between September 2016 and May 2020 with 52.9% diagnosed with metastatic prostate cancer. The EQ-5D-5L was evaluable in 442/504 (87.7%) of patients. Overall baseline EQ-5D-5L utility index score was 0.924 (interquartile range [IQR] 0.876-1.000). We observed a statistically significant difference in baseline EQ-5D-5L utility index score among different populations with a median EQ-5D-5L utility index score of 1 for Taiwan & Hong Kong, 0.897 for China and 0.838 for Malaysia. Similar trend was observed throughout multiple treatment time-points. Stage IV prostate cancer were significantly associated with a lower baseline EQ-5D-5L utility index score compared to stage I-III prostate cancer, producing a median disutility value of -0.080. Participants had a high median VAS (80, IQR 70-90), indicating good overall health on average during ADT initiation. CONCLUSIONS: The study highlights the differences in health state utility index scores among various Asian prostate cancer patients receiving ADT at real-world setting. Our findings will be informative and useful in cost-effectiveness evaluation and policy decision making.

Endoscopic management of upper tract urothelial cancer in a highly endemic area: A Taiwan nationwide collaborative study.

BACKGROUND: Endoscopic management of upper tract urothelial cancer (UTUC) is an important treatment option for low risk UTUC. Although Taiwan is an endemic area for UTUC, endoscopic treatment outcomes in Taiwan are frequently under- reported. METHODS: This study retrospectively reviewed the treatment outcomes of endoscopic management for clinically localized UTUC. Patients with biopsy or washing cytology confirmed UTUC who underwent endoscopic or percutaneous management with a curative intent were retrospectively reviewed for eligibility of analysis. Those cases without pre-intervention confirmed UTUC, and metastatic or nodal disease at diagnosis were excluded. RESULTS: In total, 307 patients who underwent endoscopic management were reviewed and 279 cases were eligible for final analysis. With a median follow-up of 44.3 months (inter-quartile range (IQR): 23.4-76.4 months), 117 cases (46.4%) were endoscopic cured after median one session (range:1-8; IQR:1-2) of endoscopic treatment. Those endoscopic cured UTUC was associated with more small-sized tumor, more low-grade biopsied-histology, less concomitant bladder UC and less pre-operative hydronephrosis. In addition, 201(79.7%) cases among 252 cases with confirmed oncological outcome were free of UTUC at the end of follow-up and only 43 (17%) patients had a UTUC related mortality. Salvage RNU offered a better tumor free survival rate (92% vs. 77.5%) than those without salvage RNU in those UTUC refractory to endoscopic management. In multivariable analyses, pre-operative hydronephrosis was the independent risk factor for OS. Multiplicity and concomitant bladder UC were independent risk factors for DFS. CONCLUSIONS: We confirmed the consistent safety and efficacy of endoscopic management of clinical localized UTUC in a highly UTUC endemic area like Taiwan. Early salvage RNU is mandatory in those UTUC refractory to endoscopic management in prevention of UTUC related death.

CYBA as a Potential Biomarker for Renal Cell Carcinoma: Evidence from an Integrated Genetic Analysis.

BACKGROUND/AIM: Oxidative stress plays an important role in various pathogenic processes, and disruption in the coordinated production of NADPH oxidase (NOX)-derived reactive oxygen species has been associated with carcinogenesis. However, little is known about whether genetic variants in NOX can contribute to the development of renal cell carcinoma (RCC). PATIENTS AND METHODS: This study aimed to bridge this knowledge gap by analysing the association of 10 single-nucleotide polymorphisms in the phagocyte NOX genes, CYBA and CYBB, with RCC risk and tumour characteristics in 630 RCC patients and controls. Differential gene expression and patient prognosis analyses were performed using gene expression data obtained from public databases. RESULTS: Multivariate analysis and multiple testing corrections revealed the A allele of rs7195830 in CYBA to be a significant risk allele for RCC, compared to the G allele [odds ratio (OR)=1.70, 95% confidence interval (CI)=1.27-2.26, p<0.001]. A pooled analysis of 17 renal cancer gene expression datasets revealed a higher CYBA expression in RCC than in normal tissues. Moreover, high CYBA expression was associated with advanced tumour characteristics and worse patient prognosis. CONCLUSION: CYBA might play an oncogenic role in RCC and serve as a predictive indicator of patient prognosis.

