An initial report of a phase-III trial comparing vindesine and vincristine for acute lymphocytic leukemia of childhood

Summary The initial results from the Children's Cancer Study Group (CCSG) study on vindesine are the subject of this report. Vindesine was shown to be active in the treatment of acute lymphocytic leukemia (ALL) in children in a phase-II clinical trial conducted by the CCSG. A phase-III trial is now in progress. The aim of this is to compare the use of vincristine and of vindesine with reference to induction rate, toxicity, and cross-resistance.The Children's Cancer Study Group investigators, institutions, and grant numbers are listed in the appendix to this paper     

Plasma kallikrein mediates retinal vascular dysfunction and induces retinal thickening in diabetic rats

OBJECTIVE

Plasma kallikrein (PK) has been identified in vitreous fluid obtained from individuals with diabetic retinopathy and has been implicated in contributing to retinal vascular dysfunction. In this report, we examined the effects of PK on retinal vascular functions and thickness in diabetic rats.

RESEARCH DESIGN AND METHODS

We investigated the effects of a selective PK inhibitor, ASP-440, and C1 inhibitor (C1-INH), the primary physiological inhibitor of PK, on retinal vascular permeability (RVP) and hemodynamics in rats with streptozotocin-induced diabetes. The effect of intravitreal PK injection on retinal thickness was examined by spectral domain optical coherence tomography.

RESULTS

Systemic continuous administration of ASP-440 for 4 weeks initiated at the time of diabetes onset inhibited RVP by 42% (P = 0.013) and 83% (P < 0.001) at doses of 0.25 and 0.6 mg/kg per day, respectively. Administration of ASP-440 initiated 2 weeks after the onset of diabetes ameliorated both RVP and retinal blood flow abnormalities in diabetic rats measured at 4 weeks’ diabetes duration. Intravitreal injection of C1-INH similarly decreased impaired RVP in rats with 2 weeks’ diabetes duration. Intravitreal injection of PK increased both acute RVP and sustained focal RVP (24 h postinjection) to a greater extent in diabetic rats compared with nondiabetic control rats. Intravitreal injection of PK increased retinal thickness compared with baseline to a greater extent (P = 0.017) in diabetic rats (from 193 ± 10 μm to 223 ± 13 μm) compared with nondiabetic rats (from 182 ± 8 μm to 193 ± 9 μm).

CONCLUSIONS

These results show that PK contributes to retinal vascular dysfunctions in diabetic rats and that the combination of diabetes and intravitreal injection of PK in rats induces retinal thickening.Diabetic macular edema (DME) is a leading cause of vision loss attributed to diabetes. The 14-year incidence of this disease in individuals with type 1 diabetes followed in the Wisconsin Epidemiologic Study of Diabetic Retinopathy was 26% (1), and the progression to clinically significant macular edema was associated with increasing retinopathy severity (2). Although intensive glycemic and blood pressure control can reduce the incidence of DME (3) once this condition develops, the treatment options include laser and vascular endothelial growth factor (VEGF)-targeted therapies, which provide substantial improvement in visual acuity for ~50% of patients with DME (4). Thus, additional treatment options for this disease are needed.DME is associated with a loss of blood-retinal barrier function, leading to increased diffusion of plasma components, thickening of the macula, and impairment in central vision (5,6). In addition to retinal thickening, increased retinal vascular permeability (RVP) alters the biochemical composition of the retinal interstitial fluid and the vitreous. Proteomic studies have begun to characterize the changes in the vitreous protein composition in people with diabetic retinopathy compared with nondiabetic subjects or diabetic subjects without diabetic retinopathy (7). We have previously reported an abundance of vasoactive plasma proteins, including components of the plasma kallikrein (PK)-kinin system (PKKS) in the vitreous of subjects with advanced diabetic retinopathy (7,8). These findings have suggested additional factors besides VEGF that may contribute to the decline in blood-retinal barrier integrity and vascular dysfunction in DME (9,10).Plasma prekallikrein (PPK) is an abundant serine protease zymogen in blood that is converted to its catalytically active form, PK, by factor XIIa (11), contributing to the innate inflammatory response and intrinsic coagulation cascades (12). The mechanisms that lead to the activation of this pathway in vivo include interactions with polyphosphates released from activated platelets and deficiency of C1 inhibitor (C1-INH), the primary physiological inhibitor of the PKKS (13,14). PK-mediated cleavage of high-molecular weight kininogen generates the nonapeptide bradykinin (BK), which activates the BK 2 (B2) receptor. Subsequent cleavage of BK by carboxypeptidases generates des-Arg⁹-BK, which activates the B1 receptor. Both B1 and B2 receptors are expressed by vascular, glial, and neuronal cell types, with the highest levels of retinal expression detected in the ganglion cell layer and inner and outer nuclear layers (15,16). Activation of B1 and B2 receptors causes vasodilation and increases vascular permeability (17–19). Previously, we have demonstrated that intravitreal injection of carbonic anhydrase-1 (CA-1) increased RVP and that this response was blocked by the inhibition of PK and by BK receptor antagonists (8). Recently, we reported that intravitreal injection of PK increased RVP in nondiabetic rats, and systemic administration of a small-molecule PK inhibitor, ASP-440, decreased RVP in rats subjected to angiotensin II (AngII)-induced hypertension (19). In the current study, we investigated the effects of PK on retinal vascular functions and retinal thickness in diabetic rats.     

