Clinical characteristics of Japanese patients with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.

Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare disease, which presents with features of myelodysplastic syndromes with ring sideroblasts and essential thrombocythemia, as well as anemia and marked thrombocytosis. SF3B1 and JAK2 mutations are often found in patients, and are associated with their specific clinical features. This study was a retrospective analysis of 34 Japanese patients with MDS/MPN-RS-T. Median age at diagnosis was 77 (range, 51-88) years, and patients had anemia (median hemoglobin: 9.0 g/dL) and thrombocytosis (median platelet count: 642 × 109/L). Median overall survival was 70 (95% confidence interval: 68-not applicable) months during the median follow-up period of 26 (range: 0-91) months. A JAK2V617F mutation was detected in 46.2% (n = 12) of analyzed patients (n = 26), while an SF3B1 mutation was detected in 87.5% (n = 7) of analyzed patients (n = 8). Like those with myelodysplastic syndromes or myeloproliferative neoplasms, patients often received erythropoiesis-stimulating agents and aspirin to improve anemia and prevent thrombosis. This study, which was the largest to describe the real-world characteristics of Japanese patients with MDS/MPN-RS-T, showed that the patients had similar characteristics to those in western countries.

Aberrant crypt foci as precursors of the dysplasia-carcinoma sequence in patients with ulcerative colitis.

PURPOSE: Long-standing ulcerative colitis (UC) predisposes patients to the development of colorectal cancer, but surveillance of colitis-associated cancer by detecting the precancerous lesion dysplasia is often difficult because of its rare occurrence and normal-looking appearance. In sporadic colorectal cancer, aberrant crypt foci (ACF) have been reported by many investigators to be precursor lesions of the adenoma-carcinoma sequence. In the present study, we analyzed the genetic background of ACF to determine whether they could be precursors for dysplasia, and we examined the usefulness of endoscopic examination of ACF as a surrogate marker for surveillance of colitis-associated cancer. EXPERIMENTAL DESIGN: ACF were examined in 28 UC patients (19 patients with UC alone and 9 patients with UC and dysplasia; 2 of those patients with dysplasia also had cancer) using magnifying endoscopy. K-ras, APC, and p53 mutations were analyzed by two-step PCR RFLP, in vitro--synthesized protein assay, and single-strand conformation polymorphism, respectively. Methylation of p16 was analyzed by methylation-specific PCR. RESULTS: ACF that appeared distinct endoscopically and histologically were identified in 27 out of 28 UC patients. They were negative for K-ras, APC, and p53 mutations but were frequently positive for p16 methylation (8 of 11; 73%). In dysplasia, K-ras and APC mutations were negative but p53 mutation (3 of 5; 60%) and p16 methylation (3 of 5; 60%) were positive. There was a significant stepwise increase in the number of ACF from patients with UC alone to patients with dysplasia and to patients with cancer. Univariate and multivariate analyses showed significant correlations between ACF and dysplasia. CONCLUSIONS: We have disclosed an ACF-dysplasia-cancer sequence in colitis-associated carcinogenesis similar to the ACF-adenoma-carcinoma sequence in sporadic colon carcinogenesis. This study suggests the use of ACF instead of dysplasia for the surveillance of colitis cancer and warrants further evaluation of ACF as a surveillance marker in large-scale studies.

[Fifth-line chemotherapy for metastatic gastric cancer--a case responding to modified FOLFOX 6].

