Human papillomavirus infection affects treatment outcomes and the immune microenvironment in patients with advanced penile squamous cell carcinoma receiving programmed cell death protein 1 inhibitor-based combination therapy.

BACKGROUND: Penile squamous cell carcinoma (PSCC) is a human papillomavirus (HPV)-associated malignancy. Immunotherapy is emerging as a potential treatment for advanced PSCC. In this study, the authors analyzed the association of HPV status with outcomes and the immune microenvironment in patients with advanced PSCC undergoing programmed cell death protein 1 (PD1) inhibitor-based combination therapy (PCT). METHODS: HPV status was assessed using quantitative polymerase chain reaction in 87 patients with advanced PSCC treated with PCT. Objective response rate (ORR), disease control rate (DCR), progression-free survival (PFS), and overall survival (OS) in the HPV+ and HPV- groups were compared. Additionally, bulk RNA sequencing was performed to investigate the potential impact of HPV on the immune microenvironment in advanced PSCC. RESULTS: Among patients receiving first-line PCT, ORR (91.7% vs. 64.6%, p = .014) and DCR (100.0% vs. 79.2%, p = .025) in the HPV+ group were higher compared to the HPV- group. Kaplan-Meier curves demonstrated that the HPV+ group exhibited superior PFS (p = .005) and OS (p = .004) for patients in the first-line setting. However, these advantages of HPV infection were not observed in multi-line PCT (p > .050). HPV status remained an independent prognostic factor for predicting better ORR (p = .024), PFS (p = .002), and OS (p = .020) in the multivariate analyses. Landmark analyses showed that the HPV-induced superiority of PFS occurred at an early stage (within 3 months) and OS occurred at a relatively late stage (within 9 months). Bioinformatic analyses identified potential immune-activated genes (GLDC, CYP4F12, etc.) and pathways (RAGE, PI3K/AKT, etc.), antitumor immune cell subtypes, and lower tumor immune dysfunction and exclusion scores in HPV+ tissues. CONCLUSIONS: HPV infection may confer treatment efficacy and survival benefits in patients with advanced PSCC receiving first-line PCT because of the possible stimulation of the antitumor immune microenvironment. PLAIN LANGUAGE SUMMARY: Human papillomavirus (HPV) infection may induce better objective response rate, progression-free survival (PFS), and overall survival (OS) for advanced penile squamous cell carcinoma (PSCC) patients receiving first-line programmed cell death protein 1 inhibitor-based combination therapy (PCT) instead of multi-line PCT. HPV infection-induced PFS advantage occurs at an early stage (within 3 months) whereas OS superiority occurs at a relatively late stage (within 9 months). Antitumor immune microenvironment could be stimulated by HPV infection in advanced PSCC tissues.

Feasibility of contrast-enhanced ultrasound and flank position during percutaneous nephrolithotomy in patients with no apparent hydronephrosis: a randomized controlled trial.

PURPOSE: To investigate the puncture accuracy and feasibility of contrast-enhanced ultrasound (CEUS) guided percutaneous nephrolithotomy (PCNL) in flank position for patients with no apparent hydronephrosis. METHODS: Between May 2018 and June 2020, 72 kidney stone patients with no or mild hydronephrosis were randomized into two groups: a CEUS-guided PCNL group and a conventional ultrasound (US)-guided group. Patients' demographics and perioperative outcomes were compared, including the success rate of puncture via calyceal fornix, the success rate of a single-needle puncture, puncture time, operative time, postoperative hemoglobin loss, stone-free rate, incidence of complications and postoperative stay. RESULTS: The success rate of puncture via calyceal fornix for CEUS-guided group was significantly higher than that for conventional US-guided group (86.1 vs. 47.2%, p = 0.002). Patients performed with CEUS-guided PCNL required shorter renal puncture time than those guided with conventional US (36.5 s vs. 61.0 s, p < 0.001). The median postoperative hemoglobin loss in the CEUS-guided group was significantly lower than that in conventional US-guided group (2.5 vs. 14.5 g/L, p < 0.01). There was no statistically significant difference in the success rate of a single-needle puncture, operative time, stone-free rate, incidence of complications and postoperative stay between the two groups. CONCLUSION: CEUS guidance facilitates identification of the renal calyx fornix, and benefits more precise renal puncture and less hemoglobin loss in PCNL. CEUS-guided PCNL in flank position is a feasible approach to the treatment of kidney stone patients with no apparent hydronephrosis. TRIAL REGISTRATION NUMBER: ChiCTR1800015417.

Lymph Node Mapping in Patients with Penile Cancer Undergoing Pelvic Lymph Node Dissection.

PURPOSE: A map of pelvic lymph node metastasis in patients with penile cancer helps to clarify the pattern of pelvic spread and define the reasonable limits of dissection, and it has not been established. We aim to provide an accurate map of lymph node metastasis in patients with penile cancer and determine the reasonable extent of pelvic lymph node dissection. MATERIALS AND METHODS: We enrolled patients with penile cancer undergoing pelvic lymph node dissection (128) at our institution from 1999 to 2018. The numbers of removed lymph nodes and positive lymph nodes at 10 distinct regions were recorded. The chi-square and Fisher exact tests were used. RESULTS: The median number of pelvic lymph nodes retrieved was 18 (IQR 10-30), with the majority being from the external iliac package (43.0%) and obturator package (31.9%). Pelvic lymph node metastasis was present in 57/128 (44.5%) patients. The median number of positive pelvic lymph nodes removed was 2 (IQR 1-4), with the majority being from the external iliac package (50.0%) and obturator package (36.6%). Advanced T-stage was related to higher risk of pelvic lymph node metastasis, which was present in 30.3%, 44.2%, 59.0% and 58.3% of patients with pT1, pT2, pT3 and pT4, respectively. Notably, 2 patients had crossover metastasis from 1 inguinal region to the contralateral pelvic region. CONCLUSIONS: We present a detailed map of pelvic lymph node metastasis in patients with penile carcinoma. The external iliac and obturator packages appear to be most commonly involved. Optimal pelvic lymph node dissection may extend to the common iliac artery, including common iliac, external iliac, internal iliac and obturator lymph nodes. Extranodal extension in inguinal nodes may not be as important as previously thought.

Radiotherapy plus chemotherapy versus chemotherapy alone in penile cancer patients with extracapsular nodal extension after inguinal lymph node surgery: a multi-institutional study.

PURPOSE: Because there is a lack of evidence, it is not generally recommended to use adjuvant radiotherapy plus chemotherapy to treat lymph node disease in penile cancer. The aim of this study was to determine the benefit of using adjuvant radiotherapy after inguinal surgery for penile cancer. METHODS: Multi-institutional data were obtained from a total of nine centers from April 2003 to April 2015 and retrospectively analyzed. pN3 patients with an extracapsular nodal extension who received adjuvant therapy after inguinal surgery were included. Cancer-specific survival (CSS) was estimated using the Kaplan-Meier method. The multivariate analysis was performed using a Cox proportional hazards model. RESULTS: A total of 93 pN3 patients met the inclusion criteria. During the study period, 32 (34.4%) and 61 (65.6%) of these patients received adjuvant radiotherapy plus chemotherapy (AR + AC) or adjuvant chemotherapy alone (AC). The median CSS in all patients was 12.0 months (interquartile range [IQR] 7.5-16.5). The Kaplan-Meier estimated 3-year CSS rate was significantly longer in the AR + AC group (28.5%) than the AC group (16.2%) (p = 0.036). AC + AR was associated with an improvement in CSS by 7.7 months (17.7 [IQR 3.8-31.6] vs. 10.0 [IQR 6.6-13.4] months). In the Cox regression analysis, AR + AC was an independent predictor of CSS [model a: HR 0.486 (95% CI 0.258-0.916), model b: HR 0.527 (95% CI 0.286-0.972)]. CONCLUSION: In conclusions, AR + AC was associated with improved CCS in patients with penile cancer who displayed an extracapsular nodal extension after inguinal surgery. This hypothesis requires further confirmation.

Prognostic significance of common preoperative laboratory variables in penile squamous cell carcinoma.

