Value of surveillance blood culture for early diagnosis of occult bacteremia in patients on corticosteroid therapy following allogeneic hematopoietic stem cell transplantation.

Bloodstream infection (BSI) is a significant complication following allogeneic hematopoietic stem cell transplantation (allo-SCT). Corticosteroids mask inflammatory responses, delaying the initiation of antibiotics. We reviewed medical records of 69 allo-SCT patients who had been on >0.5 mg/kg prednisolone to investigate the efficacy of weekly surveillance blood cultures. A total of 36 patients (52%) had positive cultures, 25 definitive BSI and 11 probable BSI. Pathogens in definitive BSI were Staphylococcus epidermidis (n=7), S. aureus (n=4), Entrococcus faecalis (n=3), Pseudomonas aeruginosa (n=5), Acenitobacter lwoffii (n=4), and others (n=10). The median interval from the initiation of corticosteroids to the first positive cultures was 24 days (range, 1-70). At the first positive cultures, 15 patients with definitive BSI were afebrile. Four of them remained afebrile throughout the period of positive surveillance cultures. Patients with afebrile BSI tended to be older (P=0.063), and had in-dwelling central venous catheters less frequently than febrile patients (P<0.0001). Bloodstream pathogens were directly responsible for death in two patients with afebrile BSI. This study demonstrates that cortisosteroid frequently masks inflammatory reactions in allo-SCT recipients given conrticosteroids, and that surveillance blood culture is only diagnostic clue for 'occult' BSI.

Disseminated tuberculosis following reduced-intensity cord blood transplantation for adult patients with hematological diseases.

Allogeneic hematopoietic stem cell transplantation (allo-SCT) recipients are prone to infections. The incidences of mycobacterial infections after allo-SCT in several case series vary from less than 0.1-5.5%. However, no study has been published on tuberculosis following unrelated cord blood transplantation (UCBT). We retrospectively reviewed medical records of 113 adult patients with a median age of 54 years who underwent reduced-intensity UCBT (RI-UCBT) at Toranomon Hospital from March 2002 to May 2004. Mycobacterium tuberculosis infections were diagnosed in three patients (2.7%), of these two patients developed primary infection and one patient developed reactivation of latent tuberculosis. The interval between RI-UCBT and the diagnosis of tuberculosis was 34, 41 and 61 days. All the patients had disseminated disease at diagnosis. Histological examination showed the lack of granuloma in caseous necrosis. Combination antituberculous treatments showed limited efficacy, and two patients died immediately after diagnosis. M. tuberculosis caused life-threatening illness, rapidly progressing in RI-UCBT recipients. The lack of granuloma in caseous necrosis suggests the impaired T-cell function in early post transplant phase of RI-UCBT. We should consider M. tuberculosis in the differential diagnoses of fever of unknown source after RI-UCBT.

Myopericarditis caused by cyclophosphamide used to mobilize peripheral blood stem cells in a myeloma patient with renal failure.

Cyclophosphamide (CPA) is widely used for peripheral blood stem cell mobilization, and a dose adjustment of CPA in the presence of renal failure has not been suggested. However, we describe a myeloma patient with renal failure (serum creatinine 4.2 mg/dl, creatinine clearance 11.2 ml/min) receiving CPA 2 g/m2 for 2 days, who developed unexpectedly severe toxicity, including myopericarditis and prolonged myelosuppression. The serial serum concentrations of CPA metabolites were persistently much higher than those in a myeloma patient with normal renal function. We consider, therefore, that the dose of CPA should be reduced in the presence of severe renal failure when used as high-dose therapy or to mobilize peripheral blood stem cells.

Suspected delayed immune recovery against cytomegalovirus after reduced-intensity stem cell transplantation using anti-thymocyte globulin.

A reduced-intensity hematopoietic stem cell transplantation (RIST) regimen was developed to induce immunosuppression to facilitate the engraftment of donor cells. However, there have been concerns that the incidence of opportunistic infection may increase after this procedure. To address this problem, we retrospectively analyzed the medical records of 24 RIST recipients who were treated over a recent 16-month period for comparison with 31 recipients of conventional allogeneic transplantation (CST). The RIST regimen consisted of cladribine (0.66 mg/kg), busulfan (8 mg/kg), and rabbit anti-thymocyte globulin (ATG; 5-10 mg/kg). All of the patients received allogeneic peripheral blood stem cells from an HLA-identical or one-locus mismatched related donor. Although the incidence of positive CMV antigenemia was comparable between the two groups (58% vs 68%), RIST patients developed positive antigenemia significantly sooner than did CST patients (P = 0.01) and showed higher initial and maximum antigenemia values (P = 0.026 and P = 0.003, respectively). These findings may suggest that immune recovery against CMV was delayed after our RIST procedure, but this did not directly translate into an increase in clinically significant CMV disease. Early therapeutic intervention with ganciclovir might play a role in preventing the progression of early CMV infection to CMV disease.

