The role of antimicrobial prophylaxis in laparoscopic nephrectomy for renal cell carcinoma.

BACKGROUND: To investigate the role of antimicrobial prophylaxis in laparoscopic nephrectomy for renal cell carcinoma. METHODS: We retrospectively enrolled 1000 patients who underwent laparoscopic nephrectomy from August 2019 to November 2021 in the Peking Union Medical College Hospital. Patients were divided into group without antimicrobial prophylaxis (n = 444) and group with antimicrobial prophylaxis (n = 556). Outcomes including 30-day postoperative infection rate, the increase rate of pre- and post-operative white blood cell counts and hospital stay were analyzed. RESULTS: The overall infection rate was 5.0% (28/556) in the group with antimicrobial prophylaxis, which was similar to 4.1% (18/444) in the group without antimicrobial prophylaxis (P = 0.461). The increase rate of pre- and post-operative white blood cell counts was significantly lower (85.5% versus 97.0%) in the group with antimicrobial prophylaxis (P = 0.004). The postoperative hospital stay was 5 (4, 6) days in both groups (P = 0.483). Logistic regression analyses identified the use of antimicrobial prophylaxis had no influence on the occurrence of infection events (odds ratio = 0.797; 95% confidence interval, 0.435-1.460; P = 0.462). Hemoglobin (odds ratio = 0.430; 95% confidence interval, 0.257-0.719; P = 0.001) and partial nephrectomy (odds ratio = 2.292; 95% confidence interval, 1.724-3.046; P < 0.001) influenced the use of antimicrobial prophylaxis independently. CONCLUSIONS: The use of antimicrobial prophylaxis had no impact on postoperative infection in patients receiving laparoscopic nephrectomy for renal cell carcinoma.

The oncogene MYBL2 promotes the malignant phenotype and suppresses apoptosis through hedgehog signaling pathway in clear cell renal cell carcinoma.

Multiple cancers have been associated with MYB-related protein B (MYBL2), its involvement in clear cell renal cell carcinoma (ccRCC) has yet to be demonstrated. Our study revealed a significant upregulation of MYBL2 in ccRCC tissues, correlating with clinicopathological features and patient prognosis. Increased MYBL2 expression promoted cell proliferation and suppressed apoptosis. RNA-seq analysis unveiled a reduction in smoothened (SMO) expression upon MYBL2 silencing. However, luciferase and chromatin immunoprecipitation (ChIP) assays demonstrated MYBL2's positive regulation of SMO expression by directly targeting the SMO promoter. Reintroduction of SMO expression in MYBL2-knocked down cells partially restored cell proliferation and mitigated apoptosis inhibition. Overall, these results indicate that MYBL2 facilitates ccRCC progression by enhancing SMO expression, suggesting its potential as an intriguing drug target for ccRCC therapy.

Comparison of AirSeal versus conventional insufflation system for retroperitoneal robot-assisted laparoscopic partial nephrectomy: a randomized controlled trial.

PURPOSE: AirSeal is a valve-less trocar insufflation system which is widely used in robotic urologic surgeries. More evidence is needed concerning the application and cost of AirSeal in retroperitoneal robot-assisted laparoscopic partial nephrectomy. METHODS: We conducted a randomized controlled trial enrolling 62 patients who underwent retroperitoneal robot-assisted laparoscopic partial nephrectomy from February 2022 to February 2023 in the Peking Union Medical College Hospital. Patients were randomly assigned into AirSeal insufflation (AIS) group and conventional insufflation (CIS) group. The primary outcome was the rate of subcutaneous emphysema (SCE). RESULTS: The SCE rate in the AIS group (12.9%) was significantly lower than that in the CIS group (35.5%) (P = 0.038). Lower maximum end-tidal carbon dioxide (CO2) (41 vs 45 mmHg, P = 0.011), PaCO2 at the end of the operation (40 vs 45 mmHg, P < 0.001), maximum tidal volume (512 vs 570 ml, P = 0.003), frequency of lens cleaning (3 vs 5, P < 0.001), pain score at 8 h (3 vs 4, P = 0.025), 12 h (2 vs 3, P = 0.029) postoperatively and at time of discharge (1 vs 2, P = 0.002) were observed in the AIS group, despite a higher hospitalization cost (68,197 vs 64658RMB, P < 0.001). Logistic regression analysis identified insufflation approach was the only influencing factor for the occurrence of SCE events. CONCLUSION: AirSeal insufflation system exhibited similar efficacy and improved safety for retroperitoneal robot-assisted laparoscopic partial nephrectomy than conventional insufflation system, despite an affordable increase of hospitalization costs.

