The development of targeted chemotherapy for CNS lymphoma-a pilot study of the IDARAM regimen.

PURPOSE: We have developed and evaluated a CNS-targeted chemotherapy regimen based on the pharmacokinetic properties of the individual drugs in the combination. PATIENTS AND METHODS: In a twin-track study, 16 patients with secondary CNS lymphoma (SCNSL) and 8 with primary CNS lymphoma (PCNSL) were treated with IDARAM which comprised idarubicin 10 mg/m(2) i.v., days 1 and 2; dexamethasone 100 mg, 12-h infusion, days 1, 2 and 3; cytosine arabinoside (ARA-C) 1.0 g/m(2), 1-h infusion, days 1 and 2; methotrexate 2.0 g/m(2), 6-h infusion, day 3 (with folinic acid rescue); and cytosine arabinoside 70 mg plus methotrexate 12 mg, intrathecally, days 1 and 8. Two cycles were delivered at 3-weekly intervals. After response assessment, patients received adjuvant cranial radiotherapy (40 Gy over 20 fractions). RESULTS: The series comprised 24 patients, 11 male and 13 female. Their median age was 53 years (range 21 to 73 years). Grade 4 neutropenia and thrombocytopenia occurred in the majority of patients treated. Of the eight PCNSL patients, seven achieved complete remission (CR). Four remained in CR at the time of this report with a median duration of follow-up of 25 months (range 11 to 42 months). Of the 16 SCNSL patients, 12 achieved CR. Seven patients remained in CR at the time of this report with a median duration of follow-up of 24 months (range 18 to 57 months). CONCLUSION: This study suggests that IDARAM is an effective regimen in both PCNSL and SCNSL and is suitable for further development and evaluation.

Elevated fibrinopeptide A levels in patients with clinically localised breast carcinoma.

58 patients with clinically localised breast carcinoma, treated by either mastectomy alone or lumpectomy plus local radiotherapy, have now been followed for up to 51 months (median 12 months). 21 of the 58 patients (36.2%) had a persistently elevated or rising fibrinopeptide A level after surgery and 11 of these patients (52%) to date have subsequently developed recurrent breast carcinoma up to 27 months after the fibrinopeptide A level became elevated (median 6 months). Conversely, only 2 (5.4%) of the 37 patients with persistently normal post-operative fibrinopeptide A levels have developed recurrent disease. Elevated fibrinopeptide A levels appear to be a marker of persistent tumour activity and precede clinical recurrence in certain patients with breast carcinoma, but normal values do not exclude recurrent or residual disease.

Unusual presentation of a large infected hemophiliac pseudotumor in an autologous indium-111 WBC scan.

A false-negative In-111 WBC scan was obtained in a case of a large, infected hemophiliac pseudotumor. Following aspiration of the abscess, a positive scan was seen, demonstrating that In-111 WBC imaging occasionally may be misleading as a diagnostic tool.

HTLV-III antibody and T-cell subset ratios in haemophiliacs and their spouses.

44% of 63 British patients with either haemophilia A or B were HTLV-III antibody positive (HTLV-VIII+). HTLV-III+ was more frequent in high factor VIII concentrate users and 75% of severely affected haemophilia A patients were HTLV-III+. All eight patients who were exposed to factor IX concentrate were HTLV-III-. 17 haemophilia A patients who received only British made factor VIII concentrate (average 12,000 units/year) were HTLV-III-. Two of 63 patients had evidence of a pre-AIDS type symptom complex and both were HTLV-III+. Information from a cohort of 21 Liverpool haemophiliacs suggests that HTLV-III was first introduced into this country in 1981. OKT4/T8 ratios were abnormal in 52% of 21 patients studied but this finding was not confined to either HTLV-III+ or HTLV-III- individuals. The spouses of 14 HTLV-III+ haemophiliacs were all HTLV-III-.

Endothelial cell proliferation in myelofibrosis.

