Clinical features and treatment of nonalcoholic fatty liver disease across the Asia Pacific region-the GO ASIA initiative.

BACKGROUND: The Gut and Obesity Asia (GO ASIA) workgroup was formed to study the relationships between obesity and gastrointestinal diseases in the Asia Pacific region. AIM: To study factors associated with nonalcoholic steatohepatitis (NASH) and advanced fibrosis, and medical treatment of biopsy-proven nonalcoholic fatty liver disease (NAFLD) patients. METHODS: Retrospective study of biopsy-proven NAFLD patients from centres in the GO ASIA Workgroup. Independent factors associated with NASH and with advanced fibrosis on binary logistic regression analyses in a training cohort were used for the development of their corresponding risk score, which were validated in a validation cohort. RESULTS: We included 1008 patients from nine centres across eight countries (NASH 62.9%, advanced fibrosis 17.2%). Independent predictors of NASH were body mass index ≥30 kg/m2 , diabetes mellitus, dyslipidaemia, alanine aminotransferase ≥88 U/L and aspartate aminotransferase ≥38 U/L, constituting the Asia Pacific NASH risk score. A high score has a positive predictive value of 80%-83% for NASH. Independent predictors of advanced fibrosis were age ≥55 years, diabetes mellitus and platelet count <150 × 109 /L, constituting the Asia-Pacific NAFLD advanced fibrosis risk score. A low score has a negative predictive value of 95%-96% for advanced fibrosis. Only 1.7% of patients were referred for structured lifestyle program, 4.2% were on vitamin E, and 2.4% were on pioglitazone. CONCLUSIONS: More severe liver disease can be suspected or ruled out based on factors identified in this study. Utilisation of structured lifestyle program, vitamin E and pioglitazone was limited despite this being a cohort of biopsy-proven NAFLD patients with majority of patients having NASH.

Randomized trial of cefepime monotherapy or cefepime in combination with amikacin as empirical therapy for febrile neutropenia.

A multicenter open randomized trial was conducted to compare cefepime monotherapy with cefepime/amikacin combination (dual) therapy in treating febrile neutropenic patients with hematologic disorders. Among the 189 evaluable patients, 5.8% had microbiologically and 10.6% had clinically documented infections. Excellent response was seen in 32.6% and 45.7% of monotherapy and dual therapy recipients, respectively, at day 3 (P=.065). At day 3, patients with neutrophil counts of <500/ mu L receiving dual therapy had a better response than did those receiving monotherapy (45% vs. 27.6%; P=.024). The same was true for patients with leukemia. Adverse events were minimal, and early death was observed in 7 patients in the dual therapy group and 5 patients in the monotherapy group. Overall, cefepime monotherapy is as effective as dual therapy for the initial treatment of febrile neutropenic patients. Further study is warranted for patients with severe neutropenia and leukemia who may benefit from dual therapy.

In vitro expansion of human basophils by interleukin-3 from granulocyte colony-stimulating factor-mobilized peripheral blood stem cells.

BACKGROUND: A number of studies support the belief that human basophils play an important role in allergic inflammation. The exact mechanism of basophil activation at the site of allergic inflammation, however, has not been well understood, mainly due to their low number in blood and difficulty in obtaining a sufficient number of highly purified basophils for investigation. OBJECTIVE: The purpose of this study is to expand human basophils in vitro with high yield and purity by culturing peripheral blood stem cells (PBSCs). METHODS: We collected PBSC-rich mononuclear cells containing CD34+ cells (0.15-4.9%) by leukapheresis from patients with malignant lymphoma and lung cancer during haematopoietic recovery after chemotherapy plus granulocyte colony-stimulating factor-induced mobilization. PBSC-rich mononuclear cells were cultured in the presence of IL-3. RESULTS: When PBSC-rich mononuclear cells containing more than 1% of CD34+ cells were cultured, 20.0-83.3% of the cells, mostly with a yield of >10%, were metachromatic cells after 3 weeks of culture. These cells resembled mature peripheral blood basophils morphologically when examined by light and electron microscopy. Flow cytometric analysis showed that they expressed both FcepsilonRI and FcgammaRII. FcepsilonRI cross-linking resulted in intracellular calcium mobilization, histamine release and synthesis of cysteinyl leukotrienes. The intracellular histamine content and the release of these chemical mediators triggered by anti-IgE antibodies were comparable to those of peripheral blood basophils. CONCLUSION: These findings suggest that PBSC-derived basophils expanded in vitro are morphologically and functionally mature and will be a useful tool for the analysis of basophil functions.

