Noriyasu Fukushima

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.

Lymphomatoid gastropathy: a distinct clinicopathologic entity of self-limited pseudomalignant NK-cell proliferation

Diagnostic errors in distinguishing between malignant and reactive processes can cause serious clinical consequences. We report 10 cases of unrecognized self-limited natural killer-cell proliferation in the stomach, designated as lymphomatoid gastropathy (LyGa). This study included 5 men and 5 women (age, 46-75 years) without any gastric symptoms. Gastroscopy showed elevated lesion(s) (diameter, ∼ 1 cm). Histologically, medium-sized to large atypical cells diffusely infiltrated the lamina propria and, occasionally, the glandular epithelium. The cells were CD2(+/-), sCD3(-), cCD3(+), CD4(-), CD5(-), CD7(+), CD8(-), CD16(-), CD20(-), CD45(+), CD56(+), CD117(-), CD158a(-), CD161(-), T cell-restricted intracellular antigen-1(+), granzyme B(+), perforin(+), Epstein-Barr early RNA(-), T-cell receptor αβ(-), and T-cell receptor γδ(-). Analysis of the 16 specimens biopsied from 10 patients led to a diagnosis of lymphoma or suspected lymphoma in 11 specimens, gastritis for 1 specimen, adenocarcinoma for 1 specimen, and LyGa or suspected LyGa for 3 specimens. Most lesions underwent self-regression. Three cases relapsed, but none of the patients died. According to conventional histopathologic criteria, LyGa is probably diagnosed as lymphoma, especially as extranodal natural killer/T-cell lymphoma, nasal type. However, LyGa is recognized as a pseudomalignant process because of its clinical characteristics. The concept of LyGa should be well recognized.

Monitoring of Hepatitis B Virus (HBV) DNA and Risk of HBV Reactivation in B-Cell Lymphoma: A Prospective Observational Study

BACKGROUND There is no standard management of reactivation of hepatitis B virus (HBV) infection in HBV-resolved patients without hepatitis B surface antigen (HBsAg), but with antibodies against hepatitis B core antigen and/or antibodies against HBsAg (anti-HBs). METHODS We conducted a prospective observational study to evaluate the occurrence of HBV reactivation by serial monthly monitoring of HBV DNA and to establish preemptive therapy guided by this monitoring in B-cell non-Hodgkin lymphoma (B-NHL) treated with rituximab plus corticosteroid-containing chemotherapy (R-steroid-chemo). The primary endpoint was the incidence of HBV reactivation defined as quantifiable HBV DNA levels of ≥ 11 IU/mL. RESULTS With a median HBV DNA follow-up of 562 days, HBV reactivation was observed in 21 of the 269 analyzed patients. The incidence of HBV reactivation at 1.5 years was 8.3% (95% confidence interval, 5.5-12.4). No hepatitis due to HBV reactivation was observed in patients who received antiviral treatment when HBV DNA levels were between 11 and 432 IU/mL. An anti-HBs titer of <10 mIU/mL and detectable HBV DNA remaining below the level of quantification at baseline were independent risk factors for HBV reactivation (hazard ratio, 20.6 and 56.2, respectively; P < .001). Even in 6 patients with a rapid increase of HBV due to mutations, the monthly HBV DNA monitoring was effective at preventing HBV-related hepatitis. CONCLUSIONS Monthly monitoring of HBV DNA is useful for preventing HBV reactivation-related hepatitis among B-NHL patients with resolved HBV infection following R-steroid-chemo (UMIN000001299).

Pretreatment EBV-DNA copy number is predictive of response and toxicities to SMILE chemotherapy for extranodal NK/T-cell lymphoma, nasal type