SHOX2 promotes prostate cancer proliferation and metastasis through disruption of the Hippo-YAP pathway.

The transcription factor SHOX2 gene is critical in regulating gene expression and the development of tumors, but its biological role in prostate cancer (PCa) remains unclear. In this study, we found that SHOX2 expression was significantly raised in PCa tissues and was associated with clinicopathological features as well as disease-free survival (DFS) of PCa patients. Phenotypic tests showed that the absence of SHOX2 inhibited PCa growth and invasion, while SHOX2 overexpression promoted these effects. Mechanistically, SHOX2 was found to activate the transcription of nephronophthisis type 4 (NPHP4), a gene located downstream of SHOX2. Further analysis revealed that SHOX2 could potentially interfere with the Hippo-YAP signaling pathway through NPHP4 activation, facilitating the oncogenic behavior of PCa cells. These findings highlight SHOX2 as an oncogene in PCa and provide a basis for developing potential therapeutic approaches against this disease.

Surgery or external beam radiation for solitary small hepatocellular carcinoma.

Background: There is little evidence on the efficacy of external beam radiation (EBR) compared to liver resection (LR) for patients with solitary small (≤5 cm) hepatocellular carcinoma (HCC). Objective: We aimed to investigate this clinical question based on the Surveillance, Epidemiology, and End Results (SEER) database. Method: SEER database was used to identify 416 patients with solitary small HCC who underwent LR or EBR. Survival analysis and Cox proportional hazards model were performed to evaluate overall survival (OS) and identify prognostic factors for OS. Propensity score matching (PSM) method was used to adjust the baseline characteristics of the two groups. Result: Before PSM, the 1- and 2-year OS rates were 92.0% and 85.2% in the LR cohort and 76.0% and 60.3% in the EBR cohort, respectively (P < 0.001). After PSM, LR (n = 62) demonstrated improved OS compared to EBR (n = 62) (1-year OS rate: 96.5% vs. 76.0%; 2-year OS rate: 89.3% vs. 60.3%, P < 0.001), despite stratification on tumor size. Multivariate Cox regression analysis indicated that treatment type was the only factor associated with OS (hazard ratio: 5.297; 95% confidence interval: 1.952-14.371, P = 0.001). Conclusion: For patients with solitary small HCC, LR may offer better survival outcomes than EBR.

Machine learning to improve prognosis prediction of metastatic clear-cell renal cell carcinoma treated with cytoreductive nephrectomy and systemic therapy.

Cytoreductive nephrectomy (CN) combined with systemic therapy is commonly used to treat metastatic clear-cell renal cell carcinoma (mccRCC). However, prognostic models for these patients are limited. In the present study, the clinical data of 782 mccRCC patients who received both CN and systemic therapy were obtained from the Surveillance, Epidemiology, and End Results (SEER) database (2010-2016), and patients were divided into training and internal test cohorts. A total of 144 patients who met the same criteria from our center (Peking Union Medical College Hospital) were placed in the external test cohort. The cancer-specific survival rate (CSS) at 1, 3, and 5 years was set as the research outcome. Then, four ML models, i.e., a gradient boosting machine (GBM), support vector machine (SVM), random forest (RF), and logistic regression (LR), were established. Fifteen potential independent features were included in this study.  Model performance was evaluated using the area under the receiver operating characteristic curves (AUC), calibration plots, and decision curve analysis (DCA). Seven clinical features, namely pathological grade, T stage, N stage, number of metastatic sites, brain or liver metastases, and metastasectomy were selected for subsequent analysis via the recursive feature elimination (RFE) algorithm. In conclusion, the GBM model performed best at 1-, 3- and 5-year CSS prediction (0.836, 0.819 and 0.808, respectively in the internal test cohort and 0.819, 0.805 and 0.786, respectively in the external cohort). Furthermore, we divided the patients into three strata (high-, intermediate- and low-risk) via X-tile analysis and concluded that clinically individualized treatment can be aided by these practical prognostic models.

A comprehensive analysis of the FOX family for predicting kidney renal clear cell carcinoma prognosis and the oncogenic role of FOXG1.

