High remission rate in T-cell prolymphocytic leukemia with CAMPATH-1H.

T-cell prolymphocytic leukemia (T-PLL) is a chemotherapy-resistant malignancy with a median survival of 7.5 months. Preliminary results indicated a high remission induction rate with the human CD52 antibody, CAMPATH-1H. This study reports results in 39 patients with T-PLL treated with CAMPATH-1H between March 1993 and May 2000. All but 2 patients had received prior therapy with a variety of agents, including 30 with pentostatin; none achieved complete remission (CR). CAMPATH-1H (30 mg) was administered intravenously 3 times weekly until maximal response. The overall response rate was 76% with 60% CR and 16% partial remission (PR). These responses were durable with a median disease-free interval of 7 months (range, 4-45 months). Survival was significantly prolonged in patients achieving CR compared to PR or no response (NR), including one patient who survived 54 months. Nine patients remain alive up to 29 months after completing therapy. Seven patients received high-dose therapy with autologous stem cell support, 3 of whom remain alive in CR 5, 7, and 15 months after autograft. Stem cell harvests in these patients were uncontaminated with T-PLL cells as demonstrated by dual-color flow cytometry and polymerase chain reaction. Four patients had allogeneic stem cell transplants, 3 from siblings and 1 from a matched unrelated donor. Two had nonmyeloablative conditioning. Three are alive in CR up to 24 months after allograft. The conclusion is that CAMPATH-1H is an effective therapy in T-PLL, producing remissions in more than two thirds of patients. The use of stem cell transplantation to consolidate responses merits further study.

Linkage analysis for major histocompatibility complex-related genetic susceptibility in familial chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) shows evidence of familial aggregation, but the genetic basis is poorly understood. The existence of a linkage between HLA and Hodgkin lymphoma, another B-cell disorder, coupled with the fact that CLL is frequently associated with autoimmune disease, led to the question of whether the major histocompatibility complex (MHC) region is involved in familial cases of CLL. To examine this proposition, 5 microsatellite markers on chromosome 6p21.3 were typed in 28 families with CLL, 4 families with CLL in association with other lymphoproliferative disorders, and 1 family with splenic lymphoma with villous lymphocytes. There was no evidence of linkage in these families to chromosome 6p21.3. The best estimates of the proportions of sibling pairs with CLL that share 0, 1, or 2 MHC haplotypes were not significantly different from the null expectation. This implies that genes within the MHC region are unlikely to be the major determinants of familial CLL. (Blood. 2000;96:3982-3984)

A case of haemophagocytic syndrome and Kikuchi-Fujimoto disease occurring concurrently in a 17-year-old female.

An unusual case in which a young Asian female presenting with fever, lymphadenopathy and cytopaenia was found to have distinct histological features of both haemophagocytic syndrome (HS) and histiocytic necrotising lymphadenitis (Kikuchi-Fujimoto disease, KFD) is presented. We review the clinical features of each of these rare, but important, diagnoses and propose the hypothesis that they may form part of a disease continuum, rather than representing separate entities.

Effect of angiotensin-converting enzyme inhibition with perindopril and beta-blockade with atenolol on retinal blood flow in hypertensive diabetic subjects.

The effect of angiotensin-converting enzyme (ACE) inhibitors on the diabetic retinal circulation has not been studied previously. The aim of this study was to evaluate the effect of ACE inhibition and beta-blockade on retinal blood flow (RBF) in a group of 45 hypertensive diabetic subjects using a randomized double-blind trial over a period of 12 months. Laser Doppler velocimetry and computed image analysis were used to measure RBF. The changes in blood pressure over 12 months were comparable (perindopril [PE]: systolic [SBP] 152.1 +/- 3.3 and diastolic [DBP] 97.2 +/- 1.7 mm Hg to SBP 136.8 +/- 3.4 and DBP 85.8 +/- 2.1; atenolol: SBP 158.9 +/- 5.1 and DBP 97.5 +/- 1.6 mm Hg to SBP 137.9 +/- 3.4 and DBP 85.1 +/- 1.6; P = .607, mean +/- SEM). RBF decreased from 17.19 +/- 2.21 microL x min(-1) to 14.18 +/- 1.50 microL x min(-1) in the PE group (n = 15, P = .208) while it increased with atenolol from 15.80 +/- 1.24 microL x min(-1) to 16.99 +/- 1.18 microL x min(-1) (n = 17, P = .399). The comparison of percentage changes in RBF (PE -7.16% +/- 11.49%; atenolol, +15.31% +/- 9.51%) reached statistical significance (P < .05). There was an increase in RBF in 33.3% of subjects receiving PE and in 70.6% of those receiving atenolol. Similar trends were found for retinal conductance. There were no significant changes in the parameters of retinal vascular permeability. Albuminuria decreased to a greater degree with PE, but did not reach significance (PE, 112.1 +/- 39.5 mg/24 h to 88.6 +/- 30.5 mg/24 h; atenolol, 87.3 +/- 51.7 mg/24 h to 82.1 +/- 47.7 mg/24 h). This suggests that ACE inhibition therapy may promote a hemodynamic milieu in the hypertensive diabetic retinal circulation that serves to protect against the progression of diabetic retinopathy, whereas beta-blockade has the opposite effect.

