Primary central nervous system lymphomas in immunocompetent individuals: histology, Epstein-Barr virus genome, Ki-67 proliferation index, p53 and bcl-2 gene expression.

Epstein-Barr virus (EBV) has been detected in the large majority of HIV-related primary central nervous system lymphomas (PCNSL) suggesting a pathogenetic role of the virus. Unlike HIV-related PCNSL, conflicting data exist with regard to the presence of EBV in non immunodeficiency-related (sporadic) PCNSL. For this reason, a population based material of 41 sporadic PCNSL was analysed for the presence of EBV genome (EBER, BHLF) using RNA in situ hybridisation (RISH). Furthermore, the expression of the gene products of the bcl-2 oncogene and the p53 tumor suppressor gene and the tumor growth fraction reactive with the monoclonal antibody Ki-67 have been evaluated. All cases but two were EBV genome negative. In the two positive cases less than 5% of tumor cells showed EBER positivity. In contrast, more than 75% of cells morphologically belonging to the tumor-cell population stained positively for EBER in two cases of HIV related PCNSL. Immunostaining for the bcl-2 oncoprotein was positive in 28 (72%) of 39 cases examined. In most cases more than 75% of tumor cells showed cytoplasmic expression. Of 37 cases investigated for p53 expression, 21 (57%) stained positively. However, in the large majority of positive cases less than 10% of the neoplastic cells stained. The percentage of Ki-67 positive cells ranged between 10% and 80% with a mean of 50%. The expression of the p53 and bcl-2 oncoproteins and the growth fraction did not have any prognostic impact. We conclude that the EBV genome is rarely detected in sporadic PCNSL, indicating that a pathogenetic role of EBV is unlikely. Like extracerebral B-cell lymphomas a large fraction of PCNSL expresses the p53 and bcl-2 oncoproteins, a feature, however, which does not seem to have prognostic implications.

Clinicopathological features, survival and prognostic factors of primary central nervous system lymphomas: trends in incidence of primary central nervous system lymphomas and primary malignant brain tumors in a well-defined geographical area. Population-based data from the Danish Lymphoma Registry, LYFO, and the Danish Cancer Registry.

It has been claimed that Primary Central Nervous System Lymphomas (PCNSL), a rare neoplasm accounting for only a small fraction of malignant brain tumors and extranodal non-Hodgkin lymphomas (NHL), occur with increasing frequency in immunologically normal as well as in immunocompromised individuals. In an attempt to characterize the clinicopathological features, outcome and prognostic factors of PCNSL we here report our experience in a large unselected series of patients from a well-defined region. In addition, we present data on trends in incidence of PCNSL and primary malignant brain tumors in a well-defined geographical area. In a Danish population-based NHL registry (LYFO) representing a population of 2.7 million all new cases of NHL were registered during the approximate 11-year period from 1st January 1983 to 31st May 1994. Incidence data of primary malignant tumors of the brain and central nervous system in western Denmark for the period 1971-1990 have been obtained from the Danish Cancer Registry. During the approximate 11-year period 3124 new cases of NHL were registered. Of these, 1152 (37%) were extranodal and 48 were non-AIDS related PCNSL accounting for 4.2% of extranodal NHL and 1.5% of all NHL, respectively. The average annual incidence rate of non-AIDS related PCNSL during the period was 1.56 cases per million population (age range: 15-85 yrs, median: 62 yrs, M/F ratio: 1). In a 23-year period there was no trend towards an increasing incidence of non-AIDS related PCNSL in a well-defined population. PCNSL accounted for 1.7% of all primary malignant brain tumors. Incidence of primary malignant brain tumors was stable, except for age ranges over 70 years. However, diagnostic artifacts might be responsible for this apparent increase. Histologically, 85% were high grade. Using the Kiel classification centroblastic diffuse (60%) and immunoblastic lymphoma (13%) were the most common subtypes. Forty-three patients had B-cell lymphoma and no T-cell lymphoma was detected. Forty-seven cases were diagnosed pre mortem. Treatment included surgical resection (26 patients), whole brain irradiation (WBRT) (43 patients) and chemotherapy (28 patients). Median survival for those receiving either WBRT or WBRT and chemotherapy was 8 months and 20 months, respectively (p = 0.78). Overall survival was 53%, 38% and 26% at 1, 2 and 5 years. Cox-regression analysis identified only one factor having independent impact on survival in PCNSL: performances score > or = 2 (p < 0.001, RR = 5.8).

Low-dose cytosine arabinoside in the treatment of relapsed and refractory acute non-lymphocytic leukaemia.

Low-dose cytosine arabinoside (ARA-C) induced complete remissions in 6 of 10 patients with acute non-lymphocytic leukaemia (ANLL) who were either refractory to combination chemotherapy with anthracyclines and conventional doses of ARA-C, or were in relapse. Three patients relapsed after 4, 19, and 20 months, whereas 3 patients are still in remission for 8-46 months. Low-dose ARA-C was rather non-toxic and may be preferable to more intensive and toxic regimens in the therapy of refractory and relapsing patients with ANLL.

The absence of factor II in a child with systemic lupus erythematosus.

This report describes a patient with active system lupus erythematosus (SLE), who developed haemorrhagic diathesis due to a lowering of plasma factor II activity. No evidence was found suggesting a plasma inhibitor of factor II. The present case indicates that in some patients with SLE, factor II activity may be low or completely absent due to impairment of factor II synthesis, further that prednisone, but not azathioprine, may ameliorate this defect.