Previous studies have confirmed that the forkhead box (FOX) superfamily of transcription factors regulates tumor progression and metastasis in multiple cancer. The purpose of this study was to develop a model based on FOX family genes for predicting kidney renal clear cell carcinom (KIRC) prognosis. We downloaded the transcriptional profiles and clinical data of KIRC patients from the Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) datasets. To build a new prognosis model, we screened prognosis-related FOX family genes using Lasso regression and Multivariate Cox regression analyses. Receiver operating characteristic (ROC) curves were used to evaluate model performance. Additionally, a prognostic nomogram was developed using clinical information and selected genes to improve the accuracy of prognostic prediction. We also investigated whether prognosis-related FOX family genes are related to the immune response in KIRC. Finally, we validated the oncogenic role of FOXG1 in KIRC using an in vitro tumor function assay. Six prognosis-related FOX family genes were screened: FOXO1, FOXM1, FOXK2, FOXG1, FOXA1, and FOXD1. The ROC curves indicated that our model was capable of making accurate predictions for 1-, 3-, and 5-year overall survival (OS). The nomogram further improved the accuracy of prognostic predictions. In addition, compared to those in patients with low-risk scores, high-risk scores predicted a decreased level of immune cell infiltration and a lower immune response rate. Moreover, the results of in vitro studies confirmed that FOXG1 supports the proliferation and invasion of KIRC.

Robot-assisted vs. laparoscopic nephroureterectomy for upper urinary tract urothelial carcinoma: a systematic review and meta-analysis based on comparative studies.

Background: Robot-assisted nephroureterectomy (RANU) and laparoscopic nephroureterectomy (LNU) are two minimally invasive surgical management for upper urinary tract urothelial carcinomas (UTUC). Though more high-tech, it remains largely unclear whether RANU provides additional benefits over LNU. We aimed to quantitatively compare the perioperative and oncologic outcomes between RANU and LNU. Methods: The systematic review was performed based on a registered protocol (registration number CRD42022319086). We searched through PubMed, EMBASE and Cochrane databases, as well as conference proceedings and references of review articles (May 2022) for comparative studies reporting perioperative and oncologic outcomes independently in RANU and LNU groups. Selection of studies and data extraction were performed independently by two researchers. Risk of bias was assessed using the modified Newcastle-Ottawa Scale. Results of random-effects meta-analyses were presented as mean differences (MD) or Odds ratio (OR), as appropriate. Subgroup and univariate meta-regression analyses were performed to identify interstudy heterogeneities. Results: The review included 8470 patients undergoing RANU and 19872 patients undergoing LNU from 12 comparative original studies. RANU was associated with fewer overall complications (OR=0.71, 95%CI: 0.62 to 0.81), longer operative time (MD=27.70, 95%CI: 0.83 to 54.60) and shorter length of stay (MD=-0.53, 95%CI: -0.98 to -0.07) compared to LNU. In addition, patients receiving RANU were more likely to have lymph node dissected (OR=2.61, 95%CI: 1.86 to 3.65). Recurrence and survival outcomes did not differ between two surgical procedures. Sample size, types of LNU and world region were major sources of heterogeneity. Conclusion: For UTUC patients, RANU offers fewer complications and shorter hospitalization. However, RANU requires longer operative time and shares similar oncologic outcomes compared to LNU. Further randomized designed studies are warranted. Systematic Review Registration: www.crd.york.ac.uk/prospero/, identifier CRD42022319086.

Adjuvant Sorafenib Following Radiofrequency Ablation for Early-Stage Recurrent Hepatocellular Carcinoma With Microvascular Invasion at the Initial Hepatectomy.