OBJECTIVE: To investigate the predictive value of common preoperative laboratory variables in patients undergoing bilateral inguinal lymph node dissection surgery for penile squamous cell carcinoma. METHODS: We retrospectively analyzed the records of 228 patients who had bilateral inguinal lymph node dissection for penile squamous cell carcinoma to assess the following clinical factors: preoperative laboratory measurements, white blood cell count, platelet count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, serum calcium, total protein, globulin, pathological factors and survival rates after surgery. RESULTS: The percentage of positive lymph nodes was 52.6%. Univariate analysis showed that the tumor stage and grade, the presence of metastasis, white blood cell count, platelet count, neutrophil-to-lymphocyte ratio, platelet-to-lymphocyte ratio, and globulin were significantly associated with the disease-specific survival (all P < 0.05). At multivariate analysis, only the neutrophil-to-lymphocyte ratio had an independent effect (hazard ratio 2.131; P = 0.035). The predictive accuracy of the neutrophil-to-lymphocyte ratio was the best among the laboratory variables. The predictive accuracy of the basic pathological factors was significantly increased by incorporating the neutrophil-to-lymphocyte ratio prognosticator. CONCLUSION: The neutrophil-to-lymphocyte ratio before inguinal lymph node dissection might be useful for predicting the prognosis of patients with penile squamous cell carcinoma.

The lncRNA DLX6-AS1 promoted cell proliferation, invasion, migration and epithelial-to-mesenchymal transition in bladder cancer via modulating Wnt/ß-catenin signaling pathway.

BACKGROUND: Bladder cancer is the most common human urological malignancies with poor prognosis, and the pathophysiology of bladder cancer involves multi-linkages of regulatory networks in the bladder cancer cells. Recently, the long noncoding RNAs (lncRNAs) have been extensively studied for their role on bladder cancer progression. In this study, we evaluated the expression of DLX6 Antisense RNA 1 (DLX6-AS1) in the cancerous bladder tissues and studied the possible mechanisms of DLX6-AS1 in regulating bladder cancer progression. METHODS: Gene expression was determined by qRT-PCR; protein expression levels were evaluated by western blot assay; in vitro functional assays were used to determine cell proliferation, invasion and migration; nude mice were used to establish the tumor xenograft model. RESULTS: Our results showed the up-regulation of DLX6-AS1 in cancerous bladder cancer tissues and bladder cell lines, and high expression of DLX6-AS1 was correlated with advance TNM stage, lymphatic node metastasis and distant metastasis. The in vitro experimental data showed that DLX6-AS1 overexpression promoted bladder cancer cell growth, proliferation, invasion, migration and epithelial-to-mesenchymal transition (EMT); while DLX6-AS1 inhibition exerted tumor suppressive actions on bladder cancer cells. Further results showed that DLX6-AS1 overexpression increased the activity of Wnt/ß-catenin signaling, and the oncogenic role of DLX6-AS1 in bladder cancer cells was abolished by the presence of XAV939. On the other hand, DLX6-AS1 knockdown suppressed the activity of Wnt/ß-catenin signaling, and the tumor-suppressive effects of DLX6-AS1 knockdown partially attenuated by lithium chloride and SB-216763 pretreatment. The in vivo tumor growth study showed that DLX6-AS1 knockdown suppressed tumor growth of T24 cells and suppressed EMT and Wnt/ß-catenin signaling in the tumor tissues. CONCLUSION: Collectively, the present study for the first time identified the up-regulation of DLX6-AS1 in clinical bladder cancer tissues and in bladder cancer cell lines. The results from in vitro and in vivo assays implied that DLX6-AS1 exerted enhanced effects on bladder cancer cell proliferation, invasion and migration partly via modulating EMT and the activity of Wnt/ß-catenin signaling pathway.

Proposal for reclassification of N staging system in penile cancer patients, based on number of positive lymph nodes.

In the present study, we aim to compare the rationality of proposed N classification based on the number of metastatic lymph nodes (LNs) with the current one. A total of 509 penile cancer patients at our institute were analyzed. Univariable and multivariable statistical analyses were used to assess cancer-specific survival (CSS) in 2 staging systems. Harrell's concordance index was applied to evaluate predictive accuracy of the current and proposed N classification in predicting CSS. We propose a new classification: pN1 (metastasis in 1-2 regional LNs), pN2 (metastasis in 3 regional LNs, or 3 or fewer regional lymph nodes with extranodal extension), and pN3 (metastasis in 4 or more regional LNs). According to the current and proposed N classification, the 5-year CSS of penile cancer patients with pN1, pN2 and pN3 was 85.8%, 39.0%, and 19.7%; and with pN1, pN2 and pN3 was 79.8%, 39.3% and 15.3%, which almost all showed significant difference (P < .001, P = .259) (P < .001, P < .001). Multivariable predictive accuracy of the proposed and current N staging was 76.48% and 70.92% (5.56% gain; P < .001). With a multivariable model of clinical features, both current (hazard ratio [HR], 7.761, 10.612; P < .001, P < .001) and proposed N stages (HR, 3.792, 3.971; P < .001, P < .001) exhibited independent effects on survival. The proposed N classification is superior to the current one, which is simpler and provides more accurate prognosis.

