Two cycles of escalated BEACOPP followed by four cycles of ABVD utilizing early-interim PET/CT scan is an effective regimen for advanced high-risk Hodgkin's lymphoma.

BACKGROUND: Escalated combination therapy with bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone (escBEACOPP) regimen is superior to cyclophosphamide, vincristine, procarbazine and prednisone alternating with doxorubicin, bleomycin, vinblastine and dacarbazine (COPP-ABVD) for advanced-stage Hodgkin's lymphoma (HL) patients. However, the original schedule of eight cycles of escBEACOPP was associated with significant toxicity. This study was conducted in an attempt to reduce the toxicity of the original schedule, while attempting to preserve improved initial tumor control. PATIENTS AND METHODS: Forty-five newly diagnosed patients with advanced-stage HL and International Prognostic Score > or = 3 received two initial cycles of escBEACOPP and then were evaluated by positron emission tomography (PET)/computed tomography scan. If a good imaging response was obtained, they were treated by four cycles of ABVD. RESULTS: Following the first two cycles of escBEACOPP, the overall response was 100% and at the end of all therapy, 40 (89%) patients were in complete response (disappearance of all clinical evidence of disease and PET negativity), three (7%) in partial response (PET-positive residual lesions and a size reduction of the majority of large masses by >50%), while two (4%) had progressive disease. After a median follow-up of 48 months, progression-free survival (PFS) and overall survival at 4 years were 78% and 95%, respectively. The 4-year PFS for early PET-negative patients (n = 31) and early PET-positive patients (n = 13) were 87% and 53%, respectively (P = 0.01). CONCLUSIONS: These data indicate that combined escBEACOPP-ABVD may improve the outcome in patients with high-risk advanced HL. The potential benefit of early-interim PET activity as a guide to continuing therapy in these patients merits further study in the future.

Chronic autoimmune thyroiditis in children and adolescents: at presentation and during long-term follow-up.

OBJECTIVE: To investigate the clinical manifestations of autoimmune thyroiditis (AIT) leading to referral in children and adolescents, in addition to disease course and long-term outcome. DESIGN: Chart review. SETTING: Major tertiary hospital. PATIENTS: 114 children/adolescents (92 female, 22 male; mean (SD) age 11.8 (35) years) with AIT referred for evaluation/treatment. MAIN OUTCOME MEASURES: Clinical characteristics at presentation, reasons for referral, treatment and long-term (mean 6 years) outcome; by thyroid and pubertal status. RESULTS: The male/female (1:4.2) ratio was lower than in adult AIT (1:10) and varied by age. Patients with noticeable goitre at presentation (39.5%) accounted for half the total number in whom goitre was eventually diagnosed. Other reasons for referral were clinical symptoms of hypothyroidism (28.9%) and findings on work-up for an unrelated problem (19.2%) or for high-risk groups (10.5%). There was no difference in management or outcome between patients who underwent ultrasound (n = 79) or not. Treatment was initiated shortly after diagnosis in all 42 hypothyroid patients and 44/48 compensated hypothyroid patients, and within 16 months in 19/24 euthyroid patients. There was no change in thyroid status in the nine untreated patients. Height standard deviation score (SDS) was normal at referral and last visit and correlated with parental height SDS. Puberty was normal. There was no significant difference in body mass index SDS at referral by pubertal or thyroid status. There was no difference from the general population in the prevalence of obesity. CONCLUSIONS: Although goitre is the main symptom leading to diagnosis of AIT, it is still often overlooked, underscoring the need for thorough thyroid evaluation on routine physical examination. Acquired hypothyroidism is not often associated with obesity, and ultrasound usually has no added diagnostic value. Adequate treatment in this age group leads to normal growth, puberty and final height.

Regenerative effect of neural-induced human mesenchymal stromal cells in rat models of Parkinson's disease.

BACKGROUND: Human bone marrow multipotent mesenchymal stromal cells (hMSC), because of their capacity of multipotency, may provide an unlimited cell source for cell replacement therapy. The purpose of this study was to assess the developmental potential of hMSC to replace the midbrain dopamine neurons selectively lost in Parkinson's disease. METHODS: Cells were isolated and characterized, then induced to differentiate toward the neural lineage. In vitro analysis of neural differentiation was achieved using various methods to evaluate the expression of neural and dopaminergic genes and proteins. Neural-induced cells were then transplanted into the striata of hemi-Parkinsonian rats; animals were tested for rotational behavior and, after killing, immunohistochemistry was performed. RESULTS: Following differentiation, cells displayed neuronal morphology and were found to express neural genes and proteins. Furthermore, some of the cells exhibited gene and protein profiles typical of dopaminergic precursors. Finally, transplantation of neural-induced cells into the striatum of hemi-Parkinsonian rats resulted in improvement of their behavioral deficits, as determined by apomorphine-induced rotational behavior. The transplanted induced cells proved to be of superior benefit compared with the transplantation of naive hMSC. Immunohistochemical analysis of grafted brains revealed that abundant induced cells survived the grafts and some displayed dopaminergic traits. DISCUSSION: Our results demonstrate that induced neural hMSC may serve as a new cell source for the treatment of neurodegenerative diseases and have potential for broad application. These results encourage further developments of the possible use of hMSC in the treatment of Parkinson's disease.

