Assessment of Elastic Laminal Invasion Contributes to an Objective pT3 Subclassification in Colon Cancer.

The extent of tumor spread influences on the clinical outcome, and which determine T stage of colorectal cancer. However, pathologic discrimination between pT3 and pT4a in the eighth edition of the American Joint Committee on Cancer (AJCC)-TNM stage is subjective, and more objective discrimination method for deeply invasive advanced colon cancer is mandatory for standardized patient management. Peritoneal elastic laminal invasion (ELI) detected using elastic staining may increase the objective discrimination of deeply invasive advanced colon cancer. In this study, we constructed ELI study group to investigate feasibility, objectivity, and prognostic utility of ELI. Furthermore, pT classification using ELI was investigated based on these data. At first, concordance study investigated objectivity using 60 pT3 and pT4a colon cancers. Simultaneously, a multi-institutional retrospective study was performed to assess ELI's prognostic utility in 1202 colon cancer cases from 6 institutions. In the concordance study, objectivity, represented by κ, was higher in the ELI assessment than in pT classification. In the multi-institutional retrospective study, elastic staining revealed that ELI was a strong prognostic factor. The clinical outcome of pT3 cases with ELI was significantly and consistently worse than that of those without ELI. pT classification into pT3 without ELI, pT3 with ELI, and pT4a was an independent prognostic factor. In this study, we revealed that ELI is an objective method for discriminating deeply invasive advanced colon cancer. Based on its feasibility, objectivity, and prognostic utility, ELI can subdivide pT3 lesions into pT3a (without ELI) and pT3b (with ELI).

Hydrogen bonds connecting the N-terminal region and the DE loop stabilize the monomeric structure of transthyretin.

Transthyretin (TTR) is a homo-tetrameric serum protein associated with sporadic and hereditary systemic amyloidosis. TTR amyloid formation proceeds by the dissociation of the TTR tetramer and the subsequent partial unfolding of the TTR monomer into an aggregation-prone conformation. Although TTR kinetic stabilizers suppress tetramer dissociation, a strategy for stabilizing monomers has not yet been developed. Here, we show that an N-terminal C10S mutation increases the thermodynamic stability of the TTR monomer by forming new hydrogen bond networks through the side chain hydroxyl group of Ser10. Nuclear magnetic resonance spectrometry and molecular dynamics simulation revealed that the Ser10 hydroxyl group forms hydrogen bonds with the main chain amide group of either Gly57 or Thr59 on the DE loop. These hydrogen bonds prevent the dissociation of edge strands in the DAGH and CBEF ß-sheets during the unfolding of the TTR monomer by stabilizing the interaction between ß-strands A and D and the quasi-helical structure in the DE loop. We propose that introducing hydrogen bonds to connect the N-terminal region to the DE loop reduces the amyloidogenic potential of TTR by stabilizing the monomer.

[A Case of Cecum Cancer with Lymph Node Metastasis and Invasion in the Superior Mesenteric Vein Treated with Combined SMV Resection and Reconstruction].

The patient was a 77-year-old woman. She visited her family doctor with a complaint of bloody stools, and was pointed out a Type 3 colon cancer in the cecum with a colonoscopy. In addition, an enlarged lymph node(#203)was found on the right side of the superior mesenteric vein(SMV). Laparoscopic surgery was initiated, and when the patient was moved to vascular processing, a firm adhesion of the lymph node(#203)was observed on the right side of the SMV. A small laparotomy was added, and a partial combined resection of the SMV was performed en bloc to complete the ileal resection. Histopathological findings showed T4b(transverse colon)N3M0, pStage Ⅲc, and metastatic lymph node(#203)showed evidence of invasion to the SMV. Adjuvant chemotherapy was administered, but lung metastases appeared 4 months and liver metastasis appeared 29 months after surgery. The patient was transferred to a different hospital for best supportive care(BSC)at 34 months after surgery.

A gain-of-function mutation in microRNA 142 is sufficient to cause the development of T-cell leukemia in mice.

