[Liver metastasis from alpha-fetoprotein-producing gastric cancer 27 years postoperation:a case report].

A 75-year-old man with a history of distal gastrectomy for gastric cancer at 48 years of age underwent abdominal computed tomography, which revealed a left hepatic lobe tumor alongside direct gastric invasion. His blood test results revealed significant increase in serum alpha-fetoprotein (AFP) levels (32240.3ng/mL). A gastroscopy revealed that the histopathological findings of the biopsy specimens of the gastric invasion area were identical to those observed in the surgical specimens of gastric cancer, which was diagnosed 27 years earlier. The evaluation of the biopsy and surgical specimens revealed AFP positivity, which confirmed the diagnosis of the late recurrence of AFP-positive gastric cancer. Herein, we presented a rare clinical case of this malignancy. Additionally, a close, long-term postoperative follow-up is warranted in patients with AFP-producing gastric cancer.

Computer-aided diagnosis of early-stage colorectal cancer using nonmagnified endoscopic white-light images (with videos).

BACKGROUND AND AIMS: Differentiation of colorectal cancers (CRCs) with deep submucosal invasion (T1b) from CRCs with superficial invasion (T1a) or no invasion (Tis) is not straightforward. This study aimed to develop a computer-aided diagnosis (CADx) system to establish the diagnosis of early-stage cancers using nonmagnified endoscopic white-light images alone. METHODS: From 5108 images, 1513 lesions (Tis, 1074; T1a, 145; T1b, 294) were collected from 1470 patients at 10 academic hospitals and assigned to training and testing datasets (3:1). The ResNet-50 network was used as the backbone to extract features from images. Oversampling and focal loss were used to compensate class imbalance of the invasive stage. Diagnostic performance was assessed using the testing dataset including 403 CRCs with 1392 images. Two experts and 2 trainees read the identical testing dataset. RESULTS: At a 90% cutoff for the per-lesion score, CADx showed the highest specificity of 94.4% (95% confidence interval [CI], 91.3-96.6), with 59.8% (95% CI, 48.3-70.4) sensitivity and 87.3% (95% CI, 83.7-90.4) accuracy. The area under the characteristic curve was 85.1% (95% CI, 79.9-90.4) for CADx, 88.2% (95% CI, 83.7-92.8) for expert 1, 85.9% (95% CI, 80.9-90.9) for expert 2, 77.0% (95% CI, 71.5-82.4) for trainee 1 (vs CADx; P = .0076), and 66.2% (95% CI, 60.6-71.9) for trainee 2 (P < .0001). The function was also confirmed on 9 short videos. CONCLUSIONS: A CADx system developed with endoscopic white-light images showed excellent per-lesion specificity and accuracy for T1b lesion diagnosis, equivalent to experts and superior to trainees. (Clinical trial registration number: UMIN000037053.).

A case of anisakiasis in the sigmoid colon.

Colonic anisakiasis is rare because most cases of anisakiasis occur in the stomach. An accurate diagnosis is sometimes difficult because of the rarity and symptom nonspecificity. We should consider the possibility of colonic anisakiasis when examining patients who have a history of consuming raw fish.

[Diagnosis of an ileal neuroendocrine tumor based on lymph node metastases: a case report].

A 72-year-old man was diagnosed with tumors outside of the stomach and mesentery of the small intestine on abdominal computed tomography. Histopathological examination of an endoscopic ultrasound-guided fine-needle aspiration biopsy specimen confirmed the diagnosis of lymph node metastasis of a neuroendocrine tumor (NET). Gastroscopy, colonoscopy, small bowel capsule endoscopy, somatostatin receptor scintigraphy, and 18F-fluorodeoxyglucose positron emission tomography were performed. However, the primary lesion could not be diagnosed. The patient underwent surgery, and an ileal submucosal tumor, which was not identified preoperatively in addition to the aforementioned abdominal tumors, was detected. All tumors were diagnosed as NET, and the ileal tumor was considered the primary lesion. The patient has shown no recurrence postoperatively. The current study presents a case of an ileal NET with lymph node metastases in a patient in whom the primary lesion remained preoperatively undiagnosed.