The distribution of laminin and collagen type IV in normal human bone marrow appeared to be limited to a small number of capillary and sinusoidal basement membranes. Cellular elements including megakaryocytes showed a negative staining reaction. In contrast, myelofibrotic bone marrow showed markedly increased quantities of both laminin and collagen type IV. This was consistent with a proliferation of endothelial cells within the marrow as confirmed by factor VIII RAG staining. It is suggested that in myelofibrosis in addition to a marked fibrous reaction proliferation of vascular elements is also prominent.

Distribution of fibronectin and laminin in normal and pathological lymphoid tissue.

Forty six lymph nodes were examined with the indirect immunoperoxidase technique for the distribution of fibronectin and laminin. Fibronectin was present in the framework of the tissue and the basal lamina of blood vessels, giving a clear outline of nodal architecture. Intracellular fibronectin was observed in cases of reactive sinus histiocytosis, when about a third of macrophages exhibited strong positivity. Mast cells were positive. A pronounced increase in extracellular fibronectin was seen in nodular sclerosing Hodgkin's disease, although heavily hyalinised areas exhibited only superficial positivity. Reed-Sternberg and mononuclear Hodgkin's cells were consistently negative for fibronectin. Laminin staining was localised to vascular and marginal sinus basement membranes. No cellular positivity was evident. The distribution of laminin indicated a pronounced increase in vascularity in nodular sclerosing Hodgkin's disease, which was especially prevalent within the dense fibrous trabeculae. In contrast, however, examination of the other Rye subtypes showed a lesser degree of vascularity with numbers of vessels similar to those observed in reactive follicular hyperplasia. Laminin was found to be more efficient than factor VIII related antigen as a vascular marker.

Elastase-alpha 1 antitrypsin complexes in acute leukaemia.

30 consecutive patients with acute leukaemia were studied prior to commencement of treatment in order to assess the incidence and significance of raised elastase (ELP) - alpha 1 antitrypsin complex level. In addition the reliability of detecting low factor XIII subunit levels as an indicator of in vivo release of ELP was evaluated. While 15 patients had raised levels of ELP alpha 1 antitrypsin complex levels, only 4 of these had reduced levels or factor XIII subunits A and S. In addition increased levels of ELP- alpha 1 antitrypsin complex were not associated with any marked disturbance of routine coagulation tests. Patients with raised ELP- alpha 1 antitrypsin complex levels had significantly higher circulating white cell and blast cell counts as compared to those patients with normal levels of this complex. In patients entering remission the levels of ELP- alpha 1 antitrypsin complex returned to normal.

Immuno-enzymatic detection of fibronectin in normal and pathological haematopoietic tissue.

Cryostat sections of bone marrow biopsies were stained immuno-enzymatically for fibronectin using the alkaline phosphatase: anti-alkaline phosphatase (APAAP) technique. In normal marrow fibronectin was present only in megakaryocytes and the walls of blood vessels. In contrast, myelofibrotic bone marrow possessed an extensive distribution of fibronectin which did not correspond to the distribution of reticulin. Infiltrated and hypercellular marrows showed an increase in fibronectin which appeared to be related to increased marrow vascularity. Again no correlation with the reticulin pattern was evident. In contrast to platelets, other circulating blood cells had no demonstrable fibronectin. This study suggests that fibronectin does not act as a mediator of haemopoiesis in vivo as has been suggested by the results of experiments in non-human models.

Fibronectin C in acute leukaemia.

Fibronectin C (FN:C) is thought to represent fibronectin complexed with other plasma proteins and can be detected by a crossed two-dimensional immunoelectrophoretic technique. While we have not detected this on examination of normal plasma, FN:C was found in 26 of 33 patients (79%) with acute leukaemia at diagnosis. FN:C persisted throughout the induction phase of chemotherapy and disappeared only when a complete remission was obtained in 16 of 17 FN:C+ patients. FN:C has reappeared in the only patient whose leukaemia has relapsed to date. FN:C was present in both acute non-lymphoblastic (85%) and acute lymphoblastic leukaemia (50%). Leukaemia remission rates were similar in patients who were FN:C+ or FN:C- (69% and 57%). Evidence is presented to suggest that the composition of FN:C is partially related to the binding of fibrinogen/fibrin to fibronectin in plasma. No significant difference in in vivo activation of coagulation was detected between FN:C+ and FN:C- patients. There was no correlation between the presence of FN:C and plasma fibronectin levels.

