[Indications and Outcomes of Laparoscopic Endoscopic Cooperative Surgery(LECS)for Gastric Gastrointestinal Stromal Tumor].

Laparoscopic and endoscopic cooperative surgery(LECS)for gastric gastrointestinal stromal tumor(GIST)has become a popular surgery with both curability and functional preservation. In this study, we examined the outcomes of 14 patients who underwent classical LECS or CLEAN-NET in our hospital. Until March 2022, classical LECS was performed in patients with intraluminal growth tumors or tumors close to the gastroesophageal junction. After April 2022, classical LECS was performed in patients with intraluminal growth tumors without ulceration, and CLEAN-NET was performed in patients with ulceration or intramural growth tumors. There were 10 males and 4 females with a median age of 80.5 years. Intraluminal growth tumor were 8 patients, close to the gastroesophageal junction tumor were 3, and intramural growth tumor were 4, respectively. Five of these patients had tumors with ulceration. Classical LECS was performed in 10 patients and CLEAN-NET in 4 patients, and the median operative time was 165.5 minutes. All patients underwent R0 resection, and no postoperative complications or recurrences were observed. LECS was performed safely, and it is important to select the surgical procedure according to the tumor site and growth type.

[A Case of HER2-Positive Advanced Gastric Cancer with Liver Metastasis Treated by Laparoscopic Surgery after Chemotherapy and Achieved Pathological Complete Response].

A 77-year-old man presented to our hospital with diarrhea and weight loss. Upper gastrointestinal endoscopy revealed advanced Type 3 gastric cancer measuring 40 mm in the lower greater curvature of the stomach. Biopsy from a gastric tumor revealed moderately differentiated tubular adenocarcinoma overexpressing HER2. Abdominal contrast-enhanced computed tomography(CT)showed multiple liver metastases in S3 and S5. We diagnosed HER2-positive gastric cancer with liver metastasis. Systemic chemotherapy was administrated, with a total of 13 courses of combination therapy with S-1, oxaliplatin and trastuzumab. After chemotherapy, the primary tumor was significantly reduced and liver metastases were almost undetectable. Laparoscopic distal gastrectomy and partial hepatectomy were performed as conversion surgery. The patient was discharged on the 9th day without any postoperative complications. Postoperative pathological findings showed no residual tumor in either gastric and hepatic specimens, and the therapeutic effect of chemotherapy was diagnosed as pathological complete response. We report a case of HER2-positive advanced gastric cancer with multiple liver metastases that achieved a pathologically complete response to chemotherapy followed by conversion surgery. Laparoscopic surgery would be one of an effective option for conversion surgery.

[A Case of Local Recurrence of Esophageal Cancer after Chemoradiation Therapy Successfully Treated with Nivolumab].

We report a case of a patient with locally recurrent esophageal cancer after chemoradiation therapy(CRT)who responded to nivolumab. The patient was an 86-year-old man with advanced esophageal cancer. Upper gastrointestinal endoscopy (EGD)revealed a type 2 lesion in the middle thoracic esophagus, and biopsy revealed squamous cell carcinoma(SCC). Contrast- enhanced CT showed invasion of the left main bronchi. The patient was diagnosed as Stage Ⅳa advanced esophageal cancer, and was treated with 5-FU plus cisplatin chemotherapy, and 60 Gy of radiation therapy. The tumor disappeared by CT and EGD, and the patient was followed up for observation. The patient experienced a feeling of tightness again, and EGD revealed an ulcerative lesion in the middle thoracic esophagus, and a biopsy detected SCC. Because of the early recurrence after CRT, the patient was judged to be resistant to 5-FU plus cisplatin chemotherapy, and 8 courses of nivolumab were administered as second-line treatment. Follow-up EGD confirmed disappearance of ulcerative lesions, and no tumors have been observed to date.

High-Mobility Group Box 1 expression predicts survival of patients after resection of adenocarcinoma of the ampulla of Vater.

