Spatial and single-cell colocalisation analysis reveals MDK-mediated immunosuppressive environment with regulatory T cells in colorectal carcinogenesis.

BACKGROUND: Cell-cell interaction factors that facilitate the progression of adenoma to sporadic colorectal cancer (CRC) remain unclear, thereby hindering patient survival. METHODS: We performed spatial transcriptomics on five early CRC cases, which included adenoma and carcinoma, and one advanced CRC. To elucidate cell-cell interactions within the tumour microenvironment (TME), we investigated the colocalisation network at single-cell resolution using a deep generative model for colocalisation analysis, combined with a single-cell transcriptome, and assessed the clinical significance in CRC patients. FINDINGS: CRC cells colocalised with regulatory T cells (Tregs) at the adenoma-carcinoma interface. At early-stage carcinogenesis, cell-cell interaction inference between colocalised adenoma and cancer epithelial cells and Tregs based on the spatial distribution of single cells highlighted midkine (MDK) as a prominent signalling molecule sent from tumour epithelial cells to Tregs. Interaction between MDK-high CRC cells and SPP1+ macrophages and stromal cells proved to be the mechanism underlying immunosuppression in the TME. Additionally, we identified syndecan4 (SDC4) as a receptor for MDK associated with Treg colocalisation. Finally, clinical analysis using CRC datasets indicated that increased MDK/SDC4 levels correlated with poor overall survival in CRC patients. INTERPRETATION: MDK is involved in the immune tolerance shown by Tregs to tumour growth. MDK-mediated formation of the TME could be a potential target for early diagnosis and treatment of CRC. FUNDING: Japan Society for the Promotion of Science (JSPS) Grant-in-Aid for Science Research; OITA Cancer Research Foundation; AMED under Grant Number; Japan Science and Technology Agency (JST); Takeda Science Foundation; The Princess Takamatsu Cancer Research Fund.

IgG4-related pancreatobiliary diseases could be associated with onset of pancreatobiliary cancer: A multicenter cohort study.

BACKGROUND: The risk and prognosis of pancreatobiliary cancer and in patients with autoimmune pancreatitis (AIP) and IgG4-related sclerosing cholangitis (IgG4-SC) remain unclear. Therefore, we retrospectively investigated the risk of pancreatobiliary cancer and prognosis in patients with AIP and IgG4-SC. METHODS: Patients with AIP and IgG4-SC at seven centers between 1998 and 2022 were investigated. The following data were evaluated: (1) the number of cancers diagnosed and standardized incidence ratio (SIR) for pancreatobiliary and other cancers during the observational period and (2) prognosis after diagnosis of AIP and IgG4-SC using standardized mortality ratio (SMR). RESULTS: This study included 201 patients with AIP and IgG4-SC. The mean follow-up period was 5.7 years. Seven cases of pancreatic cancer were diagnosed, and the SIR was 8.11 (95% confidence interval [CI]: 7.29-9.13). Three cases of bile duct cancer were diagnosed, and the SIR was 6.89 (95% CI: 6.20-7.75). The SMR after the diagnosis of AIP and IgG4-SC in cases that developed pancreatobiliary cancer were 4.03 (95% CI: 2.83-6.99). CONCLUSIONS: Patients with autoimmune pancreatitis and IgG4-SC were associated with a high risk of pancreatic and bile duct cancer. Patients with AIP and IgG4-SC have a worse prognosis when they develop pancreatobiliary cancer.

IgG4-related sclerosing cholangitis may be a risk factor for cancer.

BACKGROUND/PURPOSE: The relationship between autoimmune pancreatitis (AIP) and malignancy has been reported. However, the potential risk for cancer in patients with immunoglobulin 4 (IgG4)-related sclerosing cholangitis (IgG4-SC) is unclear. The present study aimed to evaluate the incidence of cancer in IgG4-SC patients. METHODS: We retrospectively collected clinical data for 121 patients diagnosed with IgG4-SC from 7 hospitals. We calculated the standardized incidence ratio (SIR) of cancer in IgG4-SC patients based on the national cancer rates. The SIR of the period after the diagnosis of IgG4-SC were calculated. RESULTS: The mean follow-up period was 6.4 years, with 121 IgG4-SC patients. During the follow-up period, 26 patients had cancer, and 29 cancers were diagnosed. The SIR of cancer after the diagnosis of IgG4-SC was 1.90 (95% confidence interval [CI] 1.67-2.21). The SIR of pancreatic and bile duct cancer was 10.30 and 8.88, respectively. The SIR of cancer in <1 year, 1-5 years, and >5 years after diagnosis of IgG4-SC were 2.58, 1.01, and 2.44, respectively. CONCLUSIONS: IgG4-SC patients have a high risk of cancer including pancreatic and bile duct cancer. The risk of cancer was high less <1 year and >5 years after diagnosis of IgG4-SC. Therefore, IgG4-SC patients may require careful long-term follow-up.

