Inactivation of the p16 gene by hypermethylation and loss of heterozygosity in adenocarcinoma of the lung

We investigated the aberrant promoter hypermethylation of p16, p15 and p14 genes and loss of heterozygosity (LOH) at 9p21-22 in 48 cases of adenocarcinoma of the lung. The frequencies of hypermethylation of genes were as follows: p16, 25.0%; p15, 22.9%; and p14, 18.8%. The frequency of LOH at chromosome 9p21-22 was 60.9%. The frequency of two-hit inactivation of the p16 gene by hypermethylation and LOH was 21.7%. Two-hit inactivation of the p16 gene showed loss of protein expression and was significantly correlated with tumor size, tumor grade and the Ki-67 labeling index. Hypermethylation of the p16 gene was not significantly correlated with hypermethylation of the p15 and p14 genes, both of which are close to the p16 gene locus, suggesting that hypermethylation of these genes occurs selectivity. In conclusion, biallelic inactivation of the p16 gene by hypermethylation and LOH might cause loss of p16 expression and play an important role in the development of adenocarcinoma of the lung. Therefore, controlling and monitoring for hypermethylation of the p16 gene may be partially useful for treatment and early diagnosis of adenocarcinoma of the lung.     

CD98 regulates the phosphorylation of HER2 and a bispecific anti-HER2/CD98 antibody inhibits the growth signal of human breast cancer cells

Human epidermal growth factor receptor (HER) family proteins are currently major targets of therapeutic monoclonal antibodies against various epithelial cancers. However, the resistance of cancer cells to HER family-targeted therapies, which may be caused by cancer heterogeneity and persistent HER phosphorylation, often reduces overall therapeutic effects. We herein showed that a newly discovered molecular complex between CD98 and HER2 affected HER function and cancer cell growth. The immunoprecipitation of the HER2 or HER3 protein from lysates of SKBR3 breast cancer (BrCa) cells revealed the HER2-CD98 or HER3-CD98 complex. The knockdown of CD98 by small interfering RNAs inhibited the phosphorylation of HER2 in SKBR3 cells. A bispecific antibody (BsAb) that recognized the HER2 and CD98 proteins was constructed from a humanized anti-HER2 (SER4) IgG and an anti-CD98 (HBJ127) single chain variable fragment, and this BsAb significantly inhibited the cell growth of SKBR3 cells. Prior to the inhibition of AKT phosphorylation, BsAb inhibited the phosphorylation of HER2, however, significant inhibition of HER2 phosphorylation was not observed in anti-HER2 pertuzumab, trastuzumab, SER4 or anti-CD98 HBJ127 in SKBR3 cells. The dual targeting of HER2 and CD98 has potential as a new therapeutic strategy for BrCa.     

Accumulation of Excess Visceral Fat Is a Risk Factor for Pancreatic Fistula Formation After Total Gastrectomy

Background  The effect of obesity on gastrectomy in patients with gastric cancer is controversial. The degree of abdominal fat increases the technical difficulty of abdominal surgery. This study examined the effect of visceral fat on total gastrectomy and risk factors associated with the formation of pancreatic fistula. Methods  Between February 2001 and April 2007, 191 patients with gastric cancer underwent total gastrectomy. The visceral fat area (VFA) was calculated from computed tomography (CT) scans taken at the level of the umbilicus using FatScan Software. Patients were divided into high- (≥100 cm², n = 52) and low-VFA groups (<100 cm², n = 139), and also into high- (≥25 kg/m², n = 47) and low-BMI groups (<25 kg/m², n = 144). Results  Blood loss and incidence of pancreatic fistula were significantly higher in the high- than low-VFA group. However, only blood loss was significantly different between the high- and low-BMI groups. VFA, blood loss, and splenectomy were identified as significant risk factors for pancreatic fistula formation on univariate analysis, and multivariate logistic regression analysis of these factors identified VFA (p = 0.0001) and splenectomy (p = 0.0014) as significant predictors of pancreatic fistula. Conclusions  VFA is a better indicator for pancreatic fistula formation after total gastrectomy than is BMI. Lymph node dissection must be performed carefully, especially in patients with visceral fat accumulation during total gastrectomy with splenectomy.     

Postoperative cytology for drained fluid from the pancreatic bed after "curative" resection of pancreatic cancers: does it predict both the patient's prognosis and the site of cancer recurrence?

OBJECTIVE: To evaluate the postoperative cytology of drained fluid from the pancreatic bed as a predictive indicator of local recurrence after curative (R0) resection of pancreatic cancer. SUMMARY BACKGROUND DATA: The pancreatic bed offers a common site of cancer recurrence (local recurrence), even after curative (R0) resection is performed for pancreatic cancer. If local recurrence is thereby predicted precisely, soon after surgery, we have a chance to treat it by adding radiation or some other locoregional therapy before it can grow or spread beyond the pancreatic bed. However, there have been no previous reports of cytology performed on the drained fluid after pancreatectomy. METHODS: This study includes 94 patients who had shown negative results in the peritoneal washing cytology before resection and subsequently received pancreatectomies for pancreatic tumors. They consisted of 12 benign tumors, 17 noninvasive or minimally invasive carcinomas and 65 invasive ductal carcinomas (R0 = 58; R1/2 = 7). Postoperatively, the drained fluid from the pancreatic bed was collected for 24 hours and used for cytologic examination. The cytologic results were examined in association with the histopathology of the resected tumor, patient's survival, and mode of cancer recurrence, including local recurrence. RESULTS: Patients with benign tumors or noninvasive/minimally invasive carcinomas had negative result in cytology, and none of them have died of local recurrence (limited to the pancreatic bed) to date. However, patients with invasive ductal carcinoma revealed higher cytology-positive rates: 28% (16/58) in curative (R0) resection; and 71% (5/7) in noncurative (R1/2) resection. Among 58 patients with R0 resection, the 3-year survival rate was 14% in 16 cytology-positive patients and 55% in 42 cytology-negative patients (P < 0.05). The 3-year cumulative rate of local recurrence was 85% and 23%, respectively (P < 0.05). Compared with other histopathologic parameters obtained from the resected specimens, the drain cytology was more specific in predicting the subsequent development of local recurrence. CONCLUSIONS: Drain-cytology was a quick examination that enabled us to specifically indicate both minute residual cancer and subsequent development of local recurrence even after R0 resection of pancreatic cancer.     