Development and validation of the creatinine clearance predictor machine learning models in critically ill adults.

BACKGROUND: In critically ill patients, measured creatinine clearance (CrCl) is the most reliable method to evaluate glomerular filtration rate in routine clinical practice and may vary subsequently on a day-to-day basis. We developed and externally validated models to predict CrCl one day ahead and compared them with a reference reflecting current clinical practice. METHODS: A gradient boosting method (GBM) machine-learning algorithm was used to develop the models on data from 2825 patients from the EPaNIC multicenter randomized controlled trial database. We externally validated the models on 9576 patients from the University Hospitals Leuven, included in the M@tric database. Three models were developed: a "Core" model based on demographic, admission diagnosis, and daily laboratory results; a "Core + BGA" model adding blood gas analysis results; and a "Core + BGA + Monitoring" model also including high-resolution monitoring data. Model performance was evaluated against the actual CrCl by mean absolute error (MAE) and root-mean-square error (RMSE). RESULTS: All three developed models showed smaller prediction errors than the reference. Assuming the same CrCl of the day of prediction showed 20.6 (95% CI 20.3-20.9) ml/min MAE and 40.1 (95% CI 37.9-42.3) ml/min RMSE in the external validation cohort, while the developed model having the smallest RMSE (the Core + BGA + Monitoring model) had 18.1 (95% CI 17.9-18.3) ml/min MAE and 28.9 (95% CI 28-29.7) ml/min RMSE. CONCLUSIONS: Prediction models based on routinely collected clinical data in the ICU were able to accurately predict next-day CrCl. These models could be useful for hydrophilic drug dosage adjustment or stratification of patients at risk. TRIAL REGISTRATION: Not applicable.

Impact of pathological response on oncological outcomes in patients with upper tract urothelial cancer receiving neo-adjuvant chemotherapy.

PURPOSE: The purpose of this study is to evaluate the rates of pathological complete response (ypT0N0/X) and pathological response (ypT1N0/X or less) in patients with upper tract urothelial cancer who were treated with neo-adjuvant chemotherapy and to examine their impact on oncological outcomes. METHODS: This study is a multi-institutional retrospective analysis of patients with high-risk upper tract urothelial cancer who underwent neoadjuvant chemotherapy and radical nephroureterectomy between 2002 and 2021. Logistic regression analyses were used to investigate all clinical parameters for response after neoadjuvant chemotherapy. Cox proportional hazard models were performed to assess the effect of the response on the oncological outcomes. RESULTS: A total of 84 patients with UTUC who received neo-adjuvant chemotherapy were identified. Among them, 44 (52.4%) patients received cisplatin-based chemotherapy, and 22 (26.2%) patients had a carboplatin-based regimen. The pathological complete response rate was 11.6% (n = 10), and the pathological response rate was 42.9% (n = 36). Multifocal tumors or tumors larger than 3 cm significantly reduced the odds of pathological response. In the multivariable Cox proportional hazard model, pathological response was independently associated with better overall survival (HR 0.38, p = 0.024), cancer-specific survival (HR 0.24, p = 0.033), and recurrence-free survival (HR 0.17, p = 0.001), but it was not associated with bladder recurrence-free survival (HR 0.84, p = 0.69). CONCLUSION: Pathological response after neo-adjuvant chemotherapy and radical nephroureterectomy is strongly associated with patient survival and recurrence, and it might be a good surrogate for evaluating the efficacy of neo-adjuvant chemotherapy in the future.