Rectal varix treated with endoscopic cyanoacrylate injection therapy.

There is no established treatment for rectal varices. Although endoscopic cyanoacrylate (N-butyl 2-cyanoacrylate) injection therapy is the standard treatment for gastric varices, there are few reports of its use for rectal varices. We present a case of rectal varix that was successfully treated with endoscopic cyanoacrylate injection therapy. An 80-year-old man with cirrhosis was treated for rectal varices with interventional radiology 2 years earlier. At his current presentation, he underwent colonoscopy for hematochezia and anemia, which showed recurrence of rectal varix. We performed endoscopic cyanoacrylate injection therapy for the lesion. However, since we observed bleeding from the treated varix the next day, additional cyanoacrylate was injected. Thereafter, there was no re-bleeding and no recurrence was observed at the 3-year follow-up. According to the previous reports, interventional radiology (IVR), endoscopic sclerotherapy (EIS), and endoscopic variceal ligation (EVL) have been mainly used to treat rectal varices; however, there are few reports of endoscopic cyanoacrylate injection therapy. Our case suggests that endoscopic cyanoacrylate injection therapy might be a useful and safe treatment option for rectal varices.

Efficacy of vonoprazan for initial and maintenance therapy in reflux esophagitis, nonerosive esophagitis, and proton pump inhibitor-resistant gastroesophageal reflux disease.

Proton pump inhibitors (PPIs) have been the first line treatment for gastroesophageal reflux disease (GERD). The aim of this study was to evaluate the efficacy of vonoprazan (VPZ), a potassium-competitive acid blocker for reflux esophagitis (RE), nonerosive reflux disease (NERD), and PPI-resistant GERD patients.An open-label, single-center, observational study in our hospital was performed from August 2016 to August 2017. All patients diagnosed with GERD were asked to self-report a questionnaire of frequency scale for the symptoms of GERD (FSSG) and rate their degree of satisfaction with the treatment of GERD during outpatient visit. A total of 200 (RE 47, NERD 49, PPI-resistant GERD 104) patients were included in the present study. The primary endpoint was the change of FSSG and the proportion of degree of satisfaction with the treatment at the end of the initial therapy. A percentage of improvement (improvement rate) and resolution (resolution rate) at the end of the initial therapy were evaluated. Secondary endpoint included the proportion of patients with symptomatic relapse in the 24-week maintenance phase.FSSG and the degree of satisfaction were significantly improved after the initial therapy in every group. Improvement and resolution rate after the initial therapy were 83.0% and 67.0% in RE, 66.7% and 60.4% in NERD, and 76.0% and 60.4% in PPI-resistant group. There was no significance between after the initial therapy and 24 weeks in improvement and resolution rate. Thirty-two of the total 48 patients did not take VPZ at 24 weeks. Total FSSG score in each group was 1.67 ±â€Š1.97, 2.71 ±â€Š4.91, and 4.0 ±â€Š4.93. The nonrelapse rate at 24 weeks in each group was 66.7%, 60.0%, and 50.0%. The resolution rate at 24 weeks in each group was 38.9%, 45.0%, and 30.0%.The VPZ therapy is effective for initial and maintenance therapy and improves heartburn and patient's satisfaction significantly in all 3 groups. Among patients who stopped taking VPZ during the maintenance period, 42.0% of RE and NERD group and 30% of PPI-resistant group experience complete remission from GERD at 24 weeks by introduction of VPZ.

Effect of preventive closure of the frenulum after endoscopic papillectomy: A prospective pilot study.