CX4945 suppresses the growth of castration-resistant prostate cancer cells by reducing AR-V7 expression.

PURPOSE: The aberrant expression of casein kinase 2 (CK2) has been reported to be involved in the tumorigenesis and progression of prostate cancer. The inhibition of CK2 activity represses androgen-dependent prostate cancer cells by attenuating the androgen receptor (AR) signaling pathway. In this study, we examined the effect of CK2 inhibition in castration-resistant prostate cancer (CRPC) cells, in which AR variants (ARVs) play a predominant role. METHODS: A newly synthetic CK2 selective inhibitor CX4945 was utilized to study the effect of CK2 inhibition in CRPC cells by CCK8 assay and colony formation assay. Protein and mRNA levels of full-length AR (AR-FL) and AR-V7 were determined by qPCR and western blot, respectively. The nuclear translocation of p50 and p65 was assessed to reflect the activity of the NF-κB pathway. RESULTS: CX4945 reduced the proliferation of CRPC cells in a dose-dependent and time-dependent manner. AR-V7 rather than AR-FL was downregulated by CX4945 in both the mRNA and protein level. Furthermore, CX4945 could restore the sensitivity of CRPC cells to bicalutamide. The analysis of possible mechanisms demonstrated that the inhibition of CK2 diminished the phosphorylation of p65 at ser529 and thus attenuated the activity of the NF-κB pathway. CONCLUSION: The inhibition of CK2 by CX4945 can repress the viability of CRPC cells and restore their sensitivity to anti-androgen therapy by suppressing AR-V7. This finding presents a potential option for the treatment of prostate cancer, especially CRPC.

Clinical significance of preoperative C-reactive protein and squamous cell carcinoma antigen levels in patients with penile squamous cell carcinoma.

OBJECTIVE: To evaluate the relevance of C-reactive protein (CRP) and squamous cell carcinoma antigen (SCC-Ag) levels in relation to clinicopathological factors and prognosis in penile cancer. PATIENTS AND METHODS: A total of 124 Chinese patients with penile squamous cell carcinoma (SCC), treated between November 2007 and October 2014, were analysed retrospectively. Receiver-operating characteristic curves were used to identify the combination of markers with the best sensitivity and specificity for prognosis prediction. Statistical data analysis was performed using a non-parametric method, and survival analysis was performed using the log-rank test and Cox proportional hazard model. RESULTS: Levels of CRP ≥4.5 mg/L and SCC-Ag ≥1.4 ng/mL were both significantly associated with lymph node metastasis (LNM) laterality (chi-squared trend test, P = 0.041), extranodal extension (chi-squared trend test, P < 0.001), pelvic LNM (chi-squared trend test, P = 0.024), pathological tumour status (chi-squared trend test, P = 0.002), pathological nodal status (chi-squared trend test, P < 0.001), and disease-specific survival (DSS; log-rank test, P < 0.001). Moreover, the influence of CRP and SCC-Ag levels on DSS (P = 0.033, hazard ratio 3.390, 95% confidence interval 1.104-10.411) remained after adjusting for smoking history, phimosis, tumour status, tumour cell differentiation and nodal status. CONCLUSIONS: The present study shows that the combined measurement of preoperative CRP and SCC-Ag levels may serve as an independent biomarker for LNM, advanced tumour stage and DSS in patients with penile SCC.

Case report: A collision tumor of clear cell renal cell carcinoma and clear cell papillary renal cell tumor.

