Accuracy of cone beam computed tomography in evaluation of palatal mucosa thickness.

AIM: The purpose of this study was to investigate the accuracy of the measurement of palatal mucosa thickness using cone beam computed tomography (CBCT) and to create a conversion formula to evaluate palatal mucosa thickness more accurately. We then evaluated the palatal mucosa thickness in a Japanese population using CBCT and the conversion formula. MATERIALS AND METHODS: We evaluated palatal mucosa thickness in 10 healthy subjects at 15 sites using CBCT, digital impression, and K file. Multiple regression analysis was performed to create a conversion formula to measure thickness accurately. We then obtained CBCT data from 174 patients retrospectively, applied the conversion formula, and evaluated palatal mucosa thickness. RESULTS: Sites of measurement affected measurement error. Measurement using CBCT was 0.34 ± 0.04 mm smaller than actual measurement; therefore, a conversion formula was created. Male, age ≥60 years, and probing pocket depth ≥4 mm had significant and positive associations with palatal mucosa thickness; however, no association was observed between bleeding on probing and palatal mucosa thickness. CONCLUSION: CBCT is useful for the noninvasive and accurate measurement of palatal mucosa thickness.

A phase II study of bortezomib in patients with relapsed or refractory aggressive adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is a malignancy of peripheral T-lymphocytes with a poor prognosis. This multicenter, two-stage, single-arm, phase II study assessed the efficacy and safety of bortezomib in patients with relapsed/refractory ATL who received at least one regimen of chemotherapy. The primary endpoint was the best overall response rate (ORR), and secondary endpoints included safety, the best response by lesions, and progression-free survival (PFS). Fifteen patients were enrolled in the first stage of this study. One partial remission (PR) and five stable disease (SD) were observed as the best overall responses, and ORR was 6.7% (95% confidence interval (C.I.) 0.17-31.95%). Responses according to disease sites were one complete remission (CR) in peripheral blood, two PR in measurable targeted lesions, and two PR in skin lesions. Progression-free survival (PFS) was 38 (95% CI; 18-106) days. All patients developed ≥1 adverse events (AEs), and 80% of patients had ≥1 grade 3/4 AEs; however, no new safety findings were obtained. Although these results fulfilled the planned settings to proceed to the second stage, the coordinating committee decided to terminate this study because single agent activity did not appear to be very promising for this cohort of patients.

Effect of exercise therapy on muscle mass and physical functioning in patients undergoing allogeneic hematopoietic stem cell transplantation.

PURPOSE: Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is associated with transplant-related toxicities, which may have a profound impact on a patient's physical functioning and body composition. In order to analyze the effect of exercise therapy on muscle mass and physical functioning in patients receiving allo-HSCT, we measured muscle mass and physical functioning before and after allo-HSCT. METHODS: Eighty-six patients who had undergone allo-HSCT between February 2010 and September 2013 at Imamura Bun-in Hospital participated in this study. Physical therapists performed exercise therapy with patients 5 days a week, starting 2 weeks before allo-HSCT. Body composition, 6-min walk test (6MWT) scores, and handgrip strength were evaluated 2 weeks before allo-HSCT and 6 weeks after allo-HSCT. RESULTS: Thirty-five patients were available for evaluation 2 weeks before and 6 weeks after allo-HSCT. The 6MWT (p = 0.005) and handgrip strength (p < 0.001) significantly decreased after allo-HSCT. Although upper extremity muscle mass (p = 0.001) and trunk muscle mass (p < 0.001) significantly decreased after allo-HSCT, lower extremity muscle mass remained unchanged. CONCLUSIONS: In this study, it is suggested that exercise therapy may be effective for maintaining lower extremity muscle mass in patients undergoing allo-HSCT.

Clinicopathological analysis of 17 primary cutaneous T-cell lymphoma of the γδ phenotype from Japan.

Primary cutaneous γδ T-cell lymphoma (PCGD-TCL) is an aggressive lymphoma consisting of clonal proliferation of mature activated γδ T-cells of a cytotoxic phenotype. Because primary cutaneous γδ T-cell lymphoma is a rare disease, there are few clinicopathological studies. In addition, T-cell receptor (TCR) γδ cells are typically immunostained in frozen sections or determined by TCRß negativity. We retrospectively analyzed 17 primary cutaneous T-cell lymphomas of the γδ phenotype (CTCL-γδ) in a clinicopathological and molecular study using paraffin-embedded sections. Among 17 patients, 11 had CTCL-γδ without subcutaneous panniculitis-like T-cell lymphoma (SPTCL) features and six had CTCL-γδ with SPTCL features. Immunophenotypically, some significant differences were found in CD8 and CD56 positivity between our patient series of CTCL-γδ patients with SPTCL features and SPTCL-γδ patients described in the previous literature. A univariate analysis of 17 CTCL-γδ patients showed that being more than 60 years old, presence of visceral organ involvement, and small-to-medium cell size were poor prognostic factors. In addition, the 5-year overall survival rate was 42.4% for the CTCL-γδ patients without SPTCL features and 80.0% for those with SPTCL features. Consequently, there was a strikingly significant difference in overall survival among SPTCL, CTCL-γδ with SPTCL features and CTCL-γδ without SPTCL features (P = 0.0005). Our data suggests that an indolent subgroup may exist in CTCL-γδ. Studies on more cases, including those from other countries, are warranted to delineate the clinicopathological features and the significance in these rare lymphomas.

