Phase I combining a P-glycoprotein inhibitor, MS209, in combination with docetaxel in patients with advanced malignancies.

PURPOSE: The purpose of this study was to investigate the safety and tolerability of MS209, a potent inhibitor of P-glycoprotein, when given in combination with docetaxel and to determine whether MS209 affects docetaxel pharmacokinetics. EXPERIMENTAL DESIGN: Patients with advanced solid malignancies were eligible for this phase I trial. Docetaxel as 1-hour infusion was given alone during the first cycle. MS209 was introduced as of cycle 2 and given orally 30 minutes after docetaxel infusion. The dose escalation scheme followed a modified Fibonacci model with six steps (docetaxel, 60-100 mg/m2 and MS209, 300-1,200 mg per body). RESULTS: A total of 30 patients were treated at five dose levels. Dose-limiting toxicities were febrile neutropenia, infection, stomatitis, dysphagia, and fatigue. The maximum tolerated dose was reached at level 5 (docetaxel, 80-MS: 1,200). Pharmacokinetic analysis failed to show a strong pharmacokinetic interaction between the two compounds, but at the highest dose levels, there is a trend to an increase of docetaxel AUC when this agent is given in combination with MS209. CONCLUSION: MS209 can be given in combination with docetaxel, with limited effect on docetaxel toxicity or pharmacokinetics.     

Outcome and Hepatic Hemodynamics in Liver Transplant Patients with Portal Vein Arterialization

Few cases of successful portal vein arterialization in orthotopic and auxiliary liver transplantation have been reported. AIM: To evaluate the effect of portal vein arterialization on hepatic hemodynamics and long-term clinical outcome in three patients undergoing liver transplantation. METHODS: Two patients with extensive splanchnic venous thrombosis received an orthotopic liver transplant and one with fulminant hepatic failure received an auxiliary heterotopic graft. Portal vein arterialization was performed in all cases. RESULTS: One patient died 4 months after transplant and two are still alive. Auxiliary liver graft was removed 3 months post-transplant when complete native liver regeneration was achieved. Immediate post-transplant liver function was excellent in all cases. Only one patient developed encephalopathy and variceal bleeding owing to prehepatic portal hypertension secondary to arterioportal fistula 14 months after transplant. He was successfully treated by embolization of the hepatic artery. Hepatic hemodynamic measurements demonstrated a normal pressure gradient between wedged and free hepatic venous pressures in all cases. Liver biopsy showed acceptable graft architecture in two cases and microsteatosis in one. CONCLUSIONS: Liver transplantation with portal vein arterialization is an acceptable salvage alternative when insufficient portal venous flow to the graft is present. The double arterial supply does not imply changes in hepatic hemodynamics, at least in the early months post-transplant.     

Temporary and definitive external fixation of war injuries: use of a French dedicated fixator

Purpose

External fixation is the recommended stabilization method for both open and closed fractures of long bones in forward surgical hospitals. Specific combat surgical tactics are best performed using dedicated external fixators. The Percy Fx© (Biomet) fixator was developed for this reason by the French Army Medical Service, and has been used in various theatres of operations for more than ten years.

Methods

The tactics of Percy Fx© (Biomet) fixator use were analysed in two different situations: for the treatment of French soldiers wounded on several battlefields and then evacuated to France and for the management of local nationals in forward medical treatment facilities in Afghanistan and Chad.

Results

Overall 48 externals fixators were implanted on 37 French casualties; 28 frames were temporary and converted to definitive rigid frames or internal fixation after medical evacuation. The 77 Afghan patients totalled 85 external fixators, including 13 temporary frames applied in Forward Surgical Teams (FSTs) prior to their arrival at the Kabul combat support hospital. All of the 47 Chadian patients were treated in a FST with primary definitive frames because of delayed surgical management and absence of higher level of care in Chad.

Conclusion

Temporary frames were mostly used for French soldiers to facilitate strategic air medical evacuation following trauma damage control orthopaedic principles. Definitive rigid frames permitted achieving treatment of all types of war extremity injuries, even in poor conditions.     

Characterization of antigens recognized by monoclonal and polyclonal antibodies directed against uvomorulin.

Uvomorulin is a cell surface glycