Changes in characteristics of gastroenterology center inpatients in Japan because of rapidly aging society.

BACKGROUND AND AIM: Rapidly aging societies have become a major issue worldwide including Japan. This study aimed to elucidate relative changes in the characteristics of inpatients in Japan related to this issue. METHODS: A total of 23 835 Japanese inpatients treated from 2010 to 2021 were enrolled (2010-2013, period I; 2014-2017, period II; 2018-2021, period III). Changes in clinical features were retrospectively analyzed based on ICD-10 diagnosis data. RESULTS: The percentage of patients aged over 75 years increased over time (period I, 38.0%; II, 39.5%, III, 41.4%). Emergency admissions comprised 27.5% of all in period I, which increased to 43.2% in period II and again to 44.5% in period III (P < 0.001). In period I, gastrointestinal disease, liver disease, pancreatic-biliary disease, and other disease types were noted in 47.4%, 29.5%, 19.2%, and 3.9%, respectively, while those values were 44.0%, 18.0%, 33.9%, and 4.1%, respectively, in period III (P < 0.001). The frequency of liver disease decreased by approximately 0.6-fold from periods I to III, while that of biliary-pancreatic disease increased by approximately 1.8-fold during that time. Both percentage and actual numbers of patients with biliary-pancreatic disease increased during the examined periods. Analysis of changes in the proportion of organs affected by malignancy during periods I, II, and III showed a marked increase in cases of biliary-pancreatic malignancy (11.6%, 19.5%, 26.6%, respectively) (P < 0.001). CONCLUSION: In association with the rapidly aging Japanese society, there has been an increasing frequency of biliary-pancreatic disease cases requiring hospitalization for treatment in the west Japan region of Shikoku.

Clinical features of patients with hepatocellular carcinoma treated with radiofrequency ablation therapy: developing a simple score to determine the need for immune-adjuvant therapy.

BACKGROUND/AIM: Unresectable recurrence after curative treatments for hepatocellular carcinoma (HCC) is a life-limited event. Although the IMbrave050 trial (IM050) showed a favorable reduction in recurrence with adjuvant immune-combination chemotherapy, inclusion criteria of the radiofrequency ablation (RFA) group were lower risk than that of the resection group. This study aimed to elucidate the clinical features of patients treated with RFA, which really need adjuvant-chemotherapy. METHODS: From 2000 to 2022, 528 patients with Child-Pugh A and HCC within the Milan criteria (MC), who met the IM050 criteria for RFA and undergone resection or RFA, were enrolled (71 years, HCV:HBV:HBV/HCV:alcohol:others = 337:44:5:53:89, multi-tumor = 138, RFA:resection = 309:219). Unresectable recurrence was defined as beyond the MC. Risk factors for recurrence beyond the MC were retrospectively evaluated. RESULTS: Multivariate Cox-hazard analysis showed HCV-positive (HR 1.49), AFP-L3 > 10% (HR 1.75), and DCP > 100 mAU/mL (HR1.80) as significant prognostic factors for recurrence beyond the MC (each P < 0.05). Summing of positive factors (1 point for each) was used for scoring (AD-ON score), which showed increased positive rates for micro-hepatic vein invasion (score 0:1:2:3 = 0%:1.1%:6.6%:15.8%), micro-portal vein invasion (0:1:2:3 = 2.0%:12.1%:14.1%:31.6%), and poor differentiation (0:1:2:3 = 6.0%:6.7%:15.3%:15.8%) in the resection group associated with a greater score (each P < 0.01). In patients treated with RFA, those with greater AD-ON scores showed shorter time to recurrence beyond the MC, recurrence-free time, and overall survival (score 0:1:2:3 = no-estimation:97:66:23 months, 35:27:20:12 months, and 91:82:67:52 months, respectively, each P < 0.05). CONCLUSION: HCC patients treated by RFA and with a high AD-ON score (≧2) should be considered for aggressive adjuvant-chemotherapy to prolong the period of recurrence beyond the MC.

Short- and long-term outcomes of laparoscopic radical gallbladder resection for gallbladder carcinoma: A multi-institutional retrospective study in Japan.