BACKGROUND: Expression of High-Mobility Group Box 1 (HMGB1), a multifunctional protein involved in DNA function as well as cell proliferation, inflammation, and the immune response, has been reported to be prognostic in several types of malignancies. However, the prognostic value of HMGB1 in ampullary cancer has not been studied. METHODS: Patients with adenocarcinoma of the ampulla of Vater who underwent R0 resection with pancreaticoduodenectomy between 2001 and 2011 were included in the present multi-institutional study. The degree of HMGB1 expression was examined in each resected specimen by immunohistochemical staining. RESULTS: A total of 101 patients were enrolled of which, 79 patients were eligible. High expression of HMGB1 was observed in 31 (39%) patients. Blood loss, transfusion, tumor stage, nodal status, and HMGB1 expression were identified as predictors with univariate analysis. Multivariate analysis showed that transfusion, lymph-node metastasis, and high HMGB1 expression were independent predictors of poor overall survival. Subgroup analysis showed that high HMGB1 expression was predictive, especially in patients who did not receive adjuvant chemotherapy. CONCLUSIONS: High HMGB1 expression is an independent predictor of poor prognosis in patients with adenocarcinoma of the ampulla of Vater not treated with adjuvant chemotherapy.

[A Case of Neuroendocrine Tumor G1 of the Ileum with Multiple Liver Metastases].

A 74-year-old man was admitted to our hospital with multiple liver tumors detected by routine ultrasonography. Colonoscopy showed a type 2 tumor measuring approximately 25mm in diameter at the terminal ileum. The biopsy specimen showed neuroendocrine tumor(NET)G1. The patient was diagnosed with NET G1 of the ileum with multiple liver metastases. Thus, he underwent ileocecal resection with lymph node dissection and liver(S2)biopsy. A tumor was observed at the terminal ileum with serosal invasion, and the mesenteric lymph nodes were enlarged. Multiple liver metastatic tumors were observed in S2, S5, and S8. The patient was diagnosed with NET G1 of the ileum, T4N1M1, Stage Ⅳ. He is receiving octreotide therapy and has maintained stable disease for about 24 months.

Neoadjuvant chemoradiotherapy of pancreatic cancer induces a favorable immunogenic tumor microenvironment associated with increased major histocompatibility complex class I-related chain A/B expression.

BACKGROUND: Damage-associated molecular patterns (DAMPs) are related to immune responses in malignant tumors including tumor-infiltrating lymphocytes (TILs). The aim of the present study was to determine the relationship between expression of components of DAMPs and TILs in pancreatic cancer patients who underwent neoadjuvant chemoradiotherapy (NACRT) versus those who did not. METHODS: NACRT was administered to 51 patients with borderline-resectable pancreatic cancer and not to 33 patients with resectable pancreatic cancer. Resected specimens were analyzed for the presence of DAMPs, major histocompatibility complex class I-related chain A/B (MICA/B), and CD8+ TILs, CD4+ TILs, and forkhead box P3 positive (Foxp3+ ) TILs. The Treg/TIL ratio was obtained by dividing the number of Foxp3+ TILs, a surrogate for regulatory T cells, by the sum of CD8+ and CD4+ TILs. RESULTS: Overexpression of calreticulin, Hsp70, and MICA/B were all significantly correlated with NACRT administration. In the NACRT group, high MICA/B expression was associated with a low Treg/TIL ratio, indicating a favorable immunogenic tumor microenvironment. Patients with a lower Treg/TIL ratio had longer survival. CONCLUSIONS: Overexpression of MICA/B, a component of DAMPs induced by NACRT, may play an important role in acquiring a favorable immune response for pancreatic cancer which contributes to longer survival, suggesting the potential of immunotherapy of this recalcitrant disease, especially for patients with overexpression of DAMPs.

Is Routine Prophylactic Cholecystectomy Necessary During Gastrectomy for Gastric Cancer?

