Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer.

Mammalian switch/sucrose nonfermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, an orally bioavailable proteolysis-targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 (ATP binding cassette subfamily B member 1) overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.

Targeting PIKfyve-driven lipid homeostasis as a metabolic vulnerability in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDAC) subsists in a nutrient-deregulated microenvironment, making it particularly susceptible to treatments that interfere with cancer metabolism12. For example, PDAC utilizes and is dependent on high levels of autophagy and other lysosomal processes3-5. Although targeting these pathways has shown potential in preclinical studies, progress has been hampered by the challenge of identifying and characterizing favorable targets for drug development6. Here, we characterize PIKfyve, a lipid kinase integral to lysosomal functioning7, as a novel and targetable vulnerability in PDAC. In human patient and murine PDAC samples, we discovered that PIKFYVE is overexpressed in PDAC cells compared to adjacent normal cells. Employing a genetically engineered mouse model, we established the essential role of PIKfyve in PDAC progression. Further, through comprehensive metabolic analyses, we found that PIKfyve inhibition obligated PDAC to upregulate de novo lipid synthesis, a relationship previously undescribed. PIKfyve inhibition triggered a distinct lipogenic gene expression and metabolic program, creating a dependency on de novo lipid metabolism pathways, by upregulating genes such as FASN and ACACA. In PDAC, the KRAS-MAPK signaling pathway is a primary driver of de novo lipid synthesis, specifically enhancing FASN and ACACA levels. Accordingly, the simultaneous targeting of PIKfyve and KRAS-MAPK resulted in the elimination of tumor burden in a syngeneic orthotopic model and tumor regression in a xenograft model of PDAC. Taken together, these studies suggest that disrupting lipid metabolism through PIKfyve inhibition induces synthetic lethality in conjunction with KRAS-MAPK-directed therapies for PDAC.

p300/CBP degradation is required to disable the active AR enhanceosome in prostate cancer.

Prostate cancer is an exemplar of an enhancer-binding transcription factor-driven disease. The androgen receptor (AR) enhanceosome complex comprised of chromatin and epigenetic coregulators assembles at enhancer elements to drive disease progression. The paralog lysine acetyltransferases p300 and CBP deposit histone marks that are associated with enhancer activation. Here, we demonstrate that p300/CBP are determinant cofactors of the active AR enhanceosome in prostate cancer. Histone H2B N-terminus multisite lysine acetylation (H2BNTac), which was exclusively reliant on p300/CBP catalytic function, marked active enhancers and was notably elevated in prostate cancer lesions relative to the adjacent benign epithelia. Degradation of p300/CBP rapidly depleted acetylation marks associated with the active AR enhanceosome, which was only partially phenocopied by inhibition of their reader bromodomains. Notably, H2BNTac was effectively abrogated only upon p300/CBP degradation, which led to a stronger suppression of p300/CBP-dependent oncogenic gene programs relative to bromodomain inhibition. In vivo experiments using a novel, orally active p300/CBP proteolysis targeting chimera (PROTAC) degrader (CBPD-409) showed that p300/CBP degradation potently inhibited tumor growth in preclinical models of castration-resistant prostate cancer and synergized with AR antagonists. While mouse p300/CBP orthologs were effectively degraded in host tissues, prolonged treatment with the PROTAC degrader was well tolerated with no significant signs of toxicity. Taken together, our study highlights the pivotal role of p300/CBP in maintaining the active AR enhanceosome and demonstrates how target degradation may have functionally distinct effects relative to target inhibition, thus supporting the development of p300/CBP degraders for the treatment of advanced prostate cancer.

Development of an orally bioavailable mSWI/SNF ATPase degrader and acquired mechanisms of resistance in prostate cancer.

