R-CHOEP-14 improves overall survival in young high-risk patients with diffuse large B-cell lymphoma compared with R-CHOP-14. A population-based investigation from the Danish Lymphoma Group.

BACKGROUND: Optimal treatment of young patients with high-risk diffuse large B-cell lymphoma (DLBCL) remains a matter of debate and requires improvement. The combination chemotherapy with cyclophosphamide, doxorubicin, vincristine and prednisone (CHOP) with addition of etoposide (CHOEP) has in other patient groups been shown to be effective. Further improvement has been accomplished with the use of rituximab in combination with the regimens every 2 weeks (R-CHOP-14, R-CHOEP-14). The aim of the present retrospective population-based study was to compare R-CHOP-14 with R-CHOEP-14 in a cohort of high-risk patients aged 18-60 years with two or more risk factors (stage III-IV, elevated lactate dehydrogenase levels, performance status 2-4). To our knowledge, this is the first study comparing these two regimens in this patient group. METHODS: We obtained data for the period 2004-2009 from the Danish Lymphoma Database. One hundred and fifty-nine patients were eligible to enter the study. Primary end point was overall survival (OS) and secondary end points were response to treatment, progression-free survival (PFS) and safety. RESULTS: Four-year OS was superior in the R-CHOEP-14 group: 75% compared with 62% for R-CHOP-14 (P=0.04). This superiority was also seen for PFS: 4-year PFS was 70% for the R-CHOEP-14 group compared with 58% for the R-CHOP-14 group (P=0.02). CONCLUSION: R-CHOEP-14 is a promising regimen for young patients with high-risk DLBCL with improved OS and PFS compared with R-CHOP-14.

Glycosylated hemoglobin in relation to rapid fluctuations in blood glucose in children with insulin-dependent diabetes: a comparison of methods with and without prior dialysis.

To evaluate the importance of dialysis in the determination of glycosylated hemoglobin (HbA1), we studied blood glucose and HbA1 in 38 insulin-dependent diabetic children during a morning fast and again 6 h postprandially. We used two methods to determine glycosylated hemoglobin: (1) the conventional macrocolumn method of Trivelli, which uses dialyzed hemolysate and (2) a commercially available microcolumn procedure, Isolab's Fast Hemoglobin Test System, which uses undialyzed blood samples. When the 6-h changes were assessed, the mean blood glucose had increased from 11.6 to 16.3 mmol/L (P less than 0.001). HbA1, determined by the microcolumn procedure simultaneously increased from 12.6% to 13.4% (P less than 0.001), and the increment in HbA1 correlated significantly with the increment in blood glucose (r = 0.62, P less than 0.001). HbA1 determined by the macrocolumn method increased slightly from 13.1% to 13.4% (P less than 0.01), and no correlation was present between the increment in blood glucose and HbA1 (r = -0.02, NS). When the microcolumn procedure was modified by employing dialyzed hemolysate, this method became unaffected by acute blood glucose variations. Therefore, dialysis in sample preparation appears to be important in minimizing the effect of acute changes in blood glucose on the level of glycohemoglobin. Methods in which dialyzed hemolysates are used may be more useful as an index of long-term glucose control.

Granulomatous bone marrow inflammation during treatment of chronic myeloid leukaemia with interferon alpha-2b.

A patient with chronic myeloid leukaemia developed bone marrow granulomas during treatment with interferon alpha-2b. Some granulomas had necrotic centres and giant cells and there was marked eosinophilia surrounding them. The granulomas disappeared when the interferon treatment was discontinued. Mycobacteriosis was ruled out. The most likely explanation for the granuloma formation was drug hypersensitivity.

Plasma 6-keto-PGF1 alpha, thromboxane B2 and PGE2 during diabetic ketoacidosis.

In 10 patients admitted to hospital with diabetic ketoacidosis plasma prostanoids 6-keto-PGF alpha, thromboxane B2 and PGE2 were studied before treatment and following recovery. During ketoacidosis the median plasma 6-keto-PGF1 alpha and PGE2 were significantly increased compared to those of a normal reference group: 5.2 pg/ml and 3.9 pg/ml versus 1.7 pg/ml and 0.4 pg/ml (p less than 0.01 and p less than 0.05). In response to therapy both prostanoids decreased significantly towards a normal level, 6-keto-PGF1 alpha: 0.5 pg/ml p less than 0.01 and PGE2: 0.08 p less than 0.05 respectively. The changes in plasma 6-keto-PGF1 alpha were negatively correlated to changes in pH, rho: -0.7788 p = 0.0135, whereas the changes in PGE2 were positively correlated to serum creatinine at admittance, rho: 0.6976, p = 0.0368 and to the amount of intravenous fluid and insulin used during treatment, rho: 0.7500 p = 0.0126 and rho: 0.8424, p = 0.0023 respectively. Plasma thromboxane B2 concentrations were not elevated and did not change after treatment of the ketoacidosis.