We report the case of a 51-year-old woman who was initially hospitalized in the respiratory department with cough and fever. Urinary computed tomography (CT) showed two different incidental masses in the right kidney. The patient underwent a radical right nephrectomy without lymph node dissection and postoperative adjuvant treatment. The pathological examination of the surgical specimens showed a collision tumor composed of a clear cell renal cell carcinoma (CCRCC) and a clear cell papillary renal cell tumor (CCPRCT). To the best of our knowledge, this is the first such case reported to date. No recurrence of local or distant metastasis was found during routine follow-up 14 months after the operation.

Altered tumor microenvironment heterogeneity of penile cancer during progression from non-lymphatic to lymphatic metastasis.

BACKGROUND: Lymphatic metastasis is the major challenge in the treatment of penile cancer. The prognosis of individuals with lymphatic metastasis is extremely poor. Therefore, early identification of disease progression and lymphatic metastasis is an urgent task for researchers in penile cancer worldwide. METHODS: In this study, using single-cell RNA sequencing, an immune landscape was established for the cancer ecosystem based on 46,861 cells from six patients with penile cancer (four with lymphatic metastasis [stage IV] and two without lymphatic metastasis [stage I]). Using bulk RNA sequencing, the discrepancy between the cancers and their respective metastatic lymph nodes was depicted based on seven patients with penile cancer. RESULTS: The interaction between epithelial cells, fibroblasts, and endothelial cells, and the functional cooperation among invasion, epithelial-mesenchymal transition, and angiogenesis were found to be important landscapes in the penile cancer ecosystem, playing important roles in progression of cancer and lymph node metastasis. CONCLUSIONS: This study is the first to investigate the altered tumor microenvironment heterogeneity of penile cancer as it evolves from non-lymphatic to lymphatic metastasis and provides insights into the mechanisms underlying malignant progression, the premetastatic niche, and lymphatic metastasis in penile cancer.

[Both CK2 catalytic subunits involves in androgen receptor signaling in prostate cancer cells].

OBJECTIVE: To explore the roles of different casein kinase 2 (CK2) catalytic subunits in androgen receptor (AR) signaling in prostate cancer cell lines. METHODS: Prostate cancer cell lines were maintained.Immunofluorescent staining was performed to determine AR nuclear translocation in PC-3/AR cells with R1881 pretreatment and luciferase gene reporter assay used to determine AR transactivation in LNCaP cells. And reverse transcription-polymerase chain reaction (RT-PCR) was employed to evaluate the mRNA level of prostate-specific antigen (PSA). RESULTS: R1881-induced AR nuclear localization was reduced significantly (P < 0.01).R1881-stimulated ARE-LUC reporter activity in LNCaP cells decreased with reduced level of PSA mRNA, an AR endogenous target (P < 0.05). To confirm the target specificity, the gene-specific siRNAs were used for both CK2α and CK2α' subunits. The results of ARE-LUC assay (38.5 vs 31.4) suggested that both CK2 catalytic subunits were involved in androgen-stimulated AR nuclear translocation and AR-mediated gene expression in prostate cancer cells. CONCLUSION: Both CK2 catalytic subunits are involved in androgen receptor signaling of prostate cancer cells.

Do patients receive any benefit from the addition of perioperative immunotherapy-chemotherapy for solid tumors?

BACKGROUND: Progress in the use of neoadjuvant immunotherapy combined with chemotherapy has become a highlight of cancer research. Our meta-analysis aimed to better elucidate the activity, efficacy and safety of this combination using data obtained from randomized controlled trials (RCTs). METHODS: A systematic search of PubMed, Embase, Web of Science, the Cochrane Library and conference proceedings up to January 31, 2023 was carried out to identify RCTs investigating neoadjuvant immunotherapy combined with chemotherapy for the treatment of solid tumors. Using fixed- and random-effects models, pooled odds ratios (ORs) and hazard ratios with 95% confidence intervals (CIs) were calculated for pathological complete response (pCR, defined as ypT0/is pN0) and immunotherapy treatment-related adverse events. RESULTS: A total of 1876 studies were identified, and 6 RCTs (N = 2558 patients) were included. The pCR was significantly higher with neoadjuvant immunotherapy combined with chemotherapy than with neoadjuvant chemotherapy alone (OR = 2.30, 95% CI: 1.43-3.71, P < .001). The pCR was confirmed to be statistically significant in the PD-L1-positive subgroup (OR = 2.01; 95% CI: 1.55-2.59, P = .012). The pCR was confirmed to be statistically significant in the PD-1 inhibitor subgroup (OR = 4.17; 95% CI: 1.47-11.87, P = .000), while no statistically significant was observed in the PD-L1 inhibitor subgroup (OR = 1.52; 95% CI: 1.12-2.07, P = .308). The pooled ORs of any grade treatment-related or immunotherapy-related adverse events were significant, but the grade 3-4 immunotherapy-related adverse events were not. CONCLUSION: Our study provides comprehensive data that the addition of PD1 blockade to neoadjuvant chemotherapy resulted in better treatment efficacy than neoadjuvant chemotherapy alone in patients with solid tumors and had a similar safety profile.