Bone changes during prednisone treatment.

To evaluate changes inbone composition during treatment with corticosteroids, the bone mineral content (BMC, measured by photon absorptiometry) and the degree of bone mineralization (measured as the bone phosphorus/hydroxyproline ratio) were determined in 18 patients during prednisone treatment for haematological and connective tissue diseases. The prednisone dose ranged from 12 to 51 mg/day (mean 27). The BMC decreased significantly (mean 2.5%) during the studied 12 weeks of treatment, but the change did not correlate significantly to the prednisone dose. The degree of bone mineralization remained unchanged, indicating equal losses of mineral and of collagen in bone during prednisone treatment. The changes correspond to a rapidly developing oesteoporotic state.

Folate and homocysteine status and haemolysis in patients treated with sulphasalazine for arthritis.

In an attempt to estimate the frequency of folate deficiency and haemolysis in a group of 25 outpatients with arthritis treated with sulphasalazine (SASP), haematological measurements, including plasma total homocysteine (tHcy) which is a sensitive marker of folate deficiency, serum folate (S-folate), erythrocyte (RBC) folate, S-cobalamin and routine indices of haemolysis were performed. No patient had been taking folate-containing vitamins for at least 8 weeks prior to the study. Compared to a group of 72 healthy hospital staff, the median plasma tHcy was significantly higher in the patient group (8.8 mumol 1(-1) vs. 6.8 mumol 1(-1); p = 0.003). Five patients (20%) had plasma tHcy levels that exceeded the upper normal limit of plasma tHcy (median+2 SD of the reference group). Median S-folate was significantly lower in the patient group (6.0 nmol 1(-1) vs. 8.5 nmol 1(-1); p < 0.001), and 11 (44%) patients had depressed S-folate. Only three (12%) patients had RBC folate values below the reference interval. There was no difference in the levels of RBC folate between the two groups. A comparison of S-cobalamin levels in the two groups disclosed a significantly lower level in the patient group. However, no patient had cobalamin deficiency as assessed by S-cobalamin and S-methylmalonate measurements. Thus, it is unlikely that any patient had increased plasma tHcy due to cobalamin deficiency. Of 24 patients having a HbA1c measurement performed, 12 (50%) had decreased levels indicating chronic haemolysis. Only seven (28%) patients had reticulocytosis. HbA1c was positively correlated to haptoglobin levels (r = 0.77; p < 0.001) and negatively correlated to the percentage of reticulocytes (r = -0.50; p = 0.02). The percentage of reticulocytes was negatively correlated to haptoglobin levels (r = -0.42; p = 0.04). The chronic haemolysis of the patients' blood due to SASP might explain the similar RBC folate values in the two groups because of a relatively higher folate content of young erythrocytes. In conclusion, our results support previous findings of folate deficiency and haemolysis occurring in a considerable fraction of patients receiving treatment with SASP. Measurements of plasma tHcy suggest that a substantial number of patients may have folate deficiency at the tissue level.

Incidence, clinicopathological features and outcome of primary central nervous system lymphomas. Population-based data from a Danish lymphoma registry. Danish Lymphoma Study Group, LYFO.

BACKGROUND: Primary Central Nervous System lymphomas (PCNSL), a rare neoplasm accounting for only a small fraction of malignant brain tumors and extranodal non-Hodgkin's lymphomas (NHL), seems to occur with increasing frequency in immunologically-normal as well as immunocompromised individuals. In an attempt to characterize the clinicopathological features, incidence rate and outcome of PCNSL, we here report our experience in a large unselected group of patients from a well-defined region. PATIENTS AND METHODS: In a Danish population-based NHL registry (LYFO) representing a population of 2.7 million, all new cases of NHL were registered during the 10-year period from 1st January 1983 to 31st December 1992. The number of malignant brain tumors reported to the Danish Cancer Registry from the region covered by LYFO, during the 7-year period from 1st January 1983 to 31st December 1989, is compared to the number of PCNSL. RESULTS: During the 10-year period 2687 new cases of NHL were registered. Of these, 1004 (37%) were extranodal and 42 were non-AIDS-related PCNSL, accounting for 4.2% of extranodal NHL and 1.6% of all NHL, respectively. The incidence rate for PCNSL during the ten-year period (age range: 21-85 yrs, median: 62 yrs, M/F ratio: 0.9) was 15.6 cases per million population. Eighteen and 24 cases were diagnosed during the first and the second 5-year period, respectively (p > 0.05). During the 7-year period 1866 primary malignant brain tumors were registered in the region covered by the LYFO study group. In the same period 30 cases of PCNSL were detected. Thus, PCNSL accounted for 1.6% of all primary malignant brain tumors diagnosed in Western Denmark. Histologically, 83% were high-grade. Using the Kiel classification centroblastic diffuse (62%) and immunoblastic lymphoma (12%) were the most common subtypes. Thirty-seven patients had B-cell lymphoma; no T-cell lymphomas were detected. Forty-one cases were diagnosed pre mortem. Treatment included surgical resection (23 patients), whole brain irradiation (WBRT) (37 patients) and chemotherapy (22 patients). Median survival for those receiving either WBRT or WBRT and chemotherapy was 7.5 months and 12 months, respectively (p > 0.05). Survival was 43.9%, 31.7% and 7.3% at 1, 2 and 5 years.