Yasuhiro Nagamachi

The autocrine motility factor receptor gene encodes a novel type of seven transmembrane protein1

Autocrine motility factor receptor (AMFR) is a cell surface glycoprotein of molecular weight 78 000 (gp78), mediating cell motility signaling in vitro and metastasis in vivo. Here, we cloned the full‐length cDNAs for both human and mouse AMFR genes. Both genes encode a protein of 643 amino acids containing a seven transmembrane domain, a RING‐H2 motif and a leucine zipper motif and showed a 94.7% amino acid sequence identity to each other. Analysis of the amino acid sequence of AMFR with protein databases revealed no significant homology with all known seven transmembrane proteins, but a significant structural similarity to a hypothetical protein of Caenorhabditis elegans, F26E4.11. Thus, AMFR is a highly conserved gene which encodes a novel type of seven transmembrane protein.

Cytomegalovirus cholangitis and pancreatitis in an immunocompetent patient

Cholangitis and pancreatitis associated with cytomegalovirus (CMV) infection in an immunocompetent patient is reported. Endoscopic retrograde cholangiography performed on a 55-year-old man for evaluation of the cause of jaundice and liver dysfunction revealed a distal focal irregular narrowing of the common bile duct. Microscopic findings of the resected specimen showed chronic cholangitis and CMV pancreatitis. Immunohistochemistry disclosed that epithelial cells in the inflamed bile duct were positive for CMV antigen, which was compatible with CMV cholangitis. Inflammation of the biliary tract or pancreas by CMV has been commonly reported as a complication in immunocompromised patients. Our report appears to be a rare case, but suggests that CMV cholangitis or pancreatitis should be considered in the differential diagnoses of common bile duct stenosis or pancreatitis even in immunocompetent individuals.

Orthotopic growth and metastasis of human non-small cell lung carcinoma cells injected into the pleural cavity of nude mice

We have constructed a metastatic model of human non-small cell lung cancer (NSCLC) by injection of NSCLC cell lines directly into the left pleural cavity of BALB/c nude mice. All of seven NSCLC cell lines, which are tumorigenic after subcutaneous injection, were successfully transplanted in the pleural cavity, while only three of the seven cell lines produced lung metastatic colonies after intravenous injection. Tumors grew extensively in the pleural cavity and infiltrated into the lung parenchyma directly. Furthermore, tumors metastasized to the mediastinum and contralateral pleural cavity through lymphatic routes. Since this model is easy to perform and the result is reproducible, it would be useful for studies on the biological behavior and treatment of human NSCLC in vivo.

Establishment of cell lines with high- and low-metastatic potential from PC-14 human lung adenocarcinoma

This article reports the establishment of variant cell lines with high and low metastatic potential by repeated selection and the dilution plating technique. Five clones with high metastatic potential, Lu‐2, Lu‐7, Lu‐4, Lu‐1 and Lu‐5, and four clones with low metastatic potential, 3S, 7S, 8S and 13S, were established from PC‐14 human lung adenocarcinoma. The high‐metastatic cell lines produced enhanced lung metastases, but the low‐metastatic cell lines did not produce lung metastasis by injection into the tail vein of 5‐week‐old BALB/c nude mice. The high‐metastatic cell lines produced enhanced tumors on both visceral and parietal pleurae, and enhanced metastases to the mediastinum and contralateral pleural cavity. The low‐metastatic cell lines produced reduced tumors on both visceral and parietal pleurae and reduced metastases to the mediastinum and contralateral pleural cavity after injection into the left preceral cavity of the nude mice. When the nine variant cell lines and original PC‐14 cells were embedded in collagen gels, the PC‐14 cells and the low‐metastatic cell lines gave rise to colonies with a dendritic morphology, and cells were tightly associated. The high‐metastatic cell lines were more loosely associated and scattered into three‐dimensional colonies. These nine cloned cell lines originated from heterogeneous populations of the parental PC‐14 cells should be useful tools for studying the process of metastasis of lung cancer.

Suicidal gene therapy for pleural metastasis of lung cancer by liposome-mediated transfer of herpes simplex virus thymidine kinase gene.

Pleural metastasis is one of the most common complications in lung cancers. However, no effective therapy for pleural metastasis has been established thus far. We have constructed a metastatic model of non-small cell lung cancer (NSCLC) by injecting human NSCLC cell lines directly into the left pleural cavity of BALB/c nude mice. Because this model is easy to construct and the results are reproducible, we used this model for a preclinical evaluation of gene therapy for pleural metastasis of NSCLC. We took the novel approach of in vivo lipofection of a suicidal gene to lung cancer cells metastasized to the pleural cavity. A human lung cancer cell line, PC14, was inoculated into the pleural cavity of nude mice. After 1 day, a herpes simplex virus thymidine kinase gene expression plasmid was injected intrapleurally as a DNA-liposome complex, and ganciclovir was subsequently administered for 8 days. The survival rates of the ganciclovir-treated group were significantly better than those of the control groups. Flow cytometric analysis using a green fluorescent protein expression plasmid suggested that the transfection efficiency in the pleural cavity was 13.6%. Moreover, due to a bystander effect with PC14 cells, 10% of the gene transfer efficiency was sufficient to eradicate or suppress pleural metastasis. This preclinical study suggests the therapeutic feasibility of an in vivo lipofection-based suicidal gene/prodrug strategy for pleural metastasis of NSCLC.

