[The impact of surgical treatment on the life quality of patients with locally advanced hypopharyngeal carcinoma].

Objective: To explore the impact of surgical treatment on the life quality of patients with locally advanced hypopharyngeal carcinoma. Methods: A retrospective analysis of the clinical data of 21 patients with advanced hypopharyngeal carcinoma who underwent surgery at the Shenzhen Hospital of Chinese Academy of Medical Sciences Cancer Hospital from January 1, 2017 to December 31, 2019 was conducted. There were 3 patients with recurrence after radiotherapy and chemotherapy, 4 cases of postoperative recurrence, 3 cases of postoperative recurrence after radiotherapy and chemotherapy. Three cases were hypopharyngeal carcinoma with esophageal carcinoma and 8 cases were stage Ⅳ hypopharyngeal carcinoma. Among them, 3 cases were repaired by stomach, 4 cases by free jejunum, 2 case by great saphenous vein for internal carotid artery, 1 case by artificial blood vessel for internal carotid artery, 5 cases by transfer of pectoralis major musculocutaneous flap and 2 cases by transfer of submental island flap. The 21 patients were scored using the European Cancer Research and Treatment Organization's Quality of Life Head and Neck Tumor Special Scale (EORTC QLQ-H&N35) on the 3 months before and after surgery, and the changes in postoperative life quality were compared. Results: The preoperative life quality score of 21 patients was (56.86±7.95) points and life quality score of 3 months after operation was (50.93±7.91) points. The postoperative life quality was significantly improved (P<0.05). The improvement of the postoperative life quality of the patients mainly included the improvements of the head and neck pain, swallowing function, diet, taking analgesics and indwelling nasal feeding tubes. The preoperative scores were (7.58±1.56) points, (8.46±1.63) points, (7.94±0.43) points, (1.76±0.12) points and (1.86±0.28) points, respectively, while the scores of 3 months after operation were (5.02±1.23) points, (6.28±1.58) points, (6.34±0.36) points , (1.12±0.08) points and (1.24±0.18) points, the differences were statistically significant (all P<0.05). Conclusion: The flexible selection of flap repair for locally advanced hypopharyngeal carcinoma is still feasible, and surgery can improve the life quality of patients.

A screening trial of Helicobacter pylori-specific antigen tests in saliva to identify an oral infection.

OBJECTIVE: Helicobacter pylori infection places a heavy burden on medical and economic resources. Standard diagnosis requires the presence of established H. pylori gastric disease. STUDY DESIGN AND SETTING: A multicenter screening trial assessing 2 immunochromatographic H. pylori antigen oral tests was carried out with 201 participants. The analysis also included a urea breath test (UBT), a Campylobacter-like organism test, silver stain, culture, serology, and stool tests. RESULTS: The participants were grouped into UBT positive (UBT+) and UBT negative (UBT-) people, using conventional methods with congruent clusters based on p values from McNemar's paired χ2 analysis and 95% CI estimates. Both oral tests were also positive in 82% of the seropositive UBT- people. However, oral antigen and seroprevalence divided UBT- people into 2 statistically separate CI subgroups: the UBT- symptomatic (highly positive) group and the UBT- asymptomatic (mostly negative) group. 90.5% of all people whose oral tests were both negative were also UBT-. CONCLUSIONS: Saliva H. pylori antigen is an important indicator in UBT- asymptomatic patients. Currently, its clinical significance remains uncertain, but saliva may be a reservoir from where H. pylori is transmitted to the stomach. In symptomatic patients, it is strongly associated with stomach infection.

Mutations of the VHL tumour suppressor gene in renal carcinoma.

Multiple, bilateral renal carcinomas are a frequent occurrence in von Hippel-Lindau (VHL) disease. To elucidate the aetiological role of the VHL gene in human kidney tumorigenesis, localized and advanced tumours from 110 patients with sporadic renal carcinoma were analysed for VHL mutations and loss of heterozygosity (LOH). VHL mutations were identified in 57% of clear cell renal carcinomas analysed and LOH was observed in 98% of those samples. Moreover, VHL was mutated and lost in a renal tumour from a patient with familial renal carcinoma carrying the constitutional translocation, t(3;8)(p14;q24). The identification of VHL mutations in a majority of localized and advanced sporadic renal carcinomas and in a second form of hereditary renal carcinoma indicates that the VHL gene plays a critical part in the origin of this malignancy.

