Electroacupuncture alleviates postoperative pain through inhibiting neuroinflammation via stimulator of interferon genes/type-1 interferon pathway

Objective This work explores the impact of electroacupuncture(EA)on acute postoperative pain(APP)and the role of stimulator of interferon genes/type-1 interferon(STING/IFN-1)signaling pathway modulation in the analgesic effect of EA in APP rats.Methods The APP rat model was initiated through abdominal surgery and the animals received two 30 min sessions of EA at bilateral ST36(Zusanli)and SP6(Sanyinjiao)acupoints.Mechanical,thermal and cold sensitivity tests were performed to measure the pain threshold,and electroencephalograms were recorded in the primary somatosensory cortex to identify the effects of EA treatment on APP.Western blotting and immunofluorescence were used to examine the expression and distribution of proteins in the STING/IFN-1 pathway as well as neuroinflammation.A STING inhibitor(C-176)was administered intrathecally to verify its role in EA.Results APP rats displayed mechanical and thermal hypersensitivities compared to the control group(P<0.05).APP significantly reduced the amplitude ofθ,αandγoscillations compared to their baseline values(P<0.05).Interestingly,expression levels of proteins in the STING/IFN-1 pathway were downregulated after inducing APP(P<0.05).Further,APP increased pro-inflammatory factors,including interleukin-6,tumor necrosis factor-αand inducible nitric oxide synthase,and downregulated anti-inflammatory factors,including interleukin-10 and arginase-1(P<0.05).EA effectively attenuated APP-induced painful hypersensitivities(P<0.05)and restored theθ,αandγpower in APP rats(P<0.05).Meanwhile,EA distinctly activated the STING/IFN-1 pathway and mitigated the neuroinflammatory response(P<0.05).Furthermore,STING/IFN-1 was predominantly expressed in isolectin-B4-or calcitonin-gene-related-peptide-labeled dorsal root ganglion neurons and superficial laminae of the spinal dorsal horn.Inhibition of the STING/IFN-1 pathway by intrathecal injection of C-176 weakened the analgesic and anti-inflammatory effects of EA on APP(P<0.05).Conclusion EA can generate robust analgesic and anti-inflammatory effects on APP,and these effects may be linked to activating the STING/IFN-1 pathway,suggesting that STING/IFN-1 may be a target for relieving APP.

The survival and prognostic factors of primary testicular lymphoma- two-decade single-center experience

This study aims to investigate the effect of different local testicular treatments and validate common prognostic factors on primary testicular lymphoma （PTL） patients. We retrospectively reviewed the clinical records of 32 patients from 1993 to 2017 diagnosed with PTL and included 22 patients for analysis. The Kaplan-Meier method, Log-rank test, and multivariate Cox proportional hazard regression analysis were applied to evaluate progression-free survival （PFS）, overall survival （OS）, and determine prognosis predictors. The median follow-up time was 30 months. Median OS and PFS were 96 months and 49 months, respectively. In univariate analysis, advanced Ann Arbor stage （Ill/IV） （P 〈 0.001）, B symptoms （P 〈 0.001）, and extranodal involvement other than testis （P = 0.001） were significantly associated with shorter OS and PFS. In multivariate analysis, Ann Arbor stage was significantly associated with OS （OR = 11.58, P = 0.049）, whereas B symptom was significantly associated with PFS （OR = 11.79, P = 0.049）. In the 10 patients with the systemic usage of rituximab, bilateral intervention could improve median OS from 16 to 96 months （P = 0.032）. The study provides preliminary evidence on bilateral intervention in testes in the rituximab era and validates common prognostic factors for Chinese PTL patients.

Surgical complexity and prognostic outcome of small volume renal cell carcinoma with high-level venous tumor thrombus and large volume renal cell carcinoma with low-level thrombus

