A prospective evaluation of postoperative swallowing function and dysphagia following endoscopic laryngopharyngeal surgery.

BACKGROUND: Endoscopic laryngopharyngeal surgery (ELPS) is a minimally invasive transoral surgery for superficial pharyngeal and laryngeal cancer, but dysphagia occasionally occurs post-treatment. We investigated dysphagia following ELPS and its risk factors. METHODS: Of the 145 patients who underwent ELPS, 92 were evaluated in this study using the Hyodo score, Functional Outcome Swallowing Scale, Eating Assessment Tool-10 along with the total scores for the three items of the method of intake, time, and food preoperatively and on postoperative 1, 3, and 6 months. We examined the 6-month trends of these values. Furthermore, the fasting period post-surgery, the need for swallowing rehabilitation by a speech therapist, and postoperative pneumonia episodes were set as outcomes reflecting the short-term swallowing function. We determined the associations between these outcomes and patient background factors. RESULTS: Postoperatively, the Hyodo score worsened at 1 month but recovered at 3 months. The Hyodo scores of all patients who underwent postcricoid ELPS did not worsen. The diameter of the resected specimen (DRS) was significantly associated with the need for swallowing rehabilitation and postoperative fasting time. A DRS ≥ 35 mm was considered the threshold for the need of swallowing rehabilitation, postoperative pneumonia, and prolonged postoperative fasting time. CONCLUSION: ELPS exerts a temporal and limited impact on the swallowing function, which recovers within 3 months in every swallowing evaluation. This necessitates additional care during the treatment of patients with mucosal defects ≥ 35 mm, owing to the significant association between the DRS and short-term swallowing function.

On the origin of gastric tumours: analysis of a case with intramucosal gastric carcinoma and oxyntic gland adenoma.

Most gastric cancers develop in inflamed gastric mucosa due to Helicobacter pylori infection, typically with metaplastic changes. However, the origins of gastric cancer remain unknown. Here, we present a case of intramucosal gastric carcinoma (IGC) and oxyntic gland adenoma (OGA) derived from spasmolytic polypeptide-expressing metaplasia (SPEM). Early gastric cancer adjacent to a polyp was found in the upper corpus of a 71-year-old woman without H. pylori infection and was endoscopically resected. Histological examination showed IGC and OGA, both of which had predominant MUC6 expression. Interestingly, gastric glands with enriched MUC6-positive mucous cells, referred to as SPEM, expanded between them. Whole-exome sequencing analysis revealed a truncating KRAS(G12D) mutation in IGC, OGA, and SPEM. In addition, TP53 and CDKN2A mutations and a loss of chromosome 17p were found in the IGC, whereas a GNAS mutation was observed in the OGA. These results indicated that IGC and OGA originated from the KRAS-mutated SPEM. © 2023 The Pathological Society of Great Britain and Ireland.

Thermal tissue damage caused by new endoscope model due to light absorption.

BACKGROUND AND AIM: Bright endoscopic light sources improve the visibility of the intestinal mucosa. A newly launched endoscopic system developed by Olympus Corporation (Tokyo, Japan) in 2020 required modification to prevent heat-induced tissue damage, which reportedly occurs during magnifying chromoendoscopy. We investigated the mechanism of this phenomenon by evaluating the rise in temperature of stained and unstained porcine mucosa using the new and previous endoscopic systems. METHODS: Surface temperatures of stained (India ink, 0.05% crystal violet, 0.5% methylene blue, or 0.2% indigo carmine) and unstained porcine mucosa were evaluated using infrared imaging after contact with the new endoscopic system before it was modified (system-EVIS X1; scope-GIF-EZ1500) and compared with a previous endoscopic system (system-EVIS EXERAIII; scope-GIF-H190). We performed histological analysis of the porcine mucosa stained with 0.05% crystal violet after contact with the new endoscope to evaluate the degree of tissue damage. RESULTS: Surface temperatures remained < 40°C when the new endoscope was in contact with the unstained mucosa. However, the maximum surface temperature rose to > 70°C when the new endoscope was in contact with the stained mucosa (stained other than indigo carmine). Histological analysis revealed cavity formation in porcine epithelium stained with crystal violet where the endoscope made contact for ≥ 5 s . Using the previous endoscope, the maximum surface temperature of stained mucosa remained below approximately 60°C, and the surface temperature of the unstained mucosa remained below 30°C. CONCLUSIONS: Heat transfer by light absorption could cause heat-induced tissue damage during magnifying chromoendoscopy using the new endoscope.

Expansion of Gastric Intestinal Metaplasia with Copy Number Aberrations Contributes to Field Cancerization.