Background: The efficacy of radiofrequency ablation (RFA) for patients with early-stage recurrent hepatocellular carcinoma (HCC) with microvascular invasion (MVI) at the initial hepatectomy is limited. Our study aimed to explore whether adjuvant sorafenib following RFA could improve the situation. Methods: We retrospectively included 211 patients with early-stage (tumor number of ≤3 and tumor size of 2-5 cm) recurrent HCC with MVI at the initial hepatectomy who underwent adjuvant sorafenib following RFA or RFA alone in 13 centers from June 2013 to June 2020. In the combination group, sorafenib of 400 mg twice daily was administered within 7 days after RFA. Overall survival (OS) and recurrence-free survival (RFS) were compared. Subgroup analysis based on MVI grade was performed. MVI grade was based on the practice guidelines for the pathological diagnosis of HCC and included M1 (≤5 MVI sites, all located within adjacent peritumoral liver tissues 0-1 cm away from the tumor margin) and M2 (>5 MVI sites, or any MVI site located within adjacent peritumoral liver tissues > 1 cm away from the tumor margin). Results: A total of 103 patients received the combination therapy and 108 patients received RFA alone. The combination therapy provided better survival than RFA alone (median RFS: 17.7 vs. 13.1 months, P < 0.001; median OS: 32.0 vs. 25.0 months, P = 0.002). Multivariable analysis revealed that treatment allocation was an independent prognostic factor. On subgroup analysis, the combination therapy provided better survival than RFA alone in patients with M1 along with either a tumor size of 3-5 cm, tumor number of two to three, or alpha-fetoprotein (AFP) > 400 µg/L, and in those with M2 along with either a tumor size of 2-3 cm, one recurrent tumor, or AFP ≤ 400 µg/L. Conclusions: Adjuvant sorafenib following RFA was associated with better survival than RFA alone in patients with early-stage recurrent HCC with MVI at the initial hepatectomy. Moreover, MVI grade could guide the application of adjuvant sorafenib.

The Combination of Radiation Therapy and Immunotherapy Is Effective and Well-Tolerated for Unresectable Biliary Tract Cancer.

PURPOSE: For unresectable biliary tract cancer (BTC), chemotherapy (CT) alone is associated with poor survival and severe toxicity. Immunotherapy (IO) is potentially effective for BTC, and radiation therapy (RT) may synergize with IO. We investigated CT versus combined RT and anti-programmed cell death-1 (PD-1) IO for unresectable BTC. METHODS AND MATERIALS: We prospectively observed 117 participants with unresectable BTC either at initial diagnosis or at first recurrence at a single center who chose 1 of 2 treatment options between August 2018 and October 2020. The options were (1) external beam RT combined with anti-PD-1 IO (RT/IO) or (2) CT alone. In the RT/IO group, camrelizumab (200 mg intravenously every 3 weeks) was initiated within 7 days after the completion of RT and continued until progression or intolerable side effects were noted. The median dose per fraction was 55 Gy/25 fractions (range, 50-60 Gy/20-25 fractions). In the CT group, cisplatin and gemcitabine were delivered intravenously every 3 weeks for 8 cycles. We analyzed the adverse events (AEs), overall survival (OS), and disease-free survival (DFS), and performed subgroup analysis according to tumor mutational burden (TMB) and microsatellite status in the combination group. RESULTS: Thirty-nine and 78 participants received RT/IO and CT, respectively. The crude rate of severe AEs (grade ≥3 AEs) was higher in the CT group (79.4% vs 7.7%, P < .001). The OS and DFS after RT/IO were longer than that after CT (median OS: 17.0 vs 11.5 months, P = .01; median DFS: 12.5 vs 7.9 months, P = .008). Participants with low TMB or microsatellite stability had a shorter median OS (13.6 vs 25.7 months, P = .03) and median DFS (9.8 vs 19.3 months, P = .012) than participants with high TMB or microsatellite instability. CONCLUSIONS: RT combined with anti-PD-1 IO may be well tolerated and associated with an improved response rate, DFS, and OS compared with CT alone in patients with unresectable BTC.

Cost-Effectiveness Analysis of Follow-Up Schedule for Hepatocellular Carcinoma after Radiofrequency Ablation.

Methods: A Markov model was established to evaluate the cost-effectiveness of every 2 months or 2-3 months (2- to 3-month group) versus every 3 months or 3-4 months (3- to 4-month group) posttreatment surveillance in the first two years for HCC after RFA. Transition probabilities and utility values were derived from the literature review. Costs of follow-up were estimated from our institution. The incremental cost-effectiveness ratio (ICER), which was less than $10888 per quality-adjusted life-year (QALY), was considered cost-effective. Sensitivity analyses were performed to determine the uncertainty of the model. Results: The 2- to 3-month group gained 1.196 QALYs at a cost of $2212.66, while the effectiveness and cost of the 3- to 4-month group were 1.029 QALYs and $1268.92, respectively. The ICER of the 2- to 3-month group versus the 3- to 4-month group was $5651.14 per QALY gained, which was less than the willingness-to-pay threshold of 1-time gross domestic product per capita of China ($10888/QALY). One-way sensitivity analysis showed that the model was most sensitive to the utility of progression-free survival. The probabilistic sensitivity analysis demonstrated that the 2- to 3-month group had a higher probability of being more cost-effective than the 3- to 4-month group when willingness to pay was over $1088.8. Conclusions: Every 2 months or 2-3 months of follow-up intervals were more cost-effective than 3 months or 3-4 months of follow-up intervals. Thus, the intensive follow-up interval in the first two years was recommended for Child-Pugh class A or B HCC patients within the Milan criteria following RFA.