Mammalian switch/sucrose non-fermentable (mSWI/SNF) ATPase degraders have been shown to be effective in enhancer-driven cancers by functioning to impede oncogenic transcription factor chromatin accessibility. Here, we developed AU-24118, a first-in-class, orally bioavailable proteolysis targeting chimera (PROTAC) degrader of mSWI/SNF ATPases (SMARCA2 and SMARCA4) and PBRM1. AU-24118 demonstrated tumor regression in a model of castration-resistant prostate cancer (CRPC) which was further enhanced with combination enzalutamide treatment, a standard of care androgen receptor (AR) antagonist used in CRPC patients. Importantly, AU-24118 exhibited favorable pharmacokinetic profiles in preclinical analyses in mice and rats, and further toxicity testing in mice showed a favorable safety profile. As acquired resistance is common with targeted cancer therapeutics, experiments were designed to explore potential mechanisms of resistance that may arise with long-term mSWI/SNF ATPase PROTAC treatment. Prostate cancer cell lines exposed to long-term treatment with high doses of a mSWI/SNF ATPase degrader developed SMARCA4 bromodomain mutations and ABCB1 overexpression as acquired mechanisms of resistance. Intriguingly, while SMARCA4 mutations provided specific resistance to mSWI/SNF degraders, ABCB1 overexpression provided broader resistance to other potent PROTAC degraders targeting bromodomain-containing protein 4 (BRD4) and AR. The ABCB1 inhibitor, zosuquidar, reversed resistance to all three PROTAC degraders tested. Combined, these findings position mSWI/SNF degraders for clinical translation for patients with enhancer-driven cancers and define strategies to overcome resistance mechanisms that may arise.

NSD2 is a requisite subunit of the AR/FOXA1 neo-enhanceosome in promoting prostate tumorigenesis.

The androgen receptor (AR) is a ligand-responsive transcription factor that binds at enhancers to drive terminal differentiation of the prostatic luminal epithelia. By contrast, in tumors originating from these cells, AR chromatin occupancy is extensively reprogrammed to drive hyper-proliferative, metastatic, or therapy-resistant phenotypes, the molecular mechanisms of which remain poorly understood. Here, we show that the tumor-specific enhancer circuitry of AR is critically reliant on the activity of Nuclear Receptor Binding SET Domain Protein 2 (NSD2), a histone 3 lysine 36 di-methyltransferase. NSD2 expression is abnormally gained in prostate cancer cells and its functional inhibition impairs AR trans-activation potential through partial off-loading from over 40,000 genomic sites, which is greater than 65% of the AR tumor cistrome. The NSD2-dependent AR sites distinctly harbor a chimeric AR-half motif juxtaposed to a FOXA1 element. Similar chimeric motifs of AR are absent at the NSD2-independent AR enhancers and instead contain the canonical palindromic motifs. Meta-analyses of AR cistromes from patient tumors uncovered chimeric AR motifs to exclusively participate in tumor-specific enhancer circuitries, with a minimal role in the physiological activity of AR. Accordingly, NSD2 inactivation attenuated hallmark cancer phenotypes that were fully reinstated upon exogenous NSD2 re-expression. Inactivation of NSD2 also engendered increased dependency on its paralog NSD1, which independently maintained AR and MYC hyper-transcriptional programs in cancer cells. Concordantly, a dual NSD1/2 PROTAC degrader, called LLC0150, was preferentially cytotoxic in AR-dependent prostate cancer as well as NSD2-altered hematologic malignancies. Altogether, we identify NSD2 as a novel subunit of the AR neo-enhanceosome that wires prostate cancer gene expression programs, positioning NSD1/2 as viable paralog co-targets in advanced prostate cancer.

PIKfyve controls dendritic cell function and tumor immunity.

The modern armamentarium for cancer treatment includes immunotherapy and targeted therapy, such as protein kinase inhibitors. However, the mechanisms that allow cancer-targeting drugs to effectively mobilize dendritic cells (DCs) and affect immunotherapy are poorly understood. Here, we report that among shared gene targets of clinically relevant protein kinase inhibitors, high PIKFYVE expression was least predictive of complete response in patients who received immune checkpoint blockade (ICB). In immune cells, high PIKFYVE expression in DCs was associated with worse response to ICB. Genetic and pharmacological studies demonstrated that PIKfyve ablation enhanced DC function via selectively altering the alternate/non-canonical NF-κB pathway. Both loss of Pikfyve in DCs and treatment with apilimod, a potent and specific PIKfyve inhibitor, restrained tumor growth, enhanced DC-dependent T cell immunity, and potentiated ICB efficacy in tumor-bearing mouse models. Furthermore, the combination of a vaccine adjuvant and apilimod reduced tumor progression in vivo. Thus, PIKfyve negatively controls DCs, and PIKfyve inhibition has promise for cancer immunotherapy and vaccine treatment strategies.

