Toripalimab plus axitinib versus sunitinib as first-line treatment for advanced renal cell carcinoma: RENOTORCH, a randomized, open-label, phase III study.

BACKGROUND: Immune checkpoint inhibitors in combination with tyrosine kinase inhibitors are standard treatments for advanced clear cell renal cell carcinoma (RCC). This phase III RENOTORCH study compared the efficacy and safety of toripalimab plus axitinib versus sunitinib for the first-line treatment of patients with intermediate-/poor-risk advanced RCC. PATIENTS AND METHODS: Patients with intermediate-/poor-risk unresectable or metastatic RCC were randomized in a ratio of 1 : 1 to receive toripalimab (240 mg intravenously once every 3 weeks) plus axitinib (5 mg orally twice daily) or sunitinib [50 mg orally once daily for 4 weeks (6-week cycle) or 2 weeks (3-week cycle)]. The primary endpoint was progression-free survival (PFS) assessed by an independent review committee (IRC). The secondary endpoints were investigator-assessed PFS, overall response rate (ORR), overall survival (OS), and safety. RESULTS: A total of 421 patients were randomized to receive toripalimab plus axitinib (n = 210) or sunitinib (n = 211). With a median follow-up of 14.6 months, toripalimab plus axitinib significantly reduced the risk of disease progression or death by 35% compared with sunitinib as assessed by an IRC [hazard ratio (HR) 0.65, 95% confidence interval (CI) 0.49-0.86; P = 0.0028]. The median PFS was 18.0 months in the toripalimab-axitinib group, whereas it was 9.8 months in the sunitinib group. The IRC-assessed ORR was significantly higher in the toripalimab-axitinib group compared with the sunitinib group (56.7% versus 30.8%; P < 0.0001). An OS trend favoring toripalimab plus axitinib was also observed (HR 0.61, 95% CI 0.40-0.92). Treatment-related grade ≥3 adverse events occurred in 61.5% of patients in the toripalimab-axitinib group and 58.6% of patients in the sunitinib group. CONCLUSION: In patients with previously untreated intermediate-/poor-risk advanced RCC, toripalimab plus axitinib provided significantly longer PFS and higher ORR than sunitinib and had a manageable safety profile TRIAL REGISTRATION: ClinicalTrials.gov NCT04394975.

Pelvic floor ultrasound versus urodynamics in evaluating insensible urinary incontinence: A retrospective study.

OBJECTIVE: Insensible Urinary Incontinence (IUI) is a situation when you complain of urinary incontinence but are unaware of how it occurred. Therefore, it is necessary to apply highly specific diagnostic methods to promote accuracy in the diagnosis of IUI, including pelvic floor ultrasound (PFU) and urodynamic studies (UDS). METHODS: A total of 41 women with IUI were retrospectively included. Patients were categorized into two groups: the urodynamic urinary incontinence group (UUI group, n=20) and the non-urodynamic urinary incontinence group (NUUI group, n=21), according to the urine leakage during UDS. The baseline clinical characteristics, UDS results, and PFU parameters were collected. RESULTS: Compared with the NUUI group, the UUI group had a smaller maximum cystometric capacity (P=0.008), lower maximum urethral closure pressure (P=0.005), shorter functional urethral length (FUL) (P=0.01), more bladder neck funneling (BNF) (P=0.02), greater BNF depth (P=0.04), and larger BNF area (P=0.01). The area and depth of BNF were negatively correlated with maximum urethral closure pressure (r=-0.42, P=0.01), FUL (r=-0.36, P=0.02 versus r=-0.39, P=0.01), and maximum cystometric capacity (r=-0.35, P=0.03), but positively correlated with maximum urinary flow rate (r=0.33, P=0.04 versus r=0.36, P=0.02). The canonical correlation analysis of the ultrasound parameters and UDS parameters shows that the first pair of canonical variables was statistically significant (r1=0.9, P<0.001). CONCLUSIONS: The PFU is associated with UDS in evaluating IUI. It has the advantages of low cost and high comfort, thus should be used as an auxiliary examination for IUI.

[Aldo-keto reductase family 1 B10 participates in the regulation of hepatoma cell cycle through p27/p-Rb signaling pathway].