Cytogenetic aberrations in adult acute lymphocytic leukemia: optimal technique may influence the results.

The aim of the present study was to analyse the distribution of cytogenetic aberrations in adult ALL in a population based material and compare the results with literature data. Forty-one patients were diagnosed during a 12-year period. The age varied between 14 and 82 (mean 37, median 32). Thirty-two patients were cytogenetically investigated and in all cases analysable metaphases were obtained (range 10-29, mean 24, median 25, success rate: 100%). Nine (28%) patients had a T-phenotype and 23 (72%) had a pre-B phenotype. High hyperdiploidy was found in four patients (13%). Hypodiploidy was found in 5 patients (16%), 10 (31%) had a pseudodiploid chromosome mode and four (13%) showed low hyperdiploidy (chromosome mode 47-51). Chromosomes 10 and 18 were most frequently involved in numerical aberrations. Structural aberrations most frequently involved chromosomes 6, 9 and 22. t(9;22) was seen in six cases (19%), del(6q) in five cases (16%) and der(9p) in five cases (16%). High hyperdiploid clones, which are associated with a favorable prognosis, were found with the same frequency as in other studies. The frequency of t(9;22) was 19% in our study, others have found frequencies between 11% and 30%. Compared to previously published studies our patients with t(9;22) were younger. Furthermore, those with del(6q) were older, showing a median age equivalent to the patient group as a whole. The differences between our data and previously published studies may be explained by population-based derived data and especially by an optimal technique in obtaining metaphases.

Cigarette smoking shortens the bleeding time.

The cutaneous bleeding time was shortened after smoking high nicotine cigarettes while not after smoking nicotine free cigarettes. The ADP induced primary platelet aggregation was not enhanced. The number of circulating platelet aggregates did not change due to smoking.

Lupus anticoagulant is significantly associated with inflammatory reactions in patients with suspected deep vein thrombosis.

OBJECTIVE: Lupus anticoagulant (LA) and antiphospholipid antibodies (aPL) are suggested as risk factors for development of deep vein thrombosis (DVT) among patients without systemic lupus erythematosus (SLE). Other conditions, e.g. inflammation, are reported to induce LA and it is uncertain whether the association between LA and DVT is causal. In this study the associations between aPL, LA and inflammation were investigated in 170 consecutive patients without SLE, but with a tentative diagnosis of DVT. MATERIAL AND METHODS: DVT was diagnosed in 64 patients. LA was determined according to the criteria of the International Society of Thrombosis and Haemostasis. The concentration of anticardiolipin (aCL) and beta(2)-glycoprotein I (anti-beta(2)-GPI) antibodies as well as C-reactive protein (CRP) was determined with sensitive and precise methods. RESULTS: LA was demonstrated in 8 patients with DVT and in 10 patients without DVT, relative risk 1.33 (CI: 0.55-3.18). No significant association was observed between aCL or anti-beta(2)-GPI and DVT. Patients suffering from DVT had significantly higher concentrations of CRP than patients without DVT. However, CRP was also significantly higher in patients positive for LA than in patients without LA irrespective of the presence of DVT (p<0.001). CONCLUSIONS: The present study supports a strong association between inflammatory reactions and development of LA in patients with suspected DVT, whereas no significant association was demonstrated between LA or aPL and DVT.

[Haemoglobin A1c concentration in newly detected diabetes mellitus (author's transl)]. / Hämoglobin-A1c-Konzentration bei neu entdecktem Diabetes mellitus. Verhalten nach Einleitung der Behandlung mit Glibenclamid.

Using the Trivelli method haemoglobin A1c (HbA1c) concentrations were determined in 7 patients with newly detected, non-insulin-dependent, diabetes mellitus before and after commencement of treatment with glibenclamide. Investigations were continued at weekly intervals over a period of 3 months. In all cases there was hardly any reduction of HbA1c values during the first 3 weeks of treatment. However, a continuous decrease of HbA1c values occurred thereafter. Nearly normal values were reached after patients had been adjusted to a considerably lower blood sugar level for more than 80 days. HbA1c concentration correlated significantly (p less than 0.001) both with the concurrently determined fasting blood sugar values as well as with fasting blood sugar values in each of the preceding 8 weeks.

Plasma prostaglandins: 6-keto-PGF1 alpha, TXB2 and PGE2 in juvenile-onset diabetes determined by high-pressure liquid chromatography and radio-immunoassay.