Fludarabine, cytarabine, G-CSF and idarubicin (FLAG-IDA) for the treatment of poor-risk myelodysplastic syndromes and acute myeloid leukaemia.

Nineteen patients with high-risk myelodysplastic syndrome (MDS)/acute myeloid leukaemia (AML) received fludarabine, cytarabine, granulocyte-colony stimulating factor (G-CSF), and idarubicin chemotherapy (de novo MDS/MDS-AML, nine; relapsed/refractory MDS/AML, seven; therapy-related MDS, three). Median age was 44 years and median disease duration 10 months. 16/19 (84%) patients had abnormal cytogenetics with seven (37%) harbouring abnormalities of chromosome 7. 18/19 (94.7%) patients responded to FLAG-idarubicin with 12 (63%) achieving complete remission (CR) (< 5% blasts and normal cytogenetics). 7/9 (78%) patients with de novo MDS/MDS-AML achieved CR compared to 5/10 (50%) with alternative diagnoses. Response was associated with age < 50 years, disease duration < 3 months, and cytogenetics other than abnormalities of chromosome 7. Haemopoietic regeneration was rapid in most patients and there were no toxic deaths. Nine patients received a second course of chemotherapy, three have proceeded to allogeneic bone marrow transplant and three to autologous blood stem cell/bone marrow transplantation. Follow-up is short (median 10 months). 12/19 (63%) patients remain alive and 5/12 (42%) have relapsed at a median 5 months following CR achievement. FLAG-idarubicin was well tolerated. High rates of morphological and cytogenetic remission, especially in de novo MDS, offer a window of opportunity for assessment of autologous BMT in this group of diseases where no treatment except alloBMT has led to prolongation of survival.

Regional retinal blood flow and vascular autoregulation.

The temporal retina is larger than the nasal retina and contains the metabolically active fovea. The variation in the distribution of blood between the temporal and nasal retinal circulations was investigated in 15 healthy volunteers, and the autoregulatory capacity of the temporal and nasal circulations was quantitated using 60% oxygen in the inspired air. Retinal blood flow was determined from red cell velocity using laser Doppler velocimetry and retinal vessel diameter from retinal photographs using a digital image analysis system. Volume flow was lower in the nasal than the temporal circulation by 52.49% (p < 0.001). This is a consequence of both significantly smaller vessels (20.4%, p < 0.001) and slower blood velocity in the nasal circulation (24.64%, p = 0.003) compared with the temporal vessels. After breathing 60% oxygen for 10 minutes, there was significant vasoconstriction (temporal, 10.42 +/- 1.24%, p < 0.001; nasal, 7.66 +/- 1.48%, p < 0.001), slower red cell velocity (temporal, 27.10 +/- 3.92%, p < 0.001; nasal, 27.36 +/- 5.51%, p < 0.001) and a significant reduction in the volumetric flow rate (temporal, 41.16 +/- 3.64%, p < 0.001; nasal, 37.99 +/- 5.07%, p < 0.001). The reduction in the haemodynamic parameters was comparable in the temporal and nasal circulations, indicating similar autoregulatory capacity. Retinal vascular conductance was calculated from volume flow and retinal perfusion pressure. It was 53% larger in the temporal than the nasal circulations. This provides an index of the metabolic needs of the different regions of the retina.

Role of blood flow and impaired autoregulation in the pathogenesis of diabetic retinopathy.

Several mechanisms are implicated in the pathogenesis of diabetic retinopathy. They include biochemical, hemodynamic, and hormonal factors, all of which have an important role in the development of diabetic retinopathy. These factors are not independent of each other, but rather they interact and together are responsible for the well-known lesions of vascular occlusion, microaneurysms, hemorrhages' hard exudates, and eventually new vessel formation.

The effect of experimental hypertension on retinal vascular autoregulation in humans: a mechanism for the progression of diabetic retinopathy.