[Da Vinci robot-assisted pylorus and vagus nerve-preserving partial gastrectomy for gastric cancer].

Objective: To investigate the safety and feasibility of Da Vinci robot-assisted pylorus and vagus nerve-preserving partial gastrectomy for gastric cancer. Methods: In this study, descriptive case series method was used to retrospectively analyze the data of 3 patients with gastric cancer who underwent Da Vinci robot-assisted pylorus and vagus nerve-preserving partial gastrectomy in the First Affiliated Hospital of Dalian Medical University from December 2020 to February 2021. The linear layout was adopted for the setting of trocar, and the co-axial direction was the line connecting the umbilicus and splenic hilum. The inferior pyloric arteries and veins need to be preserved. The center was the bifurcation of the right gastroepiploic vessel and the inferior pyloric vessel. Dissection and exposure were performed from the upper, lower, right and left sides, and ventral and dorsal sides to complete the dissection of the inferior pyloric lymph nodes. The superior border of the pancreas was treated by the right diaphragmatic crus approach, the left retroperitoneal approach and the esophageal approach to determine the distribution of the posterior vagal trunk and its branches, and to determine the anatomical relationship with the left gastric artery. The left gastric artery was cut off while the celiac branch of vagus nerve and cardia branch of left gastric artery were preserved. Lymph node dissection was performed on the lateral side of nerve fibers around the blood vessels. Result: All the 3 patients successfully completed the robotic surgery without conversion to laparoscopy or laparotomy. The operation time was (340.0±26.4) (300-390) minutes, the intraoperative blood loss was (13.3±3.3) (10-20) ml, the number of dissected lymph nodes was 26.7±3.9 (19-32), the length of pylorus canal preserved was (3.3±0.3) (3-4) cm, the distal margin was (2.3±0.3) (2-3) cm, and the proximal margin was (3.0±0.6) (2-4) cm. No postoperative complications occurred in all the 3 patients. The first flatus time was 2-3 days after operation, and the postoperative hospital stay was 6-7 days. The operation cost of the 3 patients was (40±7) (33-53) thousand yuan. Conclusion: Da Vinci robot-assisted pylorus and vagus nerve-preserving partial gastrectomy is safe and feasible.

Novel transglutaminase-1 mutations and genotype-phenotype investigations of 104 patients with autosomal recessive congenital ichthyosis in the USA.

BACKGROUND: Autosomal recessive congenital ichthyosis (ARCI) is a rare hereditary disorder of cornification. Mutations in the transglutaminase-1 (TGM1) gene, which encodes for the epidermal enzyme transglutaminase-1 (TGase-1), are one of the causes of ARCI. METHODS: The TGM1 mutation spectrum was characterised and genotype-phenotype correlations investigated in 104 patients with ARCI ascertained through the National Registry for Ichthyosis and Related Disorders in the USA. Methods: Germline mutations in TGM1 were identified in 55% (57/104) of patients with ARCI. Arginine residues in TGase-1 were mutated in 39% (22/57) of patients overall and 54% (20/37) of those with missense mutations. In total, 55% (12/22) of missense mutations were within CpG dinucleotides and 92% (11/12) of these mutations were C-->T or G-->A transitions. The genotype-phenotype investigation found that ARCI with TGM1 mutations was significantly associated with presence of collodion membrane at birth (p = 0.006), ectropion (p = 0.001), plate-like scales (p = 0.005) and alopecia (p = 0.001). Patients who had at least one mutation predicted to truncate TGase-1 were more likely to have more severe hypohidrosis (p = 0.001) and overheating (p = 0.0007) at onset of symptoms than were those with exclusively TGM1 missense mutations. A logistic model was developed, which predicted that individuals with collodion membrane, alopecia and/or eye problems are about four times more likely to have TGM1 mutations than patients without these findings. CONCLUSION: This is the largest investigation of patients with ARCI to date. It expands the TGM1 mutation spectrum and confirms that despite genetic and phenotypic heterogeneity in ARCI, TGM1 is the main causative gene for this disorder. The high frequency of mutated arginine codons in TGM1 may be due to the deamination of CpG dinucleotides.