Clinical and endoscopic features of acute hemorrhagic rectal ulcer

BackgroundAcute hemorrhagic rectal ulcer (AHRU) has increasingly been reported in Japan, whereas it has rarely been reported in the English literature and is not yet established as a disease entity. The aim of this study was to elucidate clinical and endoscopic characteristics of patients with AHRU.MethodsWe enrolled 20 patients with 26 ulcers diagnosed as AHRU in our department between January 2001 and October 2005. Clinical features such as the underlying disorder, Karnofsky performance status (PS), and presence or absence of anticoagulant or antiplatelet therapy, as well as endoscopic findings and type of bleeding, were evaluated. Strategies for hemostasis were also reviewed.ResultsThe most prevalent underlying disorder was diabetes mellitus, and the number of bedridden patients with PS 4 was relatively high. In addition, more than half of the patients had been treated with anticoagulant or antiplatelet agents. Endoscopically, ulcers were characteristically solitary and irregularly shaped, and they did not show any typical localization pattern. As a hemostatic strategy, clipping alone showed a favorable result, with a hemostatic success rate as high as 76.9%.ConclusionsThis study may support the establishment of AHRU as a new clinical entity. In aged patients being treated with anticoagulant or antiplatelet agents, especially bedridden patients using aspirin, the possible appearance of this disease should be kept in mind.

Intra-mesenteric artery steroid administration relieved severe refractory gastro-intestinal graft-vs.-host disease in an allogeneic bone marrow transplantation patient

We report a case of severe gastro‐intestinal (G‐I) graft‐vs.‐host disease (GVHD) successfully treated with intra‐mesenteric artery steroid administration. A 29‐year‐old man with severe aplastic anemia (SAA) was submitted to HLA‐identical unrelated allogeneic bone marrow transplantation (BMT) and was found to be suffering from grade IV G‐I GVHD. Although cyclosporine, steroid pulse therapy, and FK506 proved ineffective, 30 mg of water‐soluble prednisolone as administered into each the superior and inferior mesenteric artery with remarkable effects. This treatment was repeated two times, and the symptoms of G‐I GVHD disappeared completely. Am. J. Hematol. 56:277–280, 1997.

A Multicenter Retrospective Study of Mogamulizumab Efficacy in Adult T-Cell Leukemia/Lymphoma.

Micro‐Abstract Mogamulizumab recently became available for the treatment of adult T‐cell leukemia/lymphoma (ATL). We conducted a multicenter retrospective study of the efficacy of mogamulizumab for ATL treatment in patients in Japan and found that mogamulizumab is an effective therapeutic strategy in ATL. Some concern exists that the use of mogamulizumab in patients undergoing hematopoietic stem cell transplantation patients might cause severe graft‐versus‐host disease. Determining the optimum number of mogamulizumab administrations should be a priority for future studies. Background: Mogamulizumab, a defucosylated humanized monoclonal antibody targeting C‐C chemokine receptor 4, recently became available for the treatment of adult T‐cell leukemia/lymphoma (ATL). We conducted a multicenter retrospective study of the efficacy of mogamulizumab in ATL treatment in patients on Hokkaido Island, Japan. Materials and Methods: A total of 125 patients with ATL treated from January 2010 to December 2014 in 20 hospitals affiliated with the Hokkaido Hematology Study Group were enrolled in the present retrospective study. Results: Of the 125 ATL patients, 62 (46.6%) presented with the acute type, 51 (38.3%) with the lymphoma type, and 12 (9.0%) with the chronic type; the latter group included 7 unfavorable chronic cases. The median age at diagnosis was 68 years (range, 35‐86 years). The median survival for those with acute, lymphoma, and unfavorable chronic types was 302, 279, and 921 days, respectively. Advanced age, high lactate dehydrogenase level, poor performance status (3‐4), and the existence of B symptoms were unfavorable prognostic factors for overall survival (OS). Survival rate calculated from the day of diagnosis was significantly higher in patients treated with mogamulizumab. The OS of individuals receiving hematopoietic stem cell transplantation (HSCT) was superior to that of the non‐HSCT group. The median interval between the last mogamulizumab dose and allogeneic HSCT was 38 days (range, 21‐53 days). Of the 22 HSCT recipients who were not treated with mogamulizumab, overall acute graft‐versus‐host disease (aGVHD) and grade III‐IV aGVHD occurred in 12 (54.5%) and 3 (13.6%) patients, respectively. However, overall aGVHD and grade III‐IV aGVHD developed in 8 (88.9%) and 3 (33.3%) of the 9 HSCT recipients treated with mogamulizumab, respectively. Conclusion: Mogamulizumab improves OS in patients with ATL, although its use in HSCT patients might trigger severe GVHD. Determining the optimal pre‐HSCT mogamulizumab treatment regimen is thus a priority.