According to the National Comprehensive Cancer Network (NCCN) clinical practice guideline for gastric cancer (2006, the first edition), 5-FU/Leucovorin (LV), 5-FU-based, cisplatin (CDDP)-based, oxaliplatin (L-OHP)-based, taxane-based, and irinotecan (CPT-11)-based, ECF are recommended. We used modified FOLFOX 6 (mFOLFOX 6) for pretreatment, that is oxaliplatin-based chemotherapy, for a patient who had received 5-FU-based, CDDPbased, taxane-based, and CPT-11-based treatment for an unresectable gastric cancer case responding to mFOLFOX 6. A 73-year-old male admitted to our hospital for treatment of advanced gastric cancer was diagnosed to be inoperable. A combination chemotherapy docetaxel and CDDP and S-1 as first-line treatment, CPT-11 and CDDP as second-line treatment, weekly paclitaxel treatment as third-line treatment, and MTX and 5-FU as fourth-line treatment were performed. He had progressed after 5-FU-based, CDDP-based, taxane-based, and CPT-11-based chemotherapy. There are no effective approved drugs for gastric cancer in Japan. Oxaliplatin was reportedly effective for metastatic gastric cancer, but it is still non-approved in Japan. After receiving an explanation of oxaliplatin-based therapy, he gave informed consent. Oxaliplatin-based therapy for this patient was then evaluated and approved under an institutional review board of Higashi Sapporo Hospital. mFOLFOX 6 used for the oxaliplatin-based therapy. After 2 courses of mFOLFOX 6, he showed a partial response. Oxaliplatin-based treatment was thought to be promising for previously CDDP-treated patients with unresectable gastric cancers.

[Acute myelogenous leukemia with multilineage myelodysplasia, positive direct Coombs test, and elevated levels of platelet-associated IgG].

A 75-year-old man was admitted to our hospital in October, 2005 for examination of pre-diagnosed pancytopenia. His bone marrow showed myeloid dysplasia, and 30.4% of the nucleated cells were blasts. Our diagnosis was acute myelogenous leukemia with multilineage myelodysplasia (AML with MLD; WHO classification). A direct Coombs test proved positive, and the platelet-associated IgG (PA-IgG) level was elevated. After treatment with CAG (Ara-C + ACR + G-CSF), complete remission was obtained, showing negative on the direct Coombs test with PA-IgG levels returned to normal. The patient subsequently relapsed, testing positive on the direct Coombs test and experiencing a re-elevation of PA-IgG levels. We report here a first case of AML with MLD, direct Coombs test and PA-IgG assay.

[T-cell rich B-cell lymphoma associated with neutrophilia and thrombocytosis].

A 49-year-old man was admitted with high-grade fever, night sweating and cervical lymphadenopathy in September 2005. On examination, both neutrophilia and thrombocytosis were noted in the peripheral blood, a bone marrow examination revealed marked both myeloid and megakaryocytic hyperplasia. The sera obtained at initial presentation showed an elevated levels of granulocyte-colony stimulating factor (G-CSF) and interleukin-6 (IL-6). A pathologic diagnosis of T-cell rich B-cell lymphoma was made based on an inguinal lymph node biopsy. Following treatment with CHOP accompanied by rituximab (R-CHOP), both the neutrophilia and thrombocytosis subsided after 3 courses of R-CHOP, resulting in a complete remission after 4 courses of chemotherapy. Neutrophilia, thrombocytosis and T-cell rich B-cell lymphoma in this patient were considerably ameliorated with chemotherapy. We report here a patient with T-cell rich B-cell lymphoma associated with both neutrophilia and thrombocytosis, suggesting that the lymphoma triggered both myeloid and megakaryocytic hyperplasia.

[Appetite loss, nausea, vomiting].

Appetite loss, nausea and vomiting are most common gastrointestinal distress in patients with advanced cancers. It is worthwhile to relieve these symptoms for improving their quality of life (QOL), an inadequate treatment, on the contrary, will increase their distressing symptoms. To avoid this, it is essential to clarify the cause of illness, especially to find out whether it is due to a complete mechanical gastrointestinal obstruction or not. If it is so, the use of metoclopramide is a contraindication. Practically, the combined use of octreotide acetate, steroids and morphine will be effective to manage a severe gastrointestinal distress such as an obstinately nausea and vomiting.

Donor cell derived acute myeloid leukemia after allogeneic cord blood transplantation in a patient with adult T-cell lymphoma.

We report a patient with adult T-cell lymphoma who developed acute myeloid leukemia (AML) after allogeneic cord blood transplantation (CBT). Fluorescence in situ hybridization (FISH) studies and molecular analysis using short tandem repeat (STR) sequences proved the AML to be of donor origin. Although 25 cases of donor cell leukemia (DCL) occurring after allogeneic bone marrow transplantation have previously been reported, there have been no reports of DCL after CBT. This case is the first-reported DCL patient after CBT.

[Successful treatment with oral ribavirin of adenovirus-associated hemophagocytic syndrome in a stem cell transplantation recipient].