Better specificity and less ischemia: three-dimensional reconstruction is superior to routine computed tomography angiography in navigation of super-selective clamping robot-assisted laparoscopic partial nephrectomy.

Background: Available technologies could be used to guide surgeons in controlling highly selective tumor-bearing arteries robot-assisted laparoscopic partial nephrectomy (RALPN). Methods: Patients undergoing RALPN (from September 2018 to January 2020) for intermediate-high complex renal tumor (R.E.N.A.L. score ≥7) who underwent abdominal computed tomography (CT) scan with angiography and hyper-accuracy 3-dimensional reconstruction (H3DR). All patients underwent high-resolution CT scan with angiography and H3DR with special software, based on which two kinds of highly selective arterial clamp protocols were made for each patient and analyzed independently by two urologists and two radiologists to confirm which renal arterial branch was supplying the tumor. We chose the optimized clamping protocol with the principle of the minimized ischemic regions. During the operation, meticulous microdissection and clip ligation of the specific vascular branch was guided by optimized protocol [H3DR or computed tomography angiography (CTA) reconstruction], according to the in vivo anatomy (identified by intraoperative ultrasound). Results: Of 82 patients, the minimum-ischemic regions planning completed rate (MIRPCR) of preoperative planning with H3DR (90.2%) was higher than that with CTA (34.1%) (P<0.01). H3DR identified 78 high-order arteries (70.3%), whereas CTA identified 33 (29.7%) high-order arteries (P<0.001). H3DR detected a more optimal blocking option in 51 cases that were either missed (n=13) or misclassified by CTA (n=38). A total of 18 cases (56.3%) were converted to H3DR-guided occurred in CTA-guided surgery [5 (10.0%) occurred in group H3DR to CTA, P<0.01]. Moreover, in the CTA-guided group, the separation of renal hilum was avoided in 14 of 19 (73.7%) cases, whereas in the H3DR-guided group, it was avoided in 60 of 63 (95.3%) cases. Conclusions: For patients undergoing RALPN, H3DR-guided surgery compared with standard CTA-guided surgery has higher accuracy and feasibility in controlling arterial branches supplying the tumor and intraoperative surgical navigation. Additionally, it reduces the ischemic lesion area and simplifies vascular isolation steps, thus decreasing procedural difficulty.

Prognostic Value of Inflammation Biomarkers in Penile Squamous Cell Carcinoma Patients Without Distant Metastasis.

BACKGROUND: To investigate the value of the presurgical inflammatory biomarkers including C-reactive protein (CRP), albumin (ALB), C-reactive protein to albumin ratio (CAR), Glasgow prognostic score (GPS), the modified GPS (mGPS), and the high-sensitivity modified GPS (Hs-mGPS) in penile squamous cell carcinoma (PSCC) without distant metastasis and develop a tool to predict the overall survival (OS) of PSCC patients. METHODS: We retrospectively enrolled 271 PSCC patients without distant metastasis from 2006 to 2021. Patients were divided into 2 cohorts by a 7:3 ratio-a training cohort (n = 191) and a validation cohort (n = 80). We performed cox regression analyses on the training cohort and constructed a nomogram to predict OS over 1, 3, and 5 years. Data from the validation cohort was used to validate the nomogram's predictive power. RESULTS: According to Kaplan-Meier analysis, elevated CRP (P < .001), hypoalbuminemia (P = .008), higher CAR (P < .001), higher GPS score (P < .001), higher mGPS score (P < .001), and higher Hs-mGPS score (P = .015) were associated with a decreased overall survival. GPS score, along with age, pathology N stage, and grade, was found to be an independent risk factor for poor prognosis in the multivariate analysis. We constructed a nomogram based on the prespecified variables predicting 1-, 3- and 5-year OS. The C-indexes of the nomogram in the training and validation cohorts were 0.871 and 0.869, respectively. The decision curve analysis showed that the nomogram had a larger net benefit. The Kaplan-Meier curves showed significant differences between the risk groups categorized according to the nomogram (P < .001). CONCLUSIONS: Inflammation biomarkers of systemic inflammation and nutritional status play an important role in individual OS predictions for PSCC patients without distant monitoring. The establishment of the nomogram provided a tool to predict the survival of 1-, 3-, and 5-year OS in PSCC patients without distant metastasis.