SUCCESSFUL MANAGEMENT OF METASTASIS-INDUCED PANCREATITIS BY ENDOSCOPIC PANCREATIC DUCT STENTING IN A CASE OF LARGE CELL LUNG CANCER

The prognosis for patients with metastasis‐induced acute pancreatitis (MIAP) is extremely poor. Although chemotherapy has been shown to improve overall survival in patients with MIAP, as well as in patients with small cell lung cancer, it is poorly tolerated by patients with severe pancreatitis. Furthermore, patients with a history of chemotherapy often develop multidrug‐resistant tumors. Here we report a first case of MIAP that was successfully managed by endoscopic pancreatic duct stenting. A 54‐year‐old man with pancreatic metastasis from large cell lung cancer developed acute pancreatitis approximately three times per month, despite a continuous conventional therapy for pancreatitis. As his disease was refractory to chemotherapy, he underwent endoscopic pancreatic duct stenting. The procedure was successful in controlling his pancreatitis, and he survived 7 months after the onset of a first acute pancreatitis. Our experience with this case suggests pancreatic duct stenting as one therapeutic method for MIAP.

Extramedullary involvement of the stomach presenting as multiple white elevations in the initial diagnosis of chronic myeloid leukemia treated with dasatinib

Dear Editor, A 68-year-old man, who had been treated for diabetes mellitus and hypertension for 15 years, was admitted to our hospital because of an elevated white blood cell (WBC) count. Approximately 1 year ago, his complete blood count was within the reference range. Laboratory data on admission were as follows: WBC count, 185.4 × 10/L (myeloblasts, 2.0%; promyelocytes, 3.0%; basophils, 0.0%); hemoglobin level, 11.2 g/dL; and platelet count, 132 × 10/L. The bone marrow was hypercellular without excess blasts (myeloblasts, 3.0%; promyelocytes, 10.0%), stained strongly positive for myeloperoxidase (MPO) and CD68, and stained negative for CD34 and p53. CD31 and glycophorin A staining were positive on megakaryocytes and erythroblasts, respectively. Gitter staining revealed no reticulin fibrosis. Chromosomal analysis by G-banding in the bone marrow showed 46,XY,t(9;22)(q34;q11.2) in all 24 analyzed cells. He was diagnosed with chronic myeloid leukemia (CML). The prognostic scores for Sokal, Hasford, and EUTOS were intermediate (0.92 points), intermediate (783 points), and low (0 points), respectively. Notably, esophagogastroduodenoscopy performed as gastrointestinal screening showed multiple, white, flat elevations up to 2 cm in diameter, mainly in the corpus of the stomach (Fig. 1a–d). Histopathological findings of the biopsy specimen revealed diffuse infiltration of small round cells in the lamina propria of the gastric mucosa (Fig. 1e, f), and immunohistochemical staining was positive for MPO and CD68 and negative for CD20, CD45RO, CD56, CD34, and p53—characteristics similar to those in bone marrow leukemic cells. Although most infiltrated cells were immature myeloid cells, more differentiated myeloid cells, such as stab cells and segmented cells, were also observed (Fig. 1f). CD31-positive megakaryocytic cells were also evident; however, extramedullary hematopoiesis was excluded because glycophorin A staining was only positive for mature erythrocytes. Fluorescence in situ hybridization analysis of BCR-ABL fusion genes using paraffin-embedded gastric tissue revealed 80% positive results of the analyzed cells. Accordingly, the patient was diagnosed with blast-phase CML by extramedullary blast proliferation into the stomach. Low-dose dasatinib (50 mg qd) was administered considering the emergence of adverse effects; however, it was discontinued on day 6 before increasing the dose because of persistent bleeding from the biopsy region of the gastric mucosa. Nilotinib was then administered, but was also discontinued owing to marked hyperglycemia. Therefore, dasatinib was readministered at a lower dose of 20 mg qd considering the bleeding tendency, then gradually increased to 100 mg qd, which resulted in no further bleeding from the gastric mucosa. A month after dasatinib re-administration, complete hematological response and disappearance of all elevated lesions of the stomach were achieved. Complete cytogenetic response was obtained at 3 months; however, the major BCR-ABL1 mRNA transcript level on the international scale at 12 months was 0.2680%. Currently, the patient receives dasatinib at a dose of 70 mg bid without gastric lesion recurrence. Extramedullary blast proliferation of CML has been reported to develop in 16% of blast crisis cases in the pre-tyrosine kinase inhibitor (TKI) era [1], whereas the diagnosis of extramedullary disease at initial presentation * Akihito Fujimi akihito.fujimi@gmail.com