Familial adenomatous polyposis complicated by chronic myelogenous leukemia: response to imatinib mesylate

Familial adenomatous polyposis (FAP) is an autosomal dominant disorder characterized by colonic polyposis and a predisposition for developing colorectal cancer. FAP is frequently complicated by extracolonic disease, but complications of leukemia are rare. We present the first case of FAP complicated by chronic myelogenous leukemia (CML) in a 38-year-old man. The patient had numerous adenomas in the colorectum and a family history compatible with FAP. He was diagnosed as having FAP in February 2000. Two years after the diagnosis, he developed leukocytosis with the Philadelphia chromosome abnormality, indicating complication with CML. Imatinib mesylate was administered for the treatment of CML, and hematologic and cytogenetic remission of CML was achieved in 6 months. Numerous polyps, 2 to 3 mm in diameter, observed in the rectum prior to the administration of imatinib, regressed in size, but not in number, after 1 year of treatment with imatinib. Eighteen months later, however, the polyps were enlarged. In this patient, imatinib administration led to the remission of CML and might also have been responsible for the temporary regression of adenomatous polyps of FAP.     

The mechanism of Axl-mediated Ebola virus infection

We previously reported that expression of the receptor-type tyrosine kinase Axl, which regulates cell survival and activation, enhances both pseudotype and live Ebola virus (EBOV) infection. To clarify the mechanistic basis of this enhancement, we created a series of Axl mutants and identified amino acids/domains necessary for this function, by using a pseudotype virus carrying the EBOV glycoprotein (GP). Analyses of the Axl mutants showed the importance of extracellular and intracellular regions for Axl functions, including ligand binding and signal transduction, in EBOV GP-mediated infection. These data suggest that EBOV uses the physiological functions of Axl to enter cells.     

Ghrelin differentially modulates glucose-induced insulin secretion according to feeding status in sheep

The present study was conducted to investigate roles of ghrelin in glucose-induced insulin secretion in fasting- and meal-fed state in sheep. Castrated Suffolk rams were fed a maintenance diet of alfalfa hay cubes once a day. Hyperglycemic clamp (HGC) was carried out to examine glucose-induced insulin response from 48 to 53 h (fasting state) and from 3 to 8 h (meal-fed state) after feeding in Experiment 1 and 2 respectively. Total dose of 70 nmol/kg body weight of D-Lys3-GHRP6, a GH secretagogue receptor 1a (GHS-R1a) antagonist, was intravenously administered at 0, 60, and 120 min after the commencement of HGC. In the fasting state, the ghrelin antagonist significantly (P < 0.01) enhanced glucose-induced insulin secretion. In the meal-fed state, i.v. administration of synthetic ovine ghrelin (0.04 microg/kg body weight per min during HGC) significantly (P < 0.05) enhanced glucose-induced insulin secretion. d-Lys3-GHRP6 treatment suppressed ghrelin-induced enhancement of the insulin secretion. In conclusion, ghrelin has an inhibitory and stimulatory role in glucose-induced insulin secretion via GHS-R1a in fasting- and meal-fed state respectively.     

Deep-sea vent epsilon-proteobacterial genomes provide insights into emergence of pathogens

Deep-sea vents are the light-independent, highly productive ecosystems driven primarily by chemolithoautotrophic microorganisms, in particular by epsilon-Proteobacteria phylogenetically related to important pathogens. We analyzed genomes of two deep-sea vent epsilon-Proteobacteria strains, Sulfurovum sp. NBC37-1 and Nitratiruptor sp. SB155-2, which provide insights not only into their unusual niche on the seafloor, but also into the origins of virulence in their pathogenic relatives, Helicobacter and Campylobacter species. The deep-sea vent epsilon-proteobacterial genomes encode for multiple systems for respiration, sensing and responding to environment, and detoxifying heavy metals, reflecting their adaptation to the deep-sea vent environment. Although they are nonpathogenic, both deep-sea vent epsilon-Proteobacteria share many virulence genes with pathogenic epsilon-Proteobacteria, including genes for virulence factor MviN, hemolysin, invasion antigen CiaB, and the N-linked glycosylation gene cluster. In addition, some virulence determinants (such as the H(2)-uptake hydrogenase) and genomic plasticity of the pathogenic descendants appear to have roots in deep-sea vent epsilon-Proteobacteria. These provide ecological advantages for hydrothermal vent epsilon-Proteobacteria who thrive in their deep-sea habitat and are essential for both the efficient colonization and persistent infections of their pathogenic relatives. Our comparative genomic analysis suggests that there are previously unrecognized evolutionary links between important human/animal pathogens and their nonpathogenic, symbiotic, chemolithoautotrophic deep-sea relatives.     