A method of reconstructing coronary stent and lumen image using zero cross point image for the purpose of improving sharpness

Our purpose was to improve the sharpness of the coronary stent and lumen. We reconstructed volume rendering (VR) image and maximum intensity projection (MIP) images using the original image and a sharpened operator image with 8-neighbor Laplacian filter. The most suitable center number was 9, and the circumferential number was -1 on the sharpened operator image with 8-neighbor Laplacian filter. In the same way, the most suitable spatial filter was the FC43. VR and MIP images showed sharp stents. The VR image and MIP image fused the original image and sharpened the operator image with the 8-neighbor Laplacian filter, resulting in a clear lumen. The 8-neighbor sharpened operator image with 8-neighbor Laplacian filter was attached to the Aquilion64, and this method did not require extra hardware and software for reconstructing images of the stent and lumen.     

Long-stay patients in pediatric intensive care units: Five-years, 2-points,cross-sectional study

Objectives:To explore the changing patterns of long-stay patients (LSP) to improve the utilization of pediatric intensive care units (PICUs) resources.Methods:This is a 2-points cross-sectional study (5 years apart; 2014-2019) conducted among PICUs and SCICUs in Riyadh, Saudi Arabia. Children who have stayed in PICU for more than 21 days were included.Results:Out of the 11 units approached, 10 (90%) agreed to participate. The prevalence of LSP in all these hospitals decreased from 32% (48/150) in 2014 to 23.4% (35/149) in 2019. The length of stay ranged from 22 days to 13.5 years. The majority of LSP had a neuromuscular or cardiac disease and were admitted with respiratory compromise. Ventilator-associated pneumonia was the most prevalent complication (37.5%). The most commonly used resources were mechanical ventilation (93.8%), antibiotics (60.4%), and blood-products transfusions (35.4%). The most common reason for the extended stay was medical reasons (51.1%), followed by a lack of family resources (26.5%) or lack of referral to long-term care facilities (22.4%).Conclusion:A long-stay is associated with significant critical care bed occupancy, complications, and utilization of resources that could be otherwise utilized as surge capacity for critical care services. Decreasing occupancy in this multicenter study deserves further engagement of the healthcare leaders and families to maximize the utilization of resources.     

Multiple fragments of human TG are capable of inducing oral tolerance to whole human TG

Oral tolerance is the mechanism by which the immune system remains unresponsive to orally administered soluble antigens. Mice immunized with human TG (hTG), resulting in the induction of experimental autoimmune thyroiditis (EAT), provide an ideal in vivo system in which to examine oral tolerance to hTG. In the present study, we characterize epitopes of hTG that are capable of inducing oral tolerance. hTG is a large homodimeric protein, 660 Kd. The limited proteolysis of hTG using trypsin (TR) generates several smaller fragments of hTG ranging in size from 29 Kd to 145 Kd. Using hTG fragments h1TR (residues 1-521), h4bisTR (residues 2513-2713), h6TR (residues 522-1626), and h7TR (residues 1627-2512), prepared from both iodine rich and iodine poor hTG, we investigated the ability of these fragments to induce oral tolerance. The oral administration of iodine rich h6TR or h7TR suppresses hTG specific immune responses in a manner similar to whole hTG. In contrast, the oral administration of iodine rich h1TR or h4bisTR exacerbates hTG specific immune responses. Unlike iodine rich h1TR or h4bisTR, the oral administration of iodine poor h1TR or h4bisTR fails to augment hTG specific immune responses. In fact, h4bisTR suppresses hTG specific immune responses. These results indicate that hTG contains multiple epitopes that differentially affect oral tolerization. Tolerogenic epitopes reside within fragments h6TR and h7TR. The removal of iodine, and presumably hormone, from h4bisTR converts an immunogenic epitope to a tolerogenic epitope.     

A case of micronodular pneumocyte hyperplasia diagnosed through lung biopsy using thoracoscopy

We present a case of a 39-year-old woman with sporadic tuberous sclerosis (TSC), whose chest radiograph demonstrated bilateral diffuse nodular shadowing. A transbronchial lung biopsy specimen revealed the possibility of multiple atypical adenomatous hyperplasia (AAH), which had not been reported in TSC. Thoracoscopic lung biopsy was, therefore, performed. The specimens revealed the characteristic histological and immunohistochemical features of micronodular pneumocyte hyperplasia, which has been reported as an extremely rare pulmonary manifestation of TSC. In addition, no evidence of AAH or any other pulmonary involvements of TSC including lymphangioleiomyomatosis were detected in biopsy specimens obtained at thoracoscopy.