MicroRNAs (miRNAs) play a crucial role in regulating gene expression. MicroRNA expression levels fluctuate, and point mutations and methylation occur in cancer cells; however, to date, there have been no reports of carcinogenic point mutations in miRNAs. MicroRNA 142 (miR-142) is frequently mutated in patients with follicular lymphoma, diffuse large B-cell lymphoma, chronic lymphocytic leukemia (CLL), and acute myeloid leukemia/myelodysplastic syndrome (AML/MDS). To understand the role of miR-142 mutation in blood cancers, the CRISPR-Cas9 system was utilized to successfully generate miR-142-55A>G mutant knock-in (Ki) mice, simulating the most frequent mutation in patients with miR-142 mutated AML/MDS. Bone marrow cells from miR-142 mutant heterozygous Ki mice were transplanted, and we found that the miR-142 mutant/wild-type cells were sufficient for the development of CD8+ T-cell leukemia in mice post-transplantation. RNA-sequencing analysis in hematopoietic stem/progenitor cells and CD8+ T-cells revealed that miR-142-Ki/+ cells had increased expression of the mTORC1 activator, a potential target of wild-type miR-142-3p. Notably, the expression of genes involved in apoptosis, differentiation, and the inhibition of the Akt-mTOR pathway was suppressed in miR-142-55A>G heterozygous cells, indicating that these genes are repressed by the mutant miR-142-3p. Thus, in addition to the loss of function due to the halving of wild-type miR-142-3p alleles, mutated miR-142-3p gained the function to suppress the expression of distinct target genes, sufficient to cause leukemogenesis in mice.

Examination of colorectal cancer cases with metal allergy.

PURPOSE: To report our initiatives and treatment results for patients with colorectal cancer with metal allergy. METHODS: A total of 27 patients (2.6%) with a history of metal contact dermatitis were identified among 1027 patients who underwent curative resection of colorectal cancer from 2014 to 2020. The results of the patch test, perioperative results, and postoperative colonoscopy findings were also investigated. RESULTS: The patch test for metal allergens and staples was performed in 21 patients (77.8%), and 13 of them (61.9%) tested positive for at least one metal allergen. Ni (38.1%), Co (28.6%), and Pd (19.0%) showed higher positive rates than other metals, and 1 patient (4.8%) tested positive for staples. Stapled anastomosis/suturing was performed as planned in 15 of 27 patients. In 10 patients, the anastomosis method was changed from stapled to hand-sewn according to the no-patch test results (60%), positivity for multiple metals (20%), positivity for staples (10%), and surgeon's judgment (10%). No complications and abnormal colonoscopy findings were found to be associated with stapled anastomosis/suturing. CONCLUSION: The patch test is useful for selecting an optimal anastomosis method for patients with suspected metal allergy.

Local recurrence of submucosal invasive colorectal cancer after endoscopic submucosal dissection revealed by copy number variation.

We report a case in which analysis of copy number variation revealed local recurrence of submucosal invasive colorectal cancer after curative endoscopic submucosal dissection (ESD). An 86-year-old man with a history of abdominoperineal resection of the rectum for rectal cancer underwent resection with ESD for early-stage sigmoid cancer 5 cm away from the stoma opening. At the same time, ileocecal resection was performed for advanced cecal cancer. Twelve months after ESD, advanced cancer occurred in the area of the ESD lesion. It was unclear if the cancer was a local recurrence after ESD, implantation of cecal cancer, or a new lesion. Copy number variation analysis performed for the three lesions revealed that the new lesion originated from residual tumor cells from ESD and was unlikely to be cecal cancer.

Benefits and risks of diverting stoma creation during rectal cancer surgery.

