[Simultaneously treated thymoma and lung cancer; report of a case].

A 74-year-old man was admitted to our hospital in order to treat a mediastinal mass and 2 ground-glass attenuations in the right upper lobe detected by chest X-ray and computed tomography (CT). Partial resection of right lung and thymectomy were performed. The mediastinal mass and 2 ground-glass attenuations in the right upper lobe proved to be thymoma and bronchioloalveolar carcinomas, respectively by pathology.

Outcome and treatment of late-onset noninfectious pulmonary complications after allogeneic haematopoietic SCT.

Late-onset noninfectious pulmonary complications (LONIPCs) are life threatening for allogeneic hematopoietic SCT (allo-HSCT) recipients. However, the impact of LONIPCs on survival has not been properly evaluated and little is known about treatment efficacy. We retrospectively investigated 290 allo-HSCT recipients in our institute and reviewed the clinical aspects of 44 patients who had been diagnosed with LONIPCs. LONIPCs were significantly associated with higher rates of chronic GVHD (P<0001) and nonrelapse mortality (P=0.013), and lower rates of relapse (P=0.009). As a result of these effects, OS was significantly worse in those with LONIPCs (P=0.003). This result differs from a previous report. We then assessed short-term treatment response and final outcome. These results were defined by radiological findings, subjective symptoms, oxygen requirement and survival. Use of inhaled and systemic steroids did not affect either short-term response or final outcomes. However, administration of systemic corticosteroids earlier than at 21 days (median interval of time from onset of symptoms to systemic corticosteroids administration) was associated with a better outcome (P=0.054 for short-term response, and 0.016 for final outcome). Our study indicates that LONIPCs reduce OS, and early intervention with systemic corticosteroids may be effective.

Plasma brain natriuretic peptide is associated with hepatic veno-occlusive disease and early mortality after allogeneic hematopoietic stem cell transplantation.

Fluid retention is characteristic of veno-occlusive disease (VOD). We hypothesized that plasma brain natriuretic peptide (BNP), a neurohormone secreted in response to volume expansion, may be associated with VOD after hematopoietic stem cell transplantation (HSCT). BNP was measured before and weekly after HSCT in 46 recipients. Sixteen patients developed VOD. BNP concentrations were similar before and on day 0 in patients with and without VOD, but were significantly higher on day 7 and later in those with VOD. Patients with VOD had significantly higher peak BNP concentrations before engraftment than those without VOD (median, 634.4 versus 80.9 pg ml⁻¹; P=0.01). Multivariate analysis showed that VOD was independently associated with BNP elevation (odds ratio, 50.1; 95% CI: 5.2-478.4; P<0.01). Landmark analysis at day 7 showed that patients with peak BNP concentration of ≥ 180 pg ml⁻¹ had significantly worse 100-day survival than patients with peak BNP <180 pg ml⁻¹ (54 versus 91%; P<0.01). In multivariate analysis, BNP elevation before day 7 significantly predicted 100-day survival (hazard ratio 5.3; 95% CI: 1.1-24.3; P=0.03). These findings suggest that plasma BNP may serve as a diagnostic and prognostic marker of VOD.

Differential prognostic impact of pretransplant comorbidity on transplant outcomes by disease status and time from transplant: a single Japanese transplant centre study.

This retrospective study examined the differences in the prognostic impact of the haematopoietic cell transplantation-specific comorbidity index (HCT-CI) on transplant outcomes by disease status and time from transplant in allogeneic haematopoietic stem cell transplantation (HSCT) recipients at a Japanese transplant centre. Of 187 patients, nonrelapse mortality (NRM) at 3 years was 9.6, 21.2 and 27.8% in the low-risk (score 0), intermediate-risk (score 1-2) and high-risk (score > or =3) HCT-CI groups, respectively (P=0.03). The corresponding overall survival (OS) at 3 years was 70.1, 60.5 and 38.9%, respectively (P<0.01). In multivariate analyses, high-risk HCT-CI significantly predicted higher NRM (relative risk, (RR) 2.44 (95% confidence interval, (CI) 1.02-5.85); P=0.04) and worse OS (RR 2.02 (95% CI 1.15-3.54); P=0.01). In the subgroup analysis according to disease status, the HCT-CI was associated with OS (P<0.01) and NRM (P=0.07) in patients with low-risk diseases, but not in those with high-risk diseases. Within patients who survived without relapse >1 year after HSCT, the HCT-CI did not predict OS (P=0.59) or NRM (P=0.31). These findings can be useful to determine the role of pretransplant comorbidity in allogeneic HSCT.