Targeting the mSWI/SNF Complex in POU2F-POU2AF Transcription Factor-Driven Malignancies.

The POU2F3-POU2AF2/3 (OCA-T1/2) transcription factor complex is the master regulator of the tuft cell lineage and tuft cell-like small cell lung cancer (SCLC). Here, we found that the POU2F3 molecular subtype of SCLC (SCLC-P) exhibits an exquisite dependence on the activity of the mammalian switch/sucrose non-fermentable (mSWI/SNF) chromatin remodeling complex. SCLC-P cell lines were sensitive to nanomolar levels of a mSWI/SNF ATPase proteolysis targeting chimera (PROTAC) degrader when compared to other molecular subtypes of SCLC. POU2F3 and its cofactors were found to interact with components of the mSWI/SNF complex. The POU2F3 transcription factor complex was evicted from chromatin upon mSWI/SNF ATPase degradation, leading to attenuation of downstream oncogenic signaling in SCLC-P cells. A novel, orally bioavailable mSWI/SNF ATPase PROTAC degrader, AU-24118, demonstrated preferential efficacy in the SCLC-P relative to the SCLC-A subtype and significantly decreased tumor growth in preclinical models. AU-24118 did not alter normal tuft cell numbers in lung or colon, nor did it exhibit toxicity in mice. B cell malignancies which displayed a dependency on the POU2F1/2 cofactor, POU2AF1 (OCA-B), were also remarkably sensitive to mSWI/SNF ATPase degradation. Mechanistically, mSWI/SNF ATPase degrader treatment in multiple myeloma cells compacted chromatin, dislodged POU2AF1 and IRF4, and decreased IRF4 signaling. In a POU2AF1-dependent, disseminated murine model of multiple myeloma, AU-24118 enhanced survival compared to pomalidomide, an approved treatment for multiple myeloma. Taken together, our studies suggest that POU2F-POU2AF-driven malignancies have an intrinsic dependence on the mSWI/SNF complex, representing a therapeutic vulnerability.

Targeting the lipid kinase PIKfyve upregulates surface expression of MHC class I to augment cancer immunotherapy.

Despite the remarkable clinical success of immunotherapies in a subset of cancer patients, many fail to respond to treatment and exhibit resistance. Here, we found that genetic or pharmacologic inhibition of the lipid kinase PIKfyve, a regulator of autophagic flux and lysosomal biogenesis, upregulated surface expression of major histocompatibility complex class I (MHC-I) in cancer cells via impairing autophagic flux, resulting in enhanced cancer cell killing mediated by CD8+ T cells. Genetic depletion or pharmacologic inhibition of PIKfyve elevated tumor-specific MHC-I surface expression, increased intratumoral functional CD8+ T cells, and slowed tumor progression in multiple syngeneic mouse models. Importantly, enhanced antitumor responses by Pikfyve-depletion were CD8+ T cell- and MHC-I-dependent, as CD8+ T cell depletion or B2m knockout rescued tumor growth. Furthermore, PIKfyve inhibition improved response to immune checkpoint blockade (ICB), adoptive cell therapy, and a therapeutic vaccine. High expression of PIKFYVE was also predictive of poor response to ICB and prognostic of poor survival in ICB-treated cohorts. Collectively, our findings show that targeting PIKfyve enhances immunotherapies by elevating surface expression of MHC-I in cancer cells, and PIKfyve inhibitors have potential as agents to increase immunotherapy response in cancer patients.

Proxalutamide reduces SARS-CoV-2 infection and associated inflammatory response.