Background:Radical nephrectomy with thrombectomy is one of the most difficult and complicated urological operations.But the roles of renal tumor volume and thrombus level in surgical complexity and prognostic outcome are not clear.This study aimed to evaluate the surgical complexity and prognostic outcome between the volume of renal cell carcinoma (RCC) and the level of venous tumor thrombus.Methods:The clinical data of 67 RCC cases with renal vein or inferior vena cava (IVC) tumor thrombus from January 2015 to May 2018 were retrospectively analyzed.Among these 67 cases,21 (31.3%) were small tumors with high-level thrombus (tumor ≤7 cm in diameter and thrombus Neves Level Ⅱ-Ⅳ),while 46 (68.7%) were large tumors with low-level thrombus group (tumor >7 cm in diameter and thrombus Level 0-Ⅰ).Clinical features,operation details,and pathology data were collected.Univariable and multivariable logistic regression analyses were applied to evaluate the risk factors for small tumor with high-level thrombus.Results:Patients with small tumors and high-level thrombus were more likely to have longer operative time (421.9 ± 135.1 min vs.282.2 ± 101.9 min,t=4.685,P < 0.001),more surgical bleeding volume (1200 [325,2900] mL vs.500 [180,1000] mL,U =270.000,P =0.004),more surgical blood transfusion volume (800 [0,1400] mL vs.0 [0,800] mL,U =287.500,P =0.004),more plasma transfusion volume (0 [0,800] mL vs.0 [0,0] mL,U =319.000,P =0.004),higher percentage of open operative approach (76.2% vs.32.6%,x2 =11.015,P =0.001),higher percentage of IVC resection (33.3% vs.0%,x2 =17.122,P < 0.001),and higher percentage of post-operative complications (52.4% vs.19.6%,x2 =7.415,P =0.010) than patients with large tumors and low-level thrombus.In multivariate analysis,decreased hemoglobin (Hb)(odds ratio [OR]:0.956,95 % confidence interval [CI]:0.926-0.986,P =0.005) and non-sarcomatoid differentiation (OR:0.050,95% CI:0.004-0.664,P =0.023) were more likely to form small tumors with high-level tumor thrombus rather than large tumor with small tumor thrombus.The estimated mean cancerspecific survival times of small tumor with high-level thrombus and large tumor with low-level thrombus were 31.6 ± 3.8 months and 32.5 ± 2.9 months,without statistical significance (P =0.955).After univariate and multivariate Cox proportional hazard survival regression analyses,only distant metastasis (hazard ratio [HR]:3.839,P =0.002),sarcomatoid differentiation (HR:7.923,P < 0.001),alkaline phosphatase (HR:2.661,P =0.025),and severe post-operative complications (HR:10.326,P =0.001) were independent predictors of prognosis.Conclusions:The level of the tumor thrombus was more important than the diameter of the primary kidney tumor in affecting the complexity of surgery.In the same T3 stage,neither the renal tumor diameter nor the tumor thrombus level was an independent risk factor for prognosis.

Development and validation of a preoperative nomogram for predicting positive surgical margins after laparoscopic radical prostatectomy

Background:Positive surgical margins are independent risk factor for biochemical recurrence,local recurrence,and distant metastasis after radical prostatectomy.However,limited predictive tools are available.This study aimed to develop and validate a preoperative nomogram for predicting positive surgical margins after laparoscopic radical prostatectomy(LRP).Methods:From January 2010 to March 2016,a total of 418 patients who underwent LRP without receiving neoadjuvant therapy at Peking University Third Hospital were retrospectively involved in this study.Clinical and pathological results of each patient were collected for further analysis.Univariable and multivariable logistic regression(backward stepwise method)were used for the nomogram development.The concordance index(CI),calibration curve analysis and decision curve analysis were used to evaluate the performance of our model.Results:Of 418 patients involved in this study,142 patients(34.0%)had a positive surgical margin on final pathology.Based on the backward selection,four variables were included in the final multivariable regression model,including the percentage of positive cores in preoperative biopsy,clinical stage,free prostate specific antigen(fPSA)/total PSA(tPSA),and age.A nomogram was developed using these four variables.The concordance index(C-index)of the nomogram was 0.722 in the development cohort and 0.700 in the bootstrap validations.The bias-corrected calibration plot showed a limited departure from the ideal line with a mean absolute error of 2.0%.In decision curve analyses,the nomogram showed net benefits in the range from 0.2 to 0.7.Conclusion:A nomogram to predict positive surgical margins after LRP was developed and validated,which could help urologists plan surgical procedures.

Imaging predictors for assessment of inferior vena cava wall invasion in patients with renal cell carcinoma and inferior vena cava tumor thrombus:a retrospective study

