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Biomedical subjects

C Malm

Publications and source records attributed to C Malm.

At least 19 recordsLinked to original sources

High sustained efficacy of a prophylactic quadrivalent human papillomavirus types 6/11/16/18 L1 virus-like particle vaccine through 5 years of follow-up.

Human papillomavirus (HPV) causes cervical, vulvar, and vaginal cancers, precancerous dysplasia, and genital warts. We report data for the longest efficacy evaluation to date of a prophylactic HPV vaccine. In total, 552 women (16-23 years) were enrolled in a randomised, placebo-controlled study of a quadrivalent HPV 6/11/16/18 L1 virus-like-particle vaccine with vaccination at months 0, 2, and 6. At regular intervals through 3 years, subjects underwent gynaecologic examination, cervicovaginal sampling for HPV DNA, serum anti-HPV testing, and Pap testing, with follow-up biopsy as indicated. A subset of 241 subjects underwent two further years of follow-up. At 5 years post enrollment, the combined incidence of HPV 6/11/16/18-related persistent infection or disease was reduced in vaccine-recipients by 96% (two cases vaccine versus 46 placebo). There were no cases of HPV 6/11/16/18-related precancerous cervical dysplasia or genital warts in vaccine recipients, and six cases in placebo recipients (efficacy = 100%; 95% CI:12-100%). Through 5 years, vaccine-induced anti-HPV geometric mean titres remained at or above those following natural infection. In conclusion, a prophylactic quadrivalent HPV vaccine was effective through 5 years for prevention of persistent infection and disease caused by HPV 6/11/16/18. This duration supports vaccination of adolescents and young adults, which is expected to greatly reduce the burden of cervical and genital cancers, precancerous dysplasia, and genital warts.

Adolescent↗

Subcutaneous alemtuzumab vs ATG in adjusted conditioning for allogeneic transplantation: influence of Campath dose on lymphoid recovery, mixed chimerism and survival.

Sixty-nine consecutive patients (median age 54 years) were prospectively enrolled in a single-institution protocol for allogeneic transplantation with adjusted non-myeloablative fludarabine-melfalan-based conditioning including cyclosporin A and MMF, and one of three modes of serotherapy. Thirty-one donors (45%) were unrelated. The first cohort of 29 had ATG (Thymoglobulin 2 mg/kg x 3 days), the subsequent 26 had Campath 30 mg x 3 days subcutaneously, and the final cohort of 14 had 30 mg Campath once. The groups were similar as regards age, diagnosis and risk factors. Campath-patients had no acute toxicity, fewer days with fever and antibiotics, and required fewer transfusions than ATG-treated patients. 3-d-Campath patients showed lower lymphocyte counts from day +4, and CD4+, CD8+, CD19+ and NK cells recovered slower than in ATG-treated patients. More Campath patients developed mixed chimerism that required DLI. 3-d-Campath induced more serious and opportunistic infections than ATG, which resulted in a greater non-relapse mortality and an impaired overall survival despite a low tumor-related mortality. The change of the Campath dosing schedule to one dose abrogated the deleterious effect of 3-d-Campath on immune recovery, severe infections and survival. Subcutaneous Campath is simple and provides strong immune suppression with no early toxicity, but dose limitation to 30 mg once is recommended.

Adult↗

Infectious episodes before and after a marathon race.

The aim of this study was to investigate the incidence of self-reported infectious episodes (IE) during 3 weeks before (pre-IE) and 3 weeks after (post-IE) a marathon race and relate these figures to training status, running time, socioeconomic and demographic factors. Two questionnaires, including questions about important factors for IE incidence, were given to a representative cohort of 1694 runners (17% of all finishers) in the Stockholm Marathon 2000. Pre-IE incidence in the cohort was 17% with no difference between women and men. Post-IE incidence in the whole cohort was 19% with no significant (P>0.05) difference between women and men. The post-IE incidence in runners without a pre-IE was 16% (P>0.05 to pre-IE incidence). In the group of runners with pre-IE, 33% experienced an IE after the race also (P<0.05 to Pre-IE incidence). A logistic regression analysis showed that younger age and pre race health status and, for men only, experienced nausea during and after the race were depended factors explaining post-IE incidence. Younger runners were more prone to experience IE both before and after the race. There was no relation between training volume 6 months before the race, finishing time and socioeconomic and demographic factors and pre-IE or post-IE. This study does not support the theory of increased infection rate after exhaustive long-distance running ("The Open Window Theory") in recreational runners, but suggests that the sometimes experienced increased rate of infections among athletes can be caused by strenuous exercise too soon after an infection.