Role of Preoperational Imaging Traits for Guiding Treatment in Single ≤ 5 cm Hepatocellular Carcinoma.

BACKGROUND: Imaging traits including nonsmooth tumor margins, internal arteries, peritumoral enhancement, and absence of hypodense halos can reflect tumor aggressiveness preoperatively and may affect treatment selection. This study aimed to explore the role of these four imaging traits in treatment selection between surgical resection (SR) and radiofrequency ablation (RFA) for patients with single ≤ 5 cm hepatocellular carcinoma (HCC). PATIENTS AND METHODS: Three hundred eight-one patients with single ≤ 5 cm HCC who underwent SR (n = 202) or RFA (n = 179) in the First Affiliated Hospital of Sun Yat-sen University from April 2010 to December 2019 were retrospectively enrolled. The efficacy of SR and RFA in patients with the imaging traits that significantly influenced recurrence-free survival (RFS) or overall survival (OS) was compared and analyzed. RESULTS: Multivariable Cox regression analysis identified that having internal arteries (P = 0.001) was an independent influencing factor for RFS, while internal arteries (P = 0.005) and peritumoral enhancement (P = 0.001) were independent influencing factors for OS. In patients with internal arteries, subgroup analysis based on tumor size demonstrated that both RFS and OS of SR were superior to those of RFA in patients with 3-5 cm HCC (RFS, P = 0.023; OS, P = 0.015). In patients with peritumoral enhancement, both RFS and OS of SR were superior to those of RFA (RFS, P = 0.019; OS, P = 0.042). CONCLUSION: SR may be associated with improved survival compared with RFA in patients with single 3-5 cm HCC having internal arteries and patients with single ≤ 5 cm HCC having peritumoral enhancement.

Synergistic Effect of a Pleuromutilin Derivative with Tetracycline against Streptococcus suis In Vitro and in the Neutropenic Thigh Infection Model.

Tetracycline (TET) has been widely used in the treatment of Streptococcus suis (S. suis) infection. However, it was found that the efficacy of many antibiotics in S. suis decreased significantly, especially tetracycline. In this study, GML-12 (a novel pleuromutilin derivative) was used in combination with TET against 12 S. suis isolates. In the checkerboard assay, the TET/GML-12 combination exhibited synergistic and additive effects against S. suis isolates (n = 12). In vitro time-killing assays and in vivo therapeutic experiments were used to confirm the synergistic effect of the TET/GML-12 combination against S. suis strains screened based on an FICI ≤ 0.5. In time-killing assays, the TET/GML-12 combination showed a synergistic effect or an additive effect against three isolates with a bacterial reduction of over 2.4-log10 CFU/mL compared with the most active monotherapy. Additionally, the TET/GML-12 combination displayed potent antimicrobial activity against four isolates in a mouse thigh infection model. These results suggest that the TET/GML-12 combination may be a potential therapeutic strategy for S. suis infection.

Prognostic Role of Time to Surgery in Hepatocellular Carcinoma at Barcelona Clinic Liver Cancer Stage 0-A.

BACKGROUND: Postsurgical recurrence is common in early-stage hepatocellular carcinoma (HCC). Prolonged time to surgery (TTS) may lead to tumor progression. However, the impact of TTS on HCC prognosis is controversial in Western studies and unknown in China. We aim to investigate the impact of TTS on the prognosis of Chinese HCC patients at Barcelona Clinic Liver Cancer (BCLC) stage 0-A who underwent surgery. PATIENTS AND METHODS: We retrospectively enrolled 967 BCLC 0-A HCC patients who underwent surgery at three tertiary centers in China. Primary outcomes were recurrence-free survival (RFS) and overall survival (OS). Restricted cubic spline (RCS) was used to select the cutoff value of TTS. Propensity score matching (PSM) was performed to reduce confounding bias, and a time-dependent Cox model was utilized to investigate factors influencing TTS. RESULTS: The median TTS of BCLC 0-A HCC patients was 13 days (interquartile range: 10-21 days). For patients with TTS ≤ 70 days, the cutoff value of TTS was 13 days according to RCS. After PSM, corresponding 1-, 3-, and 5-year RFS of the TTS > 13 days and TTS ≤ 13 days groups were 75.6%, 55.3%, 46.4% and 71.2%, 52.3%, 38.8%, respectively (P = 0.103). Corresponding 1-, 3-, and 5-year OS of TTS > 13 days and TTS ≤ 13 days groups were 93.7%, 82.8%, 69.6% and 92.4%, 78.5%, 68.4%, respectively (P = 0.580). Time-dependent Cox analysis revealed that age and tumor size were factors influencing TTS. CONCLUSIONS: Our study suggests that, for patients with TTS ≤ 70 days, prolonged TTS had no impact on BCLC 0-A Chinese HCC patients receiving surgery.