BACKGROUND/PURPOSE: Laparoscopic resection of gallbladder carcinomas remains controversial. This study aimed to evaluate the surgical and oncological outcomes of laparoscopic procedures for suspected gallbladder carcinoma (GBC). METHODS: In this retrospective study, data regarding suspected GBC treated with laparoscopic radical cholecystectomy before 2020 in Japan, was included. Patient characteristics, surgical procedure details, surgical outcomes, and long-term outcomes were analyzed. RESULTS: Data of 129 patients with suspected GBC who underwent laparoscopic radical cholecystectomy were retrospectively collected from 11 institutions in Japan. Among them, 82 patients with pathological GBC were included in the study. Laparoscopic gallbladder bed resection was performed in 114 patients and laparoscopic resection of segments IVb and V was performed in 15 patients. The median operation time was 269 min (range: 83-725 min), and the median intraoperative blood loss was 30 mL (range: 0-950 mL). The conversion and postoperative complication rates were 8% and 2%, respectively. During the follow-up period, the 5-year overall survival rate was 79% and the 5-year disease-free survival rate was 87%. Recurrence was detected in the liver, lymph nodes, and other local tissues. CONCLUSION: Laparoscopic radical cholecystectomy is a treatment option with potential favorable outcomes in selected patients with suspected GBC.

Propensity score-matched analysis of the short-term outcomes of robotic versus laparoscopic surgery for rectal cancer.

PURPOSE: The advantages of robot-assisted rectal surgery (RARS) over conventional laparoscope-assisted rectal surgery (LARS) remain controversial. This study was performed to compare the short-term outcomes of RARS and LARS. METHODS: We retrospectively analyzed data of 207 patients who had undergone either RARS (n = 97) or LARS (n = 110) for rectal cancer (RC) from 2018 to 2020. A 1:1 matched propensity score-matched analysis was performed and the surgical outcomes of the two groups compared. RESULTS: After matching, a well-balanced cohort of 136 patients was analyzed (n = 68 in each group), and there was no significant difference in the median operative time. The RARS group had less intraoperative blood loss than the LARS group. There were no significant differences in length of postoperative hospital stay or complication rate between the two groups. In the subgroup of lower RC, defined as the inferior edge of the tumor being within the rectum distal to the peritoneal reflection, the rate of sphincter preservation was higher in the RARS group (81.8% vs. 44.4%, p = 0.021). CONCLUSION: This study shows that RARS is a safe and feasible approach for RC compared with LARS, RARS having the advantage of more often preserving the sphincter.

Anatomical Study of the Duodenojejunal Uncinate Process Vein: A Key Landmark for Mesopancreatoduodenal Resection During Pancreaticoduodenectomy.

Background: The mesopancreas or mesopancreatoduodenum is an important anatomical concept during pancreaticoduodenectomy (PD) in patients with periampullary carcinoma. This study investigated whether the duodenojejunal uncinate process vein (DJUV), which is defined as the vein draining from the upper jejunum to the superior mesenteric vein adjacent to the uncinate process, is a useful anatomical landmark for the caudal border of mesopancreatoduodenum resection during PD. Methods: This study enrolled 100 adult patients with hepatobiliary pancreatic disease who underwent preoperative multidetector-computed tomography (CT). The anatomy of the key blood vessels involved during PD, and the relationship between these vessels and the DJUV, were analyzed by preoperative CT. Results: The first jejunal vein was the DJUV in 85 cases, whereas the second jejunal vein was the DJUV in 15 cases. Furthermore, the DJUV was classified into two subtypes depending on its positional relationship with the superior mesenteric artery (SMA). The inferior pancreaticoduodenal artery and vein were located on the cranial side of the DJUV in all cases. The distance between the middle colonic artery, used as a guide for regional lymph nodes, and the point where the DJUV intersected the SMA was within 10 mm in 80% of cases. These results imply that using the DJUV as a landmark for the caudal border of the mesopancreatoduodenum provides a safe approach and enables sufficient dissection of regional lymph nodes and tissues around the SMA. Conclusion: The DJUV may be a useful anatomical landmark for the caudal border of the mesopancreatoduodenum resection during PD.

Clinical Usefulness of Surgical Resection Including the Complementary Use of Radiofrequency Ablation for Intermediate-Stage Hepatocellular Carcinoma.

