Kouichi Isobe

Localized aggressive non-Hodgkin’s lymphoma of the nasal cavity: a survey by the Japan Lymphoma Radiation Therapy Group

PURPOSE To clarify the role of radiotherapy and chemotherapy in the treatment of patients with localized aggressive non-Hodgkins lymphomas (NHL) originating in the nasal cavity. METHODS AND MATERIALS The survey, administered at 25 Japanese institutes in 1998, enabled us to collect the clinical data for 787 patients with localized aggressive NHL who were treated between 1988 and 1992. RESULTS There were 42 patients (5%) with nasal lymphomas. Twelve of these patients received radiotherapy alone, and 30 were treated with a combination of radiotherapy and chemotherapy. The median radiation dose was 47 Gy (22-66). Twelve patients were reviewed histopathologically according to REAL (Revised European-American Classification of Lymphoid neoplasms) classification. T-cell or natural killer (NK) cell lymphomas were detected in 9 patients (75%), and diffuse large B-cell lymphomas in 3 (25%). The 5-year overall and disease-free survival (DFS) rates of all patients were 57% and 59%, respectively. The 5-year DFS rate for the 30 patients treated with the combined therapy was 64% and that for the 12 patients treated with radiotherapy alone was 46% (p = 0.021). For the 34 patients with stage-modified International Prognostic Index (m-IPI) 0-1, the 5-year DFS rates of those treated with the combined therapy and radiotherapy alone were 68% and 45%, respectively (p = 0.020), but there was no difference in DFS rate among the two groups of patients with m-IPI 2-3. The 5-year local control rates of the patients who received >46 Gy (n = 22) and < or =46 Gy (n = 20) were 95% and 76% (p = 0.087), respectively. There was no significant difference among the 5-year DFS rates (62% vs. 67%) and local control rates (87% vs. 100%) of the patients with T-cell or NK-cell lymphoma and diffuse large B-cell lymphoma. CONCLUSIONS Patients with nasal lymphomas (m-IPI 0-1) should be treated with combined therapy. For the patients with high risk (m-IPI 2-3), the effectiveness of combined therapy was not clarified because of the small number of the patients. A high radiation dose >46 Gy may need to be used to achieve good local control.

TUMOR BULK AS A PROGNOSTIC FACTOR FOR THE MANAGEMENT OF LOCALIZED AGGRESSIVE NON-HODGKIN'S LYMPHOMA: A SURVEY OF THE JAPAN LYMPHOMA RADIATION THERAPY GROUP

PURPOSE To identify the prognostic factors that specifically predict survival rates of patients with localized aggressive non-Hodgkins lymphoma (NHL). METHODS AND MATERIALS The survey was carried out at 25 radiation oncology institutions in Japan in 1998. The 5-year event-free (EFS) and overall survival rates (OAS) were calculated, and univariate and multivariate analyses were done to identify which of the following factors, namely, gender, age, performance status (PS), serum lactate dehydrogenase (LDH) level, Stage (I vs. II), tumor bulk (maximum diameter), and treatment, were significant from the viewpoint of prognosis. RESULTS A total of 1141 patients with Stage I and II NHL were treated by the Japanese Lymphoma Radiation Therapy Group between 1988 and 1992. Of them, 787 patients, who were treated using definitive radiotherapy with or without chemotherapy for intermediate- and high-grade lymphomas in working formulation, constituted the core of this study. Primary tumors arose mainly from extranodal organs (71%) in the head and neck (Waldeyers ring: 36% and sinonasal cavities: 9%). The factors associated with poorer prognosis were age over 60 years old (p < 0. 0001), radiation therapy alone (p < 0.0001), PS = 2-4 (p = 0.0011), (sex male, p = 0.0078), a bulky tumor more than 6 cm in maximum diameter (p = 0.0088), elevated LDH (p = 0.0117), and stage II (p = 0.0642). A median dose of 42 Gy was delivered mainly to the involved fields. Short-course chemotherapy was provided in 549 (70%) patients. The 5-year OAS and EFS rates for all patients were 71% and 67%, respectively. According to the stage-modified International Prognostic Index, the 5-year EFS of the patients with risk factors from 0 to 1 was 76%, 61% for patients with two risk factors, and 26% for patients with three or more risk factors. CONCLUSION Extranodal presentation, especially Waldeyers ring and sinonasal cavities, is encountered more frequently in Japan than in Western countries. Tumor bulk is an important prognostic factor in patients with localized aggressive extranodal NHL. Short course chemotherapy followed by radiation therapy was associated with prolonged survival in patients with localized aggressive NHLs of extranodal origin and 0-1 risk factor.