BACKGROUND: Performing routine prophylactic cholecystectomy during gastrectomy in gastric cancer patients has been controversial. The frequency of cholelithiasis, cholecystitis, and cholangitis after gastrectomy has not been reported for large patient populations, so we carried out this retrospective study to aid the assessment of the necessity for prophylactic cholecystectomy. METHODS: This retrospective study reviewed 969 patients with gastric cancer who underwent distal gastrectomies with Billroth I reconstructions (DG) or total gastrectomies with Roux-en-Y reconstructions (TG), preserving the gallbladder, between January 2000 and May 2012. Risk factors for cholelithiasis, cholecystitis, and cholangitis after gastrectomy were evaluated using logistic regression analysis. RESULTS: The median follow-up period after gastrectomy was 48 months (range 12-159 months). After gastrectomy, cholelithiasis occurred in 6.1% (59/969) patients and cholecystitis and/or cholangitis occurred in 1.2% (12/969) patients. The method used for gastrectomy was an independent risk factor for both cholelithiasis (TG/DG: OR (95%CI): 1.900 (1.114-3.240), p = 0.018) and cholecystitis and/or cholangitis (TG/DG: OR (95%CI): 8.325 (1.814-38.197), p = 0.006). In patients who developed cholelithiasis, the incidence of cholecystitis and/or cholangitis was 31.3% (10/32) after TG, but only 7.4% after DG. CONCLUSIONS: Prophylactic cholecystectomy may be unnecessary in distal gastrectomy with Billroth I reconstruction.

Thrombomodulin improves rat survival after extensive hepatectomy.

BACKGROUND: Recombinant human soluble thrombomodulin (rTM) protects against disseminated intravascular coagulopathy by inhibiting coagulation, inflammation, and apoptosis. This study tests the hypothesis that rTM is hepatoprotective after extensive hepatectomy (Hx) and investigates the mechanisms underlying this effect. MATERIALS AND METHODS: Experiment 1: rats (15 per group) were injected with rTM (1.0 or 2.0 mg/kg) or saline just before 95% Hx and their 7-d survival assessed. Experiment 2: rats were assigned to either a treated (2.0 mg/kg rTM just before Hx) or control group (n = 5 per group). Five rats per group were euthanized immediately after surgery, and at 1, 3, 6, 12, and 24 h postoperatively; serum and liver remnant samples were collected for biochemical and histologic analysis, as well as reverse-transcription polymerase chain reaction and Western blotting. RESULTS: All saline-injected rats died within 52 h of Hx, whereas injection of 2.0 mg/kg rTM prolonged survival (P = 0.003). rTM increased the number of Ki67-positive cells and reduced the number of terminal deoxynucleotidyl transferase dUTP nick-end labeling-positive cells. The number of myeloperoxidase-positive cells and the expression of high-mobility group box 1 protein did not differ. Reverse-transcription polymerase chain reaction revealed that rTM significantly enhanced protease-activated receptor-1 and sphingosine kinase 1 messenger RNA expression and significantly reduced plasminogen activator inhibitor-1 and Bax messenger RNA expression. Immunohistochemistry and Western blotting demonstrated that protease-activated receptor-1 expression 24 h after Hx was significantly higher in rTM-treated than in control rats. CONCLUSIONS: rTM may improve survival after extensive Hx by inhibiting apoptosis and promoting liver regeneration.

The modified Glasgow prognostic score as a predictor of survival after hepatectomy for colorectal liver metastases.