Adult↗

Susceptibility to infections in elite athletes: the S-curve.

The susceptibility to upper respiratory tract infections (URTIs) after physical exercise has been described with a J-shaped curve, suggesting protection from infections with moderate exercise and increased risk for URTI's in elite athletes. Several factors such as time of inoculation, previous infections, pathogen exposure, other stressors than exercise etc. can influence infection outcome. Observed infections in athletes can, therefore, be either the result of increased susceptibility to a novel pathogen, or more severe symptoms of an already established infection. Moreover, the definitions of "strenuous" exercise and "elite" athletes are equivocal, making comparisons between studies difficult. Because absence of infections is inevitable to become and maintain status as an elite athlete, it is suggested that there is an S-shaped relationship between exercise load and risk of infections. To become an elite athlete one has to possess state-of-the-art physique, including an immune system able to withstand infections even during severe physiological and psychological stress.

Disease Susceptibility↗

Immune system alteration in response to two consecutive soccer games.

AIM: Changes in leucocyte and monocyte subpopulations were investigated in 10 elite male soccer players aged 16-19 years. The purpose was to perform a descriptive study of immunological alterations in elite soccer players in response to two consecutive games separated by 20 h. It was hypothesized that in response to two games the players would show signs of short-term immunosuppression. METHODS: Blood samples were taken before the first soccer game, immediately after the second game and after 6, 24, 48 and 72 h. Cell surface antigens, testosterone and cortisol were investigated. RESULTS: During the first 6 h after the second game there was a significant increase in number of circulating neutrophils, mature (CD20+ CD5+) B cells and CD4/CD8 ratio. A significant decrease was observed in the number of natural killer (NK) cells, monocytes and adhesion on lymphocytes and monocytes. In a delayed phase, 48 h after the second game the expression of both adhesion and signalling molecules increased on lymphocytes and monocytes. Changes in adhesion and signalling molecules at 48 h correlated negatively to the subjects VO2max, suggesting larger immunological response to similar exercise in subjects with lower aerobic exercise capacity. CONCLUSION: In response to competitive soccer exercise some immunological variables are enhanced while others are depressed. Observed changes may serve a purpose in adaptation to exercise by signalling via adhesion.

Adolescent↗

Immune system alteration in response to increased physical training during a five day soccer training camp.

Leukocyte and monocyte subpopulations were investigated in ten elite male soccer players before and after a 5-day training camp. It was hypothesized that with increased training intensity and duration, the immune system would show signs of depression. Blood samples were taken at rest before and after the training camp and cell surface antigens were investigated by four-colour flow cytometry. After five days of intensified training, there was a significant decrease in the number of T helper, T cytotoxic and B cells, the expression of CD11 b on leukocytes increased and the NK cell population did not change significantly. It is concluded that after a period of intensified training, soccer players may experience decreased T and B cell numbers in circulation, possibly affecting their capability to activate the immune system and resist infections. However, in contrast to the acute decrease in the number of circulating NK cells commonly observed after physical exercise, no change in this cell population was observed at rest after a period of intensified physical training. Exercise-induced immunological changes were highly differentiated between different leukocyte subpopulations.

Adult↗

Acute myeloid leukemia with inv(16)(p13q22): involvement of cervical lymph nodes and tonsils is common and may be a negative prognostic sign.

Acute myeloid leukemia (AML) with inv(16)(p13q22) or the variant t(16;16)(p13;q22), is strongly associated with the FAB subtype M4Eo. A high incidence of CNS involvement was reported in the 1980s, but otherwise little is known about the pattern of extamedullary leukemia (EML) manifestations in this AML type. We have compiled clinical and cytogenetic data on 27 consecutive AML cases with inv(16)/t(16;16) from southern Sweden. In general, these AMLs displayed the clinical features that have previously been described as characteristic for this disease entity: low median age, hyperleukocytosis, M4Eo morphology, and a favorable prognosis. However, CNS leukemia was only seen in relapse in one patient diagnosed in 1980, whereas the most common EML manifestation in our series was lymphadenopathy (5/27, 19%), most often cervical with or without gross tonsillar enlargement. A review of previously published, clinically informative cases corroborates that lymphadenopathy, with preference for the cervical region, is the most common EML at diagnosis in inv(16)-positive AML (58/175, 33%). CNS leukemia, on the other hand, has been reported in only 17% of the cases, mostly in the relapse setting, with a diminishing frequency over time, possibly due to protective effects of high-dose cytarabine. Other reported EML sites include the scalp, ovaries, and the intestine. Cervicotonsillar EML was in our series associated with a shorter duration of first remission, (P < 0.05), and may hence prove to be an important clinical parameter when deciding treatment strategies in AML with inv(16)/t(16;16).