Intestinal metaplasia (IM) is a risk factor for gastric cancer following infection with Helicobacter pylori. To explore the susceptibility of pure gastric IM to cancer development, we investigated genetic alterations in single IM gastric glands. We isolated 50 single IM or non-IM glands from the inflamed gastric mucosa of 11 patients with intramucosal gastric carcinoma (IGC) and 4 patients without IGC; 19 single glands in the noninflamed gastric mucosa of 11 individuals from our cohort and previous dataset were also included as controls. Whole-exome sequencing of single glands revealed significantly higher accumulation of somatic mutations in various genes within IM glands compared with non-IM glands. Clonal ordering analysis showed that IM glands expanded to form clusters with shared mutations. In addition, targeted-capture deep sequencing and copy number (CN) analyses were performed in 96 clustered IM or non-IM gastric glands from 26 patients with IGC. CN analyses were also performed on 41 IGC samples and The Cancer Genome Atlas-Stomach Adenocarcinoma datasets. These analyses revealed that polyclonally expanded IM commonly acquired CN aberrations (CNA), including amplification of chromosomes 8, 20, and 2. A large portion of clustered IM glands typically consisted of common CNAs rather than other cancer-related mutations. Moreover, the CNA patterns of clustered IM glands were similar to those of IGC, indicative of precancerous conditions. Taken together, these findings suggest that, in the gastric mucosa inflamed with H. pylori infection, IM glands expand via acquisition of CNAs comparable with those of IGC, contributing to field cancerization. SIGNIFICANCE: This study contributes to our understanding of gastric intestinal metaplasia as a risk factor for gastric adenocarcinoma via their multifocal expansion and acquisition of CNAs and somatic mutations.

Gastric Hyperplastic Polyps Can Shrink After Discontinuation of Proton Pump Inhibitors: A Case Series Compared With Continuation of Proton Pump Inhibitors.

GOAL: This study investigated whether gastric hyperplastic polyps (GHPs) shrink after discontinuation of proton pump inhibitor (PPI) alone. BACKGROUND: Long-term use of PPIs has been reported to increase the incidence of GHPs, which sometimes bleed and cause anemia. We experienced a patient whose recurrent hemorrhagic GHPs associated with long-term use of PPIs had disappeared after discontinuation of PPIs. STUDY: This study was conducted retrospectively at Kyoto University Hospital. Patients with histologically confirmed GHPs who had been taking PPIs for >6 months and who had undergone a repeat endoscopy within 2 years were included. Polyp shrinkage was defined as the disappearance of polyps or a reduction of >50% in the long diameter of the largest polyp. RESULTS: Six patients who discontinued PPIs were compared with 17 patients who continued PPIs. Polyp shrinkage was significantly more frequent in the PPI-discontinuation group (5/6, 83%) than in the PPI continuation group (0/17, 0%) (P<0.001). In 2 patients in the PPI-discontinuation group, the polyps completely disappeared finally. CONCLUSION: These findings suggest that discontinuation of PPIs can shrink GHPs in patients using PPIs.

A case of gastric granular cell tumor.

We herein describe an extremely rare case of gastric granular cell tumor (GCT). The gastric submucosal tumor showed a central tiny depression on the surface with a molar tooth-like appearance on esophagogastroduodenoscopy. Our case highlights that gastric GCT should be considered as differential diagnosis of gastric submucosal tumors.

Indolent feature of Helicobacter pylori-uninfected intramucosal signet ring cell carcinomas with CDH1 mutations.

BACKGROUND: In Helicobacter pylori (Hp)-uninfected individuals, diffuse-type gastric cancer (DGC) was reported as the most common type of cancer. However, the carcinogenic mechanism of Hp-uninfected sporadic DGC is largely unknown. METHODS: We performed whole-exome sequencing of Hp-uninfected DGCs and Hp-uninfected normal gastric mucosa. For advanced DGCs, external datasets were also analyzed. RESULTS: Eighteen patients (aged 29-78 years) with DGCs and nine normal subjects (28-77 years) were examined. The mutation burden in intramucosal DGCs (10-66 mutations per exome) from individuals aged 29-73 years was not very different from that in the normal gastric glands, which showed a constant mutation accumulation rate (0.33 mutations/exome/year). Unbiased dN/dS analysis showed that CDH1 somatic mutation was a driver mutation for intramucosal DGC. CDH1 mutation was more frequent in intramucosal DGCs (67%) than in advanced DGCs (27%). In contrast, TP53 mutation was more frequent in advanced DGCs (52%) than in intramucosal DGCs (0%). This discrepancy in mutations suggests that CDH1-mutated intramucosal DGCs make a relatively small contribution to advanced DGC formation. Among the 16 intramucosal DGCs (median size, 6.5 mm), 15 DGCs were pure signet ring cell carcinoma (SRCC) with reduced E-cadherin expression and a low proliferative capacity (median Ki-67 index, 2.4%). Five SRCCs reviewed endoscopically over 2-5 years showed no progression. CONCLUSIONS: Impaired E-cadherin function due to CDH1 mutation was considered as an early carcinogenic event of Hp-uninfected intramucosal SRCC. Genetic and clinical analyses suggest that Hp-uninfected intramucosal SRCCs may be less likely to develop into advanced DGCs.