Background:Renal cell carcinoma(RCC)has the propensity to lead to venous tumor thrombus(VTT).Nephrectomy with tumor thrombectomy is an effective treatment option but is a technically challenging surgical procedure that is accompanied by a high rate of complications.The aims of this study were to investigate pre-operative imaging parameters for the assessment of inferior vena cava(IVC)wall invasion due to a tumor thrombus in patients with RCC and to identify predictors from the intra-operative findings.Methods:Clinical and imaging data were collected from 110 patients who underwent nephrectomy with IVC tumor thrombectomy(levels Ⅰ-Ⅳ)for RCC and IVC tumor thrombus at the Peking University Third Hospital between May 2015 and March 2018.Univariable and multivariable logistic regression and receiver operating characteristic curves were used to assess the correlations between pre-operative imaging features and intra-operative macroscopic invasions of the IVC wall by tumor thrombus.Results:Among the 110 patients,41 underwent partial or segmental resection of IVC.There were univariate associations of pre-operative imaging parameters that could be used to predict the need for IVC resection,including those of the Mayo classification,maximum anterior-posterior(AP)diameter of the renal vein at the renal vein ostium(RVo),maximum AP diameter of the VTT at the RVo and IVC occlusion.For the multivariable analysis,the AP diameter of the VTT at the RVo and IVC occlusion were associated with a significantly increased risk of invasion of the IVC wall by tumor thrombus.The optimum imaging thresholds included an AP diameter of the VTT at the RVo larger than 17.0 mm and the presence of IVC occlusion,with which we predicted invasions of the IVC wall requiring IVC resection.The probabilities of intra-operative IVC resection for patients without both independent factors,with an AP diameter of the VTT at the RVo larger than 17.0 mm,with IVC occlusion,and with both concurrent factors were 5%,23%,56%,and 66%,respectively.Conclusion:An increase in the AP VTT diameter at the RVo and the presence of complete occlusion of the IVC are independent risk factors for a high probability of IVC wall invasion by tumor thrombus.

Development of a nomogram to predict progression-free survival in patients with locally advanced renal cell carcinoma

To the Editor:Renal cell carcinoma(RCC)accounts for approximately 3%of all malignancies in adults.[1]Locally advanced RCC has a relatively distinct and adverse prognosis with a 5-year cancer specific survival(CSS)rate ranging from 28%to 67%after curative surgery.[2]It is important to accurately stratify the risk of disease recurrence for locally advanced RCC.Several prognostic models like Stage,Size,Grade,and Necrosis(SSIGN),Leibovich,Cindolo,Yaycioglu,Memorial Sloan Kettering Cancer Center(MSKCC),Kattan,and Karakiewicz have been developed to predict the prognosis of localized RCC and the concordance index(C-index)has been found to range from 0.65 to 0.84.[3,4]To our knowledge,these models have mainly been developed based on the data from low-risk patients with RCC.In an external prospec-tive cohort comprising patients with intermediate or high-risk RCC,the performances of these models were found to be sharply decreased(C-index range from 0.587 to 0.69).[4]Thus,in this study,we aimed to develop a more accurate prognostic model for better risk stratification in locally advanced RCC.

Phloroglucinol Protects the Urinary Bladder Via Inhibition of Oxidative Stress and Inflammation in a Rat Model of Cyclophosphamide-induced Interstitial Cystitis

Background： Phloroglucinol plays an important role in oxidative stress and inflammatory responses. The effects of phloroglucinol have been proven in various disease models. The aim of the present study was to investigate the efficacy and possible mechanisms of phloroglucinol in the treatment of interstitial cystitis （IC）. Methods： Thirty-two female Sprague-Dawley （SD） rats were used in this study. IC was induced by intraperitoneal injection of cyclophosphamide （CYP）. Rats were randomly allocated to one of four groups （n = 8 per group）： A control group, which was injected with saline （75 mg/kg; i.p.） instead of CYP on days 1, 4, and 7; a chronic IC group, which was injected with CYP （75 mg/kg; i.p.） on days l, 4, and 7; a high-dose （30 mg/kg） phloroglucinol-treated group; and a low-dose （15 mg/kg） phloroglucinol-treated group. On day 8, the rats in each group underwent cystometrography （CMG）, and the bladders were examined for evidence of oxidative stress and inflammation. Statistical analysis was performed by analysis of variance （ANOVA） followed by least square difference multiple comparison po.s＇t-hoc test. Results： Histological evaluation showed that bladder inflammation in CYP-treated rats was suppressed by phloroglucinol. CMG revealed that the CYP treatment induced overactive bladder in rats that was reversed by phloroglucinol. Up-regulated tumor necrosis factor-or and interleukin-6 expression in the CYP-treated rats were also suppressed in the phloroglucinol treated rats. CYP treatment significantly increased myeloperoxidase activity as well as the decreased activities ofcatalase of the bladder, which was reversed by treatment with phloroglucinol. Conclusions： The application of phloroglucinol suppressed oxidative stress, inflammation, and overactivity in the bladder. This may provide a new treatment strategy for IC.