Adult↗

Long-term endoscopic remission of crohn disease after autologous stem cell transplantation for acute myeloid leukaemia.

A favourable course of Crohn disease has been observed after allogeneic bone marrow transplantation. and there is now mounting evidence that autologous stem cell may be an effective treatment for severe autoimmune diseases. Here, we present the first long-term endoscopic follow-up of a patient with Crohn disease undergoing autologous stem cell transplantation for haematological disease. A 54-year-old woman developed Crohn disease and was submitted to ileocaecal resection. Four months after surgery, the patient contracted acute myeloid leukaemia. She was initially treated with chemotherapy, and subsequently underwent autologous stem cell transplantation. Following transplantation, the patient has remained in clinical remission regarding both diseases, without anti-inflammatory medication. She has undergone ileo-colonoscopy with normal findings at 1, 2, 3 and 5 years after transplantation. This case suggests that autologous stem cell transplantation can change not only the clinical course, but also the natural history of intestinal inflammation in Crohn disease. This has pathophysiological as well as therapeutic implications.

Crohn Disease↗

Exercise-induced muscle damage and inflammation: fact or fiction?

Physical exercise is necessary for maintaining normal function of skeletal muscle. The mechanisms governing normal muscle function and maintenance are vastly unknown but synergistic function of hormones, neurosignalling, growth factors, cytokines and other factors, is undoubtedly important. Because of the complex interaction among these systems the lack of complete understanding of muscle function is not surprising. The purpose of exercise-induced changes in muscle cell function is to adapt the tissue to a demand of increased physical work capacity. Some of the approaches used to investigate changes in skeletal muscle cell function are exercise and electrical stimulation in animals and human models and isolated animal muscle. From these models, it has been concluded that during physical exercise, in an intensity and duration dependent manner, skeletal muscle is damaged and subsequently inflamed. The purpose of the inflammation would be to repair the exercise-induced damage. Because of the design and methods used in a majority of these studies, concerns must be raised, and the question asked whether the paradigm of exercise-induced muscle inflammation in fact is fiction. In a majority of conducted studies, a non-exercising control group is lacking and because of the invasive nature of the sampling methods used to study inflammation it does not appear impossible that observed inflammatory events in human skeletal muscle after physical exercise are methodological artefacts.

Adaptation, Physiological↗

Effect of eccentric exercise on muscle oxidative metabolism in humans.

PURPOSE: The purpose of this study was to evaluate the effects of eccentric exercise on muscle oxidative function. METHODS: Thirteen subjects performed high-intensity eccentric cycling for 30 min. Muscle oxidative function in vastus lateralis was evaluated by measurements of respiration in permeabilized muscle fibers (skinned fibers) and from the kinetics of oxyhemoglobin (oxyHb) saturation measured with near infrared spectroscopy (NIRS). RESULTS: After eccentric cycling, all subjects reported extensive delayed onset muscle soreness (DOMS), but plasma markers of muscle damage (creatine kinase and beta-glucuronidase activity) were not significantly altered. The half time of oxyHb desaturation after circulatory occlusion (128 +/- 11 s, mean +/- SE) and oxyHb resaturation after restoration of blood flow (13.8 +/- 0.7 s) were not significantly changed after eccentric cycling (N = 7). Respiration in skinned muscle fibers measured in the absence of ADP and in the presence of a submaximal (0.1 mM) or maximal ADP concentration (1 mM) was not significantly changed after eccentric cycling (N = 6). The sensitivity of respiration to ADP was not significantly changed after eccentric cycling. CONCLUSIONS: Muscle oxidative function (maximal respiration and respiratory control by ADP) was not compromised after high-intensity eccentric cycle exercise. Furthermore, NIRS indicates that after eccentric cycling muscle oxygen utilization and local oxygen transport at rest are unchanged. It is concluded that eccentric cycling, although causing DOMS, does not negatively affect skeletal muscle oxidative function.