TBH score: a new model to predict and prevent severe liver damage after chemotherapy for cancer patients.

PURPOSE: To explore a quantitative predictive model for the risk of chemotherapy-induced severe liver damage (CISLD). MATERIALS AND METHODS: In total, 3870 consecutive cancer patients initially treated with chemotherapy were retrospectively collected and randomly assigned to a training (n=2580) or internal validation (n=1290) set in a 2:1 ratio to construct and validate the model. Additional external validation was performed using another data set (n=413). A total of 486 patients were prospectively enrolled to assess the clinical significance of the model. CISLD was defined as grade ≥3 hepatotoxicity. RESULTS: CISLD was found in 255 (9.9%), 128 (9.9%) and 36 (8.7%) patients in the training, internal and external validation sets, respectively. Serum triglyceride, body mass index and history of hypertension formed the basis of the score model. Patients could be stratified into low, intermediate and high-risk groups with <10%, 10-30% and >30% CISLD occurrence, respectively. This model displayed a concordance index (C-index) of 0.834 and was validated in both the internal (C-index, 0.830) and external (C-index, 0.817) sets. The incidence of CISLD was significantly reduced in those who received preventive hepatoprotective drugs compared to those who did not among patients assessed as the intermediate risk group (8.9% vs 17.5%, p=0.042) and the high risk group (15.6% vs 55.8%, p=0.043). CONCLUSIONS: The new score model can be used to accurately predict the risk of CISLD in cancer patients undergoing chemotherapy. Clinically, this can be translated into a reference tool for oncologists in the clinical decision-making process before chemotherapy to provide appropriate prevention and interventions for patients with a high risk of CISLD.

Liver resection versus transarterial chemoembolization for the treatment of intermediate-stage hepatocellular carcinoma.

BACKGROUND: The role of transarterial chemoembolization (TACE) as the standard treatment for intermediate-stage hepatocellular carcinoma (HCC) is being challenged by increasing studies supporting liver resection (LR); but evidence of survival benefits of LR is lacking. We aimed to compare the overall survival (OS) of LR with that of TACE for the treatment of intermediate-stage HCC in cirrhotic patients. METHODS: A Markov model, comparing LR with TACE over 15 years, was developed based on the data from 31 literatures. Additionally, external validation of the model was performed using a data set (n = 1735; LR: 701; TACE: 1034) from a tertiary center with propensity score matching method. We conducted one-way and two-way sensitivity analyses, in addition to a Monte Carlo analysis with 10 000 patients allocated into each arm. RESULTS: The mean expected survival times and survival rates at 5 years were 77.8 months and 47.1% in LR group, and 48.6 months and 25.7% in TACE group, respectively. Sensitivity analyses found that initial LR was the most favorable treatment. The 95% CI for the difference in OS was 2.42-2.46 years between the two groups (P < 0.001). In the validation set, the 5-year survival rates after LR were significantly better than those after TACE before (40.2% vs. 25.9%, P < 0.001) and after matching (43.2% vs 30.9%, P < 0.001), which was comparable to the model results. CONCLUSIONS: For cirrhotic patients with resectable intermediate-stage HCC, LR may provide survival benefit over TACE, but large-scale studies are required to further stratify patients at this stage for different optimal treatments.

Novel partners with colistin to increase its in vivo therapeutic effectiveness and prevent the occurrence of colistin resistance in NDM- and MCR-co-producing Escherichia coli in a murine infection model.