Spontaneous regression of mismatch repair-deficient colorectal cancers: Case series.

Spontaneous regression (SR) has been reported in various malignant tumors. However, SR in colorectal cancer (CRC) is particularly rare and the mechanism remains unclear. We here report three cases of CRCs displaying SR, which were experienced at two institutions. Intriguingly, all of these cases displayed the common endoscopic characteristics; superficial elevated lesion accompanied by a central depression (0-IIa + IIc, in the Paris classification), with a nonpolypoid growth, located in the ascending colon. Furthermore, immunohistology of biopsy specimens revealed the lack of DNA mismatch repair proteins within the CRC lesions, suggesting that these were mismatch repair-deficient (dMMR) CRCs. One of the major features of dMMR cancers is an increase in the number of tumor-infiltrating lymphocytes. Thus, the dMMR phenotype might be associated with SR of CRCs through the activation of anti-tumor host immune responses.

Genetic analysis of a case of Helicobacter pylori-uninfected intramucosal gastric cancer in a family with hereditary diffuse gastric cancer.

Germline mutations in CDH1, encoding E-cadherin, are known to be the causative mechanism of hereditary diffuse gastric cancer (HDGC). We encountered two cases of gastric cancer in a Japanese family with HDGC. A 28-year-old man (Case 1) died of advanced gastric cancer. His younger sister aged 27 (Case 2) was diagnosed with intramucosal signet ring cell carcinoma (SRCC). Both had identical germline CDH1 mutations, but Case 1 was positive for Helicobacter pylori infection, whereas Case 2 was negative. Case 2 underwent total gastrectomy. Whole-exome sequencing of an intramucosal SRCC in Case 2 revealed seven somatic mutations including one in CDH1. The six non-CDH1 mutations were classified as non-driver mutations. Decreased expression of E-cadherin in intramucosal SRCC was confirmed by immunohistochemistry. Our report demonstrated that CDH1 mutation was the only active driver mutation in Helicobacter pylori-uninfected intramucosal SRCC.

[Evaluation of the safety and efficacy of endoscopic treatment for early gastric cancers in patients aged over 80 years].

Endoscopic treatments, including endoscopic mucosal resection or endoscopic submucosal dissection, are well accepted as standard treatments for early gastric cancers. However, there are few studies evaluating the safety and efficacy of this approach for early gastric cancers in patients aged over 80 years, and the post-treatment prognosis remains unclear. Here, we retrospectively analyzed the medical records and evaluated the safety and efficacy of endoscopic treatment for early gastric cancers in patients aged over 80 years (group A) compared with non-elderly patients aged 65-79 years (group B) and under 65 years (group C). In this study, we enrolled 53 patients (mean age, 82 years) in group A, 217 patients (mean age, 73 years) in group B, and 89 patients (mean age, 60 years) in group C who received endoscopic treatment at Kyoto University Hospital between 2001 and 2010. The incidence of treatment-related complications including aspiration pneumonia, bleeding, and perforation was 19% (10/53) in group A, 9.7% (21/217) in group B, and 6.7% (6/89) in group C, respectively. In particular, only the incidence of aspiration pneumonia was significantly higher in group A [11% (6/53) ] than in the other two groups [1.8% (4/217) in group B and 1.1% (1/89) in group C]. There was no significant difference in the curative resection rate and recurrence rate including metachronous lesions among the three groups. In group A, the median survival calculated using the Kaplan-Meier method was 8.0 years, and the 5-year survival rate was 73%. No gastric cancer-related deaths were observed in all groups. In conclusion, endoscopic treatment for early gastric cancers may contribute to an improvement in life expectancy, even among patients aged over 80 years, provided an experienced gastroenterologist selects the appropriate patients based on not only the endoscopic findings for the lesion but also the severity of any comorbidities. However, it is noteworthy that our elderly group aged over 80 years had a high risk of developing aspiration pneumonia.