A 51-year-old woman with severe aplastic anemia underwent allogeneic peripheral blood stem cell transplantation using blood stem cells from an HLA-identical sibling. Adenovirus type 11 hemorrhagic cystitis developed and progressed to nephritis and hemophagocytic syndrome. Oral ribavirin was effective not only for the hemorrhagic cystitis and nephritis but also for the hemophagocytic syndrome. Since therapeutic strategies for adenovirus infection after hematopoietic stem cell transplantation have not been established, we present our case and discuss the therapeutic approach.

[Successful treatment with antiviral agents for human herpesvirus type 6 encephalitis following reduced intensity stem cell transplantation in a patient with myelodysplastic syndrome].

We report here a patient who suffered from PCR-confirmed human herpesvirus type 6 (HHV-6) encephalitis following reduced intensity stem cell transplantation (RIST) from her HLA-matched sibling donor. A 66-year-old woman with MDS-RA underwent RIST from her HLA-matched brother. Engraftment was favorable and grade 2 GVHD (skin and intestine) was observed with good response to 60 mg of prednisolone. On day 162, she developed fever, headache, diplopia, disorientation and abnormal neurological findings including cervical stiffness and nystagmus. An analysis of cerebrospinal fluid (CSF) revealed 80 cells/microl, a glucose level of 50 mg/dl and a protein level of 97 mg/dl on day 162. Although computed tomography (CT) of the brain and electroencephalography (EEG) were nonspecific, HHV-6 was detected in the CSF using polymerase chain reaction (PCR) techniques and the patient was diagnosed as having encephalitis due to local reactivation of HHV-6. Administration of ganciclovir (GCV) and acyclovir (ACV) were started from day 162. Treatment with antiviral agents was effective, with total resolution of her symptoms and the DNA of this virus disappeared from the CSF after 23 days of treatment. This case shows that HHV-6 infection has to be considered in patients with neurological symptoms following stem cell transplantation, and suggests the necessity of PCR for HHV-6 virus from the CSF.

Recovery of neutrophil count by ganciclovir in patients with chronic idiopathic neutropenia associated with cytomegalovirus infection in bone marrow stromal cells.

Patients with chronic idiopathic neutropenia (CIN) usually show chronic inflammation in their bone marrow stromal cells, but the etiologies of this disorder are still unknown. We suspected viral infection of the bone marrow stromal cells and used polymerase chain reaction (PCR) analysis to test for cytomegalovirus (CMV) infection in 4 patients with CIN and in 6 healthy volunteers. Peripheral blood mononuclear cells did not yield signals in any of the patients or healthy volunteers, but PCR analysis for CMV DNA in bone marrow stromal cells showed positive signals in 2 of the patients with CIN. CMV DNA was not detected in the other 2 patients or in the healthy volunteers. The 2 patients who were positive for stromal CMV received 500 mg/day ganciclovir for 14 days. After this treatment, the PCR band showing the presence of stromal CMV disappeared, and the neutrophil numbers of the 2 patients who received this viral eradication therapy normalized 6 months after treatment. In conclusion, the etiology in some cases of CIN is speculated to be infection by CMV in bone marrow stromal cells, and treatment with ganciclovir may be effective in treating such patients.

[A case of inoperable advanced gallbladder cancer that has maintained stable disease status for a long period with gemcitabine and cisplatin therapy].

We report a case of inoperable advanced gallbladder cancer that responded to treatment with gemcitabine (GEM) and cisplatin (CDDP) therapy. A 54-year-old woman was diagnosed in a nearby hospital with inoperable advanced gallbladder cancer (T4, N1, H0, P1, M(-): Stage IV b) with direct invasion to the liver. Therefore, chemotherapy was performed by TS-1. Two months later, however, the disease was found to have progressed, and she was referred to our hospital for further therapy. Combined chemotherapy with GEM 1,000 mg/m2 on days 1, 8 and 15 and CDDP 50 mg/m2 on day 1 was performed starting in June 2002. No side effects were observed after the first administration during hospitalization, so the treatment was continued on an outpatient basis. Her serum CEA and CA19-9 levels thereafter gradually decreased, and the disease stabilized for over a year. She has been able to maintain good quality of life without any severe adverse effects.