Postoperative Radiation Therapy for Pituitary Adenoma

AbstractBackground: We evaluated the efficacy of postoperative radiation therapy (RT), prognostic factors for local control probability, dose response relationship and treatment sequelae in 75 patients with pituitary adenoma. Materials and methods: A total dose of 48–60 Gy (median: 50 Gy) was delivered with a conventional fractionation schedule after surgery. Of 75 patients, 55 (73%) were followed for more than 5 years and 27 (36%) were followed for more than 10 years with a median of 95 months. Results: Five- and 10-year local control probabilities were 87.1% and 85.0%, respectively. Univariate analysis revealed that age (p=0.007), tumor volume smaller than 30 cm3 (p=0.018) and the absence of prolactin secretion (p=0.003) were significantly favorable prognostic factors for local control probability. After multivariate analysis combining these 3 factors, tumor volume smaller than 30 cm3 (p=0.017) and age (p=0.039) were statistically significant. Patients with prolactinoma greater than 30 cm3 showed particularly poor local control rates. No significant improvement of the local control rate was detected with increasing total irradiation doses between 48 and 60 Gy (p=0.29). The most common side effect was hypopituitarism, and there were no severe sequelae such as optic neuropathy or brain necrosis. Conclusion: Except with prolactinoma, the dose of postoperative RT for pituitary adenoma should not exceed 50 Gy. Large prolactinoma, however, was very difficult to control with the irradiation doses between 50 and 60 Gy, and would be good candidates for stereotactic radiosurgery or stereotactic radiation therapy.

Diffuse large B cell lymphoma expressing the natural killer cell marker CD56

The expression of the natural killer (NK) cell antigen, CD56, in hematological malignancies is rare. However, there are several reports that some hematological malignancies, such as T/NK cell lymphoma, multiple myeloma (MM) and acute myeloid leukemia (AML), express this molecule. In B cell non‐Hodgkin’s lymphomas (NHL), however, very limited number of cases have been reported to express CD56 molecule. Although one study has recently described that half of microvillous B cell lymphoma (MVL), an uncommon subset of large cell lymphoma, expressed CD56, there have been no reports about most common type of B‐NHL, diffuse large B cell lymphoma (DLBL) other than a mention of weak CD56 expression in one of 83 DLBL. We herein presented the first case of diffuse large B cell lymphoma expressing CD56 clearly. The immunophenotype determined by immunostaining and flow cytometric analysis was CD10+, CD19+, CD20+, CD45RO−, CD3− and CD56+. On immunohistochemical study, neither bcl‐2 nor TIA‐1 was positive for tumor cell. Monoclonal immunoglobulin heavy chain (IgH) gene rearrangement was detected, and the sequence analysis of the variable region of IgH (VH) suggested that this tumor was derived from antigen selected post germinal center B cell. Conventional combination chemotherapy (CHOP) was administered, and the patient has still been in complete remission for 10 months.

Treatment for pyothorax-associated lymphoma.

In eight patients with pyothorax-associated lymphoma (PAL), which resulted from artificial pneumothorax for the treatment of pulmonary tuberculosis, seven patients received radiotherapy and five showed no local recurrence. All four patients treated by primary chemotherapy had disease progression. Radiotherapy of 50 Gy with wide margins is recommended to treat PAL.

V H Gene Analysis in Sporadic Burkitt's Lymphoma: Somatic Mutation and Intraclonal Diversity with Special Reference to the Tumor Cells Involving Germinal Center

We analyzed the immunoglobulin heavy chain variable region (V H ) gene in seven cases of sporadic Burkitts lymphoma (sBL) to elucidate their cell of origin. In particular, we focused on the V H gene status of tumor cells involving adjacent germinal center (GC) by microdissecting histological sections. Among the seven V H genes V H 1 family was found in two, V H 3 in four, and V H 4 in one. All rearranged V H genes demonstrated somatic mutations at percentages ranging from 1.4 to 7.5% (mean, 4.2%), which is a similar level to that seen in IgM-only B cells. Three out of four V H genes with more than 2% sequence difference from their corresponding germline counterpart showed evidence of antigen selection in their framework region 3. Three cases demonstrated signs of intraclonal diversity with a mutational frequency of 0.47-0.98%, which was 13.5-28.8 times as great as the Taq infidelity in our experimental conditions. However the level of somatic mutation and the effect of antigen selection on V H gene were diverse in these three cases, and the relationship between V H gene somatic mutation status and intraclonal diversity was unclear in sBL. In the analysis of microdissected tissues, all 20 tumor clones in the adjacent GCs showed additional replacement mutations in complementarity determining region 3, suggesting a role of antigen in tumor progression. This finding resembles the phenomenon that memory B-cells reenter into GC to undergo further affinity maturation. In contrast, 7/11 V H gene sequences irrelevant to GC were identical to those of the major tumor clone. Thus our findings suggested that sBL is derived from memory B-cells rather than GC B-cells, and that antigen stimulation is involved in the clonal expansion of a proportion of sBL.