Adult↗

Immunological changes in human skeletal muscle and blood after eccentric exercise and multiple biopsies.

1. A role of the immune system in muscular adaptation to physical exercise has been suggested but data from controlled human studies are scarce. The present study investigated immunological events in human blood and skeletal muscle by immunohistochemistry and flow cytometry after eccentric cycling exercise and multiple biopsies. 2. Immunohistochemical detection of neutrophil- (CD11b, CD15), macrophage- (CD163), satellite cell- (CD56) and IL-1beta-specific antigens increased similarly in human skeletal muscle after eccentric cycling exercise together with multiple muscle biopsies, or multiple biopsies only. 3. Changes in immunological variables in blood and muscle were related, and monocytes and natural killer (NK) cells appeared to have governing functions over immunological events in human skeletal muscle. 4. Delayed onset muscle soreness, serum creatine kinase activity and C-reactive protein concentration were not related to leukocyte infiltration in human skeletal muscle. 5. Eccentric cycling and/or muscle biopsies did not result in T cell infiltration in human skeletal muscle. Modes of stress other than eccentric cycling should therefore be evaluated as a myositis model in human. 6. Based on results from the present study, and in the light of previously published data, it appears plausible that muscular adaptation to physical exercise occurs without preceding muscle inflammation. Nevertheless, leukocytes seem important for repair, regeneration and adaptation of human skeletal muscle.

Adult↗

Frequent good partial remissions from thalidomide including best response ever in patients with advanced refractory and relapsed myeloma.

Twenty-three patients with advanced and heavily pretreated myeloma were treated with thalidomide. Starting dose was 200 mg/d, and 20 patients had dose escalations up to 400 (n = 5), 600 (n = 12) or 800 mg/d (n = 3), usually in divided doses. Nineteen patients were refractory to recent chemotherapy, and four had untreated relapse after prior intensive therapy. Ten out of 23 patients (43%) achieved partial response (PR; nine with refractory and one with relapsed disease), six patients had minor response or stabilization of the disease and four had disease progression. Another three patients died early from advanced myeloma at less than 3 weeks of thalidomide therapy. Of the 10 patients with PR, seven had a better response than after any prior therapy, despite vincristine-doxorubicin-dexamethasone (VAD)-based treatment in all but one and high-dose melphalan with autologous stem cell support in four. Time to achieve PR was rapid in patients receiving thalidomide in divided doses (median 31 d). Responses also included reduced bone marrow plasma cell infiltration and improved general status. Normalized polyclonal gammaglobulin levels were seen in four cases. Six out of 10 patients with PR remained in remission with a median time on treatment of 23 weeks (range 15-50 weeks). Sedation was common but usually tolerable, and some patients continued full- or part-time work. Four patients had skin problems, three patients had pneumonia, one hypothyrosis, one sinus bradycardia and one minor sensory neuropathy. Thalidomide may induce good partial remissions in advanced refractory myeloma with tolerable toxicity, and should be evaluated in other settings for myeloma patients. Divided thalidomide doses seem to reduce time to achieve remission and may improve response rate.

Adult↗

Effect of Q10 supplementation on tissue Q10 levels and adenine nucleotide catabolism during high-intensity exercise.

The aim of the present study was to investigate the concentration of ubiquinone-10 (Q10), at rest, in human skeletal muscle and blood plasma before and after a period of high-intensity training with or without Q10 supplementation. Another aim was to explore whether adenine nucleotide catabolism, lipid peroxidation, and mitochondrial function were affected by Q10 treatment. Seventeen young healthy men were assigned to either a control (placebo) or Q10-supplementation (120 mg/day) group. Q10 supplementation resulted in a significantly higher plasma Q10/total cholesterol level on Days 11 and 20 compared with Day 1. There was no significant change in the concentration of Q10 in skeletal muscle or in isolated skeletal muscle mitochondria in either group. Plasma hypoxanthine and uric acid concentrations increased markedly after each exercise test session in both groups. After the training period, the postexercise increase in plasma hypoxanthine was markedly reduced in both groups, but the response was partially reversed after the recovery period. It was concluded that Q10 supplementation increases the concentration of Q10 in plasma but not in skeletal muscle.