BACKGROUND: The inflammation-based Glasgow prognostic score (GPS) has been demonstrated to be prognostic for various tumors. We investigated the value of the modified GPS (mGPS) for the prognosis of patients undergoing curative resection for colorectal liver metastases (CRLM). METHODS: A total of 343 patients were enrolled onto this study. The mGPS was calculated as follows: mGPS-0, C-reactive protein (CRP) ≤10 mg/L; mGPS-1, CRP >10 mg/L and albumin ≥35 g/L; and mGPS-2, CRP >10 mg/L and albumin <35 g/L. Prognostic significance was retrospectively analyzed by univariate and multivariate analyses. RESULTS: Of the 343 patients, 295 (86.0 %) were assigned to mGPS-0, 33 (9.6 %) to mGPS-1, and 15 (4.4 %) to mGPS-2. The median disease-free survival of patients with mGPS-0, -1, and -2 was 18.3, 15.5, and 5.2 months, respectively. The median cancer-specific survival (CSS) of patients with mGPS-0, -1, and -2 was 89.5, 62.2, and 25.8 months, respectively. The CSS of patients with mGPS-0 was significantly longer than that of patients with mGPS-2. Multivariate analysis revealed a significant association between cancer-related postoperative mortality and mGPS and carcinoembryonic antigen level. CONCLUSIONS: The preoperative mGPS is a useful prognostic factor for postoperative survival in patients undergoing curative resection for CRLM.

Immunological impact of neoadjuvant chemoradiotherapy in patients with borderline resectable pancreatic ductal adenocarcinoma.

BACKGROUND: Little is known about the immunological effect of neoadjuvant chemoradiotherapy (NACRT) in the tumor microenvironment of pancreatic ductal adenocarcinoma. The objective of this study was to examine the immunological modifications induced by NACRT in patients with pancreatic cancer. METHODS: Fifty-two patients with pancreatic cancer who underwent surgical resection were enrolled in this study. NACRT was administered to 22 patients, whereas the other 30 patients underwent surgical resection without NACRT. The resected tumor specimens were analyzed for the presence of tumor-infiltrating lymphocytes by using immunohistochemical staining for CD4, CD8, CD68, CD163, Foxp3, and major histocompatibility complex class I (MHC class I) antigen. RESULTS: The number of CD4+ and CD8+ lymphocytes was significantly higher in patients who received NACRT than in those who did not receive NACRT. No significant difference in MHC class I expression was observed between the groups. In the NACRT group, patients with a high accumulation of CD8+ cells experienced longer overall survival than those with a low number of CD8+ cells. CONCLUSIONS: NACRT may induce the accumulation of CD4+ and CD8+ cells in the tumor microenvironment and a high accumulation of CD8+ cells might be a good prognostic marker for pancreatic cancer treated with NACRT.

Differential diagnosis of solid pancreatic lesions using contrast-enhanced three-dimensional ultrasonography.

PURPOSE: To investigate the usefulness of contrast-enhanced three-dimensional ultrasonography (CE 3D US) for differential diagnosis of solid pancreatic lesions. METHODS: Eighty-five patients with solid pancreatic lesions who underwent CE 3D US were retrospectively analyzed. Sixty-four patients had pancreatic ductal adenocarcinoma (PDAC), 10 had mass-forming pancreatitis (MFP), and 11 had neuroendocrine tumor (NET). Two blinded readers evaluated the enhancement patterns using four features: vascularity in the arterial phase, vascularity in the venous phase, vessel location, and vessel form. Vascularity in both phases was classified as hypervascular, isovascular, or hypovascular. Vessel location was classified into peritumoral or intratumoral. Vessel form was classified into fine or irregular. Kappa values were used to assess inter-reader agreement. The institutional review board approved this study, and informed consent was obtained. RESULTS: Kappa values of the four features were 0.75, 0.72, 0.85, and 0.65, which were graded as good or excellent. The most typical combined enhancement pattern in PDAC was hypovascularity in both phases with peritumoral and irregular vessels; MFP was isovascular in both phases with intratumoral and fine vessels; and NETs were hypervascular in both phases with intratumoral and irregular vessels. The sensitivity and positive predictive value of the three patterns were 93.8% and 96.7% for the PDAC pattern, 80.0% and 100% for the MFP pattern, and 81.8%, and 69.2% for the NET pattern, respectively. The accuracy of these diagnostic criteria was 90.5%. CONCLUSION: CE 3D US allows detailed visualization of the enhancement patterns of various pancreatic lesions and can be used for the differential diagnosis.