Reactivation of hepatitis B virus in a patient with adult T-cell leukemia-lymphoma receiving the anti-CC chemokine receptor 4 antibody mogamulizumab.

The introduction of molecularly targeted drugs has increased the risk of reactivation of hepatitis B virus (HBV), which is a potentially fatal complication following anticancer chemotherapy even in patients who have previously resolved their HBV infection. CC chemokine receptor 4 (CCR4) has been identified as a novel molecular target in antibody therapy for patients with adult T-cell leukemia-lymphoma (ATL) and peripheral T-cell lymphoma, and the humanized anti-CCR4 monoclonal antibody mogamulizumab has been developed. We reported HBV reactivation of an ATL patient with previously resolved HBV infection after mogamulizumab treatment in a dose-finding study for this antibody. Our retrospective analysis using preserved samples also revealed the detailed kinetics of HBV DNA levels before and just after HBV reactivation.

Cord blood transplantation with a reduced-intensity conditioning regimen using fludarabine and melphalan for adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma with a poor prognosis when treated with chemotherapy alone; therefore, allogeneic stem cell transplantation is a consideration. We attempted cord blood transplantation (CBT) using a reduced-intensity conditioning regimen without total body irradiation (non-TBI-RIC) to allow for the best possible timing of transplantation and improve survival outcomes, particularly in older patients. Forty-eight patients (27 male, 21 female) underwent CBT using fludarabine (Flu) 125 mg/m2 and melphalan (Mel) 140 mg/m2 as pre-transplant conditioning. The median age was 32 years (range 44-72), and 21 patients were in complete remission (CR) at the time of CBT. The median duration to neutrophil engraftment (NE) was 19.5 days (range 15-50), with a cumulative incidence of NE of 86.7% at day 50 after CBT. The 1- and 3-year overall survival (OS) rates were 40.4% and 37.7%, respectively. The 3-year OS rate in CR patients was 60.8%, compared with 18.8% in non-CR patients. In ATLL patients, CBT with non-TBI-RIC using Flu/Mel is a promising treatment strategy.

Clinical significance of a blood eosinophilia in adult T-cell leukemia/lymphoma: a blood eosinophilia is a significant unfavorable prognostic factor.

We investigated the clinical significance of a blood eosinophilia in a cohort of 158 consecutive patients with adult T-cell leukemia/lymphoma (ATLL), and multivariate analysis revealed that a blood eosinophilia was an independent and a significant unfavorable prognostic factor. Interestingly, a blood eosinophilia was independent of serum LDH level, which might reflect the tumor burden. The present study shows that measurement of the blood eosinophil count is useful for predicting the prognosis and for determining a suitable treatment strategy for ATLL patients.

18F-FDG PET/CT Imaging of Epididymal Smooth Muscle Mass Mimicking Recurrent Lymphoma.

An 84-year-old man with a history of diffuse large B-cell lymphoma in remission who had completed chemotherapy 3 years previously was referred for imaging evaluation of disease recurrence. Abnormal accumulation in the left scrotum was demonstrated on F-FDG PET/CT. Subsequent ultrasonography showed a nodular mass lesion in the left epididymis. He then underwent left orchiectomy. Histopathological examination of the mass diagnosed smooth muscle hyperplasia/hamartoma of the left epididymis. Epididymal smooth muscle hyperplasia/hamartoma should be included as a differential diagnosis for malignant scrotal tumor.

Newly identified poor prognostic factors for adult T-cell leukemia-lymphoma treated with allogeneic hematopoietic stem cell transplantation.