Objectives: The emergence of NDM- and MCR-1-co-producing Escherichia coli has compromised the use of carbapenems and colistin, which are critically important in clinical therapy, and represents a severe threat to public health worldwide. Here, we demonstrate synergism of colistin combined with existing antibiotics as a potential strategy to overcome XDR E. coli co-harbouring NDM and MCR-1 genes. Methods: To comprehensively evaluate their combined activity, antibiotic combinations were tested against 34 different E. coli strains carrying both NDM and MCR-1 genes. Antibiotic resistance profiles and molecular characteristics were investigated by susceptibility testing, PCR, MLST, S1-PFGE and WGS. Antibiotic synergistic efficacy was evaluated through in vitro chequerboard experiments and dose-response assays. A mouse model was used to confirm active combination therapies. Additionally, combinations were tested for their ability to prevent high-level colistin-resistant mutants (HLCRMs). Results: Combinations of colistin with rifampicin, rifabutin and minocycline showed synergistic activity against 34 XDR NDM- and MCR-1-co-producing E. coli strains, restoring, in part, susceptibility to both colistin and the partnering antibiotics. The therapeutic effectiveness of colistin combined with rifampicin or minocycline was demonstrated in a mouse model. Furthermore, colistin plus rifampicin showed significant activity in preventing the occurrence of HLCRMs. Conclusions: The synergism of colistin in combinations with rifampicin, rifabutin or minocycline offers viable therapeutic alternatives against XDR NDM- and MCR-positive E. coli.

Low-dose Bacillus Calmette-Guerin versus full-dose for intermediate and high-risk of non-muscle invasive bladder cancer: a Markov model.

BACKGROUND: To compare the efficacy of low dose (27 mg) Bacillus Calmette-Guérin (BCG) and a full dose (81 mg) BCG immunotherapy for patients with intermediate and high-risk non-muscle invasive bladder cancer (NMIBC) after a typical transurethral bladder resection. METHODS: We constructed a Markov model for a 20-year simulation of the disease to compare the overall survival of patients with intermediate and high-risk of NMIBC between the full-dose therapy (FD group) and the low-dose therapy (LD group). Base case analysis, one-way and two-way sensitivity analysis and a second-order Monte Carlo analysis were performed based on data from 15 published articles. RESULTS: The expected overall survivals were 9.56 (9.55-9.57) years for FD group and 9.63 (9.61-9.64) years for LD group(P < 0.001). The estimated mortality in the FD group at 5, 10, and 20 years were 34.23%, 57.51% and 83.14%, respectively. The corresponding values in the LD group were 34.11%, 57.17%, 82.16%, respectively. Age-specific mortality and metastatic rate after undergoing radical cystectomy (RC) were the most two sensitive parameters in both groups. The rate of disease recurrence with disease worsening is the determining factor when choosing the optimal dose of BCG treatment. CONCLUSIONS: A low-dose BCG treatment may act slightly better than a full-dose BCG treatment for patients with intermediate and high-risk of NMIBC. This finding will require further high-quality studies to validate.

Radiofrequency ablation plus nucleotide analogous for hepatitis B virus-related hepatocellular carcinoma: a cost-effectiveness analysis.

In the real-world, it is unclear that after the radiofrequency ablation (RFA), whether it is a cost-effective strategy to administer nucleotide analogue (NA) for patients with hepatitis B virus (HBV)-related HCC patients. The aim of this study was to estimate the cost-effectiveness of the RFA plus NA versus RFA alone in patients with HBV-related HCC within the Milan criteria in China and the USA. A Markov model was developed to simulate a cohort of patients with HCC within the Milan criteria and Child-Pugh A/B cirrhosis and underwent RFA with or without NA therapy over their remaining life expectancy. Analysis was performed in two geographical cost settings: China and the USA. The RFA plus NA therapy provided an average of 7.57 years, whereas RFA monotherapy offered 5.83 years. The RFA plus NA therapy produced 5.09 quality-adjusted life years (QALYs), whereas RFA monotherapy achieved 3.89 QALYs. The incremental cost-effectiveness ratio (ICER) of the RFA plus NA therapy versus RFA monotherapy was $10368.19/QALY in China and $38805.45/QALY in the USA. These values were below the thresholds of the cost-effectiveness in both countries. Sensitivity analysis revealed that the utility of recurrent HCC was the most sensitive parameter in all cost scenarios in both of the RFA plus NA therapy and RFA monotherapy groups. Our Markov model has shown that for the patients with HBV-related HCC within the Milan criteria and Child-Pugh A/B cirrhosis, RFA plus NA is more cost-effective than RFA monotherapy across the two different cost scenarios namely, China and the USA.