Long-term low-dose acyclovir against varicella-zoster virus reactivation after allogeneic hematopoietic stem cell transplantation.

To evaluate the efficacy of long-term administration of acyclovir as prophylaxis against varicella-zoster virus (VZV) reactivation, we analyzed the medical records of 86 consecutive adult patients who obtained engraftment after allogeneic hematopoietic stem cell transplantation from January 1996 to March 2000. We started long-term low-dose (400 mg/day) oral administration of acyclovir in June 1999, and this was continued until the end of immunosuppressive therapy after transplantation. There was no breakthrough reactivation of VZV in patients receiving acyclovir. Five patients who were receiving cyclosporine or prednisolone developed VZV reactivation after discontinuing acyclovir. With this prophylaxis, the cumulative incidence of VZV reactivation at 1 year after transplantation decreased from 33% to 10% (P = 0.025). On multivariate analysis, the use of long-term acyclovir was identified as a significant independent parameter for the development of VZV reactivation. These findings suggest the efficacy of long-term prophylaxis with low-dose acyclovir. Resumption of acyclovir upon restarting immunosuppressive therapy might be important for the further prevention of VZV reactivation. The benefit of long-term low-dose acyclovir should be confirmed prospectively.

Clinical value of serial measurement of serum C-reactive protein level in neutropenic patients.

C-reactive protein (CRP) is an acute phase reactant of inflammation. We evaluated the clinical value of serial measurement of CRP in neutropenic patients. CRP was shown to be useful to monitor the response to therapy for febrile episodes in neutropenia. However, we failed to show statistically significant differences in CRP levels between febrile episodes with or without clinically documented infection (p= 0.10) and with or without bacteremia (p = 0.55). Also, we could not predict febrile episodes within three days by the elevation of CRP value. The area under receiver-operating characteristic curve depicting the relationship between CRP levels and forthcoming febrile episodes was only 0.60. In conclusion, serial measurement of CRP was considered to be not useful to predict fever within three days, or to differentiate the types of infection.

Treatment of deep vein thrombosis using temporary vena caval filters after allogeneic bone marrow transplantation.

Bone marrow transplant (BMT) recipients have risk factors for deep vein thrombosis (DVT) including venous stasis caused by immobilization in the sterile unit, vessel wall damage caused by preparative regimen or indwelling catheters, and hypercoagulability caused by decreased natural anticoagulants. We successfully treated a patient who developed massive DVT in the superior vena cava after BMT with anticoagulation and the use of temporary vena caval filters. Considering the delayed complications, permanent filter is not appropriate for BMT recipients, because the risk factors for DVT associated with BMT are transient. We considered that temporary vena caval filter is a safe and useful device to prevent pulmonary embolism after DVT in BMT recipients.

Prognostic significance of serum soluble interleukin-2 receptor level in non-Hodgkin's lymphoma: a single center study in Japan.

Interleukin 2 receptor is expressed not only on the surface of activated T or B lymphocytes, but also on certain lymphoid malignancies. The receptor is released from the cell membrane as soluble form (sIL-2R). Serum sIL-2R level is a sensitive and quantitative marker of circulating peripheral blood mononuclear cell activation or specific tumor cell growth including non-Hodgkin's lymphoma (NHL). However, the relevance of serum sIL-2R levels relating to clinical outcome in adult patients with NHL remains uncertain. Therefore, we investigated the serial serum sIL-2R levels in 28 untreated patients with NHL to evaluate its correlation with clinical characteristics. High serum sIL-2R level (>1000 U/ml) at diagnosis was associated with a high incidence of treatment failure (p=0.03) and poor overall survival (p=0.057). The serum sIL-2R levels decreased significantly after achieving complete remission (p=0.003). Further larger studies are required to evaluate whether serum sIL-2R level is an independent prognostic factor or not. However, adding this parameter to those already employed in the International Prognostic Index would perhaps provide a better prognostic index for adult patients with NHL.

Lack of correlation between clinical characteristics and serum soluble Fas ligand levels in patients with multiple myeloma.