Homozygous deletion of the alpha- and beta 1-interferon genes in human leukemia and derived cell lines.

The loss of bands p21-22 from one chromosome 9 homologue as a consequence of a deletion of the short arm [del(9p)], unbalanced translocation, or monosomy 9 is frequently observed in the malignant cells of patients with lymphoid neoplasias, including acute lymphoblastic leukemia and non-Hodgkin lymphoma. The alpha- and beta 1-interferon genes have been assigned to this chromosome region (9p21-22). We now present evidence of the homozygous deletion of the interferon genes in neoplastic hematopoietic cell lines and primary leukemia cells in the presence or absence of chromosomal deletions that are detectable at the level of the light microscope. In these cell lines, the deletion of the interferon genes is accompanied by a deficiency of 5'-methylthioadenosine phosphorylase (EC 2.4.2.28), an enzyme of purine metabolism. These homozygous deletions may be associated with the loss of a tumor-suppressor gene that is involved in the development of these neoplasias. The relevant genes may be either the interferon genes themselves or a gene that has a tumor-suppressor function and is closely linked to them.     

The pathology of non-Hodgkin's lymphoma of childhood: II. Reproducibility and relevance of the histologic classification of "undifferentiated" lymphomas (Burkitt's versus non-Burkitt's)

The Children's Cancer Study Group conducted prospective clinical trials of 608 children with non-Hodgkin's lymphoma from 1977 to 1983. In 1980, significant differences in survival of children with disseminated disease correlated with histologic diagnosis and the randomized treatment employed. A pathology reproducibility review showed the lymphoblastic lymphoma cases to be virtually 100 per cent distinguishable histologically from the nonlymphoblastic lymphomas (Burkitt's, non-Burkitt's, and "histiocytic"). However, diagnostic reproducibility of the pathologist-of-record was 59 per cent in the Burkitt's and non-Burkitt's lymphoma group. Therefore, 159 cases, agreed on by the pathologist-of-record and the "lymphoma panel" as Burkitt's (77 cases) or non-Burkitt's lymphoma (82 cases) and designated as the "reference diagnosis," were blindly reviewed twice each by two hematopathologists to yield the "review diagnoses." Consensus agreement was achieved in 67 per cent of cases overall, 82 per cent of Burkitt's and 54 per cent of non-Burkitt's lymphoma. Using the "reference diagnoses," we found that the relative frequency of Burkitt's and non-Burkitt's lymphoma was associated with the extent of disease at diagnosis (P = 0.06) but not with other prognostic factors. Despite the difficulties in histologic classification, analyses that used either "reference diagnoses" or "consensus review diagnoses" and that were adjusted for extent of disease consistently demonstrated significantly shorter event-free survival for patients having Burkitt's lymphoma; their failure rate was four times that for patient's with non-Burkitt's lymphoma. Newer cell biologic techniques hopefully will enhance histopathologic distinctions that remain the basis for diagnosis.     

The use of tensor fascia lata interposition grafts for the treatment of posttraumatic radioulnar synostosis

PURPOSE: There is no agreement on the ideal treatment of traumatic radioulnar synostosis, especially the type of interposition material to be used. The purpose of this study is to report our experience with synostosis resection and interposition of tensor fascia lata grafts. METHODS: A chart review was conducted for all patients treated for posttraumatic radioulnar synostosis between 2000 and 2004. Demographic data, mechanism of injury, length of time to synostosis resection, range-of-motion, patient satisfaction, and postoperative complications were analyzed. RESULTS: Thirteen patients were identified for this study. The mean preoperative pronation was 14 degrees and the mean postoperative pronation was 62 degrees. The mean preoperative supination was 4 degrees and the mean postoperative supination was 62 degrees. The mean follow-up time was 30 months. CONCLUSIONS: These results indicate that synostosis resection with tensor fascia lata graft interposition is an effective technique for the treatment of posttraumatic radioulnar synostosis. TYPE OF STUDY/LEVEL OF EVIDENCE: Therapeutic, Level IV.