Early in the COVID-19 pandemic, data suggested that males had a higher risk of developing severe disease and that androgen deprivation therapy might be associated with protection. Combined with the fact that TMPRSS2 (transmembrane serine protease 2), a host entry factor for the SARS-CoV-2 virus, was a well-known androgen-regulated gene, this led to an upsurge of research investigating androgen receptor (AR)-targeting drugs. Proxalutamide, an AR antagonist, was shown in initial clinical studies to benefit COVID-19 patients; however, further validation is needed as one study was retracted. Due to continued interest in proxalutamide, which is in phase 3 trials, we examined its ability to impact SARS-CoV-2 infection and downstream inflammatory responses. Proxalutamide exerted similar effects as enzalutamide, an AR antagonist prescribed for advanced prostate cancer, in decreasing AR signaling and expression of TMPRSS2 and angiotensin-converting enzyme 2 (ACE2), the SARS-CoV-2 receptor. However, proxalutamide led to degradation of AR protein, which was not observed with enzalutamide. Proxalutamide inhibited SARS-CoV-2 infection with an IC50 value of 97 nM, compared to 281 nM for enzalutamide. Importantly, proxalutamide inhibited infection by multiple SARS-CoV-2 variants and synergized with remdesivir. Proxalutamide protected against cell death in response to tumor necrosis factor alpha and interferon gamma, and overall survival of mice was increased with proxalutamide treatment prior to cytokine exposure. Mechanistically, we found that proxalutamide increased levels of NRF2, an essential transcription factor that mediates antioxidant responses, and decreased lung inflammation. These data provide compelling evidence that proxalutamide can prevent SARS-CoV-2 infection and cytokine-induced lung damage, suggesting that promising clinical data may emerge from ongoing phase 3 trials.

PMEPA1 Is a Prognostic Biomarker That Correlates With Cell Malignancy and the Tumor Microenvironment in Bladder Cancer.

Prostate transmembrane protein androgen induced 1 (PMEPA1) has been reported to promote cancer progression, but the potential role of PMEPA1 in bladder cancer (BLCA) remains elusive. We assess the role of PMEPA1 in BLCA, via a publicly available database and in vitro study. PMEPA1 was identified from 107 differentially expressed genes (DEGs) to have prognostic value. GO, KEGG, and GSEA analysis indicated that PMEPA1 was involved in cancer progression and the tumor microenvironment (TME). Then bioinformatical analysis in TCGA, GEO, TIMER, and TISIDB show a positive correlation with the inflammation and infiltration levels of three tumor-infiltrating immune cells (TAMs, CAFs, and MDSCs) and immune/stromal scores in TME. Moreover, in vitro study revealed that PMEPA1 promotes bladder cancer cell malignancy. Immunohistochemistry and survival analysis shed light on PMEPA1 potential to be a novel biomarker in predicting tumor progression and prognosis. At last, we also analyzed the role of PMEPA1 in predicting the molecular subtype and the response to several treatment options in BLCA. We found that PMEPA1 may be a novel potential biomarker to predict the progression, prognosis, and molecular subtype of BLCA.

Efficacy of Intra-Arterial Plus Intravesical Chemotherapy for High-Risk Non-Muscle-Invasive Bladder Cancer: A Pooled Analysis.

Background: The treatment for high-risk non-muscle-invasive bladder cancer (NMIBC) remains highly debated for its high recurrence and progression risk. This work aimed to verify the efficacy and toxicity of intra-arterial chemotherapy (IAC) plus intravesical chemotherapy (IVC) in high-risk NMIBC. Methods: A comprehensive online literature search was conducted in three databases to select researches related to IAC + IVC for high-risk NMIBC. All data were analyzed using the Review Manager software version 5.3. And we used the Cochrane Risk of Bias tool to assessed the quality of these enrolled researches. Results: Seven eligible original publications were enrolled in our studies with a total of 1,247 patients. Compared with the intravesical instillation, IAC + IVC therapy showed a better therapeutic effect. The total odds ratio for tumor recurrence rate, tumor progression rate, survival rate, and tumor-specific death rate was calculated as 0.51 (95% CI: 0.36-0.72; p < 0.05), 0.51 (95% CI: 0.36-0.72; p < 0.05), 1.75 (95% CI: 1.09-2.81; p < 0.05), and 0.48 (95% CI: 0.28-0.84; p < 0.05), respectively. In patients who received IAC, most of the adverse events (AEs)in the treatment were Grade I and II. Conclusion: IAC + IVC regimen for high-risk NMIBC could effectively reduce recurrence and progression and provide a better prognosis than intravesical instillation. The adverse events of IAC were mild and acceptable.