The change in zoster-associated pain treated with oral valaciclovir in immunocompetent patients with acute herpes zoster.

We have analysed zoster-associated pain treated with valaciclovir (VCV) in immunocompetent patients with acute herpes zoster over 6 months, and evaluated the safety of VCV. We know of no reports that evaluate postherpetic neuralgia (PHN) treated with VCV for 6 months. Predisposing factors that influence PHN were age (over 60 years), clustered vesicles, severity of eruption, sleep disturbance, and hypesthesia. Timing of the administration of VCV before or after the onset of rash did not influence the incidence of PHN. No serious adverse reactions were observed during the administration of VCV.

Effective in vivo purging with rituximab and autologous peripheral blood stem cell transplantation in a woman with CD5 positive primary cutaneous diffuse large B-cell lymphoma.

Generalized subcutaneous tumors developed without any other sites of the disease in a Japanese woman. Skin biopsy revealed CD5(+) and CD20(+) atypical diffuse large cells infiltrating subcutaneous tissues. The diagnosis was CD5(+) primary cutaneous diffuse large B-cell lymphoma. Tumor-specific PCR showed the existence of malignant cells in the peripheral blood and bone marrow. After three cycles of chemotherapy, she was remained in partial remission. Peripheral blood stem cells (PBSC) were harvested after the fourth cycles of chemotherapy combined with rituximab for in vivo purging. The contamination of tumor cells in PBSC was negative with PCR. She then underwent autologous peripheral blood stem cell transplantation using purged PBSC and has remained in complete remission for the past 24 month.

Extramammary Paget's disease of the genitalia with clinically clear margins can be adequately resected with 1 cm margin.

For the treatment of extramammary Paget's disease (EMPD), wide excision has been recommended because of unpredictable spread of tumor cells. EMPD lesions are often well circumscribed. Should all the lesions of EMPD be resected with a 3 cm margin? Forty-six patients with EMPD were surgically treated with a 1 cm margin. Width of tumor cell free area from the last lesional cells at the borders to the resected edge was measured with micro-oculometer. The microscopic gap between the histopathological tumor border and the clinical border scored by scalpel tract was also measured. The tumor cell free area measured 10.2 +/- 2.48 mm. The microscopic gap between the histopathological and clinical borders measured 0.334 +/- 1.183 mm. Thus, the clinically determined border of well-defined lesions of EMPD corresponded well to the histopathologic border. No local recurrence was observed in 24 to 115 months of follow-up. Well-demarcated lesions of EMPD can be adequately managed with 1 cm margin resection.

Localized relapse in bone marrow of extremities after allogeneic stem cell transplantation for acute lymphoblastic leukemia.

We report a patient with a relapsed in bone marrow of extremities after allogeneic peripheral blood stem cell transplantation for acute lymphoblastic leukemia (ALL). The patient complained of pain in the right upper arm and left leg 15 months after transplantation. Magnetic resonance imaging (MRI) and fluorine-18 fluorodeoxyglucose positron emission tomography (FDG-PET) showed abnormal findings in bone marrow of upper and lower extremities. There were no findings of relapse in aspirates from the sternum and iliac bone marrow. Biopsy specimen from the iliac bone marrow showed normocellular marrow without leukemic cells. Biopsy specimen from the right humerus revealed marked leukemic cell infiltration in the bone marrow. This is apparently the first case of localized relapse of ALL in bone marrow of extremities. Physicians should be aware of unusual relapse sites of leukemia after allogeneic stem cell transplantation. MRI and FDG-PET may be of value in detecting this type of relapse.

Peripheral blood stem cell mobilization following CHOP plus rituximab therapy combined with G-CSF in patients with B-cell non-Hodgkin's lymphoma.