BHD mutations, clinical and molecular genetic investigations of Birt-Hogg-Dubé syndrome: a new series of 50 families and a review of published reports.

BACKGROUND: Birt-Hogg-Dubé syndrome (BHDS) (MIM 135150) is an autosomal dominant predisposition to the development of follicular hamartomas (fibrofolliculomas), lung cysts, spontaneous pneumothorax, and kidney neoplasms. Germline mutations in BHD are associated with the susceptibility for BHDS. We previously described 51 BHDS families with BHD germline mutations. OBJECTIVE: To characterise the BHD mutation spectrum, novel mutations and new clinical features of one previously reported and 50 new families with BHDS. METHODS: Direct bidirectional DNA sequencing was used to screen for mutations in the BHD gene, and insertion and deletion mutations were confirmed by subcloning. We analysed evolutionary conservation of folliculin by comparing human against the orthologous sequences. RESULTS: The BHD mutation detection rate was 88% (51/58). Of the 23 different germline mutations identified, 13 were novel consisting of: four splice site, three deletions, two insertions, two nonsense, one deletion/insertion, and one missense mutation. We report the first germline missense mutation in BHD c.1978A>G (K508R) in a patient who presented with bilateral multifocal renal oncocytomas. This mutation occurs in a highly conserved amino acid in folliculin. 10% (5/51) of the families had individuals without histologically confirmed fibrofolliculomas. Of 44 families ascertained on the basis of skin lesions, 18 (41%) had kidney tumours. Patients with a germline BHD mutation and family history of kidney cancer had a statistically significantly increased probability of developing renal tumours compared to patients without a positive family history (p = 0.0032). Similarly, patients with a BHD germline mutation and family history of spontaneous pneumothorax had a significantly increased greater probability of having spontaneous pneumothorax than BHDS patients without a family history of spontaneous pneumothorax (p = 0.011). A comprehensive review of published reports of cases with BHD germline mutation is discussed. CONCLUSION: BHDS is characterised by a spectrum of mutations, and clinical heterogeneity both among and within families.

[Association between both maternal and fetal angiotensinogen gene single nucleotide polymorphism and preeclampsia/eclampsia].

Objective: To explore the association between preeclampsia/eclampsia and maternal and fetal angiotensinogen SNPs. Methods: From January 2008 to October 2015, a case-parents/mother-control designed study was conducted among 347 preeclampsia/eclampsia cases and 700 controls to collect related information on their demographic characteristics and to detect the related angiotensinogen SNPs' genotypes. Both log-linear and unconditional logistic regression methods were employed to investigate the genetic effects of maternal/fetal angiotensinogen SNPs on preeclampsia/eclampsia. Multivariate binary unconditional logistic regression model and covariance were used to analyze the relationship between BMI before pregnancy, weight gain during pregnancy and overweight and obesity in preschool children. Results: Both fetal angiotensinogen rs3789679 GA and AA genotype were associated with the reduced risks of preeclampsia/eclampsia, with ORs as 0.73 (95%CI: 0.55-0.96) and 0.62 (95%CI: 0.39-0.98), respectively. For fetal angiotensinogen rs2493132, individuals that carrying the TT genotype, presented a positive association with the risk of preeclampsia/eclampsia, with OR as 1.60 (95%CI: 1.08-2.37). However, these associations were not statistically significant after the correction of the false discovery rate. It was observed that fetal rs3789679 could reduce the risk of preeclampsia/eclampsia (OR=0.73, 95%CI: 0.55-0.96) under the dominant model (GA+AA/GG) while fetal rs2493132 increased the risk of preeclampsia/eclampsia (OR=1.66, 95%CI: 1.13-2.44) under the recessive model (TT/CC+CT). Maternal rs5051 presented an association with preeclampsia/eclampsia (OR=1.33, 95%CI: 1.01-1.76) under the dominant model (TC+CC/TT). Conclusions: Results from the dominant model showed that both fetal rs3789679 GA and AA genotype reduced the risk of preeclampsia/eclampsia and maternal rs5051 TC while CC genotype increased the risk of preeclampsia/eclampsia. Fetal rs2493132 TT genotype seemed to be associated with the risk of preeclampsia/eclampsia under the recessive model.

Fumarate hydratase enzyme activity in lymphoblastoid cells and fibroblasts of individuals in families with hereditary leiomyomatosis and renal cell cancer.