High-dose chemotherapy and autologous peripheral blood stem cell transplantation for treatment of unspecified peripheral T-cell lymphoma presented with hepatosplenomegaly and hypercytokinemia syndrome: report of three cases.

We report here three cases of peripheral T-cell lymphoma unspecified (PTCL-US), which presented with bone marrow infiltration and hepatosplenomegaly and were successfully treated with high-dose chemotherapy (HDCT) and autologous peripheral blood stem cell transplantation (auto-PBSCT). The patients were all characterized by cytokine-induced symptoms such as fever, anasarca, cytopenia, poor general condition, and disseminated intravascular coagulation syndrome. Laboratory data showed extremely high levels of soluble interleukin-2 receptor, beta(2)-microglobulin, and ferritin. All three patients were negative for anti-adult T-cell leukemia antibody. In one patient, hemophagocytosis was revealed by a histological examination of the bone marrow. The International Prognostic Index was high for all three patients, and they all achieved complete remission after the intensive chemotherapy for remission induction. During complete remission, they were treated with HDCT [modified interleukin-converting enzyme regimen] followed by auto-PBSCT. The recovery of hematopoiesis after auto-PBSCT was prompt and sustained engraftment was obtained. No serious adverse effects other than myelosuppression were noted. One patient died due to cerebrovascular disease without relapse 18 months after auto-PBSCT. The other two patients are still alive and have not suffered from relapse. Our observations suggest that auto-PBSCT following HDCT may be an effective and safe therapeutic modality for high-risk PTCL-US patients characterized by hepatosplenomegaly and cytokine-induced syndrome.

Lymphomatous polyp of mantle cell type in the duodenum complicated by gastric cancer: a case of trisomy 3 and t(11;14)(q13;q32).

We experienced a rare case of a lymphomatous polyp of mantle cell type forming a polypoid mass lesion in the duodenum bulbous together with advanced gastric cancer. A total gastrectomy was performed, and the specimen revealed atypical small- to medium-sized lymphoid cells with indented nuclei, which infiltrated the Peyer's patch and formed a nodular mass in the lamina propria and submucosa of the duodenum. The lymphoma cells also infiltrated the lymphoid follicle of the gastric mucosa, spleen, and regional lymph node with a typical mantle zone pattern. Flow cytometric analysis of the single cells of the lymph node and immunohistochemistry of a paraffin-embedded specimen revealed that the lymphoma cells expressed surface CD5, CD19, CD20, and nuclear cyclin D1. Chromosomal analysis of this single cell suspension revealed that these lymphoma cells have trisomy 3 in conjunction with t(11;14)(q13;q32), which is frequently seen in mucosa-associated lymphoid tissue lymphomas (MALToma) in the stomach and is also reported in mantle cell lymphoma as a secondary genetic alteration. Our report suggests that trisomy 3 may be a common chromosomal abnormality in lymphomatous polyps of mantle cell type.

Recurrent idiopathic iridocyclitis after autologous peripheral blood stem-cell transplantation followed by G-CSF administration for acute lymphoblastic leukemia.

We describe a patient who experienced a recurrence of idiopathic iridocyclitis on day 12 after autologous peripheral blood stem-cell transplantation (auto-PBSCT) followed by G-CSF administration for acute lymphoblastic leukemia (ALL). Autologous SCT has been reported to be effective and safe in achieving dose intensification of chemotherapeutic drugs for the treatment of hematopoietic malignancies, but its therapeutic effect on autoimmune diseases is not definite. The findings from the present case suggest that auto-PBSCT followed by G-CSF administration for patients with a history of some kind of autoimmune disorders may induce exacerbation or recurrence of its symptoms after hematopoietic recovery.

[An early phase II study of autologous peripheral blood stem cell transplantation for acute myelogenous leukemia in first remission. Japan Blood Cell Transplantation Study Group].