We mobilized peripheral blood stem cells (PBSC) following CHOP plus rituximab (CHOP-R) therapy, and compared with the findings following CHOP therapy without rituximab. All patients were given G-CSF starting from day 11 after CHOP therapy. Patients in the CHOP-R group (n=8) were given rituximab on day 12. Target CD34(+) cells number was collected in a single leukapheresis on day 14, from all the eight patients in the CHOP-R group. PBSC mobilization kinetics, CD34(+) cells yield and colony-forming ability in the graft collection, toxicity during mobilization, and engraftment after transplantation of CHOP-R group were not significantly different from those in the CHOP group (n=8). In all patients given CHOP-R therapy, CD20(+) cells and immunoglobulin heavy chain (IgH) rearrangement in the graft collection were undetectable by flow-cytometric analysis and Southern blot analysis, respectively, but with PCR analysis two of eight grafts were positive for IgH rearrangement. While further studies are needed to evaluate the efficacy of purging and the outcome of patients undergoing autologous transplantation, CHOP-R therapy can be safely and effectively used in the mobilization phase of PBSC collection, without excess clinical toxicity or deleterious effect on PBSC mobilization kinetics or engraftment time.

IgE-dependent enhancement of Th2 cell-mediated allergic inflammation in the airways.

T helper 2 (Th2) cell-derived cytokines, including interleukin (IL)-4, IL-5 and IL-13, play important roles in causing allergic airway inflammation. In contrast to Th2 cells, however, the role of IgE and mast cells in inducing allergic airway inflammation is not understood fully. In the present study, we addressed this point using transgenic mice expressing trinitrophenyl (TNP)-specific IgE (TNP-IgE mice), which enable us to investigate the role of IgE without the influence of antigen-specific T cell activation and other immunoglobulins. When the corresponding antigen, TNP-BSA, was administered intranasally to TNP-IgE mice, a large number of CD4+ T cells were recruited into the airways. In contrast, TNP-BSA administration did not induce eosinophil recruitment into the airways or airway hyperreactivity. Furthermore, when ovalbumin (OVA)-specific Th2 cells were transferred to TNP-IgE mice and the mice were challenged with inhaled OVA, TNP-BSA administration increased OVA-specific T cell recruitment and then enhanced Th2 cell-mediated eosinophil recruitment into the airways. These results indicate that IgE-induced mast cell activation principally induces CD4+ T cell recruitment into the airways and thus plays an important role in enhancing Th2 cell-mediated eosinophilic airway inflammation by recruiting Th2 cells into the site of allergic inflammation.

Successful treatment with rituximab for autoimmune hemolytic anemia concomitant with proliferation of Epstein-Barr virus and monoclonal gammopathy in a post-nonmyeloablative stem cell transplant patient.

A 30-year-old Japanese woman who underwent nonmyeloablative stem cell transplantation from her HLA-matched sister developed autoimmune hemolytic anemia (AIHA). There was proliferation of EBV-DNA in her peripheral blood and monoclonal gammopathy, both predictive factors of post-transplant lymphoproliferative disorder (PTLD). As conventional immunosuppressive therapy for AIHA could lead to overt PTLD, we decided to give her rituximab 375 mg/m(2) once weekly for a total of four doses. After this therapy, both her AIHA and monoclonal gammopathy were resolved and EBV-DNA became undetectable. Rituximab therapy deserves consideration for treatment of post-allogeneic stem cell transplant patients with AIHA, especially for patients who cannot be given immunosuppressive therapy.

Activation of pulmonary T cells in corticosteroid-resistant and -sensitive interstitial pneumonitis in dermatomyositis/polymyositis.