Prognostic significance and immune correlates of FADD in penile squamous cell carcinoma.

Penile squamous cell carcinoma (PSCC) with a poor prognosis lacks reliable biomarkers for stratifying patients. Fas-associated death domain (FADD) could regulate cell proliferation and has shown promising diagnostic and prognostic significance in multiple cancers. However, researchers have not determined how FADD exerts its effect on PSCC. In this study, we set out to investigate the clinical features of FADD and the prognostic impact of PSCC. Additionally, we also assessed the role of affecting the immune environment in PSCC. Immunohistochemistry was carried out to evaluate the protein expression of FADD. The difference between FADDhigh and FADDlow was explored by RNA sequencing from available cases. The immune environment evaluation of CD4, CD8, and Foxp3 was performed by immunohistochemical. In this study, we found that FADD was overexpressed in 19.6 (39/199) patients, and the overexpression of FADD was associated with phimosis (p=0.007), N stage (p<0.001), clinical stage (p=0.001), and histologic grade (p=0.005). The overexpression of FADD was an independent prognostic factor for both PFS (HR 3.976, 95% CI 2.413-6.553, p<0.001) and OS (HR 4.134, 95% CI 2.358-7.247, p<0.001). In addition, overexpression of FADD was mainly linked to T cell activation and PD-L1 expression combined with PD-L1 checkpoint in cancer. Further validation demonstrated that overexpression of FADD was positively correlated with the infiltration of Foxp3 in PSCC (p=0.0142). It is the first time to show that overexpression of FADD is an adjunct biomarker with poor prognosis in PSCC and could also serve as a tumor immune environment regulator.

What Happens to the Preserved Renal Parenchyma After Clamped Partial Nephrectomy?

BACKGROUND: Most partial nephrectomies (PNs) are performed with hilar occlusion to reduce blood loss and optimize visualization. However, the histologic status of the preserved renal parenchyma years after PN is unknown. OBJECTIVE: To compare the histologic chronic kidney disease (CKD) score of renal parenchyma before and years after PN, and to explore factors associated with CKD-score increase and glomerular filtration rate (GFR) decline. DESIGN, SETTING, AND PARTICIPANTS: A retrospective review of 147 renal cell carcinoma patients who underwent PN and subsequent radical nephrectomy (RN) due to tumor recurrence was performed in 19 Chinese centers and Cleveland Clinic. Macroscopic normal renal parenchyma was evaluated at least 5 mm away from the tumor in PN specimens and at remote sites in RN specimens. INTERVENTION: PN/RN and ischemia. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Histologic CKD score (0-12) represents a summary of glomerular/tubular/interstitial/vascular status. Predictive factors for a substantial increase of CKD score (≥3) were evaluated by logistic regression. RESULTS AND LIMITATIONS: Sixty-five patients with all necessary data were analyzed. The median interval between PN and RN was 2.4 yr. Median durations of warm ischemia (n = 42) and hypothermia (n = 23) were both 23 min. The histologic CKD score was increased after RN in 47 (72%) patients, with 29 (45%) experiencing more substantial increase (≥3). There was no significant difference in the change of CKD score related to the type and duration of ischemia (p = 0.7 and p = 0.4, respectively) or interval from PN to RN (p > 0.9). However, patients with comorbidities of hypertension, diabetes, and/or pre-existing CKD (hypertension [HTN]/diabetes mellitus [DM]/CKD) demonstrated increased rate and extent of CKD-score increase. On univariate analysis, HTN/DM/CKD was the only predictor of a substantial CKD-score increase (odds ratio: 3.53 [1.12-11.1]). Decline of GFR was modest and similar between patients with/without a substantial CKD-score increase. CONCLUSIONS: Within the context of conventional, limited durations of ischemia, histologic deterioration of preserved parenchyma after PN appears to be primarily due to pre-existing medical comorbidities rather than ischemia. A subsequent decline in renal function was mild and independent of histologic changes. PATIENT SUMMARY: After clamped PN, the preserved renal parenchyma demonstrated histologic deterioration in many cases, which correlated with the presence of comorbidities such as hypertension, diabetes mellitus, or chronic kidney disease. In contrast, the type and duration of ischemia did not correlate with histologic changes after PN, suggesting that ischemia insult had only limited impact on parenchyma deterioration.

