[A Case of Long-Term Survival with S-1/Cisplatin for Liver Hilum Lymph Node Metastasis of Anal Canal Squamous Cell Carcinoma after Chemoradiotherapy].

A 70-year-old woman was admitted to a local hospital because of anal pain during defecation. Anoscopy revealed an anal mass lesion, and the patient was referred to our hospital. Colonoscopy revealed an anal canal tumor with ulceration, and biopsy showed squamous cell carcinoma. The patient was treated with chemoradiotherapy(chemotherapy with capecitabine plus mitomycin C and 54 Gy radiation in the anal region)and achieved complete response. However, metastatic recurrence was detected in a lymph node in the hepatic hilar region. We administered an S-1/CDDP combination chemotherapy (5 courses). For 3 years and 5 months since the initial treatment, the patient survived with no signs of recurrence. We report a rare case of long-term survival with S-1/CDDP for distant metastasis of anal canal squamous cell carcinoma after chemoradiotherapy.

[A Rapid Clinical Course of Pulmonary Embolism Associated with Gallbladder Mucinous Carcinoma].

A 51-year-old woman with edema of the lower extremities and exertional dyspnea was admitted to our hospital. Enhanced CT revealed thrombi of the pulmonary artery and a gallbladder tumor. After anticoagulation therapy was started on her, anemia and jaundice progressed; thus, endoscopic retrograde cholangiopancreatography(ERCP)was performed on suspicion of bleeding from a gallbladder tumor. We performed cholecystectomy in emergency to control the anemia due to hemorrhage. Oxygenation suddenly worsened intraoperatively, maintaining her blood pressure became difficult, and the patient decompensated. The histopathological diagnosis was gallbladder mucinous carcinoma with severe lymphatic invasion. Although an autopsy was not performed, pulmonary artery embolism derived from a tumor embolus was the suspected cause of the sudden change of the clinical course.

[A Resected Case of Metachronous Solitary Metastasis of Jejunum after Surgery of Triple Colon Cancers].

A 68-year-old man underwent partial colectomy and double-barrel colostomy for an obstructive colon cancer of the splenic flexure at another hospital 10 years before. He was referred to us with an examination of anemia pointed out in human dock. Lower gastrointestinal endoscopy revealed the tumor occupied the remnant descending colon. We performed remnant left hemicolectomy and diagnosed as triple colon cancers. Six months after the initial operation, he was admitted to us with the chief complaints of abdominal fulness and vomit. Abdominal CT and radiologic enteroclysis after decompression used the ileus tube revealed complete stenosis at the small intestine. We performed surgery with a suspicion of obstruction of the small intestine. The tumor, 5 cm in diameter, occupied the jejunum was detected, and partial resection of the jejunum was performed. Histologically, the tumor was diagnosed as solitary metastasis of jejunum.

Histopathological validation of optical frequency domain imaging to quantify various types of coronary calcifications.

AIMS: This study evaluated whether optical frequency domain imaging (OFDI) could identify various coronary calcifications and accurately measure calcification thickness in comparison with histopathology. METHODS AND RESULTS: A total of 902 pathological cross-sections from 44 coronary artery specimens of human cadavers were examined to compare OFDI and histological images. Histological coronary calcification was classified into four different types: (i) superficial dense calcified plates, (ii) deep intimal calcification, (iii) scattered microcalcification, and (iv) calcified nodule. The thickness of calcification was measured when both the leading and trailing edges of calcification were visible on OFDI. Of the 902 histological cross-sections, 158 (18%) had calcification: 105 (66%) were classified as superficial dense calcified plates, 20 (13%) as deep intimal calcifications, 30 (19%) as scattered microcalcifications, and 3 (2%) as calcified nodules. Superficial dense calcified plates appeared as well-delineated heterogeneous signal-poor regions with sharp borders on OFDI. Deep intimal calcifications could not be identified on OFDI. Scattered microcalcification appeared as homogeneous low intensity areas with indiscriminant borders. Calcified nodule, a high-backscattering protruding mass with an irregular surface, also appeared as a low intensity area with a diffuse border. The ROC analysis identified calcium thicknesses <893 µm as cut points for the prediction of measurable calcification (72% sensitivity and 91% specificity, area under the curve = 0.893, P < 0.001). CONCLUSION: Our study demonstrated the potential capability of OFDI to characterize various types of coronary calcifications, which may contribute to the understanding of the pathogenesis of coronary atherosclerosis.