BACKGROUND AND AIM: The usefulness of preventive closure of the frenulum after endoscopic papillectomy (EP) could reduce bleeding. The feasibility and safety of clipping were evaluated in this prospective pilot study. METHODS: This study involved 40 consecutive patients who underwent preventive closure of the frenulum by clipping just after EP. The outcome data were compared with those of the previous 40 patients in whom no preemptive closure had been performed (no-closure group) (UMIN000014783). Additionally, the bleeding sites were examined. RESULTS: The clipping procedure was successful in all patients. As compared to the no-closure group, the rate of bleeding (P = 0.026) and period of hospital stay (P < 0.001) were significantly reduced in the closure group. There was no difference in the procedure time between the two groups. Furthermore, the incidence rates of pancreatitis and perforation were comparable in the two groups. The bleeding was noted in the frenulum area rather than at any other site in 90.9% of cases. CONCLUSION: Preventive closure of the frenulum after EP is an effective, safe, rational, and economical method to reduce the incidence of delayed bleeding, without prolonging the procedure time or increasing the risk of post-procedure pancreatitis perforation.

Clinical features of isolated proximal-type immunoglobulin G4-related sclerosing cholangitis.

BACKGROUND AND AIM: Immunoglobulin G4-related sclerosing cholangitis (IgG4-SC) presents as isolated proximal-type sclerosing cholangitis (i-SC). The present study sought to clarify the imaging differences between i-SC and Klatskin tumor. Differences between i-SC and IgG4-SC associated with autoimmune pancreatitis (AIP-SC) were also studied. METHODS: Differentiating factors between i-SC and Klatskin tumor were studied. Serum IgG4 level, CA19-9 level, computed tomography (CT) findings, cholangiography findings (symmetrical smooth long stricture extending into the upper bile duct [SSLS]), endosonographic features (continuous symmetrical mucosal lesion to the hilar part [CSML]), endoscopic biopsy results, treatment, relapse, and survival were also compared between patients with i-SC and those with AIP-SC. RESULTS: For a differential diagnosis between i-SC (N = 9) and Klatskin tumor (N = 47), the cut-off value of serum IgG4 level was 150 mg/dL (sensitivity, 0.857, specificity, 0.966). Logistic regression analysis indicated that serum IgG4 level, presence of SSLS, presence of CSML, and presence of swollen ampulla are independent factor for identifying i-SC. Relapse rate was significantly higher in the IgG4-SC with AIP group than in the i-SC group (log rank, P = 0.046). CONCLUSION: Isolated proximal-type sclerosing cholangitis presents as a nodular lesion with SSLS and/or CSML mimicking a Klatskin tumor. Those endoscopic features might provide a diagnostic clue for i-SC. i-SC is likely to have a more favorable prognosis than IgG4-SC with AIP.

Is endoscopic papillary balloon dilatation really a risk factor for post-ERCP pancreatitis?

Endoscopic papillary balloon dilatation (EPBD) is useful for decreasing early complications of endoscopic retrograde cholangio-pancreatography (ERCP), including bleeding, biliary infection, and perforation, but it is generally avoided in Western countries because of a relatively high reported incidence of post-ERCP pancreatitis (PEP). However, as the efficacy of endoscopic papillary large-balloon dilatation (EPLBD) becomes widely recognized, EPBD is attracting attention. Here we investigate whether EPBD is truly a risk factor for PEP, and seek safer and more effective EPBD procedures by reviewing past studies. We reviewed thirteen randomised control trials comparing EPBD and endoscopic sphincterotomy (EST) and ten studies comparing direct EPLBD and EST. Three randomized controlled trials of EPBD showed significantly higher incidence of PEP than EST, but no study of EPLBD did. Careful analysis of these studies suggested that longer and higher-pressure inflation of balloons might decrease PEP incidence. The paradoxical result that EPBD with small-calibre balloons increases PEP incidence while EPLBD does not may be due to insufficient papillary dilatation in the former. Insufficient dilatation could cause the high incidence of PEP through the use of mechanical lithotripsy and stress on the papilla at the time of stone removal. Sufficient dilation of the papilla may be useful in preventing PEP.

Obesity with abundant subcutaneous adipose tissue increases the risk of post-ERCP pancreatitis.

