Retrospective and prospective studies of hepatitis B virus reactivation in malignant lymphoma with occult HBV carrier.

BACKGROUND: In surface antigen of hepatitis B virus (HBsAg)-positive carrier for anticancer treatment of malignant lymphoma, it is well recognized that reactivation of hepatitis B virus (HBV) occasionally occurs. However, there have been only a few studies of HBV reactivation in serum HBsAg-negative and hepatitis B core antigen (HBcAb)-positive occult HBV carriers. We looked at both retrospective and prospective studies to determine the prevalence, clinical course and risk factor of HBV reactivation during chemotherapy in lymphoma patients. PATIENTS AND METHODS: Forty-eight of 127 (37.8%) lymphoma patients were HBsAg negative and HBcAb positive, and 24 of these patients were then given liver function tests and HBsAg tests monthly and serum HBV DNA every 3 months. RESULTS: HBV reactivation was observed in two patients (4.1%) who had received intensive chemotherapy including steroid and rituximab. Immediate administration of entecavir therapy after elevation of HBV DNA level was conducted, and this resulted in reduction of it and improvement of liver function test. CONCLUSIONS: Rituximab plus steroid-containing regimens may increase the risk of HBV reactivation in HBsAg-negative and HBcAb-positive lymphoma patients. More ambitious prospective studies are required to establish clinically useful or cost-effective follow-up methods for control of HBV reactivation in lymphoma patients with occult HBV infection.

Importance of basophilia in haematopoietic disorders.

To the significance of basophilia in haematopoietic disorders, six draw attention to cases have been analyzed. Associated diseases included acute myelogenous leukaemia (AML-M2, M3, M4, and M6), refractory anaemia with excess of blasts (RAEB) and RAEB in transformation (RAEB-T). Two AML cases (M2, M6) were preceeded by myelodysplastic syndromes (MDS). All patients showed greater than 3% basophilia in peripheral blood and bone marrow. Basophils were identified successfully by metachromatic staining with toluidine blue in all cases. Three patients (M3, M4, RAEB) presented with lymphadenopathy, suggesting an association with extramedullary involvement. Neutrophil alkaline phosphatase (NAP) activity was significantly reduced in four patients with AML (M2, M3, M4) and RAEB-T. The clinical course was generally unfavourable characterized by short remission duration or disease progression except for the patient with RAEB. Haemorrhage was the main cause of death rather than infection. Cytogenetic analysis revealed unique abnormalities involving chromosomes 3q21, 5q31, and 17q11 where the genes for some haematopoietic growth factors or their receptors are located, in addition to t(6;9) and t(15;17).

Marked inhibition of the intracellular multiplication of Legionella pneumophila in monocytes isolated from carriers of human T lymphotrophic virus type I.

Intracellular growth patterns of Legionella pneumophila were examined in monocytes obtained from carriers of human T-lymphotropic virus type I (HTLV-1) and controls who were HTLV-1 seronegative. All subjects were seronegative for antibodies against L. pneumophila. Bacterial growth was determined 0, 1, 2, and/or 3 days after infecting peripheral blood mononuclear cells (PBMCs) with the bacteria. The intracellular growth of L. pneumophila was markedly inhibited in HTLV-1 carriers compared with normal controls. When the lymphocytes were depleted from the HTLV-1 carrier PBMC cultures before infection, this inhibition was abolished. Inhibition reappeared, however, when the 72-h culture supernatants of PBMCs from HTLV-1 carriers were added to the lymphocyte-depleted cultures. Culture supernatants of infected and uninfected PBMCs from HTLV-1 carriers exhibited markedly increased levels of interferon-gamma (IFN-gamma) and tumor necrosis factor alpha (TNF-alpha) compared with the HTLV-1 seronegative controls. In the HTLV-1 carriers, IFN-gamma was produced by the CD4+ lymphocytes, whereas TNF-alpha was secreted by the monocytes. Addition of anti-IFN-gamma or anti-TNF-alpha antibodies to the HTLV-1 carrier PBMC cultures diminished the inhibition of intracellular growth of L. pneumophila. Results suggest that the monocytes are activated in HTLV-1 carriers. These findings may explain why an opportunistic infection by certain intracellular pathogens is rarely seen among HTLV-1 carriers.