Background/Aim: For intermediate-stage hepatocellular carcinoma (HCC) (Barcelona Clinic Liver Cancer [BCLC]-B) cases, transarterial chemoembolization (TACE) is recognized as the standard treatment, while systemic therapy is recommended for TACE-unsuitable HCC. However, because the curative potential is not high, this study was conducted to elucidate the potential outcomes of surgical resection (SR) for BCLC-B HCC cases. Materials/Methods: From January 2000 to July 2022, 70 patients with BCLC-B HCC treated with surgery as the initial treatment were enrolled (median age 67.5 years, beyond up-to-7 criteria 44). Forty-five were treated with SR only (SR group), while twenty-five underwent that with complemental radiofrequency ablation (RFA) (Comb group). Recurrence-free survival (RFS) and overall survival (OS) were retrospectively evaluated in both groups. Results: The median albumin−bilirubin (ALBI) score was better in the SR as compared with the Comb group (−2.74 vs. −2.52, p = 0.02), while there were no significant differences between them for median RFS (17.7 vs. 13.1 months; p = 0.70) or median OS (66.6 vs. 72.0 months p = 0.54). As for those beyond up-to-7 criteria, there were no significant differences for median RFS (18.2 vs. 13.0 months; p = 0.36) or median OS (66.5 vs. 72.0 months; p = 0.57). An acceptable five-year cumulative survival rate (>50%) was obtained in both groups (54% vs. 64%). Conclusion: This retrospective study found no significant differences for RFS or OS between the present SR and Comb groups with BCLC-B HCC. When possible to perform, the outcome of SR for BCLC-B is favorable, with a five-year survival rate greater than 50%.

IgG4-related gastric disease with plasma cell-rich obliterative arteritis accompanied by early-stage gastric cancer: a case report.

BACKGROUND: Immunoglobulin G4-related disease (IgG4-RD) is an immune-mediated inflammatory disorder that can involve multiple organs. It is characterized by IgG4-positive plasma cell-rich storiform fibrosis and obliterative phlebitis associated with a high serum IgG4 level. There are few reports of gastric IgG4-RD, especially those detected prior to systemic or other organ involvement. CASE PRESENTATION: A 70-year-old man was diagnosed with type 0-IIc gastric cancer at the anterior wall of the gastric corpus by upper gastrointestinal endoscopy. In addition, a submucosal tumor (SMT) 7 mm in diameter was found at the greater curvature of the angulus. Laparoscopic distal gastrectomy with regional lymph node dissection was performed. Pathology revealed a poorly differentiated adenocarcinoma in the type 0-IIc lesion and storiform fibrosis with infiltration of a large number of IgG4-positive plasma cells in the SMT. Postoperative laboratory testing showed elevation of serum IgG4 levels; thus, we diagnosed the SMT as IgG4-RD. Intriguingly, the gastric IgG4-RD lesion demonstrated IgG4-positive plasma cell-rich arteritis as well as typical obstructive phlebitis. The patient has been followed for 2 years after surgery without recurrence of cancer, but skin lesions of IgG4-RD have appeared. CONCLUSION: We report a rare case of IgG4-RD presenting as a gastric SMT, accompanied by early-stage gastric cancer. Our case may support a newly proposed relationship between IgG4-RD and malignancies. The gastric IgG4-RD lesion showed arteritis as well as obliterative phlebitis, potentially providing novel insight into IgG4-related vascular lesions.

Neutrophil to Lymphocyte Ratio is a Predictive Factor of Malignant Potential for Intraductal Papillary Mucinous Neoplasms of the pancreas.

Intraductal papillary mucinous neoplasms (IPMNs) are cystic neoplasms with the potential for progression to pancreatic cancer. Accurate prediction of the malignant potential is challenging and a proper treatment strategy has not been well established. Preoperative neutrophil-to-lymphocyte ratio (NLR) is a biomarker of the malignant potential in patients with several types of malignancy. We explored malignant potential in patients with IPMN. The present study included 56 patients aged of 73 ± 9 years (mean ± standard deviation) who underwent curative resection for IPMN from 1996 to 2017. We analyzed the relationship between the characteristics including NLR and malignant component for predicting pathological results. The nonmalignant IPMN group (N = 21) included patients with low-grade dysplasia (LGD) and intermediate-grade dysplasia (IGD), and the malignant IPMN group (N = 35) included patients with high-grade dysplasia (HGD) and invasive carcinoma. In a univariate analysis, NLR ⩾ 2.2 (P = .001), prognostic nutritional index (PNI) < 45 (P = .016), CA 19-9 > 37 U/mL (P = .039), and cystic diameter ⩾ 30 mm (P = .010), and mural nodule (P = .010) were significantly different between the malignant IPMN and the nonmalignant IPMN groups. Multivariate analysis showed that high NLR (⩾2.2) (odds ratio 9.79; 95% confidence interval: 2.06-45.6), cystic diameter ⩾ 30 mm (4.65; 1.14-18.9), and mural nodule (4.91; 1.20-20.1) were independently predictive of malignant IPMN. These results suggest that preoperative NLR is a useful predictive biomarker for evaluating malignant potential in patients with IPMN.1.