Percent free prostate-specific antigen is effective to predict prostate biopsy outcome in Chinese men with prostate-specific antigen between 10.1 and 20.0 ng ml^-1

Percent free prostatic-specific antigen （%fPSA） has been introduced as a tool to avoid unnecessary biopsies in patients with a serum PSA level of 4.0-10.0 ng ml^-1, however, it remains controversial whether %fPSA is effective in PSA range of 10.1-20.0 ng ml^-1 in both Chinese and Western population. In this study, the diagnostic performance of %fPSA and serum PSA in predicting prostate cancer （PCa） and high-grade PCa （HGPCa） was analyzed in a multi-center biopsy cohort of 5915 consecutive Chinese patients who underwent prostate biopsy in 22 hospitals across China from January 1, 2010 to December 31, 2013. The indication for biopsy was PSA〉4.0 ng ml^-1 or/and suspicious digital rectal examination. Total and free serum PSA determinations were performed by three types of electrochemiluminescence immunoassays with recalibration to the World Health Organization standards. The diagnostics accuracy of PSA, %fPSA and %fPSA in combination with PSA （%fPSA ＋ PSA） was determined by the area under the receivers operating characteristic curve （AUC）. %fPSA was more effective than PSA in men aged ≥60 years old. The AUC was 0.584 and 0.635 in men aged ≥60 years old with a PSA of 4.0-10.0 ng ml^-1 and 10.1-20.0 ng ml^-1, respectively. The AUC of %fPSA was superior to that of PSA in predicting HGPCa in patients ≥60 years old in these two PSA range. Our results indicated that %fPSA is both statistically effective and clinical applicable to predict prostate biopsy outcome in Chinese patients aged ≥60 years old with a PSA of 4.0-10.0 ng ml^-1 and 10.1-20.0 ng ml^-1.

Multiple factors affecting surgical outcomes and patency rates in use of single-armed two-suture microsurgical vasoepididymostomy： a single surgeon＇s experience with 81 patients

Vasoepididymostomy （VE）, as the most challenging procedure in microsurgeries, is often carried out with a double-armed two-suture technique. In this study, we evaluated the efficacy and safety of the single-armed two-suture VEs on humans and studied the factors that could possibly affect the patency rates. From July 2012 to July 2013, we reviewed 81 patients with consecutive primary epididymal obstruction who underwent single-armed two-suture longitudinal intussusception microsurgical VEs by a single surgeon, Kai Hong （KH）. At the same time, we analyzed seven factors that possibly related to the patency rates. With the single-armed technique, a total of 81 men underwent the microsurgical VEs. Data on 62 patients were completely recorded. 19 patients were lost to follow-up. Mean age was 31 years old. Mean follow-up time was 8.8 （2-17） months. The patency rate was 66.1% （41/62）. Natural pregnancy rate was 34.1% （14/41）. Overall pregnancy rate was 22.6% （14/62）. No severe surgical complications were noted. With logistic regression test analysis, there were two factors related to a higher patency rate： anastomosis sites （P = 0.035） and motile sperm found in the epididymal fluid （P = 0.006）. Motile sperm found in the epididymal fluid were associated with a higher patency rate （OR = 11.80, 95% CI = 1.79, 77.65）. The single-armed two-suture longitudinal VE technique is feasible for microsurgical practice. The patency and pregnancy rates are comparable to the doubled-armed technique. Anastomosis sites and motile sperm found in the epididymal fluid were the most two important factors related to higher patency.

A novel nephrometry scoring system for predicting peri-operative outcomes of retroperitoneal laparoscopic partial nephrectomy

Background:Although the impact of tumor complexity on peri-operative outcomes has been well established using several nephrometry scoring systems,the impact of adherent perirenal fat remains poorly defined.This study aimed to develop a novel nephrometry scoring system for predicting the peri-operative outcomes of laparoscopic partial nephrectomy(LPN)by integrating and optimizing the RENAL score(RNS)and Mayo adhesive probability(MAP)score.Methods:We retrospectively evaluated 159 patients treated with retroperitoneal LPN.The patients’demographic parameters,RNSs,and MAP scores were evaluated as potential predictors of perioperative outcomes,including operation time,estimated blood loss(EBL),and margin,ischemia,and complication(MIC)achievement rate.The independent predictors were used to develop a novel nephrometry scoring system.The predictive value and inter-observer agreement for the novel nephrometry scoring system were evaluated.Results:Tumor radius(R score),nearness to the renal sinus or collecting system(N score),and posterior perinephric fat thickness were independent predictors of peri-operative outcomes and were used to develop the RNP score.The univariate analysis revealed that the RNP score was significantly associated with operation time,EBL,and MIC achievement rate(P<0.050).The RNP score was an independent predictor of operation time(P<0.001),EBL(P=0.018),and MIC achievement rate(P=0.023)in the multivariate analysis.The RNP score was not inferior to RNS in the area under the curve for predicting peri-operative outcomes and performed better in inter-observer agreement(76.7%vs.57.8%)and kappa value(0.804 vs.0.726).Conclusion:The RNP score,combining the advantages of the RNS and MAP score,demonstrated a good predictive value for the peri-operative outcomes of retroperitoneal LPN and better inter-observer agreement.