Purpose: A consensus has been reached regarding diverting stoma (DS) construction in rectal cancer surgery to avoid reoperation related to anastomotic leakage. However, the incidence of stoma-related complications (SRCs) remains high. In this study, we examined the perioperative outcomes of DS construction in patients who underwent sphincter-preserving surgery for rectal cancer. Methods: We included 400 participants who underwent radical sphincter-preserving surgery for rectal cancer between 2005 and 2017. These participants were divided into the DS (+) and DS (-) groups, and the outcomes, including postoperative complications, were compared. Results: The incidence of ileus was higher in the DS (+) group than in the DS (-) group (P<0.01); however, no patients in the DS (+) group showed grade 3 anastomotic leakage. Furthermore, early SRCs were observed in 33 patients (21.6%) and bowel obstruction-related stoma outlet syndrome occurred in 19 patients (12.4%). There was no significant intergroup difference in the incidence of grade 3b postoperative complications. However, the most common reason for reoperation was different in the 2 groups: anastomotic leakage in 91.7% of patients with grade 3b postoperative complications in the DS (-) group, and SRCs in 85.7% of patients with grade 3b postoperative complications in the DS (+) group. Conclusion: Patients with DS showed higher incidence rates of overall postoperative complications, severe postoperative complications (grade 3), and bowel obstruction, including stoma outlet syndrome, than patients without DS. Therefore, it is important to construct an appropriate DS to avoid SRCs and to be more selective in assigning patients for DS construction.

[Management of a perforated duodenal diverticulum using an endoscopic nasobiliary drainage tube:a case report].

A man in his 70s visited our hospital for abdominal pain. Upon admission, abdominal computed tomography findings suggested a duodenal diverticular perforation. Upper gastrointestinal endoscopy revealed an incarcerated enterolith in the periampullary diverticulum. We achieved conservative management by inserting an endoscopic nasobiliary drainage tube into the duodenal diverticulum to aid drainage. The patient was discharged without serious complications 35 days after admission. We report a case of duodenal diverticular perforation with an incarcerated enterolith managed conservatively using endoscopic therapy.

CHFR-Promoter-Methylation Status Is Predictive of Response to Irinotecan-based Systemic Chemotherapy in Advanced Colorectal Cancer.

BACKGROUND/AIM: We investigated whether promoter methylation of the checkpoint-with-forkhead-and-ring-finger-domains (CHFR) gene is a predictor of the efficacy of irinotecan-based systemic chemotherapy for advanced colorectal cancer (CRC) patients. MATERIALS AND METHODS: CHFR-promoter methylation was measured by quantitative methylation-specific PCR (qMSP). The histoculture drug response assay (HDRA) was used in vitro to analyze the correlation between CHFR-promoter methylation and the efficacy of the irinotecan-active-metabolite SN38 in colorectal-cancer tissues from 44 CRC patients. CHFR promoter-methylation was also analyzed for its correlation with clinical response to irinotecan-based systemic chemotherapy of 49 CRC patients. RESULTS: CHFR-promoter methylation significantly-positively correlated with inhibition of colon cancer by SN38 in the HDRA (p=0.002). CHFR-promoter methylation also significantly-positively correlated with clinical response to irinotecan-based systemic chemotherapy (p=0.04 for disease control). CHFR-promoter methylation also significantly-positively correlated (p=0.01) with increased progression-free survival for patients treated with irinotecan-containing FLOFIRI in combination with bevacizumab, the most-frequent regimen in the cohort. CONCLUSION: Sensitivity of advanced CRC patients to irinotecan-based systemic chemotherapy can be predicted by the extent of CHFR-promoter methylation.

A case of simultaneous abdominal wall metastasis of hepatocellular carcinoma with long-term relapse-free survival after laparoscopic resection.

We report our experience of an extremely rare case of a simultaneous extrahepatic metastasis of hepatocellular carcinoma (HCC) with long-term relapse-free survival, treated by laparoscopic resection of an abdominal wall tumor and subsequent radiofrequency ablation (RFA) of an intrahepatic lesion. A 76-year-old man visited a local clinic for right lower abdominal pain. He was treated with antibiotics and the symptom resolved. However, a mass was detected in the same region and he was referred to our hospital for further evaluation. Computed tomography (CT) of the abdomen showed a mass 5 cm in diameter, raising suspicions of an intra-abdominal tumor. Laparoscopic surgery was performed, and the tumor was found in the abdominal wall and completely resected. Histopathological examination yielded a diagnosis of extrahepatic HCC. Post-operative positron emission tomography (PET)-CT showed increased uptake of fluorodeoxyglucose in segment 3 (S3) of the liver. On performing a liver biopsy, HCC was diagnosed. Subsequently, the S3 lesion was treated with radiofrequency ablation. The patient has remained relapse-free for 6 years without further treatments.