Recurrence factors in patients with Keratinizing squamous metaplasia of the bladder after surgical management: a single-center retrospective study.

BACKGROUND: Keratinizing squamous metaplasia (KSM) is a clinically heterogeneous disease that lacks research that provide definitive recurrent risk factors. Therefore, we identified the recurrence factors in patients with KSM of the bladder after transurethral resection (TUR). We also attempted to investigate the association between KSM and bladder cancer. METHODS: Clinical information of 257 patients diagnosed with KSM who underwent TUR in Xiangya Hospital from January 2010 to November 2018 were retrospectively collected. Clinical information was available for follow-up of 223 patients. To determine the risk factors for recurrence, we conducted univariate and multivariate cox regression analysis respectively. To explore the association between KSM and bladder cancer, we used clinical follow-up data. RESULTS: The median follow-up time is 49 (IQR, 12-121) months. Five-year recurrence-free rate (RFR) and 1-year RFR were 86.1% and 91.9%, respectively. Thirty-one patients (13.9%) relapsed of KSM after a median follow-up of 49 months (range, 12-121 months), and none of them developed subsequent bladder cancer. Univariate Cox analysis indicated that urinary tract infection [hazard ratio (HR) =2.111; 95% confidence interval (CI): 1.043-4.271; P=0.038], and atypical urothelial hyperplasia of the bladder (HR =4.191; 95% CI: 2.006-8.756; P<0.001) were significant recurrence factors. Multivariate Cox analysis suggested that atypical urothelial hyperplasia of the bladder (HR =3.506; 95% CI: 1.663-7.392; P=0.001) was the independent risk factor for postoperative recurrence of KSM. CONCLUSIONS: The recurrence rate in patients with KSM was about 13.9%, and atypical urothelial hyperplasia of the bladder was the independent risk factor in patients with KSM recurrence. In cases with bladder atypical urothelial hyperplasia, close follow-ups are necessary. Also, we demonstrated that KSM did not increase the subsequent risk of bladder cancer.

Smoking status and pathological response to neoadjuvant chemotherapy among patients with bladder cancer: a pooled analysis.

BACKGROUND: Smoking status has been confirmed as an independent prognostic factor for bladder cancer. However, for patients who received neoadjuvant chemotherapy (NAC), the influence of smoking status on the pathological response and prognosis remains unclear. This pooled analysis aimed to investigate whether smoking status is an independent risk factor for pathological response, recurrence, and prognosis in patients with bladder cancer who undergo NAC. METHODS: We searched PubMed, Web of Science, Embase, Cochrane Library, and Google Scholar for related studies published between 1990 and 2017. In total, 10 studies comprising 1,382 patients with muscle-invasive bladder cancer were included. The odds ratio (OR) and 95% confidence interval (CI) of complete pathological response, partial pathological response, overall survive (OS), recurrence, and cancer-specific mortality (CSM) were chosen as outcome measures. Analyses were performed using Review Manager (version 5.3, The Cochrane Collaboration, UK) and Stata statistical software (version 15, Stata Corp., USA). RESULTS: Compared to nonsmokers, smokers were less likely to have a complete pathologic response (OR =0.55, 95% CI: 0.35-0.87) and partial pathological response (OR =0.57, 95% CI: 0.37-0.88). However, we found no significant association between smoking status and overall survival (OR =0.71, 95% CI: 0.28-1.80), recurrence (OR =1.35, 95% CI: 0.97-1.88), and cancer-specific mortality (OR =0.90, 95% CI: 0.62-1.32). CONCLUSIONS: Smoking reduces both complete and partial pathological response rate to NAC in patients with bladder cancer. Thus, smoking status should be given more importance when developing treatment plans and evaluating efficacy, particularly of NAC, among bladder cancer patients.

Clinicopathologic Features and Survival Outcomes for Primary Renal Neuroendocrine Neoplasms.