Natural killing activity in patients with spontaneous regression of malignant lymphoma.

Previously, we proposed a new analysis of natural killing activity, for comparison, employing an "individual effector/target cell ratio" according to the number of effector cells in blood. The activity could be measured in four patients with spontaneous regression of malignant lymphoma. Despite the absence of episodes suggesting viral infections, patients with spontaneous regression had significantly higher activities prior to their regressions than either controls or patients without regression. In one patient who had a spontaneous regression accompanied by a high level of natural killing activity, subsequent exacerbation of the disease with a reduced activity was never followed by a regression and became life-threatening. In another patient, a spontaneous regression was accelerated after greater augmentation of natural killing activity was induced by a superimposed viral infection. These facts suggest that highly elevated natural killing activity may be one of the possible mechanisms responsible for spontaneous regression of malignant lymphoma.

Differences in immune functions between human T-lymphotropic virus type I carriers and patients with adult T-cell leukemia/lymphoma.

A variety of immunologic tests were compared between human T-lymphotropic virus type I (HTLV-I) carriers and patients with adult T-cell leukemia/lymphoma (ATL). The mitogenic responses of the lymphocytes to concanavalin A and phytohemagglutinin were depressed in the ATL patients but not in the carriers, while the response to pokeweed mitogen in the carriers and ATL patients was depressed compared to the HTLV-I-seronegative controls. A positive tuberculin reaction in the carriers was as frequent as in the controls, but less frequent in the ATL patients. A marked inhibition of the intracellular multiplication of Legionella pneumophila was observed within the monocytes isolated from the carriers, but not in the ATL patients or the normal controls. These results indicate that the ATL patients have severe immunodeficiency, while the HTLV-I carriers have some activation of anti-microbial activity in monocytes although they are somewhat immunosuppressed.

Increased production of interferon gamma but not interleukin 4 in human T-lymphotropic virus type I carriers.

We investigated the production of interferon gamma (IFN-gamma), interleukin 4 (IL-4), IL-1 alpha, and tumor necrosis factor alpha (TNF-alpha) by peripheral blood mononuclear cells (PBMCs) from human T-lymphotropic virus type I(HTLV-I) carriers during short-term in vitro culture, in comparison with that by those from HTLV-I seronegative controls. PBMCs isolated from eight carriers and eight controls were cultured, and cytokine levels were measured in 1- and 3-day culture supernatants. Enhanced production of IFN-gamma was observed in all HTLV-I carriers but none of the controls. IL-4 production was not increased in the carriers except for one with a past history of toxoplasma lymphadenitis. IL-1 alpha and TNF-alpha levels were higher in the carriers. CD4+ cells were responsible for the enhanced IFN-gamma production, while monocytes were responsible for the increased IL-1 alpha and TNF-alpha production. The present study showed that the PBMCs from HTLV-I carriers consistently produced large amounts of some cytokines (IFN-gamma, IL-1 alpha, TNF-alpha) but not of other cytokines (IL-4). This imbalance in cytokine production in HTLV-I carriers may be related to the development of opportunistic infections and/or HTLV-I associated diseases including adult T-cell leukemia/lymphoma.

Ten-year survey of incidence of infection as a cause of death in hematologic malignancies: study of 90 autopsied cases.

We investigated 90 autopsied cases with hematologic malignancy, including malignant lymphoma (ML), acute leukemia (AL), and adult T-cell leukemia (ATL) peculiar to our district, during the 10-year period 1982-1991 to determine the change in incidence of infection as a cause of death. We divided the cases into two groups representing the first half decade (1982-1986) and the second half decade (1987-1991) and compared the findings made in the two groups. Although infection was the major cause of death in those autopsied cases, the incidence of fatal infections decreased during the latter period. The incidence of fatal bacterial infections decreased, while fungal infections showed a relative increase. Pneumocystis carinii pneumonia and cytomegalovirus (CMV) infection occurred more frequently in patients with ATL than in those with ML or AL. Combined infection by more than three pathogens was observed in 2 cases of ATL. Our study revealed the characteristics of ATL specific to our district, and indicated the need to apply new strategies to prevent and treat fungal and viral infections in patients with hematologic malignancies.

Spontaneous regression in adult T-cell leukemia/lymphoma.