A CRAF/glutathione-S-transferase P1 complex sustains autocrine growth of cancers with KRAS and BRAF mutations.

The Ras/RAF/MEK/ERK pathway is an essential signaling cascade for various refractory cancers, such as those with mutant KRAS (mKRAS) and BRAF (mBRAF). However, there are unsolved ambiguities underlying mechanisms for this growth signaling thereby creating therapeutic complications. This study shows that a vital component of the pathway CRAF is directly impacted by an end product of the cascade, glutathione transferases (GST) P1 (GSTP1), driving a previously unrecognized autocrine cycle that sustains proliferation of mKRAS and mBRAF cancer cells, independent of oncogenic stimuli. The CRAF interaction with GSTP1 occurs at its N-terminal regulatory domain, CR1 motif, resulting in its stabilization, enhanced dimerization, and augmented catalytic activity. Consistent with the autocrine cycle scheme, silencing GSTP1 brought about significant suppression of proliferation of mKRAS and mBRAF cells in vitro and suppressed tumorigenesis of the xenografted mKRAS tumor in vivo. GSTP1 knockout mice showed significantly impaired carcinogenesis of mKRAS colon cancer. Consequently, hindering the autocrine loop by targeting CRAF/GSTP1 interactions should provide innovative therapeutic modalities for these cancers.

Human infection by acanthocephalan parasites belonging to the genus Corynosoma found from small bowel endoscopy.

A 73-year-old man with a suspected ileus in January 2013 and subsequently suffered melena in February 2014 was endoscopically examined. As a result of the examinations, unidentified species of Corynosoma sp. and Corynosoma villosum were recovered from the small intestine, further endoscopic diagnosis suggested relevance between abdominal pain and the present infections in the small intestine. The recovered worms were composed of gravid females with developed eggs, suggesting that these parasites can survive for a long time in the intestine after infection. In this case, the short interval between infections appears to be due to the individual's eating habits which consist of regularly consuming uncooked seafood.

Laparoscopic-endoscopic cooperative surgery is a safe and effective treatment for superficial nonampullary duodenal tumors.

The use of endoscopic submucosal dissection (ESD) for duodenal neoplasms has increased in recent years, but delayed perforation and bleeding are also known to frequently occur. We present two cases in which duodenal adenoma was successfully treated with laparoscopic-endoscopic cooperative surgery. ESD was combined with laparoscopic seromuscular sutures. The lesions in both cases were located in the second portion of the duodenum. The patients requested resection of the lesion, and we performed laparoscopic-endoscopic cooperative surgery. After the laparoscopic surgeon mobilized the duodenum, the endoscopic surgeon performed ESD for the duodenal tumor without perforation. The laparoscopic surgeon sutured the duodenal wall in the seromuscular layer to strengthen the ulcer bed after ESD. Histopathological studies confirmed that the surgical margins were tumor-free in both cases. The patients were discharged with no complications. This unique laparoscopic-endoscopic cooperative procedure is a safe and effective method for resecting superficial nonampullary duodenal tumors.

[A case of advanced primary colorectal carcinoma accompanied by liver metastasis in which ileus developed due to marked fibrosis with cicatricial formation in primary colorectal cancer treated by chemotherapy including bevacizumab].

A 64-year-old woman was introduced to our hospital with liver tumors. Our examination revealed that she had advanced colon carcinoma with multiple liver metastasis. Without symptoms from the primary cancer, she underwent chemotherapy of avastin FOLFOX. After 2 courses of chemotherapy, she suffered ileus and underwent operation. The resected specimen showed marked tumor necrosis and fibrosis, but few tumor cells remained in the primary lesion. We think this was a rare case of suffered ileus because of marked response of chemotherapy in primary colon carcinoma.

Exacerbation of bloody diarrhea as a side effect of mesalamine treatment of active ulcerative colitis.