Purpose: Extranodal NK/T-cell lymphoma, nasal type (ENKL) is an Epstein–Barr virus (EBV)–associated lymphoma for which a new chemotherapeutic regimen called SMILE (steroid, methotrexate, ifosfamide, l-asparaginase, and etoposide) recently showed promising results. Experimental Design: The amount of EBV-DNA was prospectively measured in whole-blood and plasma samples by real-time quantitative PCR from 26 patients registered in the SMILE phase II study. Results: Before treatment, the EBV-DNA was detected in 22 samples of whole blood with a median number of 3,691 copies/mL (range: 0–1.14 × 107), but 15 samples of plasma with a median of 867 copies/mL (range: 0–1.27 × 107). Results of these 2 measurements of EBV-DNA well correlated (R2 = 0.994, P < 0.001). The overall response rate to SMILE was significantly higher in patients with less than 105 copies/mL of EBV-DNA in whole blood at enrollment (90% vs. 20%, P = 0.007) and in patients with less than 104 copies/mL of EBV-DNA in plasma (95% vs. 29%, P = 0.002). The incidence of grade 4 toxicity of SMILE other than leukopenia/neutropenia was significantly higher in patients with 105 copies/mL of EBV-DNA or more in whole blood (100% vs. 29%, P = 0.007) than that of others and in patients with 104 copies/mL or more in plasma (86% vs. 26%, P = 0.002). Conclusions: These findings suggest that whole blood is more sensitive for clinical use than plasma. The EBV-DNA amount in whole blood was useful for predicting tumor response, toxicity, and prognosis after SMILE chemotherapy for ENKL. Clin Cancer Res; 18(15); 4183–90. ©2012 AACR.

Japan Clinical Oncology Group (JCOG) prognostic index and characterization of long-term survivors of aggressive adult T-cell leukaemia-lymphoma (JCOG0902A)

This study evaluated the clinical features of 276 patients with aggressive adult T‐cell leukaemia‐lymphoma (ATL) in 3 Japan Clinical Oncology Group (JCOG) trials. We assessed the long‐term survivors who survived >5 years and constructed a prognostic index (PI), named the JCOG‐PI, based on covariates obtained by Cox regression analysis. The median survival time (MST) of the entire cohort was 11 months. In 37 patients who survived >5 years, no disease‐related deaths in 10 patients with lymphoma‐type were observed in contrast to the 10 ATL‐related deaths in other types. In multivariate analysis of 193 patients, the JCOG‐PI based on corrected calcium levels and performance status identified moderate and high risk groups with an MST of 14 and 8 months respectively (hazard ratio, 1·926). The JCOG‐PI was reproducible in an external validation. Patients with lymphoma‐type who survived >5 years might have been cured. The JCOG‐PI is valuable for identifying patients with extremely poor prognosis and will be useful for the design of future trials combining new drugs or investigational treatment strategies.

Clinico-pathological characteristics of p63 expression in B-cell lymphoma

A member of the family of p53‐related genes, p63 plays a role in regulating epithelial proliferation and differentiation programs, but the pathological and clinical meaning of p63 in B‐cell lymphoma has not been elucidated. We investigated the expression pattern of p63 in B‐cell malignancies, and evaluated the correlation between the expression of p63 and other germinal center markers. Ninety‐eight B‐cell lymphomas (28 FCL, 5 MCL, and 65 DLBCL) were analyzed by immunohistochemical examination for p63, bcl‐6, CD10 and MUM‐1 proteins, and for rearrangement of bcl‐2/IgH. Expression of p63 was observed in the nuclei of tumor cells obtained from 15 of 28 (54%) FCL, 22 of 65 (34%) DLBCL, but none of 5 MCL. In DLBCL, the expression of p63 and bcl‐6 showed a significant correlation (P < 0.02), but no correlation was observed between p63 and expression of CD10, MUM‐1, or bcl‐2/IgH rearrangement. RT‐PCR revealed that TAp63α‐type transcripts, a possible negative regulator of transcriptional activation of p21 promoter, were major transcripts in B‐cell lymphoma tissues. As for prognostic significance, only patients in the p63 positive group of FCL died, and in the non‐germinal center group, the p63 positive cases appeared to have inferior overall survival than other groups in DLBCL. Our preliminary results suggested that p63 expression is a disadvantageous factor for prognosis in this subgroup of B‐cell lymphomas. (Cancer Sci 2006; 97: 1050–1055)

Non-germinal cell phenotype and bcl-2 expression in primary adrenal diffuse large B-cell lymphoma