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC) is the autosomal dominant heritable syndrome with predisposition to development of renal cell carcinoma and smooth muscle tumours of the skin and uterus. OBJECTIVE: To measure the fumarate hydratase (FH) enzyme activity in lymphoblastoid cell lines and fibroblast cell lines of individuals with HLRCC and other familial renal cancer syndromes. METHODS: FH enzyme activity was determined in the whole cell, cytosolic, and mitochondrial fractions in 50 lymphoblastoid and 16 fibroblast cell lines including cell lines from individuals with HLRCC with 16 different mutations. RESULTS: Lymphoblastoid cell lines (n = 20) and fibroblast cell lines (n = 11) from individuals with HLRCC had lower FH enzyme activity than cells from normal controls (p<0.05). The enzyme activity in lymphoblastoid cell lines from three individuals with mutations in R190 was not significantly different from individuals with other missense mutations. The cytosolic and mitochondrial FH activity of cell lines from individuals with HLRCC was reduced compared with those from control cell lines (p<0.05). There was no significant difference in enzyme activity between control cell lines (n = 4) and cell lines from affected individuals with other hereditary renal cancer syndromes (n = 22). CONCLUSIONS: FH enzyme activity testing provides a useful diagnostic method for confirmation of clinical diagnosis and screening of at-risk family members.

Novel mutations in FH and expansion of the spectrum of phenotypes expressed in families with hereditary leiomyomatosis and renal cell cancer.

BACKGROUND: Hereditary leiomyomatosis and renal cell cancer (HLRCC; OMIM 605839) is the predisposition to develop smooth muscle tumours of the skin and uterus and/or renal cancer and is associated with mutations in the fumarate hydratase gene (FH). Here we characterise the clinical and genetic features of 21 new families and present the first report of two African-American families with HLRCC. METHODS: Using direct sequencing analysis we identified FH germline mutations in 100% (21/21) of new families with HLRCC. RESULTS: We identified 14 germline FH mutations (10 missense, one insertion, two nonsense, and one splice site) located along the entire length of the coding region. Nine of these were novel, with six missense (L89S, R117G, R190C, A342D, S376P, Q396P), one nonsense (S102X), one insertion (111insA), and one splice site (138+1G>C) mutation. Four unrelated families had the R58X mutation and five unrelated families the R190H mutation. Of families with HLRCC, 62% (13/21) had renal cancer and 76% (16/21) cutaneous leiomyomas. Of women FH mutation carriers from 16 families, 100% (22/22) had uterine fibroids. Our study shows that expression of cutaneous manifestations in HLRCC ranges from absent to mild to severe cutaneous leiomyomas. FH mutations were associated with a spectrum of renal tumours. No genotype-phenotype correlations were identified. CONCLUSIONS: In combination with our previous report, we identify 31 different germline FH mutations in 56 families with HLRCC (20 missense, eight frameshifts, two nonsense, and one splice site). Our FH mutation detection rate is 93% (52/56) in families suspected of HLRCC.

Construction of a 600-kilobase cosmid clone contig and generation of a transcriptional map surrounding the lung cancer tumor suppressor gene (TSG) locus on human chromosome 3p21.3: progress toward the isolation of a lung cancer TSG.

The critical region on human chromosome 3p21.3 harboring a putative lung cancer tumor suppressor gene (TSG) was previously defined by allelotyping and recently refined by overlapping homozygous deletions. We report the construction of a 700-kb (cosmid and one P1 phage) clone contig covering the deletion overlap and its flanks. The minimal set of 23 cosmids comprises 600 kb and is extended by one P1 phage to 700 kb to cover the distal breakpoint of the overlap. The clone contig was extensively characterized by restriction and expression mapping to produce high resolution physical and transcription maps of the cloned region. Potential transcribed fragments were detected by hybridization with PCR-amplified cDNA libraries, direct cDNA selection "zoo" blotting, cDNA screening, and identification of 24 CpG islands. Thus far, 15 new genes represented by partial or full-length cDNAs were isolated, characterized, and precisely positioned on the contig. Two previously cloned genes, namely GNAI-2 and GNAT-1, were also positioned. In addition, the telomeric breakpoint of the NCI H740 deletion and centromeric breakpoint of the overlapping GLC20 deletion were discovered and mapped to define precisely the candidate TSG region. This large cosmid clone contig and high resolution maps will prove crucial in the identification of the lung cancer TSG(s).

