Long-term risk of second malignancy after treatment of Hodgkin's disease: the influence of treatment, age and follow-up time.

BACKGROUND: To quantify the long-term risk of second cancers (SCs) up to 30 years after primary treatment for Hodgkin's disease (HD) Material and methods In the period 1968 to 1985, an unselected population of 1024 patients started treatment for HD at the Norwegian Radium Hospital (NRH) and were followed for SC from 1969 through 1998 by The Norwegian Cancer Registry. The median age at diagnosis of HD was 40 years, and the median time at follow-up was 14 years. RESULTS: Of 197 SCs, 14 were acute non-lymphocytic leukemia (ANLL), 31 non-Hodgkin's lymphoma (NHL) and 152 solid cancers. The standardized incidence ratio (SIR) was significantly increased for SCs as a group, and for the subgroups ANLL, NHL, lung cancer, breast cancer, stomach cancer and melanoma. ANLL was related to heavy treatment with chemotherapy (CT) and combined CT and radiotherapy (RT), NHL was not treatment related, and solid tumors were related to radiotherapy only or combined RT and CT. The SIR of ANLL and NHL reached a peak between 5 and 10 years after treatment. Solid and non-solid tumors increased with young age at diagnosis of HD and solid tumors increased with follow-up time up to 28 years CONCLUSION: In a long-term follow-up study of HD patients of all ages, the SIR of solid tumors was high in patients treated at young age and decreased with increasing age. Most solid tumors had started within or at the edge of the irradiated field, and SIR of solid tumors increased even 20-30 years after diagnosis.

Systemic pneumococcal disease after staging splenectomy for Hodgkin's disease 1969-1980 without pneumococcal vaccine protection: a follow-up study 1994.

We surveyed, during 1994, all 325 patients who underwent staging laparotomy with splenectomy for Hodgkin's disease in Norway 1969-80, before pneumococcal vaccine was available in this country. The patients were thus not immunized preoperatively. Of 162 patients (49.8%) who died before 1994, 8 (2.4% of the total study) died from pneumococcal septicaemia and 16 (6.2%) from infections totally. Of 163 patients (50.2%) who were alive in 1994, 158 cooperated and filled in a questionnaire: 22 had been hospitalized for serious infections; 2 with pneumococcal septicaemia, and 6 with pneumonia, although lacking a specified microbiological diagnosis. We observed 325 patients representing 4420 patient-years, 3066 patient-years among survivors and 1354 patient-years among the dead. This resulted in an incidence rate of systemic pneumococcal disease of 226 per 100,000 patient-years, which is a relative risk of 20.5 compared to the general Norwegian population during 1994. Septicaemia for these patients most often had an abrupt clinical start even for relapse-free individuals and occurred from 2 to 17 yr after splenectomy (mean 10 yr). The risk of developing an overwhelming pneumococcal septicaemia with high case-fatality in asplenic patients seems to persist for these patients at about the same level even 15-20 yr after splenectomy. Only 12.7% of the survivors had been given pneumococcal vaccine in the autumn of 1993. Despite the fact that medical journals and media in Norway focused upon the problem of pneumococcal disease in asplenic individuals in the autumn of 1993 and spring of 1994, a substantial proportion of these patients (55.3%) still remained unimmunized when interviewed in the autumn of 1994. None of our systemic pneumococcal disease patients was vaccinated. Our data underline the need for prophylactic immunization with effective vaccines against pneumococcal infection in splenectomized Hodgkin's disease patients.

Hodgkin's disease in a national and hospital population: trends over 20 years.

The aim of the study was to investigate the incidence rate and time trends in a national registry population of Hodgkin's disease (HD) and the effects of selection in a hospital population. A national registry population of all HD patients from Norway and a hospital population of HD patients treated at the Norwegian Radium Hospital (NRH) were studied retrospectively from 1971 to 1993. The incidence of non-Hodgkin's lymphomas (NHL) in Norway increased steadily from 1961 in contrast to a stable incidence pattern for HD before 1980 and a decreasing incidence since 1980. Due to improved diagnostic tools after 1980, an increasing proportion of patients previously diagnosed as lymphocyte depleted and unclassified HD were classified as NHL. As these histologies are dominant in older patients, the incidence of older patients with HD and the total population of HD have decreased since 1980. As a result, the proportion of young adults with a favourable histology has increased. These changes may partly explain the increased patient survival observed both in the national and the hospital population. The hospital population comprised 92% of patients aged 15-39 years, 80% of patients aged 40-59 years and 53% of patients aged > 60 years in the national population. The selection of younger patients in the hospital material may explain a higher survival rate as compared with the national population.

Mitoxantrone in the treatment of patients with non-Hodgkin's Lymphoma.

Thirty-five patients with non-Hodgkin's lymphoma, who had relapsed from or failed prior cytotoxic regimens including doxorubicin, received mitoxantrone at a dose of 14 mg/m2 iv every 3 weeks. According to the working formulation, 18, 15, and two patients had low-, intermediate-, and high-grade malignancy, respectively. Thirty-four patients were evaluable for response and all were evaluable for drug toxicity. Three patients achieved complete response, 12 achieved partial response, eight had stable disease, and 11 had progressive disease. The overall objective response rate was 43% (95% confidence limits, 25%-61%) for all patients. The response durations ranged from 7 to 11+ months. Time to treatment failure was 4.5 months (range, 1-10+). The response achieved were clustered in patients with low-grade malignancy. There was a partial response in a patient who had relapsed from prior anthracyclines. A total of 155 cycles of mitoxantrone therapy were given. The median number of courses per patient was four (range, one to ten). Myelosuppression was the dose-limiting factor. Most nonhematologic toxic effects were mild. The data indicate that mitoxantrone is effective in the treatment of non-Hodgkin's lymphoma with acceptable toxicity.