We performed a multicenter, an early phase II clinical trial to evaluate the feasibility, safety and efficacy of myeloablative therapy supported by autologous peripheral blood stem cell transplantation (auto-PBSCT) for the treatment of acute myelogenous leukemia (AML) in first remission. A total of 105 patients were enrolled in the study, and 56 patients in first complete remission received auto-PBSCT. The median age was 44 years. Of the 56 patients, 34 (60.7%) had M2 or M3 AML by the French-American-British Classification system. The median concentration of infused CD34+ cells was 2.3 x 10(6)/kg by recipient body weight. Median days to reach an absolute neutrophil count > 500/microliter and a platelet count > 20000/microliter were 14 and 16, respectively. The median disease-free survival rate was estimated to be 62.0% at a median follow-up time of 534 days. Although the study enrolled a small number of patients and the follow-up period was relatively short, the preliminary results were encouraging and indicated that myeloablative chemotherapy with auto-PBSCT is feasible and can be performed safely as a post-remission therapy for AML. A prospective randomized clinical trial of auto-PBSCT versus standard chemotherapy alone will be necessary to assess the efficacy of high-dose therapy facilitated by auto-PBSCT as a post-remission therapy for AML.

[A multicenter early phase II study of high-dose chemotherapy with autologous peripheral blood stem cell transplantation for treatment of intermediate-grade non-Hodgkin's lymphoma. Japan Blood Cell Transplantation Study Group].

We conducted a multicenter early phase II study to evaluate the feasibility and therapeutic efficacy of high-dose chemotherapy supported by autologous peripheral blood stem cell transplantation (auto-PBSCT) for the treatment of intermediate grade non-Hodgkin's lymphoma (IG-NHL). High-dose etoposide or cyclophosphamide followed by G-CSF was used for PBSC mobilization, and a sufficient number of CD34+ cells (> 1 x 10(6)/kg) were collected. Out of 81 enrolled patients, 50 received high-dose chemotherapy with auto-PBSCT; Hematologic recovery after transplantation was rapid. The incidence of grade III/IV toxicity (Bearman) was about 6%; treatment-related mortality was 6% (3/50). The Disease-free survival rate for the patients in complete remission who received high-dose chemotherapy with auto-PBSCT was better than that for the patients who were treated with conventional chemotherapy (57% vs 35%). These preliminary results indicated that high-dose chemotherapy with auto-PBSCT is feasible and effective. A prospective randomized phase III clinical trial will be required to assess the efficacy of high-dose chemotherapy with auto-PBSCT as a post-remission therapy for IG-NHL.

Detection of HTLV-I pX gene by polymerase chain reaction using newly designed primers.

Newly designed oligonucleotide primers, KI-7 and KI-8 for the human T cell lymphotropic virus type I (HTLV-I) pX gene were synthesized using an automated DNA synthesizer. Previously known HTLV-I-infected cell lines, MT-1 and MT-2, were used as positive controls and HTLV-I-uninfected cell lines, Molt-4, SBC-3, ABC-1, and EBC-1, as negative controls. Peripheral blood mononuclear cells from 17 patients with anti-HTLV-I antibody and 10 healthy individuals without anti-HTLV-I antibody were studied by polymerase chain reaction (PCR) with KI-7 and KI-8. All DNA samples from HTLV-I-infected cell lines and 17 patients with anti-HTLV-I antibodies showed positive signals of the HTLV-I pX gene. None of the DNA samples from HTLV-I-uninfected cell lines or 10 healthy individuals showed positive signals. When serially diluted DNA of MT-2 cells were amplified by 35 cycles of PCR, the detection limit of the pX gene by using the primer pairs was DNA from about 1.5 MT-2 cells. Specificity and detectable capacity of primer pairs, KI-7 and KI-8 were confirmed to be enough to use for the diagnosis of HTLV-I infection.

Detection of the pX gene of human T-lymphotropic virus type I in respiratory diseases with diffuse interstitial pulmonary shadows and lung cancer.

The presence of the HTLV-I gene in peripheral blood mononuclear cells was studied by polymerase chain reaction in 42 patients including 16 with lung cancer, 12 with diffuse panbronchiolitis (DPB), 11 with idiopathic interstitial pneumonia (IIP), and 3 with pneumoconiosis and hematological malignancy. Sequences equal to a part of the pX gene were found in 44% of the lung cancer cases, 50% of the DPB cases, 55% of the IIP cases, and 100% of the cases of pneumoconiosis and leukemia. In the lung cancer cases, detection of the pX gene was frequently associated with the existence of diffuse interstitial pulmonary shadows. The pX gene was detected in 100% of patients with anti-HTLV-I antibody, 50% of patients with HTLV-I-related reaction and 14% of patients who tested seronegative. It may be inferred from the results that respiratory diseases that produce diffuse interstitial pulmonary shadows are closely associated with HTLV-I infection and that the HTLV-I-related reaction to the immunofluorescent test might reflect the latent infection state of HTLV-I.