ß-Hemolytic Streptococcus anginosus subsp. anginosus causes streptolysin S-dependent cytotoxicity to human cell culture lines in vitro.

Background: Streptococcus anginosus subsp. anginosus (SAA) is one of the opportunistic pathogens in humans that inhabits the oral cavity. The type strain of SAA, NCTC10713T, showed clear ß-hemolysis on blood agar plates, and the sole ß-hemolytic factor revealed two streptolysin S (SLS) molecules. SLS is well known as the peptide hemolysin produced from the human pathogen S. pyogenes and shows not only hemolytic activity on erythrocytes but also cytotoxic activity in cell culture lines in vitro and in vivo, such as in a mouse infection model. However, no cytotoxic activity of SLS produced from ß-hemolytic SAA (ß-SAA) has been reported so far. Objective and Design: In this study, the SLS-dependent cytotoxicity of the ß-SAA strains including the genetically modified strains was investigated in vitro. Results: The SLS-producing ß-SAA showed cytotoxicity in human cell culture lines under the co-cultivation condition and it was found that this cytotoxicity was caused by the SLS secreted into the extracellular milieu. Conclusion: The results from this study suggest that the SLS produced from ß-SAA might indicate the cytotoxic potential similar to that of the SLS from S. pyogenes and the SLS-producing ß-SAA would be recognized as "a wolf in sheep's clothing" More attention will be paid to the pathogenicity of ß-hemolytic Anginosus group streptococci.

Evolutionary Changes in Sensitivity to Hormonally Induced Gonadal Sex Reversal in a Frog Species.

The Japanese frog Glandirana rugosa is unique in that it shows geographic variation in sex chromosome differentiation and heterogametic sex determination. To elucidate the cause of interpopulation differences in gonadal sex differentiation, we investigated hormonally induced sex reversal and the expression patterns of genes associated with sex determination during early tadpole development. We found that sex reversal was easily induced in XX females and XY males of 2 forms (West-Japan and East-Japan) of G. rugosa with the ancestral homomorphic sex chromosomes under male heterogametic sex determination. During sex reversal, expression of CYP19 and/or FOXL2 was dependent on the phenotypic sex of the gonad. In contrast, sex reversal was not induced in ZW females of a population with a heteromorphic ZW sex chromosome system or in XX females or XY males in a population with a heteromorphic XY sex chromosome system. The latter 2 populations are evolutionarily derived forms. These results indicate an evolutionary direction for the gonadal sex differentiation mechanism. The original system was highly sensitive to sex hormones and allowed almost complete sex reversal. From this ancestral form, a new system evolved that was resistant to hormones and showed a change in the heterogametic sex and the sex chromosome differentiation mechanism.

Independent degeneration of W and Y sex chromosomes in frog Rana rugosa.

The frog Rana rugosa uniquely possesses two different sex-determining systems of XX/XY and ZZ/ZW, separately in the geographic populations. The sex chromosomes of both types share the same origin at chromosome 7, and the structural differences between X and Y or Z and W were evolved through two inversions. In order to ascertain the mechanisms of degeneration of W and Y chromosomes, we gynogenetically produced homozygous diploids WW and YY and examined their viability. Tadpoles from geographic group N (W(N)W(N)) containing three populations died of edema at an early developmental stage within 10 days after hatching, while tadpoles from the geographic group K (W(K)W(K)) that contained two populations died of underdeveloped growth at a much later stage, 40-50 days after fertilization. On the contrary, W(N)W(K) and W(K)W(N) hybrid embryos were viable, successfully passed the two lethal stages, and survived till the attainment of adulthood. The observed survival implies that the lethal genes of the W chromosomes are not shared by the two groups and thus demonstrates their independent degeneration histories between the local groups. In sharp contrast, a sex-linked gene of androgen receptor gene (AR) from the W chromosome was down-regulated in expression in both the groups, suggesting that inactivation of the W-AR allele preceded divergence of the two groups and appearance of the lethal genes. Besides, the YY embryos died of cardiac edema immediately after hatching. The symptom of lethality and the stage of developmental arrest differed from those for either of WW lethal embryos. We therefore conclude that the W and Y chromosomes involve no evolutionary common scenario for degeneration.

