Growth inhibition of prostate cancer xenografts by halofuginone

BACKGROUND: Halofuginone, an inhibitor of collagen type I synthesis, is an anti-angiogenic agent. Here we evaluated the efficacy of halofuginone to inhibit prostate cancer (PC) xenografts representing various phenotypes of the disease. METHODS: An androgen-dependent (CWR22), an androgen-independent (PC3), and a neuroendocrine (WISH-PC2) PC xenograft were used. Halofuginone was given orally or injected intraperitoneally. Tumor size, collagen alpha1(I) gene expression (in situ hybridization), collagen content (sirius red staining), angiogenesis (immunohistochemistry with factor VIII antibodies), and apoptosis/necrosis (DNA fragmentation) were evaluated. RESULTS: Halofuginone inhibited the growth of all subcutaneously implanted xenografts and of WISH-PC2 when transplanted orthotopically. The effect was dose-dependent (WISH-PC2) and accompanied by decrease in plasma PSA levels (CWR22). In all xenografts, halofuginone inhibited collagen alpha1(I) gene expression, reduced collagen content, and endothelial cell number resulting in an increase in apoptosis/necrosis. CONCLUSIONS: Oral administration of halofuginone slowed the progression of PC xenografts representing a broad range of phenotypes. Halofuginone may become a new modality for PC prevention.     

Multidisciplinary and Multistage Treatment of Complex Facial Trauma: Case Report

The improved performance of modern automobiles often results in higher driving speeds, rendering traffic accidents much more devastating. Many of our facially injured patients require multidisciplinary and multistage treatment, which is often both sophisticated and radical. We present a patient with complex facial trauma, discuss his injury characteristics and the multistage treatment performed, and review the literature.     

Allogeneic hematopoietic stem-cell transplantation in AML and MDS using myeloablative versus reduced-intensity conditioning: the role of dose intensity.

Allogeneic stem-cell transplantation (SCT) with both myeloablative and reduced-intensity conditioning (RIC) is an effective therapy in AML/MDS. However, the relative merits of each may differ in different settings. To define the role of dose intensity, we analyzed SCT outcomes of 112 consecutive patients with AML/MDS. A total of 45 patients met eligibility criteria for standard myeloablative conditioning and were given intravenous-busulfan (12.8 mg/kg) and cyclophosphamide (ivBuCy). A total of 67 noneligible patients were given RIC with fludarabine and intravenous-busulfan (6.4 mg/kg, FB2, n=41) or a modified myeloablative regimen with fludarabine and myeloablative doses of intravenous-busulfan (12.8 mg/kg, FB4, n=26). The overall survival (OS) at 2 years was 50, 49 and 47% after ivBuCy, FB4 and FB2, respectively (P=NS). Nonrelapse mortality was higher after ivBuCy, 22 vs 8% (P=0.05), but relapse rates were lower. Active disease at SCT was the most significant predictor of reduced survival in multivariable analysis (HR 4.5, P=0.0001). Myeloablative and RIC regimens had similar outcomes when leukemia was in remission at SCT; however, patients with active disease could only be salvaged by myeloablative conditioning. Among the latter, OS was 45% after ivBuCy but no FB2 recipient survived (P=0.02). Patients with active disease, ineligible for standard myeloablation, could tolerate modified myeloablation well; however, long-term outcome cannot be determined yet.     

Fludarabine-based protocol for haploidentical peripheral blood stem cell transplantation in Hurler syndrome

To assess the feasibility of performing a haploidentical peripheral blood stem cell transplantation (PBSCT) in a child with Hurler syndrome after a novel conditioning regimen consisting of fludarabine monophosphate, anti-T-lymphocyte globulin, low-dose busulfan, and single-dose total body irradiation of 750 cGy. A 16-month old boy with Hurler syndrome underwent haploidentical PBSCT from his 3/6 HLA-matched sister. Pretransplant conditioning consisted of fludarabine (30 mg/m2 per day) from day -10 to day -5, busulfan (4 mg/kg per day) on days -7 and -6, rabbit anti-T-lymphocyte globulin (10 mg/kg per day) from day -4 to day -1, and total body irradiation of 750 cGy on day -1. In vitro T-cell depletion was carried out with rat antihuman CDw52 monoclonal antibody (Campath-1G). The fludarabine-based protocol was well-tolerated, with mild toxicity and no major transplant-related complications or graft-versus-host disease. Engraftment was complete and stable. Chimerism was 100% donor origin, as determined by restriction fragment length polymorphism. Cytogenetic and polymerase chain reaction-various number of tandem repeats (PCR-VNTR) analyses of peripheral blood and bone marrow showed 100% reconstitution with female donor cells. The patient underwent the transplant 30 months ago and is in good clinical condition, with normal counts, no signs of graft-versus-host disease, and no infectious episodes; neurologic signs have stabilized. Haploidentical PBSCT, T-cell-depleted by means of Campath-1G, may serve as a therapeutic alternative for patients with Hurler syndrome when a fully matched sibling is not available.     