Decrease of Smad4 gene expression in patients with essential thrombocythaemia may cause an escape from suppression of megakaryopoiesis by transforming growth factor-beta1.

Essential thrombocythaemia (ET) is characterized by the abnormal and sustained proliferation of megakaryocytes. The mechanism for this lineage-specific expansion in ET, remains unclear. We have previously reported that transforming growth factor-beta1 (TGF-beta1) is involved in negative feedback regulation of megakaryopoiesis in both healthy volunteers (HV) and patients with idiopathic thrombocytopenic purpura (ITP). The present study found that megakaryocyte colony-forming units (CFU-MK) of ET patients were less sensitive to TGF-beta1 than those of HV. The expression of Smad4 (Sma- and Mad-related protein-4) in CFU-MK of ET patients was reduced in comparison with that of HV. Finally, to confirm that the impaired TGF-beta1 sensitivity was caused by reduced expression of Smad4, we examined Smad4-transfected CFU-MK from ET patients in the presence of TGF-beta1, and verified that the transfectants were indeed as susceptible as CFU-MK from HV to TGF-beta1. Thus it was surmised that one of the mechanisms for impaired sensitivity of CFU-MK to TGF-beta1 is the reduced expression of Smad4.

[IgM type multiple myeloma expressing various surface adhesion molecules and demonstrating an aggressive clinical course].

A 70-year-old woman was admitted for anemia, elevated serum total protein and a right axillary mass. Laboratory data showed monoclonal x IgM with a decrease in serum IgG and IgA levels. An occipital punched-out lesion was detected on a cranial X-ray. A tumor lesion was detected on chest X-ray and computed tomography. Biopsy specimen revealed plasmacytoma with cytoplasmic IgM. Bone marrow aspiration revealed an elevated plasma cell count. An immunophenotype analysis of the plasma cells showed positivity of cytoplasmic IgM, x, CD5, CD38, CD11a (LFA-1), CD44 (HCAM), CD49d (VLA-4) and CD54 (ICAM-1). From the above results, we diagnosed the patient as having IgM myeloma associated with plasmacytoma. Melphalan and prednisolone therapy were prescribed, their effect on the myeloma was short term, so we changed the chemotherapy to VAD (vincristine, adriamycin and dexamethasone), but this treatment had little effect. The patient developed bacterial pneumonia and died. IgM myeloma is a rare disease and reports of immunophenotype analysis are also rare. There is no case report of plasmacytoma associated with IgM myeloma.

C(H)OP refractory chronic lymphocytic leukemia patients in whom salvage chemotherapy chosen by evaluating multiple chemotherapeutic drug-resistant factors was remarkably effective.

It is well known that the expression of anticancer drug-resistant factors is elevated in patients with primary refractory or relapsed chronic lymphocytic leukemia (CLL) who have been treated with chemotherapy. We report here two C(H)OP refractory patients with CLL in whom salvage chemotherapy chosen by evaluating anticancer drug-resistant factors (glutathione-S-transferase-Pi [GST-Pi], glycoprotein [GP]-170, multidrug resistance-associated protein [MRP], and lung resistance protein [LRP]) was remarkably effective. A 71-year-old male patient was refractory to induction therapy with cyclophosphamide, vincristine, and prednisone (COP), and his leukemic cells at diagnosis displayed overexpression of GST-Pi and GP-170. A 74-year-old female patient's condition had been stable; she had received ten courses of COP over 9 years. However, because systemic lymphadenopathies recurred, she was treated with chemotherapy consisting of cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) or dexamethasone, etoposide, ifosphamide, and carboplatin (DeVIC). However, she did not respond at all, and her leukemic cells at recurrence displayed overexpression of GST-Pi. Therefore, we chose for these patients a salvage therapy consisting of dexamethasone and high-dose cytosine arabinoside (Ara C), to which neither GST-Pi nor GP-170 show any drug resistance. In both patients, this salvage therapy proved effective.

Fatality caused by self-bloodletting in a patient with factitious anemia.