Severe factor XI deficiency caused by a Gly555 to Glu mutation (factor XI-Glu555): a cross-reactive material positive variant defective in factor IX activation.

During normal hemostasis, the coagulation protease factor (F)XIa activates FIX. Hereditary deficiency of the FXIa precursor, FXI, is usually associated with reduced FXI protein in plasma, and circulating dysfunctional FXI variants are rare. We identified a patient with < 1% normal plasma FXI activity and normal levels of FXI antigen, who is homozygous for a FXI Gly555 to Glu substitution. Gly555 is two amino acids N-terminal to the protease active site serine residue, and is highly conserved among serine proteases. Recombinant FXI-Glu555 is activated normally by FXIIa and thrombin, and FXIa-Glu555 binds activated factor IX similarly to wild type FXIa (FXIa(WT)). When compared with FXIa(WT), FXIa-Glu555 activates factor IX at a greatly reduced rate ( approximately 400-fold), and is resistant to inhibition by antithrombin. Interestingly, FXIa(WT) and FXIa-Glu555 cleave the small tripeptide substrate S-2366 with comparable k(cat)s. Modeling indicates that the side chain of Glu555 significantly alters the electrostatic charge around the active site, and would sterically interfere with the interaction between the FXIa S2' site and the P2' residues on factor IX and antithrombin. FXI-Glu555 is the first reported example of a naturally occurring FXI variant with a significant defect in FIX activation.

Laparoscopic splenectomies for idiopathic thrombocytopenic purpura: experience of sixty cases.

We performed a laparoscopic splenectomy (LS) in 60 patients (age 9-83, 45 females) with idiopathic thrombocytopenic purpura (ITP) who did not achieve sustained remission on steroid therapy. Using a modified procedure, the mean duration of LS was 78 min (range 25-240 min) and surgery was associated with only 5% major and 5% minor complications. Ten patients had a platelet count less than 50 x 10(9)/l during surgery despite the administration of immune globulin (0.4 g/kg x 3-5 days) or pulsed oral dexamethasone (40 mg/day x 4 days). Three patients were refractory to these therapies and underwent LS with a platelet count less than 5 x 10(9)/l. Bleeding complications during or after surgery were rare (5%). Accessory spleens were removed in eight patients. Convalescence was rapid and the mean hospital stay was 2.3 days (range 1-7 days). The patients were followed for a mean of 16 months (range 1-36 months), and 49 patients (84%) are in complete remission. Seven patients (12.5%) relapsed despite an initial good response in 6 of them. Two patients underwent laparoscopic removal of accessory spleens with excellent response. We conclude that LS for ITP is safe and effective and associated with low morbidity and fast recovery. Thus, LS may be considered earlier in the course of ITP.

High-dose dexamethasone for splenectomy in patients with idiopathic thrombocytopenic purpura.

High-dose intravenous immune globulin (IV IgG) is currently the treatment of choice for patients with idiopathic thrombocytopenic purpura (ITP) who undergo splenectomy; however, this treatment is extremely expensive. We report on 13 ITP patients with severe thrombocytopenia (<20 x 10(9)/l) who were prepared for laparoscopic splenectomy with a 4-day oral course of high-dose (40 mg/day) dexamethasone (DEX). Four patients had an excellent response with platelet counts that increased to above 150 x 10(9)/l. Seven patients had a good response with a platelet count that increased to between 50 and 150 x 10(9)/l (median 121 x 10(9)/l). Two patients were resistant both to DEX and IV IgG. The operation was uneventful in all the patients, including the 2 who had resistant ITP and were operated on while their platelet count was very low (5 x 10(9)/l). Thus, high-dose DEX, which is an easy, effective and inexpensive treatment, is recommended for the preparation of ITP patients prior to splenectomy.

[Pulsed high-dose dexamethasone in resistant immune thrombocytopenic purpura].