BACKGROUND: Spontaneous regression of adult T-cell leukemia/lymphoma (ATL) is considered to be extremely unusual. Of the 82 patients with ATL who the authors saw between 1981 and 1991, spontaneous regression occurred in 3 (3.7%), 2 of whom were previously untreated and one who had been previously treated. Surgical excisional biopsy triggered the spontaneous regression in these patients. METHODS: In two of these patients with spontaneous regression, gene analysis studies of human T-cell leukemia virus type I (HTLV-I) proviral DNA, and T-cell receptor (TCR) were carried out by Southern blot analysis in lymph node cells or peripheral lymphocytes before regression and after recurrence. RESULTS: One patient exhibited monoclonal integration of HTLV-I proviral DNA and the rearranged band of the TCR-beta gene at the same positions both before regression and after recurrence. The other patient showed them at the different positions before regression and after recurrence. CONCLUSIONS: The authors' studies indicated heterogeneity in ATL patients with spontaneous regression. Temporary spontaneous regression could occur in typical ATL and might be associated with a longer survival time than that for prototypic ATL.

Hyperkalaemia with renal tubular dysfunction by sulfamethoxazole-trimethoprim for Pneumocystis carinii pneumonia in patients with lymphoid malignancy.

Hyperkalaemia with renal tubular dysfunction by oral therapy of sulfamethoxazole-trimethoprim (co-trimoxazole) is described in 2 elderly Japanese patients with lymphoid malignancy, who developed Pneumocystis carinii pneumonia and improved. A high dose of cotrimoxazole induced hyperkalaemia with the elevation of serum creatinine and blood urea, and increased urinary N-acetyl glucosaminase after several days of the drug administration in these patients; one patient became unconscious. Discontinuation of co-trimoxazole normalized serum potassium level and symptoms. A repeated low dose of the drug induced hyperkalaemia. Before the treatment of co-trixomazole, their serum levels of creatinine showed upper limits of normal ranges. In the present study, our cases suggested that patients receiving a high dose of co-trimoxazole should be evaluated for these potential complications during a course of treatment, particularly in elderly patients with preexisting renal dysfunction.

Coexistence of acute monoblastic leukemia and adult T-cell leukemia: possible association with HTLV-I infection in both cases?

A 64 year-old Japanese man who developed acute monoblastic leukemia during the course of adult T-cell leukemia/lymphoma (ATL) was studied. Leukemic cells in the peripheral blood and bone marrow were monoblasts positive for alpha-naphthol butyrate esterase (alpha-NBE) staining, CD11c and CD36 antigens, whereas tumor cells in the pleural effusion were ATL cells positive for CD2, CD4, CD25, CD29 and CD45RA antigens. These two malignant cells had different chromosomal abnormalities. Monoclonal integration of human T-cell leukemia virus type I (HTLV-I) proviral DNA and T-cell receptor C beta gene (TCR C beta) rearrangement were detected in the ATL cells, but not in the leukemic monoblasts. By polymerase chain reaction (PCR) in the peripheral blood mononuclear cells (CD11c+ 98%, CD2+ 4%, CD20+ 0%) not containing ATL cells, the presence of the gag region of HTLV-I was confirmed. These facts indicate that a double positive T cell (CD29+, CD45RA+) was possibly the target cell for HTLV-I infection and that HTLV-I was not directly related to the oncogenesis of the monocyte lineage in the present case, even if it did infect the monocytes. However, there is still an outside possibility that HTLV-I induced acute monoblastic leukemia indirectly.

Cortical tremor: a variant of cortical reflex myoclonus.

Two patients with action tremor that was thought to originate in the cerebral cortex showed fine shivering-like finger twitching provoked mainly by action and posture. Surface EMG showed relatively rhythmic discharge at a rate of about 9 Hz, which resembled essential tremor. However, electrophysiologic studies revealed giant somatosensory evoked potentials (SEPs) with enhanced long-loop reflex and premovement cortical spike by the jerk-locked averaging method. Treatment with beta-blocker showed no effect, but anticonvulsants such as clonazepam, valproate, and primidone were effective to suppress the tremor and the amplitude of SEPs. We call this involuntary movement "cortical tremor," which is in fact a variant of cortical reflex myoclonus.