Since the retinal vessels have no sympathetic innervation, blood flow in response to raised blood pressure is dependent on autoregulation. To determine the effect of hypertension on retinal haemodynamics and the autoregulatory capacity of the retinal circulation under conditions of normoglycaemia and hyperglycaemia, retinal blood flow was measured before and after raising the systemic blood pressure in ten normal control subjects, ten diabetic subjects with blood glucose < 10 mmol l-1 and ten diabetic subjects with blood glucose > 15 mmol l-1. A controlled rise in systemic blood pressure was achieved using an intravenous infusion of tyramine. Retinal volume flow was determined from red cell velocity using laser Doppler velocimetry and from retinal vessel diameter measurements using digital image analysis of fundus photographs. With a 40% increase in mean arterial blood pressure (MAP), there was a significant increase in retinal blood flow of 32.9 +/- 7.1% in non-diabetic controls. In diabetics at the low blood glucose level, the increase in retinal blood flow was significant at 30% increase in MAP (23.6 +/- 8.7%, P = 0.032) and at 40% increase (49.9 +/- 12.03%, P = 0.004). Diabetics with high blood glucose failed to autoregulate at any of the increased levels of MAP (15% increase, 27.0 +/- 11.1%; 30% increase, 66.9 +/- 19.8%; and 40% increase, 101.9 +/- 21.4%; P < 0.022). The coefficients of autoregulation showed that in non-diabetic controls, retinal vascular autoregulation broke down with increases in MAP of between 30 and 40%. In diabetic subjects, it broke down between 15 and 30% in normoglycaemia and at less than 15% in hyperglycaemia. This study demonstrates an impairment in retinal vascular autoregulation in response to raised systemic blood pressure in diabetic subjects, more so at an elevated blood glucose level, thus providing a mechanism for the detrimental effect of hypertension on diabetic retinopathy.

Oxygen reactivity in diabetes mellitus: effect of hypertension and hyperglycaemia.

1. Laser Doppler velocimetry and computerized image analysis of retinal photographs were used to define retinal vascular autoregulation to 60% oxygen breathing. This normally causes vasoconstriction in the retinal circulation. Normotensive and hypertensive diabetic subjects were studied under conditions of relative normoglycaemia (< 10 mmol) and hyperglycaemia (> 15 mmol) together with control subjects. 2. Retinal blood flow was significantly higher in diabetic subjects when hypertensive and hyperglycaemic than in the same diabetic subjects when normotensive. 3. In the normotensive non-diabetic subjects the oxygen reactivity was 41.16 +/- 14.09%. It was significantly reduced in normotensive 'hyperglycaemic' diabetic subjects (21.75 +/- 15.56%), hypertensive diabetic subjects with controlled blood pressure and 'normoglycaemia' (30.49 +/- 14.20%), hypertensive diabetic subjects with controlled blood pressure and 'hyperglycaemia' (18.36 +/- 11.42%), hypertensive diabetic subjects with uncontrolled blood pressure and 'normoglycaemia' (26.91 +/- 13.43%) and hypertensive diabetic subjects with uncontrolled blood pressure and 'hyperglycaemia' (17.17 +/- 13.24%) (mean +/- SD, all P values < 0.05). 4. In conclusion, retinal vascular reactivity is impaired in diabetic subjects both when they are normotensive and when they are hypertensive. Hyperglycaemia, to a degree commonly encountered in clinical practice, impairs retinal vascular auto-regulation even further.

Effect of betaxolol on the retinal circulation in eyes with ocular hypertension: a pilot study.

This study investigated the effect of betaxolol, a beta 1 selective blocker, on the retinal circulation in 10 patients with ocular hypertension. In a masked randomised fashion, one eye of each subject received betaxolol and the fellow eye received placebo (hypromellose). Retinal blood flow (RBF) was determined in a major temporal vein of each eye just prior to instillation of drops and 2 h later, using laser Doppler velocimetry and monochromatic fundus photography. There was an increase of 15.0% in RBF (p = 0.03) in the betaxolol-treated eyes. No significant change was observed in the placebo-treated eyes. Intraocular pressure was reduced by 27.7% in the treated eyes, resulting in an increase of 16.9% in perfusion pressure (p = 0.02) compared with an 8.4% increase in placebo-treated eyes (p = 0.15). This study demonstrated that betaxolol increases RBF in eyes with ocular hypertension; this increase is probably related to the increase in perfusion pressure.

Vessel diameter changes during the cardiac cycle.