Objective: Aldo-keto reductase family 1 member B10 (AKR1B10) pathogenesis, early diagnosis and prognosis are closely related with hepatoma. Therefore, this study explores the effect and mechanism of AKR1B10 on cell cycle in hepatoma cells. Methods: HepG2 cells were infected with lentivirus LV-AKR1B10-shRNA or treated with epalrestat, an AKR1B10 inhibitor. The expression level of AKR1B10 was detected by Western blot assay and real-time fluorescence quantitative PCR (RT-qPCR). Decreased AKR1B10 activity was detected by reduced coenzyme II (NADPH) absorbance at 340 nm. The low expression of AKR1B10 and the effect of different concentrations of epalrestat on cell proliferation and cell cycle were detected by CCK-8 method and flow cytometry. The protein expression levels of p-rb, cyclin D1, E1, p27 in HepG2 cells were detected by Western blot. The mean of the two samples was tested using independent sample t-test. Results: AKR1B10 expression level in hepatoma cells was significantly increased compared to normal liver cells, and the relative expression level of AKR1B10 protein in HepG2 cells was 6.71 ± 1.11 (P = 0.012). Epalrestat was significantly inhibited with the enzymatic activity of AKR1B10 in a dose-dependent manner. AKR1B10 gene in HepG2 cells was effectively silenced. HepG2 cells treated with different concentrations of epalrestat (AKR1B10 inhibitor) for 24, 48 and 72 h had inhibited cell proliferation, promoted G0/G1 cell cycle arrest, reduced the expression of p-Rb, cyclin D1, and cyclin E1 and increased the expression of cyclin dependent kinase inhibitor p27 expression. Conclusion: AKR1B10 inhibitory expression and activity can promote G0/G1 cell cycle arrest in HepG2 cells through the p27 / p-Rb pathway.

MicroRNAs in gastric cancer: from bench to bedside.

Gastric carcinogenesis results from complex interactions between host and environmental and bacterial factors, and this leads to genetic and epigenetic deregulation of oncogenic and tumor-suppressive genes. MicroRNAs (miRNAs) are a class of small noncoding RNAs which regulate almost 30% of human genes post transcriptionally and they are crucial in the initiation and progression of various diseases; especially malignancies. Accumulated evidence documents changes in gene sequences and epigenetic modifications. These then lead to abnormal miRNA expression in gastric cancer (GC) and also to deregulated miRNAs which act as oncogenes or tumor suppressors by regulating related target genes and contributing to malignant phenotypes. This altered miRNA expression in body fluids could well provide a novel biomarker for GC patient diagnosis and prognosis. MiRNAs present a promising target for GC treatment, and more tempting, for eradication of gastric cancer stem cells. This latter sub-group of tumor cells is thought to initiate and maintain GC development. Herein, we review the aberrant expression of miRNA expression and the underlying mechanisms and consequential effects of miRNA de-regulation. This identifies the responsible gastric cancer target genes, and highlights potential clinical applications.

Treating ureteric obstruction secondary to gynecological disease assisted with retrograde ureteroscopic stenting.

OBJECTIVE: To analyze the technical experience and clinical efficacy of ureteroscopic treatment of middle and lower ureteral obstruction due to gynecological disease. PATIENTS AND METHODS: From January 2007 to December 2015, 58 cases of ureteral obstruction were collected in 55 patients caused by gynecological factors. 19 cases had the history of gynecological iatrogenic injury and 39 cases were secondary to gynecological tumors. Different situations of luminal stenosis included obliteration, suture penetration, transection and unrecognized ureteral orifice. The ureteral stents were retrogradely placed ureteroscopically assisted by holmium laser or transurethral plasma kinetic resection. RESULTS: A total of 51 cases of operations were completed successfully by one-stage ureteroscopic stenting with the mean operation time of 33.5 min. No severe complications were observed. The serum creatinine two weeks after operation had a significant decline compared with that of preoperation (p<0.05). The mean follow-up time was 5.3 months. 44 cases with successful stent placement showed nice improvement of hydronephrosis by ultrasound. CONCLUSIONS: Ureteroscopic stent placement with the use of holmium laser or plasma kinetic resection device, has good clinical effects, which provides a relatively simple and minimal-invasive treatment option to resolve middle and lower ureteral obstruction caused by complex gynecological factors.

Effect of the Schneiderian membrane on the formation of bone after lifting the floor of the maxillary sinus: an experimental study in dogs.

A titanium membrane was used to isolate the Schneiderian membrane of the bony walls of the sinus so that we could investigate their role on the formation of bone after sinus lifts compared with a control group (conventional raising of the sinus floor) in which we did not use a membrane to isolate any area. Three canine models of lifting the sinus floor using the lateral window technique were established: conventional lifting of the floor (control group), raising of the floor with the mucosa shielded (mucosal shielding group), and raising of the floor with the bony wall shielded (bony wall shielding group). The formation of bone one and three months after the sinus floor had been lifted was compared in each group both grossly and by histopathological examination. An appreciable amount of new bone had formed in the control group, with abundant areas near the inferior bony wall, and some near the raised Schneiderian membrane. Similarly, new bone had also formed in the mucosal shielding group, with abundant new bone near the inferior bony wall, but none near the raised Schneiderian membrane. However, there was considerably less new bone in the bony wall shielding group, with none in tissues adjacent to the inferior bony wall and little in tissues near the raised Schneiderian membrane. The Schneiderian membrane has osteogenic capability and participates in the formation of bone after the sinus floor has been lifted. However, its osteogenic role is weaker than that of the surrounding bony wall of the maxillary sinus.

Molecular portraits of human breast tumours.