BACKGROUND/PURPOSE: The risk factors for post-endoscopic retrograde cholangiopancreatography pancreatitis (PEP) have been widely investigated. However, studies focusing on the body mass index (BMI) and distribution of adipose tissue have not been reported. Therefore, we examined the correlation between PEP and these factors. METHODS: A total of 583 consecutive endoscopic retrograde cholangiopancreatography (ERCP)-naïve patients undergoing therapeutic ERCP were retrospectively analyzed. Subjects were categorized into four groups by BMI: underweight, normal, overweight, and obesity; the PEP rates were compared. In addition, the relationship between PEP and parameters of obesity, visceral and subcutaneous adipose tissue as well as abdominal circumference was investigated. RESULTS: PEP rate was significantly higher in obesity (30 %) and lower in normal (3 %, P < 0.001). The PEP rate in underweight (7.3 %) was conversely higher than in normal. As for parameters of obesity, only subcutaneous adipose tissue was correlated with PEP incidence (P = 0.009). The correlation of PEP incidence with BMI and subcutaneous adipose tissue was separately reconfirmed by multivariate analysis including female gender and guidewire placement; these factors showed a tendency toward differences in univariate analysis. CONCLUSIONS: Obesity could be a risk factor for PEP. In the obesity group, an excess of subcutaneous adipose tissue might be an especially important factor related to PEP incidence.

Prophylactic Efficacy of 3- or 5-cm Pancreatic Stents for Preventing Post-ERCP Pancreatitis: A Prospective, Randomized Trial.

BACKGROUND AND STUDY AIMS: Prophylactic pancreatic stent placement is effective for preventing postendoscopic retrograde cholangiopancreatography pancreatitis (PEP). The most effective type of stent, however, remains unclear. Therefore, we prospectively compared the prophylactic efficacy for PEP prevention between short (3 cm) and long (5 cm) pancreatic stent. PATIENTS AND METHODS: Between July 2012 and June 2014, 240 consecutive patients requiring therapeutic endoscopic retrograde cholangiopancreatography to remove a choledocholith or for bile drainage for obstructive jaundice were prospectively enrolled and randomized to undergo prophylactic insertion with unflanged, 5 Fr, 3 or 5-cm pancreatic stent. An efficacy of each stent for preventing PEP was evaluated as a primary endpoint. The period until stent dislodgement and the total adverse event rate were also evaluated as a secondary endpoint. RESULTS: Per-protocol analysis revealed that the PEP rate was significantly lower with the short stent than with the long stent (2.0% vs. 8.8%, P=0.035), although they were not significantly different in intention-to-treat analysis. The adverse event rate excluding PEP did not differ significantly between groups (3.0% vs. 0.9%, P=0.293). The median period until dislodgement of the short stent was significantly shorter than that of the long stent (2 vs. 4 d, P<0.001). CONCLUSIONS: The present study revealed a superiority of 3-cm stents compared with 5-cm stents for prophylactic pancreatic stent. On the basis of the past reports and the result of the present study, we recommend using a 5 Fr, 3-cm unflanged stent.This study was registered on the UMIN Clinical Trial Registry (UMIN000008290).

Pancreatic paraganglioma with draining vessels.

A pancreatic paraganglioma is a rare neoplasm that is difficult to distinguish from a pancreatic neuroendocrine tumour. Here we present a case of pancreatic paraganglioma that was surgically resected following preoperative diagnosis of a pancreatic neuroendocrine tumour. Careful evaluation of the endoscopic ultrasonography findings revealed abundant draining vessels, which could have led to a correct preoperative diagnosis of pancreatic paraganglioma.

Endoscopic nasobiliary drainage for obstructive jaundice using either a 5 Fr or 7 Fr catheter: a prospective, randomized trial.