Adenine Nucleotides↗

Effects of eccentric exercise on the immune system in men.

The effects of eccentric exercise on changes in numbers of circulating leukocytes, cell activation, cell adhesion, and cellular memory function were investigated in 12 men, aged 22-35 yr. The immunologic effects of postexercise epidermal treatment with monochromatic, infrared light were also evaluated. Blood was drawn before and 6, 24, and 48 h after exercise for phenotyping and analysis of creatine kinase activity. There was an increase in leukocyte, monocyte, and neutrophil number, no change in the number of basophils, eosinophils, B cells, and T cells, and a decrease in natural killer cell number postexercise. Some markers of lymphocyte and monocyte activation remained unchanged or decreased, whereas the expression of adhesion molecules 62L and 11b increased on monocytes. It is concluded that eccentric exercise induced decreased activation, and increased cell adhesion capacity, of monocytes. Altered trafficking of cells between lymphoid tissue and blood, selective apoptosis, or attachment/detachment from the endothelial wall can explain the observed phenotypic changes. Treatment with monochromatic, infrared light did not significantly affect any of the investigated variables. Correlations between immunologic and physiological parameters indicate a role of the immune system in adaptation to physical exercise.

Adult↗

Cytogenetic polyclonality in hematologic malignancies.

The present study was undertaken to ascertain the frequency of cytogenetic polyclonality in various hematologic malignancies and to investigate whether morphologic subgroup, age, gender, or previous genotoxic exposure influences the incidence. Among 2,243 cytogenetically investigated hematologic malignancies, 10 acute myeloid leukemias (AML), 5 myelodysplastic syndromes (MDS), 2 acute lymphoblastic leukemias (ALL), 1 acute undifferentiated leukemia (AUL), 1 atypical Philadelphia chromosome-negative (Ph-) chronic myeloid leukemia (CML), 1 chronic myeloproliferative disorder (CMD), and 1 chronic lymphoproliferative disorder (CLD) with karyotypically unrelated clones were identified, constituting 2.6% of AML, 1.6% of MDS, 0.8% of ALL, 13% of AUL, 9.1% of Ph- CML, 1.5% of CMD, and 2.8% of CLD with chromosomal abnormalities. In contrast to the cytogenetic features, the X-inactivation pattern was monoclonal in the two informative female patients that could be investigated. Among 17,733 karyotypically aberrant published cases surveyed, significant frequency differences (P < 0.001) were discerned: 1.7% of 6,526 AML, 3.4% of 2,391 MDS, 0.4% of 1,920 Ph+ CML, 2.9% of 856 CMD, 0.9% of 4,226 ALL, and 5.8% of 1,814 CLD displayed unrelated clones. The incidence of cytogenetic polyclonality did not differ significantly among the MDS, CMD, or ALL subgroups, between males and females, between children (< 16 years) and adults, or between B- and T-cell ALL, whereas the frequencies varied among the AML FAB types (P < 0.05), among the different CLD entities (P < 0.001), and between B- and T-cell CLD (P < 0.001). Furthermore, the incidence was higher in therapy-related AML and MDS than in de novo AML and MDS (P < 0.001 and P < 0.01, respectively).

Adolescent↗

Deletion of chromosome arm 3p in hematologic malignancies.

