Comparative study on the clinical application of mixed reality technology leading micro-invasive intervertebral foramen puncture location and blind puncture location.

OBJECTIVE: To discuss the function of mixed reality (MR) technology in guiding location of intervertebral foramen microscopic puncture and analyze its feasibility and clinical application value. METHODS: Sixty patients with lumbar intervertebral disc who were treated between January 2017 to October 2017 were chosen, and classified into navigation group (30 cases) and traditional control (30 cases) according to random number table. Intervertebral foramen microscopic operation was conducted for both groups. MR technology was applied for the navigation group to guide puncture and establish intervertebral foramen microscopic cannula. Traditional C-arm X-ray apparatus was used for traditional group to establish intervertebral foramen microscopic cannula. Intra-operative puncture times, fluoroscopy times, puncture time and VAS score 1d, 3m and 6m after the operation were recorded and compared. RESULTS: Postoperative waist and leg pain symptoms of both groups were relieved obviously, and straight leg raising test for the diseased limb turned to be negative. Intra-operative puncture times, fluoroscopy times, puncture time and operation time had statistical significance decrease. CONCLUSION: Mixed reality (MR) can accurately guide the establishment of intervertebral foramen microscopic cannula, solve the bottleneck problem of intervertebral foramen microscopic technology, promote puncture success rate, reduce repeated puncture times, avoid by-injury, shorten puncture time and reduce X-ray radiation quantity of operators and patients, so it deserves to be promoted and applied.

Genotype and phenotype correlation in von Hippel-Lindau disease based on alteration of the HIF-α binding site in VHL protein.

PURPOSE: Von Hippel-Lindau (VHL) disease is a rare hereditary cancer syndrome that reduces life expectancy. We aimed to construct a more valuable genotype-phenotype correlation based on alterations in VHL protein (pVHL). METHODS: VHL patients (n = 339) were recruited and grouped based on mutation types: HIF-α binding site missense (HM) mutations, non-HIF-α binding site missense (nHM) mutations, and truncating (TR) mutations. Age-related risks of VHL-associated tumors and patient survival were compared. RESULTS: Missense mutations conferred an increased risk of pheochromocytoma (HR = 1.854, p = 0.047) compared with truncating mutations. The risk of pheochromocytoma was lower in the HM group than in the nHM group (HR = 0.298, p = 0.003) but was similar between HM and TR groups (HR = 0.901, p = 0.810). Patients in the nHM group had a higher risk of pheochromocytoma (HR = 3.447, p < 0.001) and lower risks of central nervous system hemangioblastoma (CHB) (HR = 0.700, p = 0.045), renal cell carcinoma (HR = 0.610, p = 0.024), and pancreatic tumor (HR = 0.382, p < 0.001) than those in the combined HM and TR (HMTR) group. Moreover, nHM mutations were independently associated with better overall survival (HR = 0.345, p = 0.005) and CHB-specific survival (HR = 0.129, p = 0.005) than HMTR mutations. CONCLUSION: The modified genotype-phenotype correlation links VHL gene mutation, substrate binding site, and phenotypic diversity (penetrance and survival), and provides more accurate information for genetic counseling and pathogenesis studies.

Risk factors for survival in patients with von Hippel-Lindau disease.

BACKGROUND: Historically, von Hippel-Lindau (VHL) disease is characterised by a poor survival. Although genotype-phenotype correlation has been described in many studies, the risk factors for VHL survival remain unclear. This study aims to evaluate the median survival of Chinese patients with VHL disease and explore whether VHL survival is influenced by genetic and clinical factors. METHODS: In this retrospective study, we recruited 340 patients from 127 VHL families. Kaplan-Meier plot and Cox regression model were used to evaluate the median survival and assess how survival was influenced by birth year, birth order, sex, family history, mutation type, onset age and first presenting symptom. RESULTS: The estimated median life expectancy for Chinese patients with VHL disease was 62 years. Patients with early-onset age, positive family history and truncating mutation types had poorer overall and VHL-related survival. Patients with haemangioblastoma as their first presenting symptom were related to a higher risk of death from central nervous system haemangioblastoma than those with abdominal lesions (HR 8.84, 95% CI 2.04 to 38.37, P=0.004). CONCLUSIONS: This largest VHL survival analysis indicates that onset age, family history, mutation type and first presenting symptom have an effect on the survival of patients with VHL disease, which is helpful to genetic counselling and clinical decision-making.

Shorter telomere length increases age-related tumor risks in von Hippel-Lindau disease patients.