Chronic ileocolic intussusception due to transmural infiltration of diffuse large B cell lymphoma in a 14-year-old boy: a case report.

Chronic intussusception, defined as intussusception continuing over 14 days, is rare in children. We herein report a case of chronic ileocolic intussusception caused by the transmural infiltration of diffuse large B cell lymphoma in a 14-year-old boy. The patient had been suffering from anorexia and intermittent abdominal pain for 5 weeks, during which his body weight decreased by around 7 kg. Upon admission to our hospital, ultrasonography and enhanced computed tomography (CT) of the abdomen showed ileocolic intussusception. A retrospective examination of abdominal CT led us to suspect that the intussusception had initially appeared 5 weeks before admission, presumably coinciding with the beginning of the patient's abdominal symptoms. Since hydrostatic reduction was unsuccessful, laparotomy was performed, which showed unreducible ileocolic intussusception with a marked edematous ileum and mesentery. Ileocecal resection without lymph node dissection was carried out, and a histological examination of the resected specimen revealed the transmural infiltration of diffuse large B-cell lymphoma of the terminal ileum. The patient's postoperative course was uneventful, and adjuvant chemotherapy was administered. This case illustrates the diagnostic challenges of confirming 'chronic' intussusception in older children.

Characterization of various types of mast cells derived from model mice of familial gastrointestinal stromal tumors with KIT-Asp818Tyr mutation.

Sporadic mast cell neoplasms and gastrointestinal stromal tumors (GISTs) often have various types of somatic gain-of-function mutations of the c-kit gene which encodes a receptor tyrosine kinase, KIT. Several types of germline gain-of-function mutations of the c-kit gene have been detected in families with multiple GISTs. All three types of model mice for the familial GISTs with germline c-kit gene mutations at exon 11, 13 or 17 show development of GIST, while they are different from each other in skin mast cell number. Skin mast cell number in the model mice with exon 17 mutation was unchanged compared to the corresponding wild-type mice. In the present study, we characterized various types of mast cells derived from the model mice with exon 17 mutation (KIT-Asp818Tyr) corresponding to human familial GIST case with human KIT-Asp820Tyr to clarify the role of the c-kit gene mutation in mast cells. Bone marrow-derived cultured mast cells (BMMCs) derived from wild-type mice, heterozygotes and homozygotes were used for the experiments. Immortalized BMMCs, designated as IMC-G4 cells, derived from BMMCs of a homozygote during long-term culture were also used. Ultrastructure, histamine contents, proliferation profiles and phosphorylation of various signaling molecules in those cells were examined. In IMC-G4 cells, presence of additional mutation(s) of the c-kit gene and effect of KIT inhibitors on both KIT autophosphorylation and cell proliferation were also analyzed. We demonstrated that KIT-Asp818Tyr did not affect ultrastructure and proliferation profiles but did histamine contents in BMMCs. IMC-G4 cells had an additional novel c-kit gene mutation of KIT-Tyr421Cys which is considered to induce neoplastic transformation of mouse mast cells and the mutation appeared to be resistant to a KIT inhibitor of imatinib but sensitive to another KIT inhibitor of nilotinib. IMC-G4 cells might be a useful mast cell line to investigate mast cell biology.

Diffuse alveolar damage in a patient with Epstein Barr virus (EBV)-positive diffuse large B-cell lymphoma,severely low serum folate, and megaloblastic anemia: a case report of autopsy.

We report a case of a 49-year-old Japanese man, who was admitted to our hospital because of severe dyspnea. He was found to have severely low serum folate and megaloblastic anemia, which was at first suspected to cause his dyspnea. It was assumed that severely low serum folate might be related to his malnutrition, probably caused by habitual alcohol consumption. He died in several days because of acute respiratory distress syndrome. Autopsy revealed diffuse alveolar damage (DAD) in the lungs and systemic lymph node swelling by EBV-positive diffuse large B-cell lymphoma, in addition to megaloblastic anemia in the bone marrow. Together with histological hemophagocytosis and high level of serum iron and ferritin, DAD was considered to be caused by hypercytokinemia triggered by the presence of EBV-positive diffuse large B-cell lymphoma. On the other hand, pathological findings suggestive of habitual alcohol consumption were not apparent. We considered that low serum folate in this case was not by the low intake but by increased consumption of folate by rapid progression of the lymphoma.