Most patients with chronic idiopathic thrombocytopenic purpura (TTP) show a good initial response to treatment with corticosteroids. However the disease relapses in more than 90% when steroid dosage is reduced. Recently 100% success was reported for a new therapeutic protocol in 12 patients (ranging in age from 13-60, half of them women) with chronic ITP refractory to corticosteroids or to splenectomy. They were given pulsed therapy with oral dexamethasone, 40 mg/day on 4 consecutive days each month, for 6 months. This treatment protocol was used in an attempt to avoid splenectomy. 5 patients (42%) had a complete response but 7 did not. The median follow-up in those who responded was 7 months (range 6-8). Of the 7 who did not respond, 5 had not completed treatment: 3 because of urgent splenectomy and 2 because of lack of response after 3 courses of therapy accompanied by side-effects. Most patients suffered typical corticosteroid side-effects, principally restlessness, insomnia, and withdrawal effects. These were milder and better tolerated in those treated with Dexacort solution (20 mg ampules) rather than dexamethasone tablets. Despite complete response in only 5 of the 12 patients (42%), we feel that pulsed high-dose dexamethasone is effective and should be tried in TTP refractory to conventional corticosteroid therapy, before resorting to splenectomy.

Extensive bone marrow necrosis associated with antiphospholipid antibodies.

Bone marrow necrosis (BMN), defined morphologically by destruction of hematopoietic tissue, including the stroma, with preservation of the bone, is a rare syndrome. The conditions in which it is seen include sickle cell disease, acute leukemia, metastatic neoplasia, and bacterial infection, particularly when hypovolemia and septic shock are present. BMN is also associated with disseminated intravascular coagulation (DIC) following irradiation and antineoplastic therapy. The antiphospolipid syndrome (APS) is characterized by antibodies directed against the antiphospolipid substrate. Because this substrate is prominently involved in the coagulation cascade and widely distributed on cell walls, patients present with venous or arterial thromboses, recurrent abortion, thrombocytopenia, and Coombs' positive hemolytic anemia, typically with raised anticardiolipin antibodies or a diagnostic lupus anticoagulant test. BMN does not appear to have been previously recognized in this context. We report what we believe to be the first such case and suggest that the high titers of antibodies present may have played a central role in its pathogenesis.

[Conservative treatment of hemophiliac bleeding].

Since the introduction of home-care replacement therapy for hemophilic patients, life-endangering spontaneous bleeding is rare. We describe a 15-year-old boy with severe hemophilia, who without antecedent trauma developed massive abdominal bleeding and hemothorax, leading to hypovolemic shock. Although an operation was advised, intensive conservative replacement therapy and drainage of the thorax led to complete recovery. We stress that in the absence of acute trauma, bleeding due to hemophilia consists of oozing, so conservative treatment is recommended.

[Torecan-induced neuroleptic malignant syndrome].

Neuroleptic malignant syndrome (NMS) is an uncommon, life-threatening complication of treatment with neuroleptic drugs. Its main features are hyperthermia, extrapyramidal signs, and autonomic instability with fluctuating consciousness. It is believed that NMS is related to dopamine receptor blockade in the brain. We describe a case in a 52-year-old diabetic woman who developed NMS after taking Torecan (thiethylperazine), a phenothiazine drug, for 3 months to relieve dizziness. It is important to recognize this syndrome early and to treat immediately.

Severe hypophosphatemia in hospitalized patients.

Severe hypophosphatemia (serum phosphorus less than or equal to 0.48 mmol/L [less than or equal to 1.5 mg/dL]) was found in 120 patients admitted to a major university hospital, during a period of 16 months. Fifty-one patients (42.5%) developed hypophosphatemia postoperatively. Medications known to precipitate hypophosphatemia were a causative factor in 82% of the patients, with glucose administered intravenously, antacids, diuretics, and steroids being the most common agents associated with profound hypophosphatemia. Gram-negative septicemia was observed in 16 patients, and it was the second most common cause of severe hypophosphatemia. The mortality rate was 20% in patients with a serum phosphorus concentration between 0.36 and 0.48 mmol/L (1.1 and 1.5 mg/dL) (group A) and 30% in patients with a serum phosphorus concentration of less than or equal to 0.32 mmol/L (less than or equal to 1.0 mg/dL) (group B). The cause of death and its temporal association with the lowest observed values of phosphorus concentration indicate that severe hypophosphatemia might be a contributory factor to mortality. Our data indicate that severe hypophosphatemia in hospitalized patients is the result of a combination of factors. Surgery, followed by a period of fasting with intravenous administration of glucose, and gram-negative septicemia are the most common causes.