Mesalamine has been used as the first-line therapy for the treatment of ulcerative colitis (UC) because of its efficacy and fewer side effects. However, earlier study showed that mesalamine occasionally causes diarrhea. We are presenting a patient with active UC in whom bloody diarrhea accompanied by abdominal pain and fever occurred and the symptoms were aggravated after administration of mesalamine. In order to clarify the reason of symptoms aggravation, drug lymphocyte stimulation test and rechallenge trial with mesalamine were performed. The results indicated the possibility that aggravation was related to allergic reaction and was dose-dependent. Furthermore, we examined colonoscopic views but there was no remarkable change in before and after rechallenge trial. Based on the above result, the patient was diagnosed with mesalamine intolerance. In order to differentiate whether the exacerbation of bloody diarrhea is due to the side effects of the mesalamine or a true relapse of UC, taking careful history before and after increasing mesalamine dosage as well as being aware of side effects of mesalamine are required. Clinicians should be aware of diarrhea as a side effect of mesalamine particularly after onset of mesalamine formulation, change in mesalamine formulation, or change in mesalamine dose.

[A long term survivor of advanced gastric cancer treated with multi-drug combination chemotherapy].

We report a case of 70-year-old man who was admitted to our hospital due to hematemesis in June 2004. He was diagnosed by gastroscopy as having a type III moderately-poorly differentiated adenocarcinoma. A computed tomography (CT) scan revealed multiple lymph nodes swelling (#13, #16), finally he was diagnosed with gastric cancer stage IV (cT3, cN3, cM1). He was treated with S-1, but lymph nodes swelling increased in size, and then in March 2005, the treatment was changed to a second-line chemotherapy consisting of CPT-11 and CDDP. Abdominal CT scan showed a remarkable reduction of #16b1 lymph node, and the second-line chemotherapy was continued until 23 courses. But in April 2007, gastroscopy revealed the enlargement of gastric lesion. He was treated by third-line chemotherapy consisting of paclitaxel and doxifluoridine. This therapy was effective and continued until 7 courses. However, the treatment gradually became resistant and he died in May 2008, which was 4 years since the initial diagnosis.

A Phase I trial of arterial infusion chemotherapy with gemcitabine and 5-fluorouracil for unresectable advanced pancreatic cancer after vascular supply distribution via superselective embolization.

BACKGROUND: We previously reported that arterial infusion chemotherapy improved the response rate and survival of the patients with pancreatic cancer at advanced stages in an open trial. We conducted a Phase I trial of arterial infusion chemotherapy with gemcitabine and 5-fluorouracil for advanced pancreatic cancer after vascular supply distribution via superselective embolization. METHODS: Patients were treated after arterial embolization for hemodynamic change to restrict the blood flow into the pancreas (mainly to the great pancreatic artery and the caudal pancreatic artery). Arterial infusion chemotherapy consisted of gemcitabine in doses that were increased from 600 to 1000 mg/m(2) in subsequent cohorts on Day 1 plus continuous infusion of 5-fluorouracil 300 mg/m(2)/day on Days 1-5 every 2 weeks. Result Twelve patients were enrolled. The maximum tolerated dose of gemcitabine was determined to be Level 3 (1000 mg/m(2)). Only very mild hematological and non-hematological toxicities were noted. The overall response rate was 33.3%. The median survival time was 22.7 (95% CI; 9.5-24.5) months and the 1- and 2-year overall survival rates were 83.3 and 25.0%, respectively. CONCLUSION: Arterial infusion chemotherapy using 1000 mg/m(2) gemcitabine on Day 1 and 300 mg/m(2)/day 5-fluorouracil on Days 1-5 every 2 weeks warrants a Phase II study.

[A case of intraductal papillary mucinous neoplasm with internal pancreatic fistula causing left ureteral obstruction].