Cloning of a breast cancer homozygous deletion junction narrows the region of search for a 3p21.3 tumor suppressor gene.

Chromosome 3p abnormalities and allele loss are frequent in lung and breast cancers, and several lung cancer cell lines exhibit homozygous deletions of 3p indicating potential sites of tumor suppressor genes at regions 3p21.3, 3p14.2 and 3p12. We have identified and characterized a new 3p21.3 homozygous deletion in a breast cancer cell line and the primary tumor that overlaps those previously described in small cell lung cancer (SCLC). This homozygous deletion is approximately 220 kb in length and represents a somatically acquired change in the primary breast cancer. Cloning and sequencing of the breakpoint demonstrated that this resulted from an interstitial deletion and precisely pinpoints this deletion within the three SCLC homozygous deletions previously reported. This deletion significantly narrows the minimum common deleted region to 120 kb and is distinct from the previously reported region that suppresses tumor formation of the murine A9 fibrosarcoma cells. These findings suggest that a common homozygous deletion region on 3p21.3 is important in both lung and breast cancers. It is likely that this very well characterized region either contains one tumor suppressor gene common to both tumor types or two closely linked tumor suppressor genes specific for each tumor.

CALL gene is haploinsufficient in a 3p- syndrome patient.

The 3p- syndrome results from deletion of a terminal segment of the short arm of one chromosome 3 (3p25-->pter), and is characterized by multiple congenital anomalies and mental retardation. Due to its variable expression, it is assumed this disorder is a contiguous gene syndrome with an undefined number of genes contributing to the phenotype. In an effort to discover genes contributing to mental defects in 3p- syndrome, we determined whether the CALL gene, mapped to 3p26.1 and coding for a neural recognition molecule, is deleted in a boy with this disorder. We found that the break in this patient is distal to the VHL gene, removing D3S18 and the CALL loci. The deletion of one copy of the CALL gene might be responsible for mental defects in patients with 3p- syndrome. Am. J. Med. Genet. 86:482-485, 1999. Published 1999 Wiley-Liss, Inc.

Two single nucleotide polymorphisms (SNPs) in the CALL gene for association studies with IQ.

A number of genes underlie the molecular bases of intelligence. Among these is probably CALL, a novel member of the L1 gene family of neural cell adhesion molecules. By using the single strand conformation polymorphism (SSCP) protocol, we screened the regions of the CALL gene corresponding to the 5' and 3' untranslated regions (UTRs) of the CALL mRNA, searching for polymorphisms that could be useful in association studies in the field of intelligence. We report the finding of T-to-A and T-to-C single nucleotide polymorphisms (SNPs) in the 3' UTR of CALL. These SNPs have an index of heterozygosity of 0.13 and 0.10, respectively. Research is in progress to understand the association between these variants and high IQ.

[Localization of oncoprotein P21ras in the human liver cancer].

Using the human liver cancer DNA transfected NIH/3T3 cell line, the human N-ras oncogene and the over expression of the oncoprotein P21ras was demonstrated, BALB/C mice were immunized. The spleen cells from the immunized mice were fused with SP2/0 myeloma cells. After the HAT medium selection and screening, two hybridoma cell lines, SCI-Oncogema 1 and 2, were established. In the immunoprecipitation test, the molecular weight of the protein reacting to Oncogema 1 was 21,000. This M.W 21,000 protein possessed the capability to bind with GTP, i.e. the character of P21ras. These data indicate that the Oncogema 1 is the monoclonal antibody against P21ras. Using Oncogema 1, specimens from 6 liver cancer patients were studied by immunopathology. With ABC stain, it was observed that the malignant cells in all the samples showed dark staining; the P21ras revealed over expression. Although the staining was heterogeneous, it implied that the ras oncogene was involved in the carcinogenesis of these six samples. No over expression was seen in the normal liver cells even in those around the cancerous lesion. However, dysplastic cells were moderately stained which means that the ras oncogene was activated and P21ras over expressed in these cells. The results suggest that the ras oncogene and P21ras play an important role in the early stage of liver cancer carcinogenesis.

A retrospective clinical study of bevacizumab combined with gemcibabine or paclitaxel in the treatment of recurrent ovarian cancer.