Multiple myeloma is characterized by the accumulation of malignant plasma cells in the bone marrow and rarely cured by chemotherapy. Villunger et al. showed that the neoplastic plasma cells express Fas ligand (FasL), which transmits a signal of apoptosis upon ligation to Fas, and suggested that the FasL suppresses the T-cells activated against malignant cells, resulting in escape from tumour immunity. We examined serum soluble FasL (sFasL) levels in 35 multiple myeloma patients to evaluate the correlation between sFasL levels and clinical characteristics. The serum sFasL levels were not affected by the disease status, serum monoclonal protein levels, or other prognostic factors. We could not determine whether the expression of FasL is involved in the poor clinical course of the disease.

Pyogenic granuloma of the tongue early after allogeneic bone marrow transplantation for multiple myeloma.

Oral complications occur frequently after bone marrow transplantation (BMT). Some of them are caused by regimen-related toxicity of the preparative regimen, and others by infections. In addition, oral tissues are targets of graft-versus-host disease (GVHD). Oral granulomatous lesions are not a common complication after BMT, and are especially rare on the tongue. Such rare lesions reported in the literature, developed late after BMT with oral chronic GVHD. We present here a patient who developed pyogenic granuloma of the tongue early after allogeneic BMT done for multiple myeloma. Regimen-related mucositis, oral acute GVHD, the administration of cyclosporine A, and the preexisting macroglossia might be responsible for the formation of granuloma.

A high serum-soluble interleukin-2 receptor level is associated with a poor outcome of aggressive non-Hodgkin's lymphoma.

Soluble interleukin-2 receptor (sIL-2R) is produced by activated T and B cells, and the level of this receptor is elevated in patients with non-Hodgkin's lymphoma (NHL). The present study demonstrated that the sIL-2R level was high in the following groups of patients with aggressive NHL; those aged > or = 60 yr, those with a poor PS, those in Ann Arbor stage III or IV, and those in the high intermediate or high risk group according to the International Prognostic Index (IPI). Overall survival was significantly poorer when the sIL-2R level was 2000 U/ml or more. In addition, the overall survival of patients in the low (L) and low-intermediate (L-I) risk groups with an sIL-2R level of 3000 U/ml or more was significantly poorer, suggesting that the sIL-2R level could be particularly useful for identifying patients with a poor prognosis among the L and L-I risk groups. Univariate analysis identified some significant prognostic factors, and multivariate analysis of these factors plus the five IPI prognostic factors showed that the sIL-2R level was an independent prognostic indicator. In conclusion, the present findings established that the sIL-2R level is a significant independent prognostic factor in patients with aggressive NHL.

Combination therapy with irinotecan (CPT-11), mitoxantrone, and dexamethasone in relapsed or refractory non-Hodgkin's lymphoma: a pilot study.

Irinotecan hydrochloride (CPT-11) is a topoisomerase I inhibitor with a broad antitumor spectrum. In the present study, we combined CPT-1 and mitoxantrone (MIT) with dexamethasone because the effect elicited by this combination was additive or better in a preclinical study. This study was performed to determine the efficacy and toxicities of this combination. Thirty-two patients were evaluable. CPT-11 combined with MIT achieved a complete remission in 11 patients (34.4%) and a partial remission in 9 patients (28.1%). The median follow-up period was 20 months. The 4-year survival rate was 31.8% (95% confidence intervals: 11.2-64.6%), and the 3-year event-free survival rate was 16.1% (95% confidence intervals: 8.2-24.6%). Grade 3 or higher hematological toxicity included neutropenia in 96.9%, anemia in 3.1%, and thrombocytopenia in 15.6%. Grades 1, 2, and 3 nonhematological toxicity included diarrhea in one patient, nausea/vomiting in five patients, and hematuria in one patient, respectively. CPT-11 combined with MIT was safe even for elderly patients and was effective even in patients who had received pretreatment with doxorubicin. In addition, this regimen can be used on an outpatient basis. This combination should be tested further to determine the optimum doses and administration schedule.

Human herpes virus-8 associated with two cases of primary-effusion lymphoma.

Primary-effusion lymphoma (PEL) is a rare form of non-Hodgkin's lymphoma which predominantly occurs in patients with acquired immunodeficiency syndrome and is characterized by the presence of a malignant effusion in one or more of the body cavities, generally in the absence of a primary tumor mass. Recently, we encountered two cases of PEL presenting as cardiac tamponade. In both cases, a diagnosis of diffuse large B-cell lymphoma was made by examination of the pericardial fluid. Because human herpes virus-8 (HHV-8) antibodies were positive and human immunodeficiency virus antibodies were negative, HHV-8 seemed likely to be an etiologic agent for the PEL. One of the two patients (case 1) was not treated for religion reasons and died. The other (case 2) achieved complete remission after treatment using the CHOP regimen and is alive at present. The prognosis of this disease is believed to be poor, therefore more cases should be collected to establish reliable therapy for PEL.