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant cancer syndrome caused by alterations of VHL gene. Patients are predisposed to develop pheochromocytomas and solid or cystic tumors of the central nervous system, kidney, pancreas, and retina. Remarkable phenotypic heterogeneity exits in organ involvement and tumor onset age between and within VHL families. However, no reliable markers have been found to predict the age-related tumor risks in VHL patients. A large Chinese cohort composed of 300 VHL patients and 92 healthy family controls was enrolled in our study. Blood relative telomere length was measured in 184 patients and all the controls available for genomic DNA samples. Age-related risks for the five major VHL-associated tumors were evaluated using Kaplan-Meier plots and Cox regression analysis. Differences in clinical phenotype were observed between Chinese cohort and the United Kingdom cohort. VHL patients showed significantly shorter telomere length than healthy family controls(P = 0.0183), and a positive correlation was found between telomere length and onset age of the five major tumors, respectively. Moreover, patients in the shorter telomere group (age-adjusted telomere length ≤ 0.44) suffered higher age-related risks for VHL-associated central nervous system hemangioblastomas (HR: 1.879, P = 0.004), renal cell carcinoma (HR: 2.126, P = 0.002) and pancreatic cyst and neuroendocrine tumors (HR: 2.093, P = 0.001). These results indicate that blood shorter telomere length is a new biomarker for age-related tumor risks in VHL patients, which will be crucial to genetic counseling and future research about the role of telomere shortening in the pathogenesis of VHL-associated tumors.

Higher programmed cell death 1 ligand 1 (PD-L1) mRNA level in clear cell renal cell carcinomas is associated with a favorable outcome due to the active immune responses in tumor tissues.

Renal cell carcinoma is one of the most common urological tumors. The role of programmed cell death 1 ligand 1 (PD-L1) in renal cell carcinomas in predicting outcome of the patients is yet unclear. We analyzed the clinical and RNA-seq data of 522 kidney clear cell cancer, 259 kidney papillary cell carcinoma and 66 kidney chromophobe patients from The Cancer Genome Atlas (TCGA) database. In kidney clear cell cancer patients with high PD-L1 mRNA level and low PD-L1 mRNA level in tumors, the median overall survival periods were 45.0 and 37.1 months respectively (p=0.002). Multivariate Cox regression tests found that PD-L1 mRNA level in tumor was an independent predictor for overall survival status in kidney clear cell cancer patients (HR=0.7, 95% CI 0.5-0.9, p=0.007). However, no significant difference in overall survival status was found between high and low PD-L1 groups in kidney papillary cell carcinoma and kidney chromophobe cohorts. Gene-set enrichment analysis on the data from databases of TCGA and GSE53757 dataset in Gene Expression Omnibus databases showed that several pathways relating to immunological functions were activated in kidney clear cell cancers with high PD-L1 mRNA expression, and glycolysis and epithelial-mesenchymal transition pathways relating to tumor progression and metastasis were increased in kidney clear cell cancers with low PD-L1 mRNA level. In conclusion, higher PD-L1 mRNA level in kidney clear cell cancer tissues was associated with a favorable outcome due to the higher immunological responses in tumor tissues.

Association between FBP1 and hypoxia-related gene expression in clear cell renal cell carcinoma.

Fructose-1,6-bisphosphatase 1 (FBP1) is a rate-limiting enzyme in gluconeogenesis. Recently, the catalytic activity-independent function of FBP1, hypoxia-induced factor (HIF) repression in the nucleus, was identified. The aim of the present study was to investigate the association between FBP1 and hypoxia-related gene expression in clear cell renal cell carcinoma (ccRCC). The protein expression levels of FBP1, HIF-1α, HIF-2α, erythropoietin (EPO) and carbonic anhydrase IX (CA9) were assessed by immunohistochemical staining of ccRCC paraffin blocks from 123 patients using the tissue microarray technique. The expression level of FBP1 was then correlated with various clinicopathological factors, and the protein expression levels of HIF-1α, HIF-2α, EPO and CA9. Clinicopathological factors, including age, gender, T stage and Fuhrman grade, were not significantly different between patients with low and high FBP1 expression in ccRCC (P>0.05). FBP1 protein expression level was significantly correlated with the expression levels of HIF-1α (P=0.005) and EPO (P=0.010), but not significantly correlated with the expression levels of HIF-2α (P=0.123) and CA9 (P=0.513) in ccRCC tissues. The current findings confirm the association between FBP1 and hypoxia-related gene expression, and may facilitate understanding of the mechanisms of ccRCC tumorigenesis.

Telomere shortening is associated with genetic anticipation in Chinese Von Hippel-Lindau disease families.

Von Hippel-Lindau (VHL) disease is a rare autosomal dominant cancer syndrome. A phenomenon known as genetic anticipation has been documented in some hereditary cancer syndromes, where it was proved to relate to telomere shortening. Because studies of this phenomenon in VHL disease have been relatively scarce, we investigated anticipation in 18 Chinese VHL disease families. We recruited 34 parent-child patient pairs (57 patients) from 18 families with VHL disease. Onset age was defined as the age when any symptom or sign of VHL disease first appeared. Anticipation of onset age was analyzed by paired t test and the other two special tests (HV and RY2). Relative telomere length of peripheral leukocytes was measured in 29 patients and 325 healthy controls. Onset age was younger in child than in parent in 31 of the 34 parent-child pairs. Patients in the first generation had older onset age with longer age-adjusted relative telomere length, and those in the next generation had younger onset age with shorter age-adjusted relative telomere length (P < 0.001) in the 10 parent-child pairs from eight families with VHL disease. In addition, relative telomere length was shorter in the 29 patients with VHL disease than in the normal controls (P = 0.003). The anticipation may relate to the shortening of telomere length in patients with VHL in successive generations. These findings indicate that anticipation is present in families with VHL disease and may be helpful for genetic counseling for families with VHL disease families and for further understanding the pathogenesis of VHL disease.