Retinal vessel diameter, which is an important parameter in blood flow measurement, is affected by pulsation during the cardiac cycle and by vasomotion. This project studied these changes by analysing three monochromatic fundus photographs taken in eight arbitrary parts of the cardiac cycle of 10 healthy subjects. It was found that the venous diameter decreased in early systole, increasing thereafter to a maximum level in early diastole and then declined towards end diastole. The maximum change of 4.82% (between early systole and early diastole) (p = 0.03) represents a 9.83% change in volumetric blood flow. The arterial diameter peaked in mid-late systole, increasing by 3.46% (p = 0.01); this represents a blood flow increase of 7.04%. Vasomotion led to changes of 3.71% and 2.61% in arteries and veins respectively. It is concluded that for accurate measurement of retinal blood flow, fundus photographs should be taken synchronised with the electrocardiogram.

Accurate vessel width measurement from fundus photographs: a new concept.

Accurate determination of retinal vessel width measurement is important in the study of the haemodynamic changes that accompany various physiological and pathological states. Currently the width at the half height of the transmittance and densitometry profiles are used as a measure of retinal vessel width. A consistent phenomenon of two 'kick points' on the slopes of the transmittance and densitometry profiles near the base, has been observed. In this study, mathematical models have been formulated to describe the characteristic curves of the transmittance and the densitometry profiles. They demonstrate the kick points being coincident with the edges of the blood column. The horizontal distance across the kick points would therefore indicate the actual blood column width. To evaluate this hypothesis, blood was infused through two lengths of plastic tubing of known diameters, and photographed. In comparison with the known diameters, the half height underestimated the blood column width by 7.33% and 6.46%, while the kick point method slightly overestimated it by 1.40% and 0.34%. These techniques were applied to monochromatic fundus photographs. In comparison with the kick point method, the half height underestimated the blood column width in veins by 16.67% and in arteries by 15.86%. The characteristics of the kick points and their practicality have been discussed. The kick point method may provide the most accurate measurement of vessel width possible from these profiles.

Idarubicin for remission induction of acute myeloid leukemia: United Kingdom multicenter experience.

Ninety-eight adult patients with acute myeloid leukemia were given variable remission induction/consolidation regimens containing idarubicin. Sixty-nine (70%) were new cases (median age, 56 years) and 29 (30%) were in relapse (n = 24) or had primary refractory disease (n = 5) (median age, 46 years). Complete remission (CR) rates were 57% (39 of 69 patients) of the newly diagnosed patients, with no difference for those below or above 55 years of age (56% v 59%) or for patients exhibiting white blood cell counts of less or more than 50 x 10(9)/L (52% v 69%; P = .8). Of the 39 patients who achieved CR, 26 (67%, 38% of the total number of patients) remain in CR with a median follow-up of 3 months (range, 0 to 61 months). Forty-two percent of the relapsed cases (10 of 24 patients) and 60% of the primary refractory disease cases (three of five patients) achieved CR. Of these 13 responders, six are alive (three continuing in CR and three relapsed) with a median follow-up of 3 months (range, 1 to 20 months), and seven have died with a median survival of 7 months (range, 0 to 12 months). Of the 52 patients who have achieved CR, 84% did so with one course of treatment and 16% with two courses. The presence of normal cytogenetic analysis or favorable chromosomal aberrations significantly improved overall CR rates. The patients in this study had significantly more unfavorable cytogenetic abnormalities than the historic controls. Reported toxicity was hepatic in 13%, cardiac in 9%, and renal in 7% of all cases. These data suggest a comparable efficacy of idarubicin to other anthracyclines in remission induction of acute myeloid leukemia, with a promising role in relapsed/refractory disease.

Successful allogeneic bone marrow transplantation in juvenile CML: conditioning or graft-versus-leukaemia effect?

Allogeneic BMT is the treatment of choice for juvenile CML (JCML). This has been successful following conditioning with cyclophosphamide (120 mg/kg) and total body irradiation (TBI) (10-15.75 Gy). However, busulphan (16 mg/kg) and cyclophosphamide (200 mg/kg) (Bu/Cy) conditioning has been reported to be insufficient to eradicate the malignant clone in JCML. We report successful BMT and eradication of the disease at 18 months follow-up in a child 15 months old at presentation, who was conditioned with busulphan 20 mg/kg and cyclophosphamide 200 mg/kg, with the addition of splenic irradiation. Despite using higher than conventional doses of busulphan, pharmacokinetic analysis revealed very low busulphan peak levels and rapid excretion. As a possible consequence, only partial chimerism was achieved, but full engraftment ensued following the discontinuation of cyclosporin A, rebound donor lymphocytosis and the onset of acute GVHD. We suggest that host resistance to engraftment and tumour elimination was overcome by removing a suppressive effect on donor lymphocytes, allowing a graft-versus-leukaemia effect.