Survival outcomes and prognostic factors for first-line abiraterone acetate or enzalutamide in patients with metastatic castration-resistant prostate cancer.

PURPOSE: To investigate the survival outcomes of metastatic castration-resistant prostate cancer (mCRPC) patients receiving first-line novel androgen receptor axis-targeted therapies (ARATs) and prognostic factors for patient survival. METHODS: This retrospective study obtained data from 202 patients who started abiraterone acetate or enzalutamide as first-line therapy for mCRPC between 2016 and 2021 from a single academic center. The primary endpoint was overall survival (OS) defined as the interval from the start of ARAT to death, loss to follow-up, or the end of the study period. The secondary endpoints were PSA decline, PSA nadir, and time to nadir (TTN) after ARATs. Kaplan-Meier survival analyses were applied for depicting OS. Cox proportional hazards model with inversed probability of treatment weighing-adjustment was used to validate the effect of patient, disease, and treatment response factors on OS. RESULTS: Among 202 patients, 164 patients were treated with first-line ARATs alone and 38 patients received second-line chemotherapy. The median OS was not reached in patients with first-line ARATs alone and was 38.8 months in those with subsequent chemotherapy after failure from ARATs. OS was not different between the use of abiraterone and enzalutamide, though enzalutamide showed a higher rate of PSA decline ≧ 90% (56% versus 40%, p = 0.021) and longer TTN (5.5 versus 4.7 months, p = 0.019). Multivariable analysis showed that PSA nadir > 2 ng/mL [hazard ratio (HR) 7.04, p < 0.001] and TTN<7 months (HR 2.18, p = 0.012) were independently associated with shorter OS. Patients with both of these poor prognostic factors had worse OS compared to those who had 0-1 factors (HR 9.21, p < 0.001). CONCLUSIONS: Patients with mCRPC who received first-line ARATs had better survival if they had a PSA nadir[Formula: see text]2 ng/mL or a TTN[Formula: see text]7 months. Further study is needed to determine if an early switch in therapy for those in whom neither is achieved may impact OS.

External Validation of the Augmented Renal Clearance Predictor in Critically Ill COVID-19 Patients.

The ARC predictor is a prediction model for augmented renal clearance (ARC) on the next intensive care unit (ICU) day that showed good performance in a general ICU setting. In this study, we performed a retrospective external validation of the ARC predictor in critically ill coronavirus disease 19 (COVID-19) patients admitted to the ICU of the University Hospitals Leuven from February 2020 to January 2021. All patient-days that had serum creatinine levels available and measured creatinine clearance on the next ICU day were enrolled. The performance of the ARC predictor was evaluated using discrimination, calibration, and decision curves. A total of 120 patients (1064 patient-days) were included, and ARC was found in 57 (47.5%) patients, corresponding to 246 (23.1%) patient-days. The ARC predictor demonstrated good discrimination and calibration (AUROC of 0.86, calibration slope of 1.18, and calibration-in-the-large of 0.14) and a wide clinical-usefulness range. At the default classification threshold of 20% in the original study, the sensitivity and specificity were 72% and 81%, respectively. The ARC predictor is able to accurately predict ARC in critically ill COVID-19 patients. These results support the potential of the ARC predictor to optimize renally cleared drug dosages in this specific ICU population. Investigation of dosing regimen improvement was not included in this study and remains a challenge for future studies.

Prostate Health Index Density Outperforms Prostate-specific Antigen Density in the Diagnosis of Clinically Significant Prostate Cancer in Equivocal Magnetic Resonance Imaging of the Prostate: A Multicenter Evaluation.