Instability of IGF-IGFBP complex as a cause of the different performance of serum and EDTA-plasma after storage: EDTA-plasma is preferable for evaluating bioactive IGF especially in the mouse.

OBJECTIVE: The insulin-like growth factor (IGF) signaling pathway is recognized as a potential target for treating several cancers, and strategies targeting the IGF type 1 receptor (IGF-1R) have been evaluated in many clinical trials. These suggested that the pretreatment level of circulating free IGF gives an estimate of IGF bioactivity and might be a predictive biomarker of the response to anti-IGF-1R antibodies. However, there is no defined protocol for measuring free and bioactive IGF concentrations, partly because the measurement procedures, including sample collection and handling, have not been standardized. We investigated the effects of sample collection methods and storage conditions on bioactive IGF measurement using a modified kinase receptor activation (KIRA) assay in human and mouse samples. DESIGN: Blood samples were obtained from healthy men and women, and from healthy male and female wild-type BALB/c mice. Serum and ethylenediaminetetraacetic acid (EDTA)-plasma samples were collected and used immediately or stored in small quantities at 4 °C or -80 °C for 3, 7, or 14 days. A bioassay directed against the phosphorylated IGF-1R using western blot analysis was developed as a modification of the KIRA assay, in which the level of phosphorylation of IGF-1R represented the IGF bioactivity in blood samples. RESULTS: The levels of bioactive IGFs in mouse serum stored at 4 °C increased markedly in a time-dependent manner; the increase was slightly reduced in samples stored at -80 °C. Analysis of mouse EDTA-plasma stored at 4 °C showed a similar pattern, but the time-dependent increase was less than in the serum samples. By contrast, the levels of bioactive IGFs in EDTA-plasma stored at -80 °C were stable over 14 days. The levels of human bioactive IGFs in both serum and EDTA-plasma stored at 4 °C increased slightly with time, but the increases were much smaller than in mouse samples. The levels of human bioactive IGF in both serum and EDTA-plasma stored at -80 °C were stable over 14 days. CONCLUSIONS: The use of EDTA-plasma avoids the problems with long-term storage. Therefore, EDTA-plasma should be used when measuring circulating IGF bioactivity, especially in mouse samples. All samples should be stored at -80 °C when long-term storage is unavoidable. Because of the large difference in the stability of the IGF-IGF-binding protein complex between the human and mouse in vitro, all samples should be handled carefully to ensure the accurate evaluation of IGF bioactivity, especially in mouse samples.

Bioactive insulin-like growth factors as a possible molecular target for non-islet cell tumor hypoglycemia.

Non-islet cell tumor hypoglycemia (NICTH) is a paraneoplastic syndrome characterized by persistent, severe hypoglycemia with a wide variety of solid tumors. It is considered to cause hypoglycemia by increasing the insulin-like bioactivity of the circulating insulin-like growth factor (IGF) system, however, the precise mechanism of hypoglycemia remains unclear. In this manuscript, we report on a patient suffering from NICTH caused by a small cell carcinoma of the colon. This is the first report focusing on the role of bioactive IGFs for this pathological condition. First, we demonstrated that the IGF signal pathway has been activated in this tumor in an autocrine and/or paracrine manner using immunohistochemical analysis. Second, we confirmed that bioactive IGFs in the patient's serum were increased using a modified kinase receptor activation assay, thus bioactive IGFs (mainly IGF-2) could be considered to play a major pathogenic role in enhanced hypoglycemic insulin-like activity. Third, increased IGF bioactivity in the patient's serum was completely inhibited by an anti-IGF neutralizing antibody in vitro. These results suggest that neutralization of bioactive IGFs might become a novel therapeutic strategy for NICTH to relieve the hypoglycemic symptoms together with the tumor suppressive effect.

[Pancreatic cancer in a patient with congenital agenesis of the dorsal pancreas].

A 65-year-old man with back pain showed a hypovascular lesion of the head of the pancreas on dynamic computed tomography and abdominal ultrasonography. The distal portion of the pancreas was not visible. Endoscopic retrograde cholangiopancreatography revealed pancreatic duct obstruction, and the duodenal minor papilla was not visible. Therefore, we diagnosed the patient's condition as stage IVa pancreatic cancer with congenital agenesis of the dorsal pancreas. The patient underwent successful chemotherapy with 3 courses of gemcitabine and S-1, which was followed by pancreaticoduodenectomy. Pathological staging revealed invasive ductal carcinoma, pT3, pN0, pM0, stage III. We report a rare case of pancreatic cancer with congenital agenesis of the dorsal pancreas.