BACKGROUND: The influence of size on the effectiveness of nasobiliary catheters has not yet been studied. We compared biliary drainage effectiveness and procedure-related discomfort and adverse events in 5 French (Fr) and 7 Fr nasobiliary catheters. METHODS: We prospectively studied 100 patients undergoing endoscopic biliary drainage for obstructive jaundice, who were randomly allocated to a 5 Fr or 7 Fr nasobiliary catheter group. As the primary endpoint, the effectiveness was evaluated by the serum total bilirubin decreasing rate and the success rate of jaundice relief. As the secondary endpoint, the degree of discomfort was investigated using a questionnaire survey after catheter removal. RESULTS: The bilirubin decrease rate was significantly higher in the 7 Fr catheter group than in the 5 Fr group (53.0 ± 21.4% vs 40.5 ± 29.9%, respectively; P = 0.019). The success rate of jaundice relief tended to be higher in the 7 Fr catheter group, although the difference was not statistically significant (98% vs 88%, respectively; P = 0.056). The questionnaire survey demonstrated that total discomfort was significantly greater in the 7 Fr group (3.9 ± 1.5 vs 3.2 ± 1.4, respectively; P = 0.018). Larger-diameter catheters tended to increase difficulty in eating, although the difference between the groups was not statistically significant. CONCLUSIONS: 7 Fr nasobiliary catheters are recommended for patients requiring rapid and reliable relief of obstructive jaundice. However, because they can cause greater discomfort, 5 Fr nasobiliary catheters are preferred in other settings. TRIAL REGISTRATION: On July 1, 2012; UMIN000008288 (Japan Primary Registries Network).

Endoscopic papillary large-balloon dilation versus endoscopic papillary regular-balloon dilation for removal of large bile-duct stones.

BACKGROUND: Endoscopic papillary large-balloon dilation (EPLBD) became popular for the treatment of large common bile-duct stones (CBDS), and its feasibility has been reported in comparison to endoscopic sphincterotomy. However, the comparison between EPLBD and endoscopic papillary regular-balloon dilation (EPBD) has not been reported. In the present study, the efficacy and complications of EPLBD were compared with those of EPBD. METHODS: We retrospectively assessed 334 consecutive patients with CBDS of any size that were treated by either EPLBD or EPBD between January 2008 and December 2012. RESULTS: In cases with large CBDS (>10 mm), EPLBD and EPBD had similar results in terms of the success rate of stone removal in the first (65% vs. 84%) and total attempts (100% vs. 95%), use of mechanical lithotripter (64% vs. 80%), and procedure time (48.0 ± 17.8 min vs. 44.1 ± 17.1 min). The necessity for crushing stones with a mechanical lithotripter was significantly decreased in EPLBD compared to EPBD (25% vs. 80%). In all cases with CBDS, there was no significant difference in complication rates between EPLBD and EPBD (3.3% vs. 4.7%). CONCLUSIONS: Compared to EPBD, EPLBD appears safe and effective for removing large CBDS and decreases the necessity of lithotripsy.

[A case of advanced hepatocellular carcinoma with lung, brain and lymph node metastases recurred 8 years after hepatectomy successfully treated by operation, radiation and systemic chemotherapy using S-1/CDDP].

A 30-year-old man underwent a left lobectomy and S5/6 partial hepatectomy in August 2001 for hepatocellular carcinoma (HCC). A lung tumor was detected by positron emission tomography (PET-CT) 8 years after the surgery. In May 2010, he received pulmonary tumor resection and the histopathological findings revealed metastasis of HCC. However a metastatic brain tumor was detected by computed tomography (CT) in September 2010, therefore surgery and radiation therapy were subsequently performed. Thereafter, metastatic hilar lymph node appeared in December 2010, therefore we performed systemic chemotherapy using S-1/cisplatin combined with radiation therapy for the metastatic tumor. The tumor was markedly decreased and no shadow was detected by PET-CT. He has been followed up in the outpatient clinic with no recurrence.

A case of spindle cell type anaplastic carcinoma of the pancreas -review of Japanese case report-.

We present a case of spindle cell type anaplastic carcinoma of the pancreas in a 63-year-old woman. A pancreatic mass was incidentally detected by routine abdominal ultrasonography examination for her hepatitis B infection, and she was admitted to our hospital for further examination. Computed tomography revealed a hypo-vascular mass measuring 25mm in maximal dimension at the pancreas body. Endoscopic ultrasonography showed a hypoechoic mass as the pancreas body and a swollen lymph node near the tumor. Endoscopic retrograde pancreatography revealed disruption of the main pancreatic duct, and carcinoma cells were detected in pancreatic juice obtained via an endoscopic nasopancreatic drainage tube. We diagnosed this case as an invasive ductal adenocarcinoma of the pancreas body, therefore the distal pancreatectomy with splenectomy (D1+α) was performed. The histopathological diagnosis for this case was a "spindle cell type anaplastic carcinoma of the pancreas". The patient has remained well with no evidence of recurrence for 9 months since her operation.