Laparoscopic Surgery Is Acceptable for Elderly Patients With Colorectal Cancer: A Propensity Score-matched Study.

BACKGROUND/AIM: The study was performed to examine the suitability of laparoscopic surgery for elderly patients with colorectal cancer. PATIENTS AND METHODS: The subjects were 242 patients aged ≥80 years who underwent primary tumor resection of colorectal cancer using laparoscopic assisted colectomy (LAC, n=145) or open colectomy (OC, n=97). Propensity score matching used to balance the characteristics of the groups resulted in 76 patients being assigned to each group. RESULTS: Before matching, Glasgow Prognostic Score (GPS), American Society of Anesthesiologists physical status (ASA-PS), and previous abdominal surgery differed significantly between the groups (p<0.05), but after matching, all covariates were balanced (p≥0.05). Short-term outcomes were better after LAC (p<0.05), including fewer postoperative complications and less delirium. Regarding long-term outcomes, 5-year overall survival did not differ significantly between the groups (p=0.91). CONCLUSION: In elderly patients with colorectal cancer, short-term results are better after LAC than OC and long-term results are similar. These findings indicate that LAC is acceptable in this patient population.

Rectal metastasis from bladder urothelial carcinoma: a case report.

BACKGROUND: Urothelial carcinoma arises from transitional cells in the urothelial tract. In advanced cases, it can metastasize locally to surrounding organs or distally to organs such as the lungs, bones, or liver. Here we describe a case of rectal metastasis from urothelial carcinoma treated with multiple sessions of transurethral resection of bladder tumor (TURBT). CASE PRESENTATION: A 72-year-old woman presented to our department with abdominal bloating andobstructed defecation. She had undergone two sessions of TURBT for early urothelial carcinoma in another hospital at 64 and 65 months ago, respectively. Cystoscopy at 3 months after the second TURBT session had indicated disease recurrence, and thus, she had been referred to our hospital for further examination, followed by TURBT for the third time at 59 months ago and for the fourth time at 48 months ago; thereafter, she had been followed up with cystoscopy every 6 months without any recurrence. However, she returned to our hospital, complaining of difficult defecation. Subsequent colonoscopy demonstrated an obstructive tumor in the rectum, which was pathologically diagnosed as metastatic urothelial carcinoma of the bladder. Laparoscopic examination revealed two small areas of peritoneal dissemination in the pelvis. A sigmoid colostomy was performed without rectal tumor resection. She has been receiving chemotherapy and is still alive 10 months after surgery. CONCLUSIONS: Rectal metastasis is a rare site of metastasis for urothelial carcinomas. It is important to consider the possibility of annular rectal constriction caused by infiltrating or metastasizing urothelial carcinoma when managing patients with urothelial carcinoma and with difficult defecation.

Colorectal Perforation in Patients with Connective Tissue Disease.

PURPOSE: The goal of this retrospective study was to identify prognostic factors associated with mortality after surgery for colorectal perforation among patients with connective tissue disease (CTD) and to review postoperative outcomes based on these prognostic factors. METHODS: The subjects were 105 patients (CTD group: n=26, 24.8%; non-CTD group: n=79, 75.2%) who underwent surgery for colorectal perforation at our department. Cases with iatrogenic perforation due to colonoscopic examination were excluded from the study. We retrospectively investigated perioperative clinicopathological factors in patients undergoing surgery for colorectal perforation. RESULTS: There were 7 patients (6.7%) who died within 28 days after surgery in all patients. In multivariate analysis, CTD and fecal peritonitis emerged as significant independent prognostic factors (p=0.005, odds ratio=12.39; p=0.04, odds ratio=7.10, respectively). There were 5 patients (19.2%) who died within 28 days after surgery in the CTD group. In multivariate analysis, fecal peritonitis emerged as a significant independent prognostic factor in the CTD group (p=0.03, odds ratio=31.96). The cumulative survival curve in the CTD group was significantly worse than that in the non-CTD group (p=0.006). An analysis based on the presence of fecal peritonitis indicated no significant difference in cumulative survival curves for patients without fecal peritonitis in the CTD and non-CTD groups (p=0.55) but a significant difference in these curves for patients with fecal peritonitis in the two groups (p<0.0001). CONCLUSIONS: This study demonstrated that cumulative survival in patients with CTD is significantly worse than that in patients without CTD after surgery for colorectal perforation.