To study the activation states and cytokine profiles of pulmonary T cells in corticosteroid-resistant and corticosteroid-sensitive interstitial pneumonitis (IP) in dermatomyositis (DM)/polymyositis (PM), we examined the activation markers and cytokine profiles of T cells in bronchoalveolar lavage fluids (BALF) from patients with IP in DM/PM before prednisolone therapy and then compared the activation states of T cells according to the therapeutic response of IP to prednisolone therapy. CD25+ CD4+ T cells in BALF were significantly increased in both corticosteroid-resistant and corticosteroid-sensitive IP in DM/PM as compared with those in controls without IP. Furthermore, CD25+ CD4+ T cells in BALF were significantly more increased in corticosteroid-resistant IP than those in cortico teroid- sensitive IP. Moreover, CD25+ CD8+ T cells in BALF were significantly increased only in corticosteroid-resistant IP, but not in corticosteroid-sensitive IP or controls without IP. IFN-gamma mRNA was detected in BALF T cells in corticosteroid-resistant and corticosteroid-sensitive IP but not in controls without IP, whereas IL-4 mRNA was virtually undetected in BALF T cells in both the IP groups. However, there were no significant differences in CD4/CD8 ratio of BALF T cells, HLA-DR+ BALF T cells or CD25+ and HLA-DR+ peripheral blood T cells between the two IP groups. These results indicate that activated Th1-type pulmonary T cells play an important role in the development of corticosteroid- resistant IP in DM/PM and that the increase in CD25+ CD8+ T cells in BALF is a useful indicator for corticosteroid-resistant IP in DM/PM and hence may be an indicator for early use of cyclosporin.

Transplantation for accidental acute high-dose total body neutron- and gamma-radiation exposure.

Accidental exposure to acute high-dose total body neutron radiation is rare. We report a 35-year-old man exposed to a total body dose of 5.4 Gy neutron- and 8.5-13 Gy gamma-radiation in a radiation criticality accident. He received a blood stem cell transplant from his HLA-identical sister. There was bone marrow recovery with complete donor chimerism. Random chromatid breaks were observed in donor cells suggesting a bystander effect of neutron exposure. The subject died 82 days after the accident (75 days post transplant) from multi-organ failure.

Clinical correlates of prolonged pain in Japanese patients with acute herpes zoster.

To determine which risk factors are relevant to the occurrence of post-herpetic neuralgia in Japanese patients with acute herpes zoster, correlations between the prolongation of pain and various disease factors were examined in 263 adult patients presenting within 10 days of the onset of rash at 17 institutions in the Hyogo region of Japan. All patients in whom pain persisted for more than 3 months were over 60 years of age. The pain also tended to be more prolonged in those with clustered vesicles, disturbed sleep and hypanaesthesia. Other factors such as underlying disease states, critically involved regions, scar tissue, generalized rash and allodynia were not relevant to the duration of pain. Although decreased pain persistence was observed in patients in whom acyclovir therapy was initiated within 72 h of the onset of symptoms in comparison with those in whom it was initiated after this time, the difference between the two groups of patients was not statistically significant. Our results suggest that advanced age, the presence of clustered vesicles, and disturbed sleep and hypanaesthesia influence the prolongation of herpes zoster pain.

Notch1 inhibits differentiation of hematopoietic cells by sustaining GATA-2 expression.

Notch signaling is involved in cell fate decisions in many systems including hematopoiesis. It has been shown that expression of an activated form of Notch1 (aNotch1) in 32D mouse myeloid progenitor cells inhibits the granulocytic differentiation induced by granulocyte colony-stimulating factor (G-CSF). Results of the current study show that aNotch1, when expressed in F5-5 mouse erythroleukemia cells, also inhibits erythroid differentiation. Comparison of the expression levels of several transcription factors after stimulation for myeloid and erythroid differentiation, in the presence or absence of aNotch1, revealed that aNotch1 did not change its regulation pattern with any of the transcription factors examined, except for GATA-2, despite its inhibitory effect on differentiation. GATA-2 was down-regulated when the parental 32D and F5-5 were induced to differentiate into granulocytic and erythroid lineages, respectively. In these induction procedures, however, the level of GATA-2 expression was sustained when aNotch1 was expressed. To ascertain whether maintenance of GATA-2 is required for the Notch-induced inhibition of differentiation, the dominant-negative form of GATA-3 (DN-GATA), which acted also against GATA-2, or transcription factor PU.1, which was recently shown to be the repressor of GATA-2, was introduced into aNotch1-expressing 32D (32D/aNotch1) cells that do not express GATA family proteins other than GATA2. Both DN-GATA and PU.1 reversed the phenotype of 32D/aNotch1 inducing its differentiation when G-CSF was added. Furthermore, enforced expression of HES-1, which is involved in Notch signaling, delayed differentiation of 32D, and again this phenotype was neutralized by DN-GATA. These results indicate that GATA-2 activity is necessary for the Notch signaling in hematopoietic cells.