Overexpression of interleukin-2 receptor alpha mRNA in pulmonary lymphocytes of lung cancer patients associated with interstitial pulmonary shadow.

The activity of pulmonary lymphocytes was evaluated by the detection of interleukin-2 (IL-2) receptor alpha mRNA expression in lung cancer patients associated with diffuse interstitial shadow on roentgenograms of their lungs. Reverse transcription coupled with the polymerase chain reaction was used to detect mRNA expression. In 5 of 6 patients, IL-2R alpha mRNA expression was increased in pulmonary lymphocytes compared with 4 normal controls. The expression in this mRNA in peripheral blood lymphocytes was almost undetectable in either normal controls or these patients. These results suggest that pulmonary lymphocytes in patients with lung cancer associated with diffuse interstitial shadows are activated and may promote the inflammatory process generating pulmonary fibrosis.

[The significance of soluble IL-2 receptors in rheumatoid arthritis with interstitial pneumonia].

Interstitial pneumonia is well known as one of the complications of rheumatoid arthritis (RA). While interleukin-2 (IL-2) regulates the immune response through IL-2 receptor (IL-2R), the exact role of the soluble form of IL-2R (sIL-2R), recognized as a part of the alpha chain or IL-2R, is still obscure. So, the immunological significance of sIL-2R in serum and in bronchoalveolar lavage fluid (BALF) of those of RA patients with or without interstitial pneumonia was studied. The sIL-2R was measured with an ELISA kit (T-Cell Science Ltd). The levels of sIL-2R in the sera of RA patients without interstitial pneumonia were significantly higher than those of normal controls. Furthermore, the levels of sIL-2R showed a statistically significant correlation with ESR and Lansbary's index. The levels of sIL-2R of RA patients with interstitial pneumonia were higher than in those without interstitial pneumonia although the evaluation of class and stage of arthritis in those RA patients with or without interstitial pneumonia revealed no significant difference. A high sIL-2R/albumin ratio in BALF of RA patients with interstitial pneumonia was shown in comparison with those of normal control. These data indicate that the estimation of sIL-2R in RA patients could be useful in estimating the disease activity and that high levels of sIL-2R reflect the active immune response in the lungs of RA patients with interstitial pneumonia.

[Adriamycin, cyclophosphamide, ftorafur and tamoxifen (ACFT) in patients with advanced breast cancer].

One hundred and six patients with advanced breast cancer were treated with chemoendocrine therapy consisting of adriamycin (40 mg/m2) i.v. on day 1 and cyclophosphamide (130 mg/m2) i.v. daily for 5 days every 3 weeks, ftorafur (500 mg/m2) and tamoxifen (40 mg) orally daily. Of 82 evaluable patients, 16 showed complete response (20%), 32 partial response (39%), 32 no change (39%), and two progressive disease (2%). The overall response rate was 59%, and the median duration of response was 16.3 (3.5-67+) months with a median survival time from the start of chemoendocrine therapy of 25.5 (3.5-67+) months. The median survival time of responders (32.5 months) was significantly longer than that of non-responders (15.3 months). The major toxicities were hair loss, G1 symptoms, and hematological toxicity, but these were clinically well tolerated. No serious cardiac, renal or liver damage was seen. These results indicated that the addition of tamoxifen to the ACF regimen increased the number of complete responses and prolonged the survival time of responders.

[Combination chemotherapy of 5-fluorouracil (5-FU), adriamycin (ADM), cis-diamminedichloroplatinum (II) (CDDP) and mitomycin C (MMC) (FAP.MMC) in advanced gastric cancer].

Twenty patients with advanced gastric cancer were treated with FAP.MMC (5-FU 350 mg/m2 i.v. on days 1-3, ADM 40 mg/m2 i.v. on day 1, CDDP 20 mg/m2 i.v. on days 1-3, MMC 6 mg/m2 i.v. on day 1), administering 5-FU, ADM and CDDP every 4 weeks and MMC every 8 weeks. Fourteen patients were evaluable for responses. Four (29%) partial responses and two minor responses were observed. The median duration of partial response was 3.8 months (range 2.5-7 months). The median overall survival time was 5 months (range 1.5-15 months). Leukopenia was relatively severe, with a median WBC nadir of 1,300/mm3. Nausea and vomiting were frequent but moderate. However, these toxicities were clinically manageable. FAP.MMC was thus considered effective for advanced gastric cancer.