Intrahepatic cholangiocarcinoma arising 28 years after excision of a type IV-A congenital choledochal cyst: report of a case.

This report presents a rare case of intrahepatic cholangiocarcinoma (IHCC) arising 28 years after excision of a type IV-A congenital choledochal cyst. The patient underwent excision of a congenital choledochal cyst (Todani's type IV-A) at 12 years of age, with Roux-en-Y hepaticojejunostomy reconstruction. She received a pancreaticoduodenectomy (PD) using the modified Child method for an infection of a residual congenital choledochal cyst in the pancreatic head at the age of 18. She was referred to this department with a liver tumor 22 years later. Left hemihepatectomy with left-side caudate lobectomy was performed and the tumor was pathologically diagnosed to be IHCC. The cause of the current carcinogenesis was presumed to be reflux of pancreatic juice into the residual intrahepatic bile duct during surgery. This case suggests that a careful long-term follow-up is important for patients with congenital choledochal cysts, even if a separation-operation was performed at a young age, and especially after PD.

Endoscopic ultrasonographic findings predict the risk of carcinoma in branch duct intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND: The preoperative diagnosis of branch duct intraductal papillary mucinous neoplasm (IPMN) of the pancreas can be very difficult, since low-risk and high-risk lesions can be difficult to differentiate even after cytological analysis. The purpose of this study was to evaluate the preoperative diagnostic value of endoscopic ultrasonography (EUS) in differentiating low-risk and high-risk IPMNs. METHODS: We retrospectively identified 36 patients who underwent preoperative EUS for branch duct IPMNs. The pathological diagnosis after surgical resection was low-grade dysplasia (n = 26), moderate dysplasia (n = 1), high-grade dysplasia or carcinoma in situ (n = 5), and invasive carcinoma (n = 4). We divided the patients into two groups: low risk (low-grade dysplasia or moderate dysplasia) and high risk (high-grade dysplasia or carcinoma). We focused on the diameter of the cystic dilated branch duct, the main pancreatic duct, and the mural nodule as measured using the EUS findings. RESULTS: The cystic dilated branch duct diameter (31.5 mm vs. 41.9 mm, P = 0.0225) was significantly correlated with low-risk and high-risk IPMNs, but the main pancreatic duct diameter (5.37 mm vs. 5.44 mm, P = 0.9418) was not significantly correlated with the low-risk and high-risk IPMNs. The mural nodule diameter of the papillary protrusions (4.3 mm vs. 16.4 mm, P < 0.0001) and the width diameter of the mural nodule (5.7 mm vs. 23.2 mm, P < 0.0001) were significantly correlated with low-risk and high-risk IPMNs. CONCLUSIONS: The mural nodule of papillary protrusions diameter and width diameter observed using EUS was a reliable preoperative diagnostic finding capable of distinguishing low-risk and high-risk IPMNs.

FOXP3+ regulatory T cells and tumoral indoleamine 2,3-dioxygenase expression predicts the carcinogenesis of intraductal papillary mucinous neoplasms of the pancreas.

BACKGROUND AND AIMS: FOXP3+ regulatory T cells (Tregs) play a central role in self-tolerance and suppress the effective antitumor immune response. A recent study revealed that indoleamine 2,3-dioxygenase (IDO)-mediated tryptophan depletion was able to affect local tumor-infiltrating lymphocytes. The aim of this study was to investigate the clinical significance of the tumor-infiltrating Tregs and tumoral IDO expression during the progression of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas. METHODS: We investigated the prevalence and localization of FOXP3+ Tregs, CD8+ lymphocytes, and IDO expression in IPMNs by immunohistochemistry. We recruited 39 cases with IPMNs (IPMA: adenoma, n = 11; IPMB: borderline malignancy, n = 9; IPMC: noninvasive carcinoma, n = 7; I-IPMC: invasive IPMC, n = 12). RESULTS: The prevalence of Tregs increased step by step during the carcinogenesis of IPMNs (Kruskal-Wallis test: p < 0.0001). IDO expression in the tumor was observed in 5 cases with IPMNs (IPMC, n = 1; I-IPMC, n = 4). IDO expression in the tumor was positively correlated with the prevalence of Tregs in IPMNs. CONCLUSIONS: FOXP3+ Tregs play a role in controlling the immune surveillance against IPMNs at the premalignant stage. IDO expression in the tumor is one of the late-stage phenomena of multistage carcinogenesis of IPMNs.

Hepatocellular carcinoma occurring in a young Crohn's disease patient.

Reported herein is a case of hepatocellular carcinoma (HCC) occurring in a 25-year-old Japanese man who was diagnosed with Crohn's disease (CD) at 14 years of age; treatment included predonisolone, azathioprine, and infliximab. The tumor was located in right upper lobe and the size was 8 cm in diameter; histology was poorly differentiated HCC with pleomorphic cellular changes. Adjacent normal liver showed no evidence of cirrhosis or viral hepatitis. Until now, only six cases of HCC arising in patients with CD have been reported in the English-language literature. Most of these patients had early onset of CD and HCC: none had cirrhosis or virus hepatitis. Most patients had a long disease history of CD and were being medicated with several immunosuppressive agents. Some factors associated with CD might indirectly or directly be related to the development of HCC in CD patients, although the possibility that these HCC occurred coincidentally in CD patients, including the present patient, cannot be ruled out. Accumulation of cases is necessary to evaluate the relationship between CD and HCC precisely.

Rapid screening assay for KRAS mutations by the modified smart amplification process.

Previously, the smart amplification process version 2 (SMAP-2) was developed to detect mutations from tissue and in crude cell lysates and has been used for rapid diagnosis of specific somatic mutations with single-nucleotide precision. The purpose of this study was to develop a rapid and practical method to detect cancer and metastasis in specimens using the SMAP-2 assay. We developed modified SMAP-2 assays that enabled detection of any change in a single codon using a single assay. Rapid SMAP-2 screening assays are suitable for routine clinical identification of critical amino acid substitutions such as codon 12 mutations in KRAS. Primers bracketing the first two nucleotides of KRAS codon 12 were designed so that all possible alleles would be amplified by the SMAP-2 assay. In combination with the peptide nucleic acid (PNA) with exact homology to the wild-type allele, our assay amplified all mutant alleles except for the wild-type sequence. With this new assay design (termed PNA-clamp SMAP-2), we could detect KRAS mutations within 60 minutes, including sample preparation. We compared results from PNA-clamp SMAP-2 assay, polymerase chain reaction-restriction fragment length polymorphism, and direct sequencing of clinical samples from pancreatic cancer patients and demonstrated perfect concordance. The PNA-clamp SMAP-2 method is a rapid, simple, and highly sensitive detection assay for cancer mutations.

Targeting of CDC20 via small interfering RNA causes enhancement of the cytotoxicity of chemoradiation.

BACKGROUND: Cell division cycle 20 homologue (CDC20), which encodes a protein that promotes chromosomal separation, is highly expressed in several carcinomas, including pancreatic cancer. MATERIALS AND METHODS: To ascertain whether this gene could be a potential therapeutic target, the RNA interference technique was applied using small interfering RNA (siRNA) to knockdown CDC20 expression. RESULTS: The CDC20 siRNA showed more than 90% inhibition of CDC20 expression at both the transcriptional and translational levels and the specific knockdown of CDC20 expression inhibited the cell growth of human pancreatic carcinoma cells in vitro. Suppression of CDC20 induced accumulation of the cells in the G2/M-phase of the cell cycle. In addition, the knockdown of CDC20 caused enhancement of the cytotoxicity of paclitaxel and increased the effect of gamma-irradiation against pancreatic carcinoma cells. CONCLUSION: CDC20 is a promising target for gene specific therapy in human pancreatic cancer.