BACKGROUND: Bevacizumab, a recombinant humanized monoclonal antibody that blocks angiogenesis by inhibiting vascular endothelial growth factor A, was described to be effective in the treatment of recurrent or platinum-resistance ovarian cancer. The present retrospective study was performed to further evaluate the clinical efficacy and toxicity of bevacizumab in the treatment of Chinese recurrent ovarian cancer patients who had been previously treated by platinum-based chemotherapy. MATERIALS AND METHODS: We reviewed the hospital database and finally included 26 recurrent ovarian cancer patients who were treated with bevacizumab combined with gemcibabine or paclitaxel or single agent. All included patients received >3 cycle of bevacizumab treatment. The tumor response, overall survival, and toxicities were documented. RESULTS: Under the treatment of bevacizumab combined with gemcibabine or paclitaxel, 2 complete response (7.7%), 8 partial response (30.8%), 7 stable disease (26.9%) and 9 progression disease (34.6%) was documented with the objective response rate of 38.5% and disease control rate of 65.4%. The median overall survival from the first application of bevacizumab was 15.3 months [Figure 1] for all of the 26 patients. The median overall survival time was 16.2 and 14.0 months for bevacizumab + gemcitabine and bevacizumab + paclitaxel treatment schedule respectively. The overall survival was not different between bevacizumab + gemcitabine and bevacizumab + paclitaxel treatment regimen hazard ratio = 0.80 (95% confidence interval: 0.32-2, P = 0.64). The hypertension and proteinuria were the major bevacizumab related toxicities. CONCLUSIONS: Bevacizumab combined with gemcibabine or paclitaxel was a promising treatment schedule for platinum-resistance recurrent ovarian cancer.

Localization of the human vascular endothelial growth factor gene, VEGF, at chromosome 6p12.

Using overlapping cosmids representing the vascular endothelial growth factor (VEGF) locus, the VEGF gene was mapped by fluorescence in situ hybridization to chromosome 6p12. This localization permits linkage analysis and the identification of gene interaction in the region, as well as alterations of the VEGF structure or expression in cancer cells with chromosome abnormalities.

A genetic linkage map of 96 loci on the short arm of human chromosome 3.

We constructed a genetic map of 96 loci on the short arm of human chromosome 3 (3p) in 59 families provided by the Centre d'Etude du Polymorphisme Humaine (CEPH). Twenty-nine continuously linked loci were placed on the map with likelihood support of at least 1000:1; one locus, D3S213, was placed on the map with likelihood support of 871:1; D3Z1, an alpha satellite centromeric repeat probe, was placed on the map with likelihood support of 159:1; 65 loci were assigned regional locations. The average heterozygosity of the uniquely ordered markers was 49%. The map extends from 3p26, the terminal band of 3p, to the centromere (from D3S211 to D3Z1). Multipoint linkage analysis indicated that the male, female, and sex-averaged maps extend for 102, 147, and 116 cM, respectively. The mean genetic distance between uniquely ordered loci on the sex-averaged map was 4.0 cM. Probe density was greatest for the region of 3p between D3F15S2e and the telomere. The sex-averaged map contained two intervals greater than 10 cM. Seventeen probes were localized by fluorescence in situ hybridization. The loci described in this report will be useful in building an integrated genetic and physical map of this chromosome.

PANORAMA: an integrated Web-based sequence analysis tool and its role in gene discovery.

As the exponential growth of DNA sequence information in databases continues, the task of converting this deposited information into knowledge becomes more dependent on integrative sequence analysis and visualization tools. PANORAMA is an Internet-accessible software package that performs a variety of informatics analyses on a given DNA sequence and returns a visual and interactive representation of the results. Its design is modular, so that further sequence analysis tools can be integrated with minimal effort. The utility of PANORAMA is demonstrated in the analysis of 650 kb of human genomic DNA from chromosome region 3p21.3, a region of potential tumor suppressor genes involved in lung cancer, breast cancer, and other forms of cancer. PANORAMA aided in the discovery of genes and alternate splice forms of known exons, in the demarcation of intron-exon boundaries, and in the identification of promoter regions and polymorphisms, all of which contributed to a better understanding of the region. PANORAMA is available on the World Wide Web at http://atlas.swmed.edu.