Intensive treatment in order to minimize the Ph-positive clone in CML. Danish-Swedish CML Group.

With the rationale that a significant reduction of the malignant clone in CML might prolong time to metamorphosis, intensive treatment was given to patients < or = 55 years. Six months of hydroxyurea and high dose interferon-alpha (IFN-alpha) was followed by one to three courses of intensive chemotherapy. Patients who had a donor were allotransplanted and patients who became Ph-negative in bone marrow were autotransplanted. On 1 May 1995, 160 patients were registered in the study. Fifty-one percent of the patients who received six months IFN-alpha and hydroxyurea had a significant Ph-reduction and 5% became Ph-negative. The corresponding figures after two intensive chemotherapy courses were 47 and 28%, respectively. Twenty-seven of 30 autotransplanted patients have been analysed for Ph. Seventeen have relapsed cytogenetically, while ten are Ph-negative 1-64 + months after ABMT. BMT was performed in 59 patients. The actuarial 6-year survival from diagnosis of all 160 registered patients is 68%, which seems to be better than for age-matched historical controls.

Autologous splenic implantation in pigs. A comparison of two methods.

Two methods of autologous splenic implantation, with sliced or with minced splenic tissue, were compared in six pigs. The two procedures were carried out simultaneously in each pig and the splenic remnants were surgically removed three months later. These remnants were histomorphometrically quantified by point counting. Statistical analysis showed the mincing procedure to be significantly superior, since 33% of the originally implanted tissue remained, in contrast to 21% of sliced, implanted tissue. At microscopy the tissue remaining after both procedures was in all cases indistinguishable from normal pig spleen. No necrotic splenic tissue was found. The authors conclude that minced tissue and omental pouch technique are preferable for autologous splenic implantation.

Demonstration of splenic functions following splenectomy and autologous spleen implantation.

Autologous splenic tissue was implanted in 14 patients undergoing splenectomy for traumatic rupture or peroperatively arising lesion of the spleen. To demonstrate function of the implanted splenic tissue, spleen scintigraphy using 99mTc-labelled heat-damaged autologous erythrocytes, and percentage measurement of vacuolated erythrocytes in peripheral blood were performed one and three months after the splenectomy. The spleen scans were positive in eight patients after one month and in 12 patients after three months, demonstrating splenic phagocytic function. The numbers of vacuolated erythrocytes also indicated some restoration of the pitting function due to the implanted splenic tissue. No alterations were seen in serum immunoglobulins, but a moderate thrombocytosis still persisted after three months. The clinical significance of implantation of autologous splenic tissue is discussed.

Polymeric Bence Jones proteins in serum in myeloma patients with renal insufficiency.

The polymeric forms of Bence Jones protein (BJ) in serum and the influence on renal function were investigated in 59 patients with multiple myeloma and 2 with Waldenström's macroglobulinemia. Eight of 35 patients with kappa and 26 with lambda type BJ protein had decreased renal function. The investigation showed a considerable variation between patients in serum concentrations of tetrameric (T), dimeric (D) and monomeric (M) forms of BJ protein. A significantly higher fraction of D forms of BJ protein resulting in a high D/M ratio was found in the myeloma patients compared with polyclonal light chains in 10 normal controls. The renal function in multiple myeloma was, however, not correlated to the D/M ratio or to the BJ protein tetramers. This suggests that the nephrotoxicity of BJ proteins is not associated with polymerization of BJ proteins in serum. BJ proteins of aberrant size were found in 3 patients with rapidly decreasing renal function. Histological investigation in 2 of these patients revealed nodular glomerulosclerosis.

Autoantibodies, immune complexes and HLA-D in thyrogastric autoimmunity.

Forty-one patients with Hashimoto's thyroiditis (HT) and 82 with Pernicious anaemia (PA) were investigated. All 123 patients were HLA-D typed and results correlated to thyroglobulin antibodies (TgAB), microsomal antibodies (MAb), parietal cell antibodies (PCA), circulating immune complexes (IC), and intrinsic factor antibodies (IFA). In PA, TgAb was found less frequently in Dw2 positive patients than in Dw2 negative patients. IFA was rarely found in Dw5 positive PA patients. In HT, patients positive for Dw5 had lower levels of TgAb. IC were present in 67% of patients with HT, but only in 2.5% of patients with PA (p less than 0.01). Dw5 was associated with low levels of IC in HT. In conclusion, HT and PA seem to be related by their association with HLA-D types, but a heterogeneity in the pattern of antibodies and IC could be seen. The organ specific antibodies characteristic for each disease were present in lower levels in patients with Dw5.

The cellular immune response after splenectomy in humans. Impaired immunoglobulin synthesis in vitro.