High serum lactate dehydrogenase level predicts short survival after vincristine-doxorubicin-dexamethasone (VAD) salvage for refractory multiple myeloma.

We evaluated possible prognostic factors just before salvage therapy with vincristine, doxorubicin, and dexamethasone (VAD) for 36 patients with refractory multiple myeloma. The median duration from diagnosis to the first VAD salvage was 14 months (range 2-76 months). Among parameters that have been shown to be associated with poor survival, a high serum lactate dehydrogenase (LDH) level was the sole significant predictor of survival. The median survival of patients with high LDH levels was 4 months, whereas that of patients with low LDH levels was 20 months. A multivariate analysis identified high LDH and high age as independent prognostic factors. More aggressive therapies might be indicated for high-LDH patients with refractory myeloma.

Simple prognostic model for patients with multiple myeloma: a single-center study in Japan.

The range of survival duration in myeloma patients is wide and several percent of patients live longer than 10 years. Therefore, a precise prediction of survival for the individual patient is required to decide treatment. We evaluated possible prognostic factors at diagnosis for 116 Japanese patients with multiple myeloma. Twelve parameters reported to affect survival were analyzed using a log rank test and stepwise Cox proportional hazards regression. Factors identified as adversely affecting survival were age over 60 years, male sex, blood hemoglobin less than 8.5 g/dl, platelets less than 100 x 10(9)/l, serum creatinine level more than 2.0 mg/dl, serum C-reactive protein (CRP) level more than 6.0 mg/l, and serum beta2-microglobulin level more than 6.0 mg/l. Among them, only high age and high serum CRP level were independently prognostic for poor survival. In conclusion, we have established a simple prognostic model for Japanese myeloma patients only, using factors that can be determined in routine examinations without the need of subjective information.

The clinical significance of CD34 expression in response to therapy of patients with acute myeloid leukemia: an overview of 2483 patients from 22 studies.

BACKGROUND: Although many studies have been performed to evaluate the prognostic significance of CD34 expression in acute myeloid leukemia (AML), the findings have been inconsistent. In this study, the authors reviewed such previous studies to establish a definite conclusion. METHODS: Using MEDLINE, the authors identified studies that evaluated the prognostic significance of CD34 expression in AML. The outcome measure was the complete remission rate. They used the random-effect method to combine the results. Results were presented as odds ratios (ORs) with 95% confidence intervals (CIs). The ORs were less than 1 if the complete remission occurred more frequently in the CD34 negative group. RESULTS: Twenty-two studies including 2483 patients were reviewed. The combined OR was 0.38 (95% CI, 0. 26-0.57), which suggested that CD34 expression was associated with a poor remission rate. However, the authors found statistical evidence of marked heterogeneity among trials (P < 0.001), especially according to time of publication. The combined OR in studies published in or after 1994 was 0.70 (95% CI, 0.47-1.09). The authors divided the studies into several subgroups, but they could not determine the reason for the heterogeneity. CONCLUSIONS: At present, CD34 expression should not be considered a marker of poor prognosis because it is not supported by the combined data from recent studies. Further studies should be conducted to investigate the intensity of CD34 expression in specific populations of patients, such as those with t(8;21) or t(15;17) translocations or the AML-M0 subtype.

The diagnostic value of kappa/lambda ratios determined by flow cytometric analysis of biopsy specimens in B-cell lymphoma.

Flow cytometry (FC) is widely utilized in the diagnosis of lymphoma and the light chain ratio (LCR) is especially useful in the diagnosis of B-cell malignancy. In this study we analysed, retrospectively, the predictive value of the LCR in the diagnosis of B-cell lymphoma in 105 consecutive patients with persistent lymph node enlargement or extranodal masses who underwent biopsy. We used a receiver-operating characteristic curve to establish a LCR threshold value of 2.0. The specificity, sensitivity, positive and negative predictive values were 92.3%, 73.1%, 90% and 77%, respectively. We concluded that determination of LCR is a useful adjunct to pathological diagnosis.

Clinical and pathologic findings in 52 consecutively autopsied cases with multiple myeloma.

We studied clinical features and pathologic findings in 52 consecutively autopsied patients with multiple myeloma in our center between 1979 and 1998. Distant extraosseous involvement was found in 33 patients (63.5%). Thirty-one patients (59.6%) were proven to have infection at autopsy, among which pneumonia was most common site of infection. Amyloidosis was shown in 8 patients. Second malignancies were observed in 4 cases. The three major causes of death were hemorrhage, infection, and renal failure, which accounted for death in approximately 70% of the patients. Advances in the anticancer and antimicrobial chemotherapies might have decreased deaths due to myeloma itself or infection.