Impaired liver function tests in patients treated with antithymocyte globulin: Implication for liver transplantation

Antithymocyte globulin (ATG) is traditionally used as a conventional immunosuppression agent in various pathological states including severe aplastic anaemia (SAA), graft versus host disease (GVHD), and for the prevention and treatment of graft rejection and GVHD post bone marrow and liver transplantation. We reviewed the liver functions of 16 haematological patients with no previous liver disorders who received ATG as part of their pre-bone marrow transplantation (BMT) conditioning regimen, and the liver function tests of five SAA patients who received ATG as part of their treatment. Liver functions were evaluated at day — 1 pre-, and days +3 and +10 post-ATG treatment. All patients had normal liver functions before treatment. In the haematological patients, the mean serum lactic dehydrogenase (LDH) levels increased from 408.7 ± 37.7 U/l pre-treatment to 1394.4 ± 488.7 U/l 3 days post-treatment (n = 16;p < 0.029), and then declined to 561.4 ± 61.3 U/l 10 days post-treatment (n = 16;p < 0.043). The mean alanine aminotransferase (ALT) levels increased from 51.9 ± 11.3 U to 184.6 ± 74.6 U (n = 16;p < 0.036), and then declined to 121.9 ± 61.3 U (n = 16; NS). The mean aspartate amino transferase (AST) levels increased from 31.2 ± 5.7 U to 152.0 ± 67.0 U (n = 16;p < 0.44) and then declined to 46.0 ± 14 (n = 16;p < 0.049). The mean r-glutamyltransferase (GTP) levels increased from 93.0 ± 34 to 188.0 ±36 (n = 16;p < 0.02), and were 168.0 ± 37.0 at day +10 (n = 16; NS). The mean bilirubin levels increased from 18.0 ± 1.9μM I^-1 to 22.7 ± 2.8 (n = 16); NS), at day +3 and to 31.9 ± 6.9 at day +10 (n = 16; NS). In contrast, no significant changes in liver function tests were demonstrated in the SAA patients treated with ATG. The possible pathophysiologic mechanisms and the clinical implications for liver transplantation are discussed.     

Effets tardifs des radiations ionisantes sur les tissus de la sphère otorhinolaryngologique

Numerous structures are included in the irradiated volume of patients presenting with head and neck cancer: skin, mucosa, bone, teeth, cartilage, muscles, salivary glands, etc. Curative intent treatment of such tumours requires aggressive approach which can lead to severe sequellae. These sequellae are in most cases dose-dependent and volume-dependent. However, an appropriate technique might decrease the severity of such sequellae. Details of these late changes are presented, including their pathophysiology, clinical syndromes, potential treatment, and prevention.     

Ambulatory blood pressure monitoring

Ambulatory blood pressure monitoring (ABPM) in adults is proving to be useful. The aim of this study was to determine if ABPM is accurate in the lower blood pressure range encountered in children and, equally important, whether it is acceptable to children. Thirty one children, between the ages of 6 and 18 years, were assessed using an ambulatory blood pressure monitor that uses an auscultatory method. Blood pressure was measured in the contralateral arm with a mercury sphygmomanometer and an oscillometric device at the beginning and end of the study for comparison. Over a blood pressure range of 90-130 mm Hg systolic and 40-80 mm Hg diastolic, a close agreement was found with the sphygmomanometer; the limits of agreement (+/- 2 SD) were 11.6 mm Hg for systolic blood pressure and 13.6 mm Hg for diastolic blood pressure. The bias was less than 1.0 mm Hg. The ambulatory device was worn by all patients for at least 16 hours with an average of 52 recordings per patient. The majority found the device comfortable to wear and were not woken from sleep.