An anterior cervical mass due to infection with absidia.

Absidiosis , diagnosed after biopsy of an anterior cervical mass, is described in a patient who was in remission from acute myeloid leukaemia.

Computed tomography: qualitative and quantitative recognition of liver disease in haemophilia.

Thirty haemophiliac patients have been investigated by computed tomography (CT). Quantitative studies using dual energy scans with and without contrast enhancement, together with autocorrelation function analysis of the characteristics of the liver and spleen, revealed significant changes in the liver. The CT findings corresponded to the presence of liver disease, including chronic active hepatitis and cirrhosis, in 13 patients confirmed by percutaneous liver biopsy.

Skin infiltration associated with chronic myelomonocytic leukaemia.

Chronic myelomonocytic leukaemia (CMML) is typically associated with a prolonged clinical course and is not usually very responsive to chemotherapeutic intervention. Skin infiltration has not been recognized previously as a feature of this illness. We have seen four patients recently with CMML, who during the the course of their illness developed marked skin infiltration. Whilst sensitivity to chemotherapy could be demonstrated in the peripheral blood cell population, skin infiltration was quite resistant to treatment. Skin infiltration heralded a more aggressive phase of the disease although no discernible change in morphology, cytochemistry or membrane marker analysis of the leukaemic cell population could be demonstrated in three of the patients studied; one patient, however, transformed to an acute leukaemia shortly thereafter.

Diabetes, a hypercoagulable state? Hemostatic variables in newly diagnosed type 2 diabetic patients.

37 type 2 diabetic patients with no clinical evidence of retinopathy or vascular disease were studied at diagnosis and following control of hyperglycaemia for evidence of abnormalities of coagulation, fibrinolysis and platelet behaviour. 38% showed hyperactive platelets, demonstrating either in vitro hyperaggregability, circulating platelet aggregates, or raised plasma beta-thromboglobulin levels. 36% showed abnormally raised factor VIII coagulant activity (FVIIIc) levels, though this was mainly in female patients. The mean level of FVIIIc decreased with treatment. Anti-thrombin III (AT-III) levels were decreased, and 33% of the patients had levels less than 80%. In this group AT-III increased following treatment. No abnormalities of fibrinolysis were demonstrated. These findings support the concept that diabetes can be associated with a hypercoagulable state, which is not necessarily dependent on the presence of overt vascular disease, or correlated with the degree of chronic hyperglycaemia (HbA1c levels).

Circulating plasmin-antiplasmin complexes in acute leukaemia.

Thirty consecutive patients presenting with acute leukaemia were studied throughout their hospital course to determine if plasma-alpha 2 antiplasmin (P-AP) complexes could be detected during episodes of increased fibrinolytic activity and to correlate this finding with other more conventional laboratory parameters. Increased fibrinolytic activity was a common finding, it was detected in 19 (63%) patients. This was usually present at diagnosis, but occasionally occurred later as a transient phenomenon. Increased fibrinolytic activity could not clearly be associated with either infection or chemotherapy. P-AP complexes were found in 11 (37%) patients and were almost always accompanied by additional laboratory evidence of increased fibrinolysis. These complexes were present in most instances at diagnosis and disappeared following successful chemotherapy. Forty-five per cent of patients with P-AP complexes had low alpha 2-antiplasmin levels and 36% had low plasminogen levels which returned to normal following successful chemotherapy. At diagnosis six of eight patients with P-AP complexes had major haemorrhagic manifestations.