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.

Ovine (Ovis aries) blastula from an in vitro production system and isolation of primary embryonic stem cells.

Livestock embryo production in in vitro systems has been highlighted due to the emergence of interest in embryo stem cells (ESC). ESC potency and their wide potential applications have been recognized in medicine, fundamental research fields and commercial markets due to ESC totipotency or pluripotency and self-renewal. Ovine ESC probably is a useful technical platform for transgenic livestock and animal cloning, but ESC lines have not yet been founded because of difficulties in ESC isolation and the lack of blastula materials. We have established an IVP (in vitro production) system in our laboratory, including in vitro maturation, in vitro fertilization and in vitro culture, to produce sheep blastula using fresh ovaries and testes collected from livestock production. This system can achieve rates of mature eggs and blastulas of 65 and 50% respectively, and can provide enough blastulas for ICM (inner cell mass) isolation. Furthermore, ESC-like clones were isolated from the ICM on ovine embryonic fibroblast (OEF) feeder cells and in ES-DMEM supplemented with the cell factors LIF and SCF, and these survived to the third passage, which was primarily identified by AKP staining and morphology. This work provides a basis for ovine ESC isolation and foundation of ESC lines.

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.

[The behaviour of rabbit ICM in culture system in vitro].

The behaviour of ICMs isolated from early blastocysts of rabbit by microsurgery and incubated in cultural system in vitro, are varied according to the growing state of ICM. The band type growing extends from the proximal to the distal end, while the differentiation of cells in this kind initiates from the distal toward the proximal and gradually. The band type ICM possesses obvious polarity. The differentiation of different kind of cells appear one after another in order and the arrangement of differentiated germinal layer are clearcut. Therefore, the band type ICM is a good model for the investigation of differentiation cell and cell lineage. Whereas the ball type of growing ICM possesses no polarity. The cell in this type of ICM appears to differentiate from the outer surface of the ball toward the center gradually. The cellular differentiation starts later and the rate of proliferation of differentiated cells are lower than those of the band type ICM. After 7 days of incubation in vitro most of the ICM remain undifferentiation. The ball type ICM is a good model for the isolation of the embryonic stem cell line. There are two steps that the extraembryonic endoderm of rabbit are differentiated from ICM. The first kind of extraembryonic endoderm formed from ICM after 3 days of incubation in vitro. It is the parietal extraembryonic endoderm which migrate so far from the primitive ectoderm. The second kind of extraembryonic endoderm differentiates from ICM after 4 days of incubation in vitro. It is the visceral endoderm, most of which followed the migration of the first endoderm and the rest of them invade into the trophectoderm near the primitive ectoderm.

[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.

[Quantitative study on the osteogenic potential of vascularized iliac periosteal].

The effect of pedical blood supply, recipient environment, blood supply to the osteogenic capacity of iliac periosteal was investigated. An iliac periosteal flap based on the circumflexa femoris lateralis vessels was developed in a canine model. The vascularied iliac periosteal was rotated onto the quadriceps femoris musculus or epigastrica inferior fibrous-connective tissues in one side and the free flap was done in the same way in another side. 2, 2, 4, 6 animals were killed at 2, 4, 8, 12 week after operation and the flaps were studied by new bone Ca, P content, bone dense measure, double tetracycline labeling, bone histomorphometry analysis and light microscopy. The following results were obtained: (1) Iliac periosteal has good osteogenic capacity; (2) The early good blood supply is much more important than the recipient environment blood supply, it make the bone formation speed 2-4 weeks forward.

Iliac periosteal graft with vascular pedicle in the treatment of avascular necrosis of the femoral head. Experimental study and clinical application.

From March 1983 to June 1987, 6 patients with avascular necrosis of the femoral head were treated with vascular pedicled iliac periosteum graft. Follow-up for 3 to 7.5 years showed satisfactory results. The patients experienced no hip pain, could walk freely, and resumed work after the treatment. X-ray films showed that the original defect of the femoral head was filled up and its outline was clear and smooth. The bone density of the femoral head and neck normalized. The experimental study indicated that the vascularized periosteum improves the blood supply and initiates the revascularization and osteogenesis of the femoral head. The authors conclude that the technique is suitable for the treatment of avascular necrosis of the femoral head of Stage II and III.

Aortic compliance in human hypertension.

Aortic compliance in normotensive and hypertensive Chinese subjects undergoing diagnostic cardiac catheterization was compared by using a newly described method that allows for determination of the pressure dependence of compliance if one assumes a value for the exponential coefficient of the pressure-volume relation of the large arteries. Under baseline conditions in the normotensive and hypertensive groups at mean aortic pressures of 96.3 and 128.6 mm Hg, aortic compliance averaged 1.47 and 0.80 ml/mm Hg, respectively. Compliance in the hypertensive group at a diastolic pressure of 99.4 mm Hg (which was nearly equal to the mean normotensive pressure) was 1.072 ml/mm Hg--still significantly lower than in the normotensive group. During nitroprusside infusion, however, the compliances in the hypertensive group increased to levels equal to or greater those in the normotensive group. Thus, these data confirm that aortic compliance is lower in hypertensive than in normotensive humans. They further demonstrate that the lower compliance cannot be attributed entirely to the elevated blood pressure, suggesting that excess smooth muscle tone may be partly responsible.

Transposition of iliac periosteum with vascular pedicle and compression screw fixation for transcervical fracture of femur. Experimental research and clinical application.

The vascular pedicled periosteum was used in 11 cases in our hospital for the treatment of femoral neck fracture with good result. The follow-up period ranged from 2 to 6 years, with an average of 4 years. Animal experiment was made to elucidate the repairing process. It demonstrated that the pedicled periosteum played double roles, namely, blood supply and osteogenesis. The clinical and experimental results are presented.

[Treatment of traumatic shortening of the legs in adults].

Non-traumatic shortening of lower extremities can be lengthened by osteotomy, traction or bone grafting. In traumatic shortening, treatment is limited by several reasons and emphasis should be put on bone healing and preserving of loading and walking functions. The lengthening of lower extremities has some difficulties. Recently, we have adopted a method in which we transposed muscle-skin flap to repair the stick-bone scar in the early stage, and performed traction with Hoffman extra-frame (when osteotomy is needed) in the mid-stage and bone grafting (with or without vascularity) in the late stage. From April 1984 to April 1986, seven patients were treated by this method. The result was satisfactory. In this article is discussed the pathologic characteristics of traumatic shortening of the lower extremities and the role of the gastrocnemius in repairing skin defect.