To explore pre-transplantation prognostic factors for adult T-cell leukemia-lymphoma (ATL), we retrospectively analyzed allogeneic hematopoietic stem cell transplantation (allo-HSCT) in 70 patients at our institute (63 acute type and seven lymphoma type patients). Forty-five patients died after HSCT and the three-year overall survival (OS) rate was 35.2%. By univariate analysis, the adverse prognostic factors for OS were performance status ≥2, hematopoietic cell transplantation-specific comorbidity index (HCT-CI) score ≥3, European Group for Blood and Marrow Transplantation (EBMT) risk score ≥5, HSCT from an HLA-mismatched donor, serum soluble interleukin-2 receptor (sIL-2R) level ≥10,000 U/mL, lymphocyte count ≥4000/µL, and hemoglobin <9 g/dL at the time of HSCT. EBMT risk score and sIL-2R were identified as significant adverse prognostic factors using multivariate analysis. This analysis clearly demonstrates for the first time that HCT-CI and EBMT risk scores are reliable prognostic factors for ATL patients receiving allo-HSCT.

Detection of an early adult T-cell leukemia-lymphoma clone in lymph nodes with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma involvement.

A 58-year-old man was admitted to our hospital with systemic lymphadenopathy and was diagnosed with anaplastic lymphoma kinase-negative anaplastic large cell lymphoma (ALCL) by lymph node biopsy. Although he was a human T-cell leukemia virus type I (HTLV-1) carrier, Southern blot analysis of the lymph node did not show monoclonal integration of HTLV-1 provirus deoxyribonucleic acid (DNA). He achieved complete remission after chemotherapy and subsequently, autologous peripheral blood stem cell transplantation (auto-PBSCT) was performed. Fifteen months after the auto-PBSCT, abnormal lymphocytes in the peripheral blood gradually increased. Southern blot analysis revealed monoclonal integration of HTLV-1 provirus DNA and monoclonal rearrangement of TRB. He was diagnosed with chronic type adult T-cell leukemia-lymphoma (ATL), which immediately progressed to the acute type. He died of tumor progression despite intensive chemotherapy. We analyzed genomic alterations of the ALCL and ATL cells using array comparative genomic hybridization. We found that the genomic alteration pattern differed between the two diseases. T-cell receptor clonality analysis using polymerase chain reaction (PCR) showed that the T-cell clone of the ATL was present in the lymph nodes with ALCL involvement, but not in peripheral blood. This finding suggests that lymph nodes can serve as a niche for ATL development.

Human T-lymphotropic virus type I proviral loads in patients with adult T-cell leukemia-lymphoma: Comparison between cutaneous type and other subtypes.

Adult T-cell leukemia-lymphoma (ATL), characterized by various clinicopathological features, is divided into four clinical subtypes, namely, acute, lymphoma, chronic and smoldering types, and the treatment strategy differs according to the clinical subtype. The designation cutaneous type ATL has been proposed to describe a peculiar subgroup of smoldering type ATL in which the skin is predominantly affected. However, diagnostic criteria and prognostic factors for cutaneous type ATL remain to be determined. Therefore, we performed a retrospective study to obtain a precise method for subtype classification and to clearly define cutaneous type ATL. A total of 87 ATL patients (acute, n = 31; lymphoma, n = 6; chronic, n = 24; smoldering, n = 26) were enrolled. The human T-lymphotropic virus type I (HTLV-1) proviral load in peripheral blood and the serum soluble interleukin-2 receptor (sIL-2R) level were evaluated with respect to the clinical features of the different types of ATL. The HTLV-1 proviral load was significantly increased in the acute and chronic type and the serum sIL-2R level was increased in the acute and lymphoma type. The HTLV-1 proviral load was significantly lower in cutaneous than other smoldering types of ATL without skin lesions. The clinical findings of cutaneous type ATL were also different from other subtypes. These results indicate that, in combination, determination of the HTLV-1 proviral load and the serum sIL-2R level is useful for distinguishing among the different types of ATL, and strongly suggest that cutaneous type ATL is a distinct clinical entity.

Arsenic trioxide induces apoptosis in HTLV-I infected T-cell lines and fresh adult T-cell leukemia cells through CD95 or tumor necrosis factor alpha receptor independent caspase activation.

Arsenic trioxide (As2O3) has been reported to induce apoptosis in human T-cell leukemia virus type-I (HTLV-I) infected T-cell lines and fresh adult T-cell leukemia (ATL) cells and to induce G1 phase accumulation in HTLV-I infected T-cell lines. The present study aimed to clarify the pathway of As2O3-induced apoptosis in HTLV-I infected T-cell lines, MT-1 and MT-2, and fresh ATL cells separated from peripheral blood of patients with acute or chronic type ATL. Cells were treated up to 72 h at clinically tolerable concentrations of As2O3 (1-2 micromol/l) shown to be safe in patients with acute promyelocytic leukemia (APL). Activation of caspases 3, 8, and 9, loss of mitochondrial transmembrane potential and cleavage of poly (adenosine diphosphate-ribose) polymerase (PARP) were observed during As2O3 treatment. Furthermore, prior exposure to a broad-spectrum caspase inhibitor blocked As2O3-induced apoptosis but not G1 phase accumulation. While pre-treatment with a CD95 receptor-blocking antibody (Ab) or a TNF-alpha neutralizing Ab did not show such inhibitions in these cells. In conclusion, As2O3 induces apoptosis in HTLV-I infected T-cell lines and fresh ATL cells through CD95 or TNF-alpha receptor independent caspase activation.