Cytogenetic aberrations resulting in deletion of 3p are common in solid tumors, indicating the presence of tumor suppressor genes (TSG) on this chromosome arm. The present study was undertaken to investigate 3p loss in hematologic disorders. Ten acute myeloid leukemias (AML), two myelodysplastic syndromes (MDS), one Philadelphia chromosome-positive chronic myeloid leukemia (CML), three acute lymphoblastic leukemias (ALL), one chronic lymphoproliferative disorder (CLD), and three non-Hodgkin's lymphomas (NHL) with abnormalities leading to 3p deletions were identified, constituting 2.9% of AML, 0.7% of MDS, 1.0% of CML with changes in addition to t(9;22), 1.5% of ALL, 4.2% of CLD, and 1.1% of NHL with cytogenetic abnormalities analyzed at our Department. Among 19042 karyotypically aberrant published cases, 1.2% of 6260 AML, 1.3% of 2285 MDS, 0.8% of 840 chronic myeloproliferative disorders (CMD), 0.7% of 1894 CML with additional aberrations to t(9;22), 0.6% of 3589 ALL 2.4% of 1602 CLD, 4.5% of 178 Hodgkin disease (HD), and 3.1% of 2394 NHL displayed partial loss of 3p (0.6-4.5%; P < 0.001); the majority occurring together with other abnormalities. The frequencies of 3p loss did not differ significantly among the MDS, ALL, and CLD morphologic subgroups, between B and T cell ALL, CLD, and NHL, among low-, intermediate-, and high-grade NHL, or between therapy-related MDS and de novo MDS, whereas the incidence of 3p deletions was higher in treatment-associated AML (P < 0.001) than in de novo AML and varied among the AML FAB groups (P < 0.001). The most frequently deleted chromosome bands were 3p25 in AML, 3p26 in MDS, 3p14 in CMD, 3p25, 3p23, and 3p21 in CML, 3p26 and 3p25 in ALL, 3p26 and 3p25 in CLD, 3p26 in HD, and 3p26 in NHL. These deletion hot spots are more distal than those reported in most solid tumor types, suggesting that different TSG are involved in hematologic malignancies and solid neoplasms.

Chromosome Aberrations↗

Effects of ubiquinone-10 supplementation and high intensity training on physical performance in humans.

This study investigated the effects of oral supplementation with ubiquinone-10 (Q10) (n = 9) compared with a placebo (n = 9) on aerobic and anaerobic physical performance over 22 days of supplementation. The supplementation period included 5 days of high intensity anaerobic training between days 11 and 14. The results demonstrated, that on an anaerobic (10 x 10 s) cycling test, the placebo group showed a significantly greater improvement than the Q10-group after a supplementation and training period (P < 0.001). Further, the Q10 group had a significantly lower increase in total work performed during the seven training sessions (15 x 10 s) compared with the placebo group (P < 0.001). There was a significant increase in maximal blood lactate accumulation during cycling in the both groups, when compared with levels before the training and recovery period. There was no significant difference between the groups, either in VO2max determined during running, or in submaximal and peak VO2, Rate of Perceived Exertion, respiratory quotient, blood lactate concentration or heart rate determined during submaximal and maximal cycling. Although insignificant (P = 0.1-0.3), there was evidence of higher submaximal VO2 (55-80% of VO2peak) during cycling in the Q10-group compared with the placebo group after training and recovery. It is concluded that with high intensity anaerobic training, there was a significantly greater increase in anaerobic performance in the placebo group compared with the Q10 group. The results suggest less increase in physical performance with Q10 supplement and high intensity anaerobic training, compared with placebo.

Adult↗

Poor survival in t(8;21) (q22;q22)-associated acute myeloid leukaemia with leukocytosis.

Twenty-nine consecutive cases with a t(8;21)(q22;q22) in the bone marrow (BM) karyotype were retrospectively studied concerning clinical, morphological and cytogenetic data. All had been diagnosed as acute myeloid leukaemia (AML), 27 FAB subtype M2 and two M1, comprising 5% of all cytogenetically analysed AML during 18 yr. Auer rods were the most consistent t(8;21)-associated morphological finding and were demonstrated in 92% of the reviewed BM specimens, whereas BM eosinophilia was seen in only 24%. The median age was 53 yr, and 30% of the patients were > 60 yr old. Twenty-four patients had received induction chemotherapy; 22 of these (91%) entered a complete remission (CR). The median survival time in treated patients was 18 months. Leukocytosis at diagnosis (> or = 20 x 10(9)/1) was significantly (p = 0.01) associated with shorter survival time. All four children are still in first CR after 9-80 months. Seven cases (25%) developed granulocytic sarcomas, discovered either at diagnosis (n = 4) or at first relapse (n = 3). Secondary chromosome abnormalities were found in 62% of the cases, most often loss of a sex chromosome. The presence of such secondary aberrations did not correlate with any morphological or clinical characteristics, including survival. This first Scandinavian study of AML with t(8;21) corroborates the previous findings that these AMLs are characterized by distinct morphological features, a high frequency of CR and a striking tendency to develop extramedullary leukaemic manifestations. Leukocytosis at diagnosis indicates a less favourable prognosis.

Adolescent↗