Primary adrenal lymphoma is a rare subtype observed in only 0.83% of all non-Hodgkin lymphoma [1], although the adrenal gland may be involved in up to 25% of NHL cases, by autopsy [2]. The immunophenotype of primary adrenal lymphoma is usually B-cell, with a few T-cell types reported [1,3 – 6]. About 60% of primary adrenal lymphoma patients have bilateral involvement and two-thirds show adrenal insufficiency. Previous reports found that most primary adrenal lymphoma patients belonged to high-risk group by IPI classification, associated with poor prognosis with only 4 months over all survival [1]. It was recently shown that diffuse large B-cell lymphoma (DLBCL) can be divided into three prognostically important subgroups: germinal center B-cell-like (GCB)/DLBCL, activated B-cell-like DLBCL, and type 3, based on gene expression profiles using a cDNA microarray [7,8]. Germinal center B-cell-like DLBCL has a better prognosis than either activated B-cell or type 3. Hans et al. proposed that the immunohistochemical expression pattern of CD10, Bcl-6 and MUM-1 could classify cases of DLBCL into GCB and non-germinal center B-cell type (non-GCB), and predict survival similar to the cDNA microarray [9]. The majority of primary adrenal lymphoma cases are diffuse large B-cell lymphoma, but no precise immunohistochemical examination has been reported. We examined the phenotype of primary adrenal diffuse large B-cell lymphoma (PA-DLBCL) using immunohistochemistry for CD10, Bcl-6, MUM-1 and bcl-2. We found four cases (1.0%) of primary adrenal lymphoma among 390 cases of NHL diagnosed at Saga University Hospital from 1997 to 2006. PAL was diagnosed when the extra nodal site was the only adrenal gland mass, or when the bulk of disease was confined to site of adrenal gland [10] and tissue sample could be obtained only from adrenal mass. The four cases included three men and one woman from 48 to 78 years old, and CT or MRI showed bilateral adrenal masses in all cases. These tumors appeared to be complex masses with variable density in CT scan, no apparent hemorrhage or fibrotic change, and detectable normal adrenal glands. Adrenal insufficiency was present in Case 2 and 4, and bulky mass (410 cm) was observed in Case 2 and 4. Only Case 3 was stage IE, the other cases being stage IV. Case 1 showed B-symptom (fever), a high level of lactate dehydrogenase (LDH) was observed in Case 1, 2 and 4, and a high level of soluble IL-2 receptor (sIL-2R) were present in all cases. International prognostic index (IPI) was high or high-intermediate in three of these cases. The definitive diagnostic procedures for histopathological diagnosis were resection (Case 1 and 4) and ultrasound scan guided needle biopsy (Case 2 and 3). Hematoxylin and eosin staining showed that all cases demonstrated diffuse proliferation of large lymphoid cells [Figure 1(a)]. Case 2 included pleomorphic features, with most of these cells noncleaved/centroblastic morphology; Case 2 and 4 had fibrosis in various degrees; and Case 4 had

A fully integrated and automated detection system for single nucleotide polymorphisms of UGT1A1 and CYP2C19.

The need for examinations of single nucleotide polymorphisms (SNPs) on drug metabolizing enzymes is accelerating. Especially, SNPs of UTG1A1 and CYP2C19 are important for patients who are treated with irinotecan and proton pump inhibitors, respectively. Thus, a method for the rapid, fully automated, and accurate measurement of these SNPs is desired. We genotyped 109 Japanese volunteers for UGT1A1*6, UGT1A1*28, CYP2C19*2, and CYP2C19*3 with the quenching probe (QP) method. Only 90 min after whole blood was applied, QP method enabled to detect these SNPs automatically. The results obtained by QP method were absolutely identical to those examined by the conventional direct sequencing. These findings indicate that the QP method will enable point-of-care testing in clinical laboratories and patient-oriented therapy with its convenience and speed for patients who are treated with irinotecan or proton pump inhibitors.