[A study of the usefulness of pancreatic juice cytology obtained via an endoscopic nasal pancreatic drainage (ENPD) tube].

We studied the usefulness of pancreatic juice cytology obtained via an indwelling endoscopic nasal pancreatic drainage (ENPD) tube. In general, cytology was performed three times. The sensitivity was 0.35 on the first time and 0.59 after three times (p<0.01). The sensitivity in relation to tumor size of pancreatic cancer was 0.77 for Tis (3 cases) and TS1 (10 cases), 0.76 for TS2 (29 cases), 0.56 for TS3 (9 cases) and 0 for TS4 (4 cases). A significant difference of p=0.01 was recognized among the 4 groups, and the sensitivity for small tumors was higher than that for large tumors. The pancreatic juice can be obtained repeatedly via the ENPD tube and that contributes to improving the diagnostic accuracy. It is useful as a definitive diagnosis method in early stage pancreatic cancer because it is easier to detect positive results in smaller tumor, furthermore, it is possible to diagnose carcinoma in situ.

Localized malignant pleural mesothelioma showing a thoracic mass and metastasizing to the stomach.

Malignant mesothelioma typically shows either diffuse tumors or multiple pleura-based nodules. Localized malignant mesothelioma is rare. In this case report, a 70-year-old man with left chest wall tumor underwent tumor resection, and the lesion was pathologically diagnosed as biphasic malignant mesothelioma. Tumor recurrence was detected in the stomach due to vomiting of blood, and also spread to the mediastinal lymph node, and bone 3 months postoperatively. Total gastrectomy was performed and the histopathological diagnosis of metastasis of mesothelioma was made. In the previously reported cases, all of the localized malignant mesothelioma arose in the pleural space and there was no metastasis of localized malignant mesothelioma to the stomach. In the present case, gross and histological examinations were performed for both the primary lesion and gastric metastatic tumor. Though it was very difficult to distinguish mesothelioma from sarcoma and other chest wall tumors, immunochemical staining was able to facilitate making the diagnosis. This case suggests that localized malignant mesothelioma is capable of showing multiple forms and a variety of clinical courses. Localized malignant mesothelioma can arise primarily from the chest wall.

[Eosinophilic gastroenteritis in the esophagus, stomach, and small intestine in a patient with a choking feeling in the esophagus].

A 75-year-old man was admitted to our hospital with the chief complaint of a choking feeling around the esophagus. Laboratory examinations revealed eosinophilia, and high levels of serum immunoglobulin (Ig) E. A computed tomography scan (CT) showed wall thickening of the esophagus and terminal ileum, and ascites around the liver. An endoscopic examination revealed mild mucosal edema in the esophagus, stomach, and small intestine. Biopsy specimens showed diffuse eosinophilic infiltration in the mucosa. We therefore diagnosed eosinophilic gastroenteritis. Oral prednisolone relieved clinical conditions and the CT image improved. This case was considered valuable, because there have been few reports of eosinophilic esophagitis in Japan.

[Successful bi-weekly paclitaxel treatment of an AFP-producing gastric cancer patient with peritoneal dissemination and multiple liver metastasis].

The patient was a 71-year-old man. Chemotherapy was conducted in two courses combining TS-1 (120 mg) and CDDP (80 mg) under the diagnosis of AFP-producing gastric cancer with multiple liver metastasis and peritoneal dissemination. Peritoneal dissemination disappeared, liver metastasis almost disappeared after completion of two courses, and the therapeutic efficacy was rated as PR. Then, the patient underwent distal gastrectomy and lymph node dissection. He received TS-1 monotherapy after surgery, but his condition gradually became worse. TS-1 and CDDP combination were given again, but an ileus resulted due to peritonitis carcinomatous. We therefore administered bi-weekly paclitaxel (80 mg/m(2)) intravenously. The ileus disappeared after one week, liver metastatic lesions and ascites were improved after completion of one course, and therapeutic efficacy was rated as PR. Grade 3 neutropenia and grade 1 alopecia occurred, but no other adverse reaction occurred. This therapy made it possible to eat foods, conduct chemotherapy safely while ambulatory. Paclitaxel can be expected to show good therapeutic efficacy and improve QOL of a peritonitis carcinomatosa patient with TS-1 resistant advanced gastric cancer.