Augmentation of the activity of an immunotoxin, anti-Tac(Fv)-PE40KDEL, in T cell lines infected with human T cell leukemia virus type-I.

Therapy with an immunotoxin, anti-Tac(Fv)-PE38, which is a conjugate of the variable domains of an anti-Tac monoclonal antibody and Pseudomonas exotoxin, was reported to be useful for adult T cell leukemia (ATL) patients but a considerable amount of the immunotoxin is needed for the therapy and some side effects were also observed. We have previously demonstrated that an immunotoxin, anti-Tac(Fv)-PE40KDEL, showed strong cytotoxic effects on malignant cells from ATL patients. Therefore, we searched for agents that enhance the effects of the immunotoxin. PAK-200, FK-506, quinidine, cepharanthine and cyclosporine A (CsA) augmented the ability of the immunotoxin to inhibit protein synthesis in two human T cell leukemia virus type-I infected T cell lines, KUT-1 and KUT-2. CsA was the most potent agent in both the cell lines. Augmentation of the cytotoxic effect of the immunotoxin by these agents, especially CsA, may be useful in the immunotoxin therapy of ATL.

Serum levels of endogenous thrombopoietin and granulocyte-colony stimulating factor in patients with acute or lymphoma type adult T-cell leukemia during multicycle chemotherapy.

Recent multidrug chemotherapy for adult T-cell leukemia (ATL) showed improved findings, however, these protocols often induced persistent myelosuppression. Among 67 patients with acute and lymphoma type ATL treated between January 1996 and December 1998, 42 patients died during this period and showed chemotherapy-induced myelosuppression. To characterize the relation between the severity of myelosuppression and the endogenous thrombopoietin (TPO) or granulocyte-colony stimulating factor (G-CSF) levels in ATL patients, we measured these hematopoietic factors using ELISA method. Nineteen patients with acute or lymphoma type ATL and 16 healthy individuals were examined. During thrombocytopenia, the serum TPO levels were significantly higher than that of controls (P < 0.0001) and were inversely correlated with the platelet counts (r = -0.687 P < 0.001). Later in the chemotherapy cycle, severe persistent thrombocytopenia occurred and TPO levels elevated and remained at a high level approximating the TPO levels of exogenous TPO administration (0.3 microg/kg body weight). On the other hand, the serum G-CSF levels with absolute neutrophil counts (ANC) below 0.5 x 10(9)/L were significantly higher than controls (P = 0.009) and inversely correlated with ANC (r = -0.382 P = 0.0034). However, G-CSF levels in six samples obtained after 6 h of G-CSF (100-150 microg per body) administration was approximately 50-fold higher than that in the neutropenic states. These findings suggested that G-CSF can effectively reduce the severity and duration of intensified chemotherapy-induced neutropenia and higher dose exogenous TPO (higher than 0.6 microg/kg per day) therapy may be required to enhance platelet recovery after intensive chemotherapy in ATL patients.

Effect of anti-CCR4 monoclonal antibody (mogamulizumab) on adult T-cell leukemia-lymphoma: cutaneous adverse reactions may predict the prognosis.

Adult T-cell leukemia-lymphoma (ATL) is one of the most malignant lymphomas with poor prognosis. ATL cells express CC chemokine receptor 4 (CCR4) and mogamulizumab, a monoclonal antibody against CCR4 that exhibits very strong cytotoxicity for ATL cells via antibody-dependent cellular cytotoxicity. Although its effect is dramatic in ATL, serious adverse reactions such as Stevens-Johnson syndrome have been reported. However, these eruptions can appear as therapeutic signs of mogamulizumab. We evaluated the effectiveness of mogamulizumab in five acute-type ATL patients. Peripheral blood (PB) and lymph nodes (LN) were affected in three and four patients, respectively. In PB, complete response (CR) was obtained in all three patients and partial response (PR) was recorded in LN of one patient. In skin lesions, four of five patients manifested CR; in two, the lesions worsened after the start of mogamulizumab treatment and subsequently improved. In these lesions, CD4(+) 8(-) 25(+) ATL cells were replaced by CD3(+) 8(+) cytotoxic T cells. Cutaneous adverse reactions (CAR) developed in two patients with CR; they did not show a relapse of ATL over the course of 9 months. Our findings suggest that mogamulizumab should be continued and surface marker evaluation should be performed even in patients whose skin lesions show aggravation, and that CAR may be a marker for a favorable prognosis.