Therapeutic management in cardiac lymphoma

1 Division of Hematology, Respiratory Medicine and Oncology, Department of Internal Medicine, 2 Department of Medical Science Technology, School of Health Sciences at Fukuoka, International University of Health and Welfare, Fukuoka, Japan, 3 Department of Thoracic and Cardiovascular Surgery, 4 Division of Cardiology, Department of Internal Medicine 5 Department of Laboratory and Blood Transfusion Medicine, Faculty of Medicine, Saga University, Saga, Japan and 6 Department of Hematology and Oncology, Research Institute for Radiation Biology and Medicine, Hiroshima University, Hiroshima, Japan

Lenalidomide in combination with dexamethasone induced rhabdomyolysis in a multiple myeloma patient treated with pravastatin

A 77-year-old Japanese man was diagnosed with multiple myeloma (MM, IgG-j type, Durie-Salmon stage I, ISS stage I in 2007). He was additionally diagnosed with hypercholesterolemia, and had been administered pravastatin since February 2009. He was treated with a single course of melphalan plus prednisolone, intermittently administered with dexamethasone (DEX), which was followed by 12 courses of melphalan plus DEX. As his symptoms aggravated, he was treated with thalidomide plus DEX from August 2009 to August 2010. This treatment was discontinued due to peripheral neuropathy. From 8 November 2010, we began treating the patient with lenalidomide 25 mg daily plus DEX. He had additionally been on treatment regimens of allopurinol for 4 years, mecobalamin for 1 year, sulfamethoxazole trimethoprim for 1 year, brotizolam for 9 months, warfarin for 2 months, and fluconazole for 3 weeks. On the night of November 13, he developed sudden myalgic pains in both upper arms, weakness of the extremities, abasia, and fever (38.1 C), and was thus immediately admitted to our hospital. His leukocyte count was 5.0 9 10/L, hemoglobin was 7.8 g/dL, and platelets count were 14.5 9 10/L. Biochemical analysis revealed BUN 14.5 mg/dL, creatinine 1.49 mg/dL, AST 71 IU/L, ALT 47 IU/L, LDH 299 IU/L, Na 139 mEq/L, K 3.4 mEq/L, creatine kinase (CK) 3,445 IU/L. Isozymes of CK-MB, -MM, and -BB were 1, 99, and 0%, respectively. Urine myoglobin was 153,000 ng/mL (normal 0–4 ng/mL). His thyroid function was normal (TSH 2.13 lIU/ml, free T4 1.1 ng/ml). He was diagnosed with rhabdomyolysis based on the following symptoms: pain in the proximal limb muscles, faintness, CK increase, myoglobinuria, and slightly impaired renal function. Neurologic examination revealed no tetraparesis. Computed tomography of the head revealed no acute infarction or hemorrhage. We discontinued oral administration of lenalidomide and pravastatin on the day of hospitalization and initiated hydration (1.5 L/day). Although he experienced myalgic pain in both thighs on day 2 and CK increased to 16,126 IU/L, the symptoms were alleviated promptly. On day 10, both the muscular symptoms and laboratory test values returned to normal and he was discharged on day 36. Rhabdomyolysis occurs secondary to the breakdown of skeletal muscle, which leads to the release of intracellular substances into the bloodstream and can be induced by various factors, such as external injury, exercise stress, heatstroke, dehydration, hypokalemia, hypothyroidism, infectious disease, and medication. Among the latter, statins are among the best-known pharmaceutical triggers. Standard statin doses are associated with very low rates of rhabdomyolysis incidence: fewer than 1 in 10,000 patients are treated. However, when combined with other factors such as use of higher doses, concomitant drugs, age, and renal impairment, the incidence of muscle toxicity is higher [1]. It is known that rhabdomyolysis can occur in a concentration-dependent manner, especially when a patient is administered statins concomitantly with a CYP450-mediated medication [1]. Lenalidomide is an imunomodulatory drug related to thalidomide. 25 mg of lenalidomide plus DEX was given safely in Japanese patients with relapsed or refractory MM [2]. This is the first case of rhabdomyolysis among more than 1,500 registered patients according to a C. Urata M. Yoshimura (&) H. Itamura T. Hisatomi Y. Kubota N. Fukushima E. Sueoka S. Kimura Division of Hematology, Respiratory Medicine, and Oncology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga 849-8501, Japan e-mail: tanakam8@cc.saga-u.ac.jp