The activation-associated antigen 4F2 predicts patient survival in low-grade B-cell lymphomas.

Expression of the activation-associated 4F2 antigen, transferrin receptor and interleukin-2 (IL-2) receptor on suspended cells from 75 biopsied low-grade non-Hodgkin lymphomas (L-NHL) of B-cell origin was correlated to patient survival, clinical prognostic parameters and estimated DNA synthesis. 4F2 antigen expression correlated significantly with poor patient survival, high DNA synthesis and transferrin receptor expression. Transferrin receptor expression was associated with high DNA synthesis and treatment response, but not with patient survival. On the other hand, IL-2 receptor was correlated neither to patient survival nor to other studied markers for cell activation, but seemed to be expressed on certain subsets of lymphomas. We suggest that monoclonal antibody (MAb) against the activation-associated 4F2 antigen could be used to select patients with L-NHL for aggressive chemotherapy.

3H-thymidine uptake in B cell lymphomas--relationship to treatment response and survival.

Cell suspensions were obtained from biopsy tissue from 149 patients with B cell lymphomas and analysed with regard to DNA-synthesis as assessed by 3H-thymidine uptake, response to therapy and survival. The 3H-thymidine uptake was significantly increased in lymphomas of high versus low grade malignancy (p = 0.0001), in patients with stage I and II versus stage III and IV (p = 0.014), and in patients with general symptoms (p = 0.0025) as opposed to asymptomatic cases. The complete response rate was significantly higher in patients with increased thymidine uptake than in those with low uptake, 26/51 (51%) cases versus 24/83 (29%) cases, respectively (p = 0.014). 55 patients with increased 3H-thymidine uptake survived for significantly shorter times than (94 patients) with low uptake (p = 0.0056). Furthermore, a markedly larger group of high-risk patients was identified by the 3H-thymidine assay than by histopathology alone, 55 cases versus 23 cases, respectively. Among the patients (126 cases) with low grade tumours, those with increased 3H-thymidine uptake (40 cases) had poorer outcome than those with low uptake (86 cases) (p = 0.045). The data suggest that DNA-synthesis in this study, as assessed by 3H-thymidine uptake, is an independent indicator of survival in NHL. Furthermore, it may be a useful parameter in laying down guidelines for therapy in B cell neoplasms, especially in low grade tumours.

Transferrin receptor and B-lymphoblast antigen--their relationship to DNA synthesis, histology and survival in B-cell lymphomas.

The reactivity of two monoclonal antibodies identifying antigens related to B-cell activation, B3/25 (the transferrin receptor) and BB-I (the B-lymphoblast-I-antigen), was examined on cell suspensions from 75 cases of monoclonal B-cell lymphomas. The expression of B3/25 antigen was correlated to DNA synthesis as measured by spontaneous 3H-thymidine incorporation (p = 0.0003) and histopathologically high-grade malignancy (p = 0.00003). Furthermore, B3/25 expression was associated with survival since the patients with B3/25-negative tumors survived longer than those with B3/25-positive tumors (p = 0.018). B3/25 expression also defined a larger group of patients with shorter survival than did histopathology alone, 28 cases versus 16 cases, respectively. On the other hand, the BB-I antigen did not reveal an association with DNA synthesis, high-grade malignancy or survival. However, the findings indicated that BB-I may be related to B-cell maturation/differentiation.

Immunological subsets in human B-cell lymphomas.

Fifty human B-cell lymphomas have been studied with regard to surface markers (surface immunoglobulins (sIg) and complement receptors (CR)), capping of sIg, and relative amounts of sIg by single-cell flow cytometry. The results show that these lymphomas can be subdivided into distinct immunological subsets. Whereas one histological subgroup (lymphocytic) consisted of only one immunological subtype, others were heterogeneous with regard to immunological subtypes. This was most striking in nodular lymphomas of germinal centre cell origin (centroblastic/centrocytic). Our studies provide further evidence for the existence of a large number of subsets in the B-cell compartment of the immune system, sIgD was only found in association with sIgM. The relative amounts of sIgD varied, especially in nodular lymphomas. A discrepancy between capping of sIgM and sIgD was also found in some lymphomas belonging to this group. These findings together with other observations suggest that sIgD plays a role in B-cell maturation and differentiation events taking place in germinal centres and becomes lost during this process. A close association was found between the presence of CR and capping of sIgM but not capping of sIgD or sIgG. Nodular lymphomas expressing sIgG only, lacked CR. These findings suggest that CR may become lost during maturation and differentiation processes also taking place in germinal centres. Lymphoplasmacytoid lymphomas, which show morphological evidence of differentiation towards plasma cells, could be subdivided into three immunological subsets, indicating that plasma cell maturation may take place from different subsets of B cells.