[A Case of Systemic Chemotherapy Combined with Molecular Drug Treatment Following Biliary Stent Implantation for Obstructive Jaundice Due to Metastases of Liver Gland Lymph Node after Colorectal Cancer Surgery].

We report a case of systemic chemotherapy after biliary stent placement for obstructive jaundice due to hepatic portal lymph node metastasis after colorectal cancer surgery. The patient was a 40s woman. Laparoscopic anterior resection for rectosigmoidRS cancer was performed. The pathological diagnosis was T3N0M0PUL0R0, pStage Ⅱ according to the 8th edition of colorectal cancer handling regulations. Because multiple liver metastases were observed 8 months after the surgery, partial resection of the posterior region of the liver was performed. Multiple lung metastases were observed 1 year after hepatectomy, but she wantedto undergo follow-up observation. Jaundice was observed 1 year after the diagnosis of lung metastasis, and obstructive jaundice due to hepatic portal lymph node metastasis was diagnosed. Endoscopic retrograde biliary drainage(ERBD)was performed, and a bile duct stent was placed. After improving jaundice, 12 courses of mFOLFOX6 plus cetuximab therapy were performed. Currently, because of the exacerbation of lung metastasis, FOLFIRI plus bevacizumab therapy is being administered. Systemic chemotherapy containing a molecular-targeted drug is being administered in our case, but complications relatedto the biliary stent have not been observed. There are few reports on similar cases, andfollow - up observation with careful attention to long-term safety is necessary.

The Association between Absence of Abdominal Pain and Mortality in Lower Intestinal Perforation in Patients with Autoimmune Rheumatic Diseases.

OBJECTIVE: To determine mortality and predictive factors for lower intestinal perforation (LIP) among patients with autoimmune rheumatic diseases. METHODS: This retrospective, single-center, observational study analyzed mortality rates in 31 autoimmune rheumatic disease patients with LIP who were admitted to our hospital from January 2002 to June 2017. The primary outcome was the mortality rate during hospitalization. RESULTS: The median age at the time of LIP was 61 years, and the survival rate at discharge was 64.5%. Eleven patients died of sepsis during hospitalization. Cox univariable analysis for mortality during hospitalization showed that absence of abdominal pain (hazard ratio (HR) 5.61, 95% confidence interval (CI) 1.38-22.9), higher age (HR 1.06, 95% CI 1.01-1.11), chronic kidney disease (HR 6.89, 95% CI 1.85-25.7), systemic vasculitis (HR 3.95, 95% CI 1.14-13.6), higher blood urea nitrogen (HR 1.02, 95% CI 1.01-1.04), higher serum creatinine (HR 1.41, 95% CI 1.06-1.87), and LIP due to malignancy (HR 14.3, 95% CI 1.95-105.1) significantly increased mortality. CONCLUSION: Abdominal pain was absent in 16% of LIP patients with autoimmune rheumatic diseases, and this absence was a poor prognostic factor in this cohort. Moreover, higher age, chronic kidney disease, systemic vasculitis, and LIP due to malignancy were associated with significantly increased mortality. Physicians should be aware of LIP in autoimmune disease patients with higher age, chronic kidney diseases, or systemic vasculitis even if patients reveal mild abdominal symptoms.

Recommendation of long-term and systemic management according to the risk factors in rectal NETs patients.