PURPOSE: We compare Prostate Health Index, Prostate Health Index density, and PSA density in predicting clinically significant prostate cancer in MRI-guided prostate biopsy. MATERIALS AND METHODS: This is a multicenter evaluation of prospectively maintained prostate biopsy databases at 10 urology centers. Men with Prostate Health Index and MRI-guided targeted and systematic prostate biopsy performed and without prior prostate cancer diagnosis were included. The additional value of PSA density, Prostate Health Index, and Prostate Health Index density to MRI PI-RADS (Prostate Imaging Reporting & Data System) score was evaluated with multivariable analyses, area under the curve, and decision curve analyses. The proportion of unnecessary biopsies that can be avoided are estimated for clinically significant prostate cancer (International Society of Urological Pathology group ≥2 prostate cancer). RESULTS: A total of 1,215 men were analyzed. Prostate cancer and clinically significant prostate cancer were diagnosed in 51% (617/1,215) and 35% (422/1,215) of men, respectively. Clinically significant prostate cancer was diagnosed in 4.4% (3/68), 15% (72/470), 39% (176/446), and 74% (171/231) of highest PI-RADS score of 2, 3, 4, and 5 lesions, respectively. In multivariable analyses, independent predictors for clinically significant prostate cancer detection included Prostate Health Index (OR 1.04), prostate volume (OR 0.97), and PI-RADS score 4 (OR 2.81) and 5 (OR 8.34). Area under the curve for clinically significant prostate cancer of PI-RADS + Prostate Health Index density (0.85) was superior to PI-RADS + PSA density (0.81), Prostate Health Index density (0.81), Prostate Health Index (0.78), PI-RADS (0.76), PSA density (0.72), and PSA (0.60) in the whole cohort, and the superiority of Prostate Health Index density was also observed in PI-RADS 3 lesions. Decision curve analysis showed Prostate Health Index density achieving the best net clinical benefit in PI-RADS 3 or 4 cases. Among PI-RADS 3 lesions, using cutoffs of PSA density 0.15, Prostate Health Index 38.0, and Prostate Health Index density 0.83 could reduce 58%, 67%, and 72% of unnecessary biopsies, respectively. CONCLUSIONS: Prostate Health Index density outperformed Prostate Health Index or PSA density in clinically significant prostate cancer detection in men with multiparametric MRI performed, and further reduced unnecessary biopsies in PI-RADS 3 lesions.

Preoperative hydronephrosis is an independent protective factor of renal function decline after nephroureterectomy for upper tract urothelial carcinoma.

Objectives: To evaluate the predictive role of pre-nephroureterectomy (NU) hydronephrosis on post-NU renal function (RF) change and preserved eligibility rate for adjuvant therapy in patients with upper tract urothelial carcinoma (UTUC). Patients and methods: This retrospective study collected data of 1018 patients from the Taiwan UTUC Collaboration Group registry of 26 institutions. The patients were divided into two groups based on the absence or presence of pre-NU hydronephrosis. Estimated glomerular filtration rate (eGFR) was calculated pre- and post-NU respectively. The one month post-NU RF change, chronic kidney disease (CKD) progression, and the preserved eligibility rate for adjuvant therapy were compared for each CKD stage. Results: 404 (39.2%) patients without and 614 (60.8%) patients with pre-NU hydronephrosis were enrolled. The median post-NU change in the eGFR was significantly lower in the hydronephrosis group (-3.84 versus -12.88, p<0.001). Pre-NU hydronephrosis was associated with a lower post-NU CKD progression rate (33.1% versus 50.7%, p< 0.001) and was an independent protective factor for RF decline after covariate adjustment (OR=0.46, p<0.001). Patients with pre-NU hydronephrosis had a higher preserved eligibility rate for either adjuvant cisplatin-based chemotherapy (OR=3.09, 95%CI 1.95-4.69) or immune-oncology therapy (OR=2.31, 95%CI 1.23-4.34). Conclusion: Pre-NU hydronephrosis is an independent protective predictor for post-NU RF decline, CKD progression, and eligibility for adjuvant therapy. With cautious selection for those unfavorably prognostic, non-metastatic UTUC patients with preoperative hydronephrosis, adjuvant rather than neoadjuvant therapy could be considered due to higher chance of preserving eligibility.