Extracellular domain c-kit mutation with duplication of Ser501Ala502 found in gastrointestinal stromal tumors is more imatinib- and nilotinib-sensitive than that with duplication of Ala502Tyr503.

The great majority of gastrointestinal stromal tumors (GISTs) have gain-of-function mutations of the c-kit gene, which encodes KIT receptor tyrosine kinase. Most of the mutations are located at exon 11, but some are at exon 9 or at other exons. Mutation types at exon 11 vary, while most mutations at exon 9 are a particular duplication of Ala502Tyr503 (KIT-Dup-Ala502Tyr503). Recently a duplication of Ser501Ala502 (KIT-Dup-Ser501Ala502) at exon 9 has been reported in two cases of pediatric mastocytosis and one case of adult mast cell leukemia. Although KIT-Dup-Ser501Ala502 had not been reported in GISTs, we found two GIST cases possessing the mutation in 45 GIST cases with exon 9 c-kit gene mutations, among a total of approximately 500 GIST cases examined. In this report, we briefly summarize clinicopathological findings of the two cases, and characterize the biology of the mutation. When autophosphorylation of KIT-Dup-Ser501Ala502 was examined by transient transfection of c-kit cDNA with Dup-Ser501Ala502 into CHO-K1 cells, KIT-Dup-Ser501Ala502 was ligand-independently activating. The inhibitory effect of selective tyrosine kinase inhibitors, imatinib and nilotinib, on KIT-Dup-Ser501Ala502 was examined and compared with that of KIT-Dup-Ala502Tyr503. Imatinib efficiently inhibited constitutive activation of KIT-Dup-Ser501Ala502 at a concentration of 0.1 µM, whereas it inhibited that of KIT-Dup-Ala502Tyr503 at a concentration of 10 µM. Constitutive activation of KIT-Dup-Ser502Ala503 was not inhibited by nilotinib even at a concentration of 10 µM but that of KIT-Dup-Ala501Tyr502 was almost completely inhibited at a concentration of 1 µM. The results suggest that imatinib and nilotinib could be more effective on GISTs with KIT-Dup-Ser501Ala502 than those with KIT-Dup-Ala502Tyr503. In fact, a patient with KIT-Dup-Ser501Ala502 showed long-term stable disease with administration of the usual dose of 400 mg imatinib. Although mutation sites of KIT-Dup-Ser501Ala502 and KIT-Dup-Ala502Tyr503 are closely located, imatinib- and nilotinib-sensitive KIT-Dup-Ser501Ala502 are distinguishable from KIT-Dup-Ala502Tyr503.

Characterization of novel germline c-kit gene mutation, KIT-Tyr553Cys, observed in a family with multiple gastrointestinal stromal tumors.

We found a novel type germline mutation at exon 11 of the c-kit gene, which results in a substitution of Tyr to Cys at codon 553 of the c-kit gene product (KIT-Tyr553Cys), in a 68-year-old female patient with multiple gastrointestinal stromal tumors (GISTs). In the present study, we carried out mutational analysis in her family members to determine the carriers and characterized the mutation by introducing the corresponding mutation (murine KIT-Tyr552Cys) into expression vector possessing murine c-kit cDNA. Mutational analysis of peripheral blood leukocytes of her family members revealed that a 44-year-old son had the same mutation, but at present he had neither apparent symptoms nor images of multiple GISTs. By transfection with the expression vector possessing the murine mutant c-kit cDNA, interleukin-3-dependent Ba/F3 murine lymphoid cells started growing autonomously without any growth factors, indicating that the mutation was considered to be of gain-of-function. Imatinib, a small molecule of tyrosine kinase inhibitor, effectively inhibited autophosphorylation of KIT-Tyr552Cys. Nilotinib, another small molecule of the KIT inhibitor, also effectively inhibited autophosphorylation of KIT-Tyr552Cys. In fact, proliferation of Ba/F3 cells expressing KIT-Tyr552Cys was effectively inhibited by both imatinib and nilotinib. These findings indicate that the novel type human KIT-Tyr553Cys mutation is the cause of the present familial and multiple GISTs, and that both imatinib and nilotinib might effectively inhibit the growth of GISTs developing in the patients of this family.