Peking University Third Hospital score:a comprehensive system to predict intra-operative blood loss in radical nephrectomy and thrombectomy

Background:Radical nephrectomy and thrombectomy is the standard surgical procedure for the treatment of renal cell carcinoma (RCC) with tumor thrombus (TT). But the estimation of intra-operative blood loss is only based on the surgeon’s experience. Therefore, our study aimed to develop Peking University Third Hospital score (PKUTH score) for the prediction of intra-operative blood loss volume in radical nephrectomy and thrombectomy.Methods: The clinical data of 153 cases of renal mass with renal vein (RV) or inferior vena cava tumor thrombus admitted to Department of Urology, Peking University Third Hospital from January 2015 to May 2018 were retrospectively analyzed. The total amount of blood loss during operation is equal to the amount of blood sucked out by the aspirator plus the amount of blood in the blood-soaked gauze. Univariate linear analysis was used to analyze risk factors for intra-operative blood loss, then significant factors were included in subsequent multivariable linear regression analysis.Results: The final multivariable model included the following three factors: open operative approach (P < 0.001), Neves classification IV (P < 0.001), inferior vena cava resection (P = 0.001). The PKUTH score (0-3) was calculated according to the number of aforementioned risk factors. A significant increase of blood loss was noticed along with higher risk score. The estimated median blood loss from PKUTH score 0 to 3 was 280 mL (interquartile range [IQR] 100-600 mL), 1250 mL (IQR 575-2700 mL), 2000 mL (IQR 1250-2900 mL), and 5000 mL (IQR 4250-8000 mL), respectively. Meanwhile, the higher PKUTH score was, the more chance of post-operative complications (P = 0.004) occurred. A tendency but not significant overall survival difference was found between PKUTH risk score 0vs. 1 to 3 (P = 0.098).Conclusion: We present a structured and quantitative scoring system, PKUTH score, to predict intra-operative blood loss volume in radical nephrectomy and thrombectomy.

A novel nomogram provides improved accuracy for predicting biochemical recurrence after radical prostatectomy

Background:Various prediction tools have been developed to predict biochemical recurrence(BCR)after radical prostatectomy(RP);however,few of the previous prediction tools used serum prostate-specific antigen(PSA)nadir after RP and maximum tumor diameter(MTD)at the same time.In this study,a nomogram incorporating MTD and PSA nadir was developed to predict BCR-free survival(BCRFS).Methods:A total of 337 patients who underwent RP between January 2010 and March 2017 were retrospectively enrolled in this study.The maximum diameter of the index lesion was measured on magnetic resonance imaging(MRI).Cox regression analysis was performed to evaluate independent predictors of BCR.A nomogram was subsequently developed for the prediction of BCRFS at 3 and 5 years after RP.Time-dependent receiver operating characteristic(ROC)curve and decision curve analyses were performed to identify the advantage of the new nomogram in comparison with the cancer of the prostate risk assessment post-surgical(CAPRA-S)score.Results:A novel nomogram was developed to predict BCR by including PSA nadir,MTD,Gleason score,surgical margin(SM),and seminal vesicle invasion(SVI),considering these variables were significantly associated with BCR in both univariate and multivariate analyses(P<0.05).In addition,a basic model including Gleason score,SM,and SVI was developed and used as a control to assess the incremental predictive power of the new model.The concordance index of our model was slightly higher than CAPRA-S model(0.76 vs.0.70,P=0.02)and it was significantly higher than that of the basic model(0.76 vs.0.66,P=0.001).Time-dependent ROC curve and decision curve analyses also demonstrated the advantages of the new nomogram.Conclusions:PSA nadir after RP and MTD based on MRI before surgery are independent predictors of BCR.By incorporating PSA nadir and MTD into the conventional predictive model,our newly developed nomogram significantly improved the accuracy in predicting BCRFS after RP.