Rectal neuroendocrine tumors (NETs) are often found as small lesions, which can be treated by endoscopic resection. However, high risk cases with lymph node (LN) metastasis are indication of radical surgery. Furthermore, rectal NETs are often associated with late recurrences and/or multiple cancer development. Therefore, proper surgical indication and patients' management are required. We investigated the clinicopathological features of 79 rectal NET cases in order to elucidate risk factors for synchronous LN metastasis, recurrence, and multiple cancers. Recently, we reported that in pancreatic NET patients, a loss of heterozygosity (LOH) in PHLDA3 was associated with poorer prognosis, and that LOH of both PHLDA3 and MEN1 was frequently observed. Therefore, PHLDA3 and MEN1 LOH were also assessed in rectal NET patients for their association with clinicopathological features. Of the 79 patients, LN metastases were found in 12.7%, recurrences in 3.8%, and multiple cancers in 30.4% of the subjects. PHLDA3 and MEN1 LOH were found in 60.0% and 66.7% of the subjects, respectively. Lymphatic invasion and WHO classification 2010 were found to be independent risks for LN metastasis. There were three cases of recurrence, all of which occurred more than 3 years after resection and two of which exhibited LN metastasis. Older age and LOH in PHLDA3 were associated with the presence of multiple cancers. Long-term and systemic management of patients with rectal NETs is therefore recommended in accordance with these risk factors.

Serum oxidative stress is an independent prognostic marker in colorectal cancer.

BACKGROUND: Few previous studies have investigated the relationship between serum oxidative stress and the status of patients with colorectal cancer. Our aim in the current study was to investigate the significance of serum oxidative stress as a prognostic marker in these patients. METHODS: The subjects were 53 patients who underwent curative resection of high-risk stage II or stage III colorectal cancer. The correlation of serum oxidative stress (Reactive Oxygen Metabolites Test: d-ROMs Test) with recurrence-free survival was examined. RESULTS: There were no significant differences in d-ROMs between the recurrence and non-recurrence groups at four time points (0M: before the start of postoperative adjuvant chemotherapy; and 1M: 1 month; 3M: 3 months; and 6M: 6 months after the start of postoperative adjuvant chemotherapy). Only the 3M/0M d-ROMs (the value at 3M relative to the value at 0M) was increased compared with the other time points in the recurrence group, as well as with all time points in the non-recurrence group. In univariate analysis, there were significant differences in recurrence-free survival with respect to N classification (P=0.004) and 3M/0M d-ROMs (P=0.002). In multivariate analysis, both N classification and serum oxidative stress were found to be significant independent prognostic factors (P=0.02, HR=4.49; P=0.02, HR=5.61, respectively). CONCLUSIONS: The results of this study demonstrate the prognostic value of serum oxidative stress in colorectal cancer.

Effects of Receptor for Advanced Glycation End-Products (RAGE) Signaling on Intestinal Ischemic Damage in Mice.

OBJECTIVE: Superior mesenteric artery ischemia and nonocclusive mesenteric ischemia are representative diseases of the vascular emergency known as irreversible transmural intestinal necrosis (ITIN). The receptor for advanced glycation end-products (RAGE) belongs to the immunoglobulin superfamily of extracellular ligands, which also includes high-mobility group box 1 (HMGB-1) and proteins of the S100 family. The HMGB-1 ligands have been implicated in the pathogenesis of various inflammatory disorders. This study was designed to investigate the relation between RAGE and ITIN in a murine acute intestinal ischemic model. MATERIALS AND METHODS: ITIN was induced by clipping the cranial mesenteric artery and the peripheral blood vessels. Mucosal and blood samples were collected and analyzed by reverse-transcription PCR and immunohistochemistry for mucosal inflammation and levels of RAGE-related proteins. The influence of RAGE signaling on intestinal cell reproduction was investigated using the cell scratch test, an in vitro wound-healing assay. Finally, RAGE-related proteins and their respective inhibitors were administered intraperitoneally to ITIN model mice to determine their effects. RESULTS: RAGE-expressing cells were located at the base of the intestinal crypts at day 0. As ITIN progressed, most of the damaged intestinal cells expressed RAGE, and ligands of RAGE such as HMGB-1, S100 A8/A9, and S100ß were present in the crypt cells from the bottom to the top. The quantities of S100 A8/A9 and S100ß were particularly high, above the levels found in other diseases. When S100 A8/A9 and S100ß were applied to small intestinal epithelial cells in vitro, regeneration was significantly impeded. Inflammatory Gr1+ neutrophils and F4/80+ macrophages are involved in tissue ischemia. S100 A8/A9 enhances inflammatory myeloid cell influx. CONCLUSIONS: RAGE-related proteins are elevated in ITIN model mice and impede intestinal regeneration in vitro. RAGE-related proteins may be a new therapeutic target or a new marker for ITIN.