The in vitro immune functions of peripheral blood lymphocytes have been studied in 70 splenectomized patients. 45 patients were splenectomized due to traumatic rupture of the spleen; in 22 of these patients residual splenic tissue was detected, employing a selective spleen scintigraphy. 14 patients were splenectomized due to hereditary spherocytosis and 11 patients due to immune thrombocytopenia or autoimmune haemolytic anaemia; they were all without ectopic splenic tissue. The study revealed that splenectomized patients have (i) an elevated number of blood lymphocytes, (ii) an elevated relative number of EA-RFC, but normal %s of E, EAC-RFC and SmIg positive cells, (iii) normal T-cell mitogenic responses induced by PHA, but enhanced responses induced by ConA and PWM, (iv) normal cell-mediated enhancement of the PWM-induced proliferative B-cell response, (v) no cell-mediated inhibition of the T-cell dependent and PWM-induced proliferative B-cell response and (vi) an impaired number of PFC after stimulation with PWM. The findings were unrelated to the cause of the splenectomies or to the presence of residual splenic tissue. It is possible that the impaired B-cell response as shown by the reduced number of PFC after stimulation with PWM may be of significance for the in vivo resistance to infections in splenectomized patients.

Interferon production, cellular and humoral immunity in splenectomized patients.

Undetectable levels of circulating interferon were found in 35 splenectomized patients and in 14 controls. In addition, no differences in virus, purified protein derivative (PPD), and phytohaemagglutinin (PHA) induced interferon production were observed between the patients and the controls. Virus induced lymphocyte transformation tended to be reduced after splenectomy, but only the herpes simplex virus (HSV) induced transformation index was significantly reduced in splenectomized patients without residual splenic tissue (P less than 0.05). In contrast, the PHA lymphocyte transformation was unchanged in patients and controls. The number of natural viral antibodies in splenectomized patients did not differ from that of controls. Furthermore, there were no major differences in the magnitude of the titers of the sero-positive cases between the various groups. Thus, splenectomy does not interfere with interferon production in vitro, and as seen from natural viral antibodies, no impairment of humoral immunity was observed. The reduced HSV lymphocyte transformation may indicate an impaired lymphocyte function after splenectomy.

Failure of pneumococcal vaccination in a splenectomized child.

Recurrent Streptococcus pneumoniae septicaemia occurred in a splenectomized child with idiopathic thrombocytopenic purpura. Fatal infection took place 1 year after pneumococcal vaccination and was caused by sero-type 18C which was included in the vaccine. The efficacy of pneumococcal vaccination is discussed in relation to specific pneumococcal polysaccharide antibody titers, and it is concluded that vaccination alone is insufficient in preventing overwhelming infections in splenectomized individuals.

Immune thrombocytopenia due to antazoline (Antistina).

Antazoline (Antistina)-induced thrombocytopenic purpura occurring on three occasions in a 21-year-old woman is reported. After withdrawal of the drug ther recovered promptly. In vitro investigation demonstrated the presence of an antibody in serum, which in association with antazoline caused complement fixation when added to test platelets. Also platelet agglutinins could be detected in the patient's serum when antazoline was added. The reactions were drug specific and they could still be demonstrated 9 months after the last exposure to the drug.

Abrupt withdrawal of beta-blocking agents in patients with arterial hypertension. Effect on blood pressure, heart rate and plasma catecholamines and prolactin.

Chronic treatment with beta-blockers was interrupted abruptly in six patients with arterial hypertension. Three patients, who had experienced symptoms during a previous withdrawal, again complained of transient palpitations, tremor, sweating, headache and general malaise. A significant increase in standing blood pressure (BP) and heart rate (HR) was noted after 24 h. The standing HR reached a maximum after 48 h and had decreased significantly on the 7th day (p less than 0.005). There was a strong tendency to greater increase in standing BP and HR in the patients who experienced symptoms than in those who did not. Plasma concentrations of noradrenaline, adrenaline and prolactin did not change significantly. Thus, beta-blocker withdrawal symptoms are reproducible and are indicative of a transient sympathetic hyperresponse. The increased activity is not likely to be caused by increased production of circulating catecholamines, but rather by increased sensitivity of the beta-receptor.

Plasma prolactin during lithium treatment.

Plasma prolactin was determined in a longitudinal study, where -9 manic-depressive patients were examined before lithium treatment and at various times during the treatment with the aim of unravelling a possible association between initial changes in water and sodium balance during lithium treatment and changes in plasma prolactin level. No significant changes were found, nor could any correlation between serum lithium and plasma prolactin be established. Some reports have indicated association between breast cancer and prolonged elevated plasma prolactin, such as is seen during treatment with phenothiazines and reserpine. In a transversal study, determination of plasma prolactin during long-term lithium treatment in 26 patients did not reveal any elevation compared with 16 controls. Lithium is accordingly not among the drugs which produce prolonged elevation of plasma prolactin.