Radiation-induced chromosome aberrations in ataxia telangiectasia cells: high frequency of deletions and misrejoining detected by fluorescence in situ hybridization

Abstract Kawata, T., Ito, H., George, K., Wu, H., Uno, T., Isobe, K. and Cucinotta, F. A. Radiation-Induced Chromosome Aberrations in Ataxia Telangiectasia Cells: High Frequency of Deletions and Misrejoining Detected by Fluorescence In Situ Hybridization. Radiat. Res. 159, 597–603 (2003). The mechanisms underlying the hyper-radiosensitivity of AT cells were investigated by analyzing chromosome aberrations in the G2 and M phases of the cell cycle using a combination of chemically induced premature chromosome condensation (PCC) and fluorescence in situ hybridization (FISH) with chromosome painting probes. Confluent cultures of normal fibroblast cells (AG1522) and fibroblast cells derived from an individual with AT (GM02052) were exposed to γ rays and allowed to repair at 37°C for 24 h. At doses that resulted in 10% survival, GM02052 cells were approximately five times more sensitive to γ rays than AG1522 cells. For a given dose, GM02052 cells contained a much higher frequency of deletions and misrejoining than AG1522 cells. For both cell types, a good correlation was found between the percentage of aberrant cells and cell survival. The average number of color junctions, which represent the frequency of chromosome misrejoining, was also found to correlate well with survival. However, in a similar surviving population of GM02052 and AG1522 cells, induced by 1 Gy and 6 Gy, respectively, AG1522 cells contained four times more color junctions and half as many deletions as GM02052 cells. These results indicate that both repair deficiency and misrepair may be involved in the hyper-radiosensitivity of AT cells.

Diffuse Pulmonary Involvement by Mycosis Fungoides: High-resolution Computed Tomography and Pathologic Findings

The authors report the high-resolution computed tomography (HRCT) appearance of diffuse pulmonary involvement by mycosis fungoides in a 74-year-old woman whose clinical and radiographic manifestations simulated pneumonia. The HRCT showed multiple, dense, peribronchovascular nodules with surrounding ground-glass opacity and several wedge-shape peripheral opacities. The autopsy specimen revealed angiocentric and peribronchovascular involvement of mycosis fungoides and pulmonary infarctions distal to angiocentric infiltration of the tumor cells.

Clinicopathological evaluation of the Revised European-American Classification of Lymphoid Neoplasms (REAL) in Japan.

After the publication of a Revised European-American Classification of Lymphoid Neoplasms (REAL classification) in 1994, there have been reports from Europe and America regarding its practical utility and clinical significance. However, no studies have been published from Eastern countries including Japan. It has been well recognized that the distribution of malignant lymphoma in Japan is quite different from that seen in Western countries. In addition, some new entities have also been described in the REAL classification. Therefore, it seems important to examine its practical utility and clinical significance in Japan. Of the 579 cases reviewed, approximately 68% were B-cell non-Hodgkins lymphoma (NHL) followed by 27% T-cell lymphomas. Hodgkins disease (HD) comprised only 5% of all cases, making the ratio of NHL to HD 20.6. The most common type was diffuse large B-cell lymphoma which represented about 37% of all cases. Peripheral T-cell lymphomas, unspecified (PTCL), occurred in 15% whereas marginal zone B-cell lymphoma followed (14.9%). However, follicle center lymphoma (FCL) was less common (4.4%) as has been previously reported. We evaluated the clinical significance of the new REAL classification in 244 cases. International Prognostic Index (IPI) was a powerful predictor of survival (p<0.0001), and the immunophenotype was significant (p<0.05). Furthermore, here, we also attempt to establish a prognostic scheme based on the histologic type. In conclusion, the REAL classification appears to be useful and clinically significant in Japan.

A Comparison of Chromosome Repair Kinetics in G0 and G1 Reveals that Enhanced Repair Fidelity under Noncycling Conditions Accounts for Increased Potentially Lethal Damage Repair

Abstract Potentially lethal damage (PLD) and its repair were studied in confluent human fibroblasts by analyzing the kinetics of chromosome break rejoining and misrejoining in irradiated cells that were either held in noncycling G0 phase or allowed to enter G1 phase of the cell cycle immediately after 6 Gy irradiation. Virally mediated premature chromosome condensation (PCC) methods were combined with fluorescence in situ hybridization (FISH) to study chromosomal aberrations in interphase. Flow cytometry revealed that the vast majority of cells had not yet entered S phase 15 h after release from G0. By this time some 95% of initially produced prematurely condensed chromosome breaks had rejoined, indicating that most repair processes occurred during G1. The rejoining kinetics of prematurely condensed chromosome breaks was similar for each culture condition. However, under noncycling conditions misrepair peaked at 0.55 exchanges per cell, while under cycling conditions (G1) it peaked at 1.1 exchanges per cell. At 12 h postirradiation, complex-type exchanges were sevenfold more abundant for cycling cells (G1) than for noncycling cells (G0). Since most repair in G0/G1 occurs via the non-homologous end-joining (NHEJ) process, increased PLD repair may result from improved cell cycle-specific rejoining fidelity of the NHEJ pathway.