Complications in the central nervous system during chemotherapy for childhood acute lymphoblastic leukemia: JACLS ALL-02 study

We evaluated central nervous system (CNS) complications treated under the ALL-02 protocol of the Japan Association of Childhood Leukemia Study (JACLS) from April 2002 to March 2005. According to NCI Toxicity Criteria, 17 events of grade 3 and 4 CNS complications were reported in 15 out of 541 patients. Out of these CNS complications, leukoencephalopathy was seen in 5 patients; seizure in 5; cerebrovascular disease in 3; conscious disturbance in 2; and hypertensive encephalopathy and reversible posterior leukoencephalopathy syndrome in one patient each. The complications were intensively observed during induction therapy and the last of the early phase chemotherapy. The protocol treatment was stopped or modified in most patients after CNS complications. MRI imaging demonstrated no improvement in one patient with leukoencephalopathy who developed an isolated CNS relapse, while other patients were alive and remain in their first complete remission without any neurological sequelae. Further studies will be required to analyze risk factors for CNS complications during chemotherapy not accompanied by irradiation and to establish alternative treatments after the appearance of such CNS complications.     

Early relapse of Burkitt's lymphoma with t(8;14) and t(14;18) after rituximab-combined CODOX-M and IVAC therapy

A 43-year-old female was admitted with therapy-resistant pancreatitis and an abdominal tumor around the pancreatic head. Laboratory data revealed leukocytosis with a white blood cell count of 18200/microl, 25% atypical cells and an LDH of 13410 IU/l. The bone marrow was comprised of 78.4 percent lymphoblastoid cells which were positive for CD10, CD19 and CD20, and the cytogenetic study of which demonstrated the presence of t(8;14) (q24;q32) and t(14;18) (q32;q21) in the same clone. The patient was diagnosed as having Burkitt's lymphoma (BL) with t(8;14) and t(14;18). Although CODOX-M and IVAC therapy combined with rituximab achieved complete remission, she died of rapid progressive disease during whole brain irradiation before autologous peripheral blood stem cell transplantation. Even if the intensive chemotherapy with rituximab is given adequately, durable remission may not be achieved in BL with translocation of t(8;14) and t(14;18). A more effective therapy remains to be established for the treatment of this disease.     

Breakthrough pulmonary mucormycosis during voriconazole treatment after reduced-intensity cord blood transplantation for a patient with acute myeloid leukemia

A 59-year-old man was admitted to our hospital with a diagnosis of acute myeloid leukemia in September 2004. He developed invasive pulmonary aspergillosis (IPA) and candidiasis, which were improved by administration of micafungin and amphotericin B (AMPH-B). He received reduced-intensity unrelated cord-blood transplantation without induction chemotherapy. He developed grade IV graft-versus-host disease (GVHD) and the administration of steroids against GVHD was prolonged. Voriconazole (VRCZ) was used for a long period to prevent recurrence of the IPA. Afterwards, infiltrates in the bilateral upper lung fields were detected on a chest CT scan, and a diagnosis of pulmonary mucormycosis was made following detection of Mucor circinelloides from the patient's sputum culture. He then began receiving AMPH-B but died of massive hemoptysis. Mucormycosis usually occurs in immunocompromised hosts such as neutropenic patients with hematologic diseases and is a fatal fungal infection characterized by a rapid and progressive clinical course. Some overseas investigators have recently reported that VRCZ prophylaxis may result in breakthrough mucormycosis in hematopoietic stem cell transplant recipients. These findings suggest that it is very important to pay attention to mucormycosis in hematopoietic stem cell transplant recipients in this country.     

Treatment of malignant ascites in patients with advanced cancer: peritoneovenous shunt versus paracentesis

BACKGROUND: Malignant ascites in patients with advanced cancer is often difficult to treat and effective palliation is not achieved. METHODS: We performed peritoneovenous shunt (PVS) placement in patients with malignant ascites, who were admitted to our institution between January 2000 and March 2005. The outcome of PVS placement was compared with paracentesis as a treatment option during the same period. Comparisons included changes in abdominal girth, hematocrit (Hct), blood urea nitrogen (BUN) and creatinine (Cr) measurements before and after PVS placement. The number of procedures, changes in the postoperative performance score, the median survival, possibility of discharge, and complications were compared between the two groups. RESULTS: Twenty patients underwent PVS placement and 49 patients were subjected to paracentesis. After PVS, abdominal girth and Hct decreased significantly. BUN and Cr tended to decrease. The median number of procedures was less in the PVS group than in the paracentesis group (one vs two, respectively; P < 0.0001). The postoperative performance score showed a significant improvement following PVS placement (P = 0.0026). Median survival was significantly longer for patients undergoing PVS placement than for those undergoing paracentesis (42 days vs 18 days, respectively; P = 0.003). The rate of possible discharge was significantly higher for patients undergoing PVS placement (P = 0.0076). Severe complications were observed in one patient in the PVS group and in seven patients in the paracentesis group. CONCLUSIONS: PVS placement provides an effective treatment option for patients with refractory malignant ascites in advanced cancer, and yields a higher likelihood of discharge compared with conventional paracentesis.