PURPOSE: Primary renal neuroendocrine neoplasms (NENs) are exceedingly rare. We used the Surveillance, Epidemiology, and End Results (SEER) data to summarize clinicopathologic characteristics, treatment outcomes, and prognostic factors of primary renal NENs. METHODS: Data were identified from the SEER database. Clinicopathologic characteristics were compared by the Pearson chi-square or correction test, in which continuous variables were analyzed by t test. Kaplan-Meier analyses and log-rank tests were used to compare the differences in overall survival (OS). Univariable and multivariable regression model analyses of OS were conducted using the Cox proportional hazard model. Also, we used directed acyclic graphs to guide the multivariable regression model and to try to determine the impact of each of surgery, chemotherapy, and radiotherapy on OS. RESULTS: A total of 132 patients were enrolled. There were significant differences in age, grade, tumor size, SEER stage, surgery, and chemotherapy between patients with carcinoid tumors and those with neuroendocrine carcinomas. Patients with disease with carcinoid tumors, younger age, smaller tumor size, and lower SEER exhibited better survival outcomes. Univariable and multivariable regression models analyses indicated that age, sex, tumor size, and SEER stage were independent prognostic factors for OS. Directed acyclic graphs guided the respective inclusion of variables in the multivariable regression model to assess the causal effect of surgery, chemotherapy, and radiotherapy on OS. The results showed that surgery, chemotherapy, and radiotherapy did not improve OS. CONCLUSION: Primary renal NENs are exceedingly rare and exhibit different biological behavior. Older age, male sex, larger tumor size, and tumors not confined to the renal parenchyma may indicate poor prognosis. Resection of all visible disease remains the reference-standard treatment of choice. Longer-term studies with a larger patient cohort are needed to determine systemic therapeutic options.

Effect of neoadjuvant chemotherapy on locally advanced upper tract urothelial carcinoma: a pooled analysis.

BACKGROUND: The outcome of neoadjuvant chemotherapy (NAC) has been established in bladder cancer but remains controversial in upper tract urothelial carcinoma (UTUC). In this work, we explored the therapeutic effect of NAC in patients with locally advanced UTUC. METHODS: We conducted a literature search on articles published from 1995 up to April 2020 in PubMed/Medline, the Cochrane Library, Embase, Google Scholar. A total of 19 eligible studies with 6,283 patients were identified, from which the overall survival (OS), cancer-specific survival (CSS), progression-free survival (PFS), disease-free survival (DFS), pathological complete response (pCR) rate and pathological partial response (pPR) rate were extracted. All analyses were conducted using Review Manager 5.3 and Stata statistical software (version 15). RESULTS: In total, 6,283 UTUC patients were included from 19 eligible studies out of which 1,474 patients received NAC and subsequent radical nephroureterectomy (RNU), whereas 4,809 patients received RNU only. Compared with single RNU, patients with NAC and subsequent RNU exhibited longer OS, CSS, PFS, DFS by hazard ratio (HR) 2.14 [95% confidence interval (CI): 1.75-2.63; P<0.001], HR 2.07 (95% CI: 1.49-2.87; P<0.001), HR 2.00 (95% CI: 1.42-2.83; P<0.001), and HR 3.76 (95% CI: 2.16-6.56; P<0.001). pCR rate and pPR rate of NAC are 0.10 (0.07-0.13) and 0.40 (95% CI: 0.32-0.49, P <0.001) respectively. CONCLUSIONS: This work revealed that NAC and subsequent RNU provided better survival outcomes in patients with locally advanced UTUC when compared with single RNU.

A preoperative nomogram predicting the pseudocapsule status in localized renal cell carcinoma.