Development and Validation of a Nomogram for the Prediction of Inguinal Lymph Node Metastasis Extranodal Extension in Penile Cancer.

PURPOSE: To determine whether a clinicopathologic and laboratory-based nomogram is capable of predicting the risk of lymph node extranodal extension (ENE) in patients with penile cancer. MATERIALS AND METHODS: From June 2006 to January 2021, 234 patients who underwent bilateral inguinal lymph node dissection (ILND) surgery were included in the analysis. A Lasso regression model was utilized to select the most useful predictive features from among 46 laboratory variables. Then, a logistic regression analysis was used to develop the prediction model. Calibration curves, concordance index (C-index) and Areas under the receiver-operating characteristic curves (AUCs) were performed to evaluate the performance of the nomogram. We also investigated model fit using changes in Akaike Information Criteria (AICs). Decision curve analyses (DCAs) were applied to assess the clinical usefulness of this nomograms. Its internal validation was confirmed. RESULTS: Among the 234 patients, 53 were confirmed to have ENE. The platelet-lymphocyte ratio (PLR) and Squamous cell carcinoma antigen (SCC-Ag) were significantly associated with ENE (P<0.05). The individualized prediction nomogram, including the PLR, SCC-Ag, lymphovascular invasion (LVI), and pathologic tumor stage(pT-stage), showed good discrimination, with a C-index of 0.817 (95% CI, 0.745 to 0.890) and good calibration. Clinical-laboratory nomogram (AIC, 180.034) become the best-fitting model. DCA findings revealed that the clinical-laboratory nomogram was more clinically useful than the pT-stage or tumor grade. CONCLUSIONS: This study presents a clinicopathologic and laboratory-based nomogram that incorporates PLR, SCC-Ag, lymphovascular invasion (LVI), and pT-stage, which can be conveniently utilized to facilitate the individualized prediction of lymph node metastasis ENE in patients with penile cancer.

A Novel Nomogram for Predicting the Survival of Patients with Invasive Upper Tract Urothelial Carcinoma.

Purpose: Available tools for the prediction of the prognosis of patients with upper tract urothelial carcinoma (UTUC) are unified. We determined whether a novel nomogram is effective in estimating the survival of patients with invasive UTUC. Methods: From January 2004 to December 2015, 4796 invasive UTUC patients in the Surveillance, Epidemiology and End Results database underwent radical nephroureterectomy (RNU) for invasive UTUC. The medical records of the patients were randomly (7:3) divided into the training and validation cohorts. The independent factors included in the nomogram were selected by multivariate analyses. The nomogram was developed based on the training cohort. Bootstrap validation was applied to validate the nomogram, whereas external validation was performed using the validation cohort. The accuracy and discrimination of the nomogram were assessed using concordance indices (C-indices) and calibration curves. Results: The multivariate Cox regression model identified that age, tumor stage, node stage, metastasis stage and grade were associated with survival. In the training set, the nomogram, which included the above factors, exhibited discrimination power superior to that of the 8th American Joint Committee on Cancer (AJCC) TNM classification (Harrell's C-index, 0.74 vs. 0.71; P < 0.001). The nomogram showed better probability of survival agreement with the C-index than the AJCC-TNM staging system in the bootstrap validation (0.74 vs. 0.70; P < 0.001) and validation set (Harrell's C-index, 0.77 vs. 0.73; P < 0.001). The validation revealed that this nomogram exhibited excellent discrimination and calibration capacities. Conclusion: An accurate novel nomogram that is superior to the current AJCC-TNM staging system was established for the prediction of CSS after RNU for invasive UTUC.