The effect of acetazolamide on the retinal circulation.

The effect of the carbonic anhydrase inhibitor, acetazolamide, on the retinal circulation was studied in 10 healthy volunteers. Acetazolamide was administered intravenously at a dose of 500 mg. Retinal blood flow was determined from red cell velocity using laser Doppler velocimetry and vessel diameter measurement using computerised digital image analysis of monochromatic fundus photographs. There was a significant increase in retinal blood flow at 30 minutes and 60 minutes after acetazolamide injection (p = 0.002). Retinal vessels showed vasodilatation reaching significant levels 60 minutes after the injection (p < 0.03). An increase in red cell velocity was observed at 30 and 60 minutes (p < 0.002). A significant reduction in intraocular pressure occurred at 30 and 60 minutes after the injection (p < 0.001). The mechanisms responsible for the increase in retinal blood flow acted via significant increases in perfusion pressure (p < 0.05), red cell velocity (p < 0.002) and retinal vessel dilatation (p < 0.03). An increase in tissue PCO2 and a reduction in pH are thought to be responsible for the vascular dilatation. The increase in retinal blood flow with acetazolamide may serve to limit optic disc and retinal ischaemia in acute glaucoma and central retinal artery occlusion respectively.

Abnormalities of chromosome 16q in myeloid malignancy: 14 new cases and a review of the literature.

Fourteen patients with abnormalities of chromosome 16q, 13 with acute myelogenous leukaemia (AML), and one with refractory anaemia with excess of blasts (RAEB), are described. Seven patients had inv(16)(p13q22), two had del(16)(q22), and five had other abnormalities of 16q. Six of the seven patients with inv(16) had AML M4Eo and, following treatment with adriamycin, cytosine arabinoside, and 6-thioguanine, all achieved complete remission (CR). Neither patient with del(16)(q22) had typical M4Eo morphology at diagnosis; CR was achieved in one and one had resistant leukaemia. Patients with other abnormalities of 16q had blasts of diverse morphology and, although morphologically abnormal eosinophils were seen in three patients, this was not as marked as in the patients with inv(16). CR was achieved in two of the four patients with other abnormalities of 16q but duration of remission was short in both cases. These results suggest that most patients with del(16)(q22) and other abnormalities of 16q22 do not have typical AML M4Eo. Such patients tend to have a worse prognosis, and are more likely to have complex karyotypes typical of secondary leukaemia.

Retinal vessel measurement: comparison between observer and computer driven methods.

A method of semi-automated image analysis for the measurement of retinal vessel diameters is described. This was compared with an observer-driven method for reproducibility and accuracy. The coefficient of variation for the data from the semi-automated method was 1.5-7.5% (depending on the vessel diameter) compared to 6-34% with the observer-driven method. The mean vessel diameters using the observer-driven method tended to be higher; however, this did not reach significance. The speed and low inter- and intra-observer variability for the semi-automated method make it a useful technique for measuring retinal blood vessel diameters. A larger variability was found between photographs taken at different times. This may be due to changes in retinal vessel diameter with changes in retinal perfusion pressure during the cardiac cycle.

The effect of beta blockers on retinal blood flow in diabetic patients.

The effect of a single oral dose of propanolol 80 mg, dilevalol 200 mg, salbutamol 4 mg, and placebo on the systolic (BPs), diastolic blood (BPd), intraocular pressure (IOP), on retinal vessel diameter (D), blood velocity (Vmax) and volumetric retinal blood flow (RBF), was measured at baseline, 90 minutes and three hours after administration in normotensive diabetic volunteers. These drugs were chosen to demonstrate a range of beta receptor activity. Propanolol is a non-specific beta blocker, affecting beta 1 and beta 2 receptors, dilevalol has beta 1 antagonist and beta 2 agonist effects and salbutamol has beta 2 agonist effects. Retinal blood flow was measured by bidirectional laser Doppler velocimetry (BLDV) and red free photography. Dilevalol reduced the mean BPs by 10.4 mmHg (SD 4.2, P less than 0.05), the mean BPd by 7 mmHg (SD 3.8, P less than 0.05), whereas propanolol, salbutamol and placebo had no significant effect. Propanolol reduced the mean intraocular pressure by 4.88 mmHg (SD 1.8, P less than 0.01). No treatment had a significant effect on retinal perfusion pressure. In all treatments the vessel diameter and volumetric flow remained unchanged, and there was no significant difference between the treatments. The mechanisms of action of these drugs are analysed and the possible implications of their use in patients with retinal disease are discussed.