BACKGROUND: Tumor enucleation (TE) surgery for localized renal cell carcinoma (RCC) relies on a complete peritumoral pseudocapsule (PC). Study objective was to develop a preoperative model to predict PC status. METHODS: The prediction model was developed in a cohort that consisted of 170 patients with localized RCC, and data was gathered from 2010 to 2015. Multivariable logistic regression analysis and R were used to generate this prediction model. The statistical performance was assessed with respect to the calibration, discrimination, and clinical usefulness. RESULTS: The prediction model incorporated the systemic inflammatory markers [neutrophil-lymphocyte ratio (NLR); albumin-globulin ratio (AGR)], CT imaging features (tumor size and necrosis), and clinical risk factors (BMI). The model showed good discrimination, with a C-index of 0.85 (0.78-0.91), and good calibration (P=0.60). The sensitivity and specificity were 62% and 94% respectively. Decision curves and clinical impact curve demonstrated that the current model was clinically useful. CONCLUSIONS: We constructed a model that incorporated both the systematic inflammatory markers and clinical risk factors. It can be conveniently used to preoperatively predict the individualized risk of PC invasion and identify the best candidates to receive TE surgery.

A nomogram incorporating PD-L1, NLR, and clinicopathologic features to predict inguinal lymph node metastasis in penile squamous cell carcinoma.

BACKGROUND: Accurate preoperative prediction of inguinal lymph node metastasis (LNM) aids in clinical decision making, especially for patients with penile cancer with clinically negative lymph nodes. We aim to develop a nomogram to predict the preoperative risk of LNM by incorporating clinicopathologic features and tumor biomarkers. METHODS: Eighty-four patients with penile cancer with clinically negative lymph nodes were enrolled. The programmed death ligand 1 (PD-L1) expression profile was detected by immunohistochemistry. The neutrophil-to-lymphocyte ratio (NLR) was calculated based on parameters of a routine blood examination. Multivariate logistic regression analysis was utilized to construct predictive nomograms for LNM based on data of 64 patients. The nomogram performance was assessed for calibration, discrimination, and clinical use. RESULTS: Tumor grade, lymphovascular invasion, PD-L1, and NLR were independent predictors of LNM. Then, 4 prediction models were constructed. Clinical model included tumor grade and lymphovascular invasion. NLR model was built by adding the NLR to clinical model. PD-L1 model was built by adding the PD-L1 to clinical model. Finally, a combined model was built by adding both PD-L1 and NLR to clinical model. Combined model showed the best performance compared with other models. It showed good discrimination with a C-index of 0.89, and good calibration. In addition, decision curve analysis suggested that model 4 was clinically useful. CONCLUSIONS: We developed a nomogram that incorporated tumor grade, lymphovascular invasion, PD-L1, and NLR that could be conveniently used to predict the preoperative individualized risk of inguinal LNM in patients with penile cancer.

Do cerebral and somatic tissue oxygen saturation measurements correlate with each other during surgery?

Intraoperative maintenance of optimal tissue oxygenation is critical; however, it is uncertain whether measurements of different tissue beds correlate with each other. Cerebral tissue oxygen saturation (SctO2) measured on the forehead and somatic tissue oxygen saturation (SstO2) measured on limbs, using a tissue near-infrared spectroscopy, were simultaneously recorded every 2 s in patients having spine surgery or robotic hysterectomy. Simple linear regression was used to determine the static correlation between SctO2 and SstO2 using the median values of each min for each patient. The dynamic correlation between SctO2 and SstO2 was assessed by Pearson's correlation coefficient (CC) for each non-overlapping 2-min epoch. In patients having spine surgery (n = 99), SctO2 and SstO2 (mean ± SD) were 69.8 ± 4.9% and 75.5 ± 8.7%, whereas in patients having robotic hysterectomy (n = 106), the corresponding values were 74.9 ± 6.8% and 83.7 ± 6.2%. The static correlation between SctO2 and SstO2 was inconsistent (r ranging from - 0.86 to 0.93 in spine surgery and from - 0.74 to 0.85 in robotic hysterectomy). The proportional durations with CC ≤ - 0.3 (negative correlation), - 0.3 < CC < 0.3 (poor correlation) and CC ≥ 0.3 (positive correlation) were 18.3 ± 9.6%, 52.6 ± 12.1% and 29.0 ± 9.6%, respectively, in patients having spine surgery and 19.6 ± 9.0%, 58.6 ± 13.1% and 21.8 ± 8.0%, respectively, in patients having robotic hysterectomy. There are a large discrepancy and inconsistent correlation between intraoperative SctO2 and SstO2 measurements, suggesting their non-interchangeability.