A 75-year-old man had been admitted to another hospital because of left abdominal pain, and was given a diagnosis of left hydronephrosis and acute pancreatitis. After a JJ stent insertion and medication, he was transferred to our hospital for further examinations. US and EUS revealed a chronic pancreatitis-like pattern and multicystic lesion in the pancreas head and body. At that time enhanced CT findings showed an extrapancreatic low density area to be inflammatory change, extending from the pancreas body to the left crus of the diaphragm and posteriorly the spreading from the left crus of the diaphragm via the left urinary duct into the left iliopsoas muscle, in which MRI revealed partial high intensity. ERCP and MRCP showed focal irregular narrowing of the pancreatic duct of unknown cause, and we decided that an internal pancreatic fistula due to pancreatitis had induced left ureteral obstruction, caused by a protein plug or alcohol. Follow-up 6 months later showed that extrapancreatic spreading of the low density area had markedly regressed without any change in the ureteral obstruction.

Aberrant crypt foci: detection, gene abnormalities, and clinical usefulness.

Human aberrant crypt foci (ACF) were first identified as lesions consisting of large thick crypts in colonic mucosa of surgical specimens after staining with methylene blue. Previously we succeeded in identifying ACF by using magnifying endoscopy and analyzed the number, size, and dysplastic features of ACF in normal controls and patients with adenoma or cancer patients. On the basis of these analyses, we strongly suggested that ACF, particularly dysplastic ACF, are precursor lesions of the adenoma-carcinoma sequence in humans. In most sporadic ACF, K-ras mutations were positive, but APC mutations were negative irrespective of nondysplastic or dysplastic features. Conversely, in most ACF from familial adenomatous polyposis patients, APC mutations were positive but K-ras mutations were negative. These results may suggest that the molecular mechanism of sporadic colon carcinogenesis is not necessarily the same as that of familial adenomatous polyposis. It was shown that ACF acquired resistance to apoptosis induced by bile salts, whereas normal colonic epithelial cells are turning over consistently by apoptosis. This apoptosis resistance was closely associated with glutathione S-transferase P1-1 expression. One of the most important clinical applications of ACF observation with magnifying endoscopy is its use as a target lesion for chemoprevention. Because ACF are tiny lesions, they should be eradicated during a short time by administration of chemopreventive agents. In fact, we performed an open chemopreventive trial of sulindac and found that the number of ACF was reduced markedly in 2 months. We currently are proceeding with a randomized double-blind trial targeting ACF.

[A case of metastatic liver tumor from colorectal carcinoma--continued arterial infusion chemotherapy through a microcatheter located in replaced right hepatic artery].

The patient was a 78-year-old male with a history of colon cancer. After surgical resection of colon cancer, he suffered a multiple liver metastasis. We treated him by arterial infusion chemotherapy with the catheter edge embedded at the common hepatic artery. For a long period, the lesions were defined as partial response on WHO-criteria, but a wide area of the common hepatic artery was shrunk. After changing the treatment to systemic intravenous chemotherapy, the metastatic lesions began to enlarge. Then, we somehow were able to put a microcatheter into the replaced right hepatic artery (rRHA), and could restart arterial infusion chemotherapy. We continued this procedure for over a year without any complication.

Glutathione-S-transferase P1-1 protects aberrant crypt foci from apoptosis induced by deoxycholic acid.