Death by bloodletting among patients with factitious anemia has never been reported to our knowledge. We report the first known case. A 25-year-old woman with severe iron deficiency anemia confessed her habit of bloodletting at her first visit to our hospital, in March 1998. We prescribed oral iron and referred her to a psychiatrist. The diagnosis was borderline personality disorder. The psychiatrist began counseling the patient and prescribed a major tranquilizer. The patient's method of bloodletting was to insert an 18-gauge needle without syringe into her vein after inducing congestion in her arm. This method was considered to involve risk of death, because once the patient fell into a faint caused by blood loss, the bloodletting could not be stopped. Although we attempted to persuade the patient to stop bloodletting by this method, she died after self-bloodletting in September 1999. It is not known whether the death was intentional suicide or an accident.

[Chemotherapy with ubenimex corresponding to patient age and organ disorder for 18 cases of acute myelogeneous leukemia in elderly patients--effects, complications and long-term survival].

Ubenimex was concurrently administered to 18 elderly patients with acute myelocytic leukemia (AML), and a chemotherapy protocol was prepared corresponding to patient age and organ disorders. The dose-reduced protocol of the Japan Adult Leukemia Study Group (JALSG) '95 or aclarubicin 14 mg/m2 day 1-4, cytosine arabinoside 15 mg/m2 day 1-14, granulocyte colony stimulating factor (G-CSF) 150 micrograms/body day 1-14 (CAG therapy) were administered. In addition, ubenimex 30 mg/day was administered orally after induction of remission. As per the JALSG protocol for dose reduction when organ disorder is absent, 85% and 70% of the dose were administered to the patients aged 65-69 years and 70-74 years, respectively. For patients aged 75 years or more and patients with mild disorders of the heart, kidney, and liver, CAG therapy was administered. As a result, the complete remission (CR) rate was 67%, and the three-year survival rate was 32%. This protocol may be useful for elderly AML.

Interaction between leukemic-cell VLA-4 and stromal fibronectin is a decisive factor for minimal residual disease of acute myelogenous leukemia.

Bone-marrow minimal residual disease (MRD) causes relapse after chemotherapy in patients with acute myelogenous leukemia (AML). We postulate that the drug resistance is induced by the attachment of very late antigen (VLA)-4 on leukemic cells to fibronectin on bone-marrow stromal cells. We found that VLA-4-positive cells acquired resistance to anoikis (loss of anchorage) or drug-induced apoptosis through the phosphatidylinositol-3-kinase (PI-3K)/AKT/Bcl-2 signaling pathway, which is activated by the interaction of VLA-4 and fibronectin. This resistance was negated by VLA-4-specific antibodies. In a mouse model of MRD, we achieved a 100% survival rate by combining VLA-4-specific antibodies and cytosine arabinoside (AraC), whereas AraC alone prolonged survival only slightly. In addition, overall survival at 5 years was 100% for 10 VLA-4-negative patients and 44.4% for 15 VLA-4-positive patients. Thus, the interaction between VLA-4 on leukemic cells and fibronectin on stromal cells may be crucial in bone marrow MRD and AML prognosis.

Thrombopoietin concentrations in peripheral blood correlated with platelet numbers in two patients with thrombocytopenia by chronic graft-versus-host disease.

Thrombocytopenia is well known to be one of the clinical manifestations of chronic graft-versus-host disease (cGVHD). However, there exist cases in which the cause of thrombocytopenia has been unexplained. Recently, thrombopoietin (TPO) from bone marrow (BM) stromal cells and transforming growth factor (TGF)-beta from platelets and megakaryocytes have been identified as strong positive and negative regulators of megakaryopoiesis in vivo. We hypothesized that the decreased TPO production from BM could be one of the causes of thrombocytopenia in the patients with cGVHD. In the present study, therefore, TPO and TGF-beta concentrations in peripheral blood (PB) and BM were measured serially in two patients with acute leukemia who had received fully matched stem cell transplantation from relatives and subsequently developed extensive cGVHD with thrombocytopenia. The results showed that platelet numbers correlated well with the TPO concentrations, which were consistently higher in BM than in PB. The difference in TPO concentrations between BM and PB was decreased when the platelet levels were low, indicating that the amount of TPO production from BM decreased throughout the duration of thrombocytopenia. TGF-beta concentrations were normal during all periods in which measurements were carried out. Thus, our results suggest that one mechanism of thrombocytopenia in patients with cGVHD is low TPO production by BM cells.