Endoscopic Submucosal Dissection Decreases Additional Colorectal Resection for T1 Colorectal Cancer.

BACKGROUND There are 3 methods of treating T1 colorectal cancer (T1 CRC), which include endoscopic resection, endoscopic resection followed by additional colorectal resection, and surgical resection. In this retrospective study, changes in the management of T1 CRC after introduction of endoscopic submucosal dissection (ESD) were investigated by comparison with the 10-year period before introduction of ESD. MATERIAL AND METHODS During a 20-year period from 1996 to 2015, 835 patients with T1 CRC were treated, including 331 patients before introduction of ESD (Group A) and 504 patients after introduction of ESD (Group B). Clinicopathological findings and treatment methods were compared between these 2 groups. RESULTS As the initial treatment, endoscopic treatment was performed in 185 patients (55.9%) in Group A and 288 (57.1%) in Group B. In Group B, ESD was performed in 161 patients (55.9%), accounting for more than half of the T1 CRC patients receiving endoscopic treatment. In Groups A and B, observation after endoscopic resection was selected for 54.2% and 67.3% of T1a patients, respectively (p=0.04). A similar trend was noted for T1b patients, and there was no significant difference of the treatment approach. Among all T1 CRC patients, the percentage undergoing observation after endoscopic resection was significantly higher in Group B than in Group A (34.3% vs. 26.9%, p=0.02), and the percentage of patients undergoing additional colorectal resection was significantly lower in Group B (22.8% vs. 29.0%, p=0.04). CONCLUSIONS After introduction of ESD, it was performed in more than half of all patients with T1 CRC undergoing endoscopic treatment. The percentage of patients undergoing observation following endoscopic resection of T1 CRC increased after introduction of ESD.

Characterization of Non-amyloidogenic G101S Transthyretin.

Transthyretin (TTR) is a tetrameric beta-sheet-rich protein that is important in the plasma transport of thyroxine and retinol. Mutations in the TTR gene cause TTR tetramer protein to dissociate to monomer, which is the rate-limiting step in familial amyloid polyneuropathy. Amyloidogenicity of individual TTR variants depends on the types of mutation that induce significant changes in biophysical, biochemical and/or biological properties. G101S TTR variant was previously identified in a Japanese male without amyloidotic symptom, and was considered as a non-amyloidogenic TTR variant. However, little is known about G101S TTR. Here, we found slight but possibly important biophysical differences between wild-type (WT) and G101S TTR. G101S TTR had slower rate of tetramer dissociation and lower propensity for amyloid fibril formation, especially at mild low pH (4.2 and 4.5), and was likely to have strong hydrophobic interaction among TTR monomers, suggesting relatively higher stability of G101S TTR compared with WT TTR. Cycloheximide (CHX)-based assay in HEK293 cells revealed that intracellular G101S TTR expression level was lower, but extracellular expression was higher than WT TTR, implying enhanced secretion efficiency of G101S TTR protein compared with WT TTR. Moreover, we found that STT3B-dependent posttranslational N-glycosylation at N98 residue occurred in G101S TTR but not in other TTR variants, possibly due to amino acid alterations that increase N-glycosylation preference or accelerate rigid structure formation susceptible to N-glycosylation. Taken together, our study characterizes G101S TTR as a stable and N-glycosylable TTR, which may be linked to its non-amyloidogenic characteristic.