Human breast tumours are diverse in their natural history and in their responsiveness to treatments. Variation in transcriptional programs accounts for much of the biological diversity of human cells and tumours. In each cell, signal transduction and regulatory systems transduce information from the cell's identity to its environmental status, thereby controlling the level of expression of every gene in the genome. Here we have characterized variation in gene expression patterns in a set of 65 surgical specimens of human breast tumours from 42 different individuals, using complementary DNA microarrays representing 8,102 human genes. These patterns provided a distinctive molecular portrait of each tumour. Twenty of the tumours were sampled twice, before and after a 16-week course of doxorubicin chemotherapy, and two tumours were paired with a lymph node metastasis from the same patient. Gene expression patterns in two tumour samples from the same individual were almost always more similar to each other than either was to any other sample. Sets of co-expressed genes were identified for which variation in messenger RNA levels could be related to specific features of physiological variation. The tumours could be classified into subtypes distinguished by pervasive differences in their gene expression patterns.

[Treatment of ischemic necrosis of femoral head by the transfer of vascular pedicled iliac periosteum].

OBJECTIVE: To investigate the therapeutical effect of treatment of ischemic necrosis of femoral head by the transfer of vascular pedicled iliac periosteum. METHODS: From June 1983 to August 1997, 106 cases with ischemic necrosis of femoral head (II stage in 64 cases, III stage in 39 cases, IV stage in 3 cases) were treated by the transfer of vascular pedicled iliac periosteum with ascending branch of lateral femoral circumflex vessel or deep circumflex iliac vessel pedicle. RESULTS: Followed up 2 years and 4 months to 16 years, there were excellent in 54 cases, better in 38 cases, moderate in 9 cases, poor in 5 cases, and 86.8% in excellent rate according to the criterion of the therapeutical effect on the repair and reconstruction of adult ischemic necrosis of femoral head. CONCLUSION: Treating ischemic necrosis of femoral head by the transfer of vascular pedicled iliac periosteum has the advantage of constant pedicle, easily drawing materials and reliable therapeutical effect.

Distinctive gene expression patterns in human mammary epithelial cells and breast cancers.

cDNA microarrays and a clustering algorithm were used to identify patterns of gene expression in human mammary epithelial cells growing in culture and in primary human breast tumors. Clusters of coexpressed genes identified through manipulations of mammary epithelial cells in vitro also showed consistent patterns of variation in expression among breast tumor samples. By using immunohistochemistry with antibodies against proteins encoded by a particular gene in a cluster, the identity of the cell type within the tumor specimen that contributed the observed gene expression pattern could be determined. Clusters of genes with coherent expression patterns in cultured cells and in the breast tumors samples could be related to specific features of biological variation among the samples. Two such clusters were found to have patterns that correlated with variation in cell proliferation rates and with activation of the IFN-regulated signal transduction pathway, respectively. Clusters of genes expressed by stromal cells and lymphocytes in the breast tumors also were identified in this analysis. These results support the feasibility and usefulness of this systematic approach to studying variation in gene expression patterns in human cancers as a means to dissect and classify solid tumors.

Expression of extracellular glutathione peroxidase in human and mouse gastrointestinal tract.

Extracellular glutathione peroxidase (EGPx) is a glycosylated selenoprotein capable of reducing hydrogen peroxide, organic hydroperoxides, free fatty acid hydroperoxides, and phosphatidylcholine hydroperoxides. We found that human large intestinal explant cultures synthesize EGPx and cellular glutathione peroxidase (CGPx) and secrete EGPx. The level of EGPx mRNA expression relative to alpha-tubulin was similar throughout the mouse gastrointestinal tract. EGPx mRNA transcripts have been localized to mature absorptive epithelial cells in human and mouse large intestine. Western blot analysis of mouse intestinal protein has demonstrated the presence of EGPx protein in the small intestine, cecum, and large intestine, with the highest protein levels found in the cecum. Immunohistochemistry studies of human large intestine and mouse small and large intestine sections demonstrated the presence of EGPx protein within mature absorptive epithelial cells. In human large intestine and mouse small intestine, EGPx protein is also present in the extracellular milieu. These results suggest a role for EGPx in protection of the intestinal tract from peroxidative damage and/or in intercellular metabolism of peroxides.

[Induction of gastric adenocarcinoma in Wistar rats following neonatal exposure to MNNG and neoplastic transformation assay of DNA of the induced cancer].

Adenocarcinoma, adenoma and dysplasia of the stomach of adult Wistar rats were induced following administration of MNNG for 10 days by gavage when they were new-born. The incidence of the three types of pathological lesions at the dose of 0.4 mg MNNG per rat being 39%, 50% and 100% respectively. Induction of gastric adenocarcinoma is dose-dependent. The incidence of adenocarcinoma in male rats being significantly higher then that of female rats (P < 0.02). 23 of 33 (70%) induced cancers were found in the gastric antrum. By the use of DNA cotransfection technique and the assay of carcinogenicity in the Balb/c nude mice, it was also found that the DNA of 4 of the 6 induced gastric carcinomas could transform NIH/3T3 cells into malignant cells, an indication that the induced cancer DNA contains transforming gene.