Some studies have recently reported increased production of platelet thromboxane and decreased vascular prostacyclin in patients with diabetes mellitus. The impact of these changes on platelet and vascular functions in vivo is still speculative. Using radio-immunoassay and high pressure liquid chromatography we have studied the plasma levels of 6-keto-PGF1 alpha, TXB2 and PGE2 in 23 juvenile-onset diabetics. There was no significant difference in these plasma prostaglandins between the diabetics and a control group. The prostaglandins were neither correlated to blood-glucose nor the degree of glycosylation (HbA1c). Our results can not support the hypothesis that decreased vascular prostacyclin and increased platelet production of TXB2 are important factors in diabetic patients.

Some aspects of the pharmacokinetics of fluorescein in normal and in diabetic subjects.

A method for measuring the free fraction of fluorescein in plasma by ultrafiltration is tested. The coefficient of variation is 3%. Changes in pH and temperature from in vivo conditions at 37 degrees C to in vitro conditions are slight (less than 6%) and tend to minimize each other. To study the pharmacokinetics of fluorescein, 25 control subjects and 38 insulin-treated diabetics were examined after an intravenous injection of sodium fluorescein, 17 mg/kg body weight. 5, 45 and 120 min later, free fluorescein was significantly lower in the diabetics (5 min: 2.4 +/- 0.5 vs. 2.1 +/- 1.0, 45 min: 0.62 +/- 0.13 vs. 0.52 +/- 0.14, 120 min: 0.27 +/- 0.07 vs. 0.17 +/- 0.07 X 10(-5) g/ml, p less than 0.01 (mean +/- SD)). The renal excretion of fluorescein is reflected in a positive relation between serum creatinine and total plasma fluorescein at 45 and 120 minutes in the group of diabetics (Spearmans rho = 0.52, p = 0.04 and 0.53, p = 0.08, respectively).

Plasma 6-keto-PGF1 alpha, thromboxane B2 and PGE2 in type 1 (insulin-dependent) diabetic patients during exercise.

The capacity of prostacyclin production determined as plasma 6-keto-PGF1 alpha was investigated in 12 type 1 (insulin-dependent) diabetic patients with a median duration of diabetes of 14 years during ordinary metabolic control. Using high pressure liquid chromatography preceding radioimmunoassay, the plasma concentration of 6-keto-PGF1 alpha, the stable metabolite of prostacyclin, was determined at rest and after a standardised bicycle exercise test. The plasma 6-keto-PGF1 alpha in diabetic patients at rest did not differ from that of 25 healthy volunteers; 2.9 pg/ml (range less than 0.2-15.3) versus 1.7 pg/ml (range less than 0.2-16.6). During the exercise test plasma 6-keto-PGF1 alpha increased significantly in the diabetic patients as well as in the control group (p less than 0.05). The increment of 6-keto-PGF1 alpha in the diabetic patients was neither related to the metabolic regulation, duration of diabetes nor to changes in platelet volume, platelet number or the production of thromboxane B2 and prostaglandin E2. Our results do not support the hypothesis that Type 1 diabetic patients have a decreased capacity of prostanoid production, as suggested from in vitro studies.

Glycosylated haemoglobin (HbA1c) in iron- and vitamin B12 deficiency.

Glycosylated haemoglobin (HbA1c) was measured in 10 patients with iron deficiency anaemia, 10 patients with vitamin B12 deficiency anaemia and 10 healthy controls. Initially there were no significant differences between the groups (P greater than 0.4), but after treatment with iron and vitamin B12 for 3 and 6 weeks, the glycosylated haemoglobin concentration decreased significantly (P less than 0.01). It was concluded that glycosylated haemoglobin is a sensitive marker of the changes in the erythrocyte population that are observed when predominantly immature erythrocytes are being produced.

Anagrelide treatment in 52 patients with chronic myeloproliferative diseases.

In this retrospective multi-centre study, we report our experience with anagrelide in the treatment of thrombocytosis in patients with chronic myeloproliferative diseases. Our study included 52 patients (age 20-78 years). The initial anagrelide dose was, in general, 0.5 mg once daily and mean maintenance dosage was 1.7 mg/day. The overall response rate was 79% including 75% complete remission and 4% partial remission. Forty-two patients (81%) had adverse effects and in 29% of the study population, the adverse effects necessitated cessation of anagrelide. The most common adverse effect was moderate anaemia (50%). Two patients experienced erectile dysfunction which has been described only once previously in association with anagrelide treatment. One patient progressed to acute leukaemia. However, this patient had been pre-treated with two potentially leukaemogenic drugs and had only been in short-term treatment with anagrelide. Furthermore, a total of 13 events were recorded. More than 25% of these events occurred in patients with platelet counts between 400 and 600 x 10(9)/l and almost 40% of all events occurred in patients with platelet counts above 400 x 10(9)/l. This observation supports the hypothesis that aggressive control of thrombocytosis to a platelet count <400 x 10(9)/l might reduce the number of thrombohaemorrhagic events. Anagrelide is safe and effective in reducing the platelet counts, but a high proportion of the patients discontinue treatment because of the adverse effects of the drug.