Cytogenetic studies of Hynobiidae (Urodela) XIX. Morphological variation of sex chromosomes pairing behavior of sex lampbrush chromosomes in Hynobius quelpaertensis (Mori) from Cheju Island, South Korea.

Using Giemsa staining, C-banding and Ag-NOR staining techniques, we analyzed chromosomes in adult male and female Hynobius quelpaertensis and in embryos of this species in egg sacs collected from eight localities of Cheju Island, South Korea. Chromosome pair 21 was consistently homomorphic in male specimens, while it was heteromorphic in female specimens, suggesting the occurrence of ZZ/ZW sex chromosome constitution in this species. The W chromosome, being much larger than the Z chromosome, was of three morphologically distinct types: WA, WB and WC. Lampbrush chromosomes examined in the oocytes of one female specimen having the WA chromosome showed that the short arm of the WA chromosome and the long arm of the Z chromosome paired closely and hence are genetically homologous. We also tried to analyze the structural relationship among the three types of W chromosomes based on their C-banding and Ag-NOR patterns.

Carcinoma with shared pathologic characteristics of both hepatocellular carcinoma and cholangiocarcinoma.

BACKGROUND: α-Fetoprotein (AFP) is a useful marker of hepatocellular carcinoma (HCC), and protein induced by vitamin K absence or antagonist II (PIVKA-II) and fucosylated AFP (AFP-L3) are specific tumor markers. OBJECTIVE: The aim of this article was to report a case of intrahepatic cholangiocarcinoma (CC) with high levels of expression of AFP, AFP-L3, and PIVKA-II. METHODS: A 70-year-old man weighing 66 kg with a diagnosis of intrahepatic CC presented with a liver tumor 4.0 cm in diameter and elevated concentrations of carbohydrate antigen 19-9 (575 U/mL), PIVKA-II (379 mAU/mL), and AFP (497 ng/mL; AFP-L3, 88.1%). On extended medial hepatic segmentectomy, microscopy showed that the tumor was a CC without HCC. The patient subsequently underwent immunohistochemical assessments using cytokeratin-19, epithelial membrane antigen (EMA), hepatocyte paraffin-1 (HP-1), PIVKA-II, and AFP. RESULTS: In all specimens, desmoplasia was observed. However, results of immunohistochemistry showed positive results for cytokeratin-19 and EMA; HP-1 results were negative. Results of PIVKA-II and AFP testing in the tumor were positive. CONCLUSIONS: The case presented here showed characteristics of CC and HCC, whereas the histologic expression of the tumor suggested CC. Based on the literature search, this is the first known report of a case of a CC expressing AFP and PIVKA-II confirmed on immunohistochemical staining. This case is interesting with regard to the ability of the progenitor cells to differentiate HCC and CC.

Role of aromatase and androgen receptor expression in gonadal sex differentiation of ZW/ZZ-type frogs, Rana rugosa.

To elucidate the mechanisms of amphibian gonadal sex differentiation, we examined the expression of aromatase and androgen receptor (AR) mRNAs for days 17-31 after fertilization. The effects of inhibitors and sex steroid hormones were also examined. In ZZ males, expression of AR decreased after day 19, while aromatase expression was low throughout the sampling period. Males treated with 17beta-estradiol (E2) showed increasing aromatase expression after day 21, and formed ovaries. AR antagonist treatment also induced high-level aromatase expression and ovarian differentiation. In males co-treated with an aromatase inhibitor and E2, the undifferentiated gonads developed into testes despite high-level aromatase expression. Males treated with androgen and E2 before and during an estrogen sensitive period, respectively, also formed testes. In ZW females, AR expression persisted at a low-level, while aromatase expression increased after day 18. Short-term treatment with an aromatase inhibitor was ineffective in preventing ovarian differentiation, whereas long-term treatment resulted in testes developing from ovarian structure. Compared with the ZZ males and ZW females, WW females did not exhibit detectable expression of AR, suggesting that the active AR gene(s) itself, or a putative gene regulating AR gene expression, is located on Z chromosomes. From the time lag of aromatase expression between ZW females and ZZ males treated with E2 and the effect of AR antagonist, it was found that in males elevated AR expression suppresses aromatase expression directly or indirectly. Consequently, endogenous androgens, accumulated by blocking estrogen biosynthesis, induced testicular differentiation. The gonadogenesis of males is dependent on sex hormone, whereas that of females has evolved to hormone-independence.