[A phase I study of carboplatin].

A phase I study of carboplatin was conducted using a single dose schedule. Escalating doses of 200, 300, 400 and 500mg/m2 were administered without hydration up to a total of 21 cycles in 18 patients with various solid tumors. A dose-limiting factor was thrombocytopenia, and leukopenia was also dose-related. A major clinical toxicity was gastrointestinal toxicity, while nephrotoxicity was extremely mild. The optimal dose for phase II trials was judged to be 300mg/m2 q 4w in poor-risk patients and 400mg/m2 q 4w in good-risk patients, respectively. Pharmacokinetics were studied in 11 patients.

[Phase II study of medroxyprogesterone acetate in advanced breast cancer].

A phase II study of high-dose medroxyprogesterone acetate (MPA) was performed in 18 patients with advanced breast cancer. MPA was administered at a dosage of 1,200mg orally per day. Of the 15 evaluable patients, partial response was obtained in 3, minor response in 1, no change in 5 and progressive disease in 6 patients. The response rate was 20%, which was as effective as that of tamoxifen. As the responders had been previously treated with tamoxifen, the result suggested that MPA showed no cross-resistance to the latter. Eight patients (53%) experienced weight gain which, in 4 cases (27%), necessitated discontinuation of the treatment. One patient exhibited an allergic reaction and the drug was discontinued. Palpitation in 4 patients (27%), vaginal bleeding in 2 (13%), and edema in 1 (7%) were observed, but these effects were tolerable. We therefore conclude that high-dose MPA is an effective therapy for advanced breast cancer, and that further study is warranted.

[Current status of chemotherapy of advanced gastrointestinal tumors].

In general, progress of chemotherapy for advanced gastrointestinal tumors has been slow, however, introduction of cisplatin has improved the results of chemotherapy in esophageal cancer. Cisplatin has been also recognized to be active for gastric cancer and study of combinations containing it is underway. Adriamycin appears to be the most active for hepatoma and 5-fluorouracil for pancreatic and colorectal cancers. Thus, combinations containing these drugs have been extensively studied but none has shown a definitive superiority over single agent efficacy of both drugs.

[Combination chemotherapy of cis-diamminedichloroplatinum (CDDP) and 5-fluorouracil (5-FU) in gastrointestinal tumors].

Twenty-five patients with gastrointestinal tumors (stomach 13, colon 8, pancreas 2, liver 2) were treated with a combination chemotherapy regimen consisting of CDDP (30 mg/m2/day d 1, 2) and 5-FU (500 mg/m2/day d 1-3), repeated every 3 or 4 weeks. The patients comprised 14 males and 11 females with a median age of 50 years (range 24-69), and a median performance status of 80% (range 40-100%). Thirteen patients had had prior chemotherapy. Partial response was observed in 2 patients (colon and liver), which lasted for 2 months each, respectively. No objective response was observed in 11 patients evaluable for gastric cancer. Non-hematological toxicities were nausea (92%), vomiting (56%), proteinuria (17%), transient elevation of BUN (8%), and hepatotoxicity (11%). Leukopenia and thrombocytopenia were observed in 71% and 25%, respectively. However, these toxicities were mild to moderate, and generally well tolerated.

[Brain metastasis from breast cancer].

Thirty-seven patients with breast cancer who developed brain metastasis were analyzed. At the diagnosis of brain metastasis, all patients had widespread metastasis, and 36 patients were receiving chemotherapy. Thirty patients were treated by radiotherapy to the brain at doses of 4,000 rads. There were 6 CRs (20%) and 5 PRs (17%). The median survival time for all patients was 53 months (8-177+) from diagnosis of the primary tumor, 24 months (7-126+) from the first recurrence, and 6 months (1-47+) from diagnosis of brain metastasis. Patients who achieved CR or PR survived longer than non-responders (11+ months vs. 6 months: p less than 0.01). Several backgrounds factors were analyzed, and the results indicated that patients with better performance status survived significantly longer than those with poorer performance status (11 months vs. 4 months: p less than 0.001).