BACKGROUND & AIMS: Aberrant crypt foci, precursors of colonic adenoma, are frequently positive for glutathione-S-transferase P1-1. Because deoxycholic acid is an apoptosis-inducing xenobiotic in the colon, we examined the possibility that aberrant crypt foci, through the cytoprotecting function of glutathione-S-transferase P1-1, resist deoxycholic acid-induced apoptosis, thereby surviving to become adenomas and subsequently cancer. METHODS: Glutathione-S-transferase P1-1 or cyclooxygenase-2 expression and the percentage of apoptotic cells in aberrant crypt foci were examined by immunohistochemistry and by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate nick-end labeling, respectively. Glutathione-S-transferase P1-1 was transfected into colon cancer cells (M7609) and human lung fibroblasts, and deoxycholic acid-induced apoptosis was evaluated by a dye-uptake assay and flow cytometry. Binding of deoxycholic acid to glutathione-S-transferase P1-1 was analyzed by circular dichroism and immunoprecipitation. Caspase activities were determined by colorimetric protease assay, and sulindac binding to glutathione-S-transferase P1-1 was determined by inhibition assay of glutathione-S-transferase P1-1 activity. RESULTS: Aberrant crypt foci showed positive immunostaining for glutathione-S-transferase P1-1 but negative staining for cyclooxygenase-2. The percentage of apoptotic cells in aberrant crypt foci was significantly lower than in healthy epithelium, and the difference became more apparent with deoxycholic acid treatment. The impaired sensitivity of aberrant crypt foci to deoxycholic acid was restored by the glutathione-S-transferase P1-1-specific inhibitor gamma-glutamyl-S-(benzyl)cysteinyl-R-phenylglycine diethylester. By transfection of glutathione-S-transferase P1-1, M7609 cells became more resistant to deoxycholic acid-induced apoptosis than mock transfectants. Direct binding of glutathione-S-transferase P1-1 to deoxycholic acid was proven by circular dichroism and by immunoprecipitation. The aberrant crypt foci in adenoma patients treated with sulindac, which was shown to bind to glutathione-S-transferase P1-1, underwent apoptosis in 4 days and mostly regressed in 2-3 months. CONCLUSIONS: Glutathione-S-transferase P1-1 protects aberrant crypt foci from deoxycholic acid-induced apoptosis and may play a pivotal role in early colon carcinogenesis.

Chemoprevention of colorectal cancer.

Colorectal cancer is a disease with a high mortality rate and it has been increasing in prevalence worldwide. Chemoprevention, as well as primary and secondary prevention, for colorectal cancer have attracted much attention. Many chemopreventive trials have been performed, and several agents, including nonsteroidal antiinflammatory drugs, such as aspirin and sulindac, cyclooxygenase-2 selective inhibitors, such as celecoxib, vitamin D, folate, and calcium, have been shown to have some effect. In these chemopreventive trials, the targeted lesions used for evaluation were mainly polyps. However, the chemopreventive effects of some agents on polyps may require several years to evaluate. Further, larger polyps may not be susceptible to chemopreventive agents. Aberrant crypt foci (ACF) are tiny lesions at the earliest stage of colorectal carcinogenesis, which consist of large, thick crypts identified by dense, methylene blue staining. We succeeded in identifying human ACF in situ using magnifying endoscopy and found that the number of ACF, particularly dysplastic ACF, increased significantly from normal subjects to adenoma patients and then to cancer patients. We also found that the number, size, and dysplastic features of ACF are significantly correlated with the number of adenomas in adenoma patients. Thus, it was surmised that ACF are precursor lesions of the adenoma-carcinoma sequence in humans and that ACF may be the most appropriate lesions as targets for chemoprevention. We have shown that the number of ACF was significantly reduced in patients treated with sulindac. We are currently proceeding with a randomized, double-blind, chemopreventive trial targeting ACF.

Advanced pancreatic carcinoma showing a complete response to arterial infusion chemotherapy.

We report a patient with advanced carcinoma of the pancreatic body and tail with multiple liver metastases who showed a complete response to hepatic and splenic arterial infusion chemotherapy (HSAIC) with gemcitabine and 5-fluorouracil, following transcatheter peripancreatic arterial embolization (TPPAE) and partial splenic embolization (PSE). Nonresectable advanced pancreatic carcinoma tends to have a low response to medical treatment, with the median survival time being 6 months or less for stage IV cases. We disclose herein that the median survival time of patients receiving HSAIC after TPPAE is more than three times longer than the survival time attained with conventional treatments. However, in patients with advanced carcinoma of the pancreatic tail, for which TTPAE is not applicable, survival times remain low. Thus, in the patient described here, we also performed embolization of the left gastric and short gastric arteries as well as PSE to increase the flow within the great pancreatic and caudal pancreatic arteries via the splenic artery, and gemcitabine and 5-fluorouracil were administered via the splenic artery. As a result of these procedures, marked reduction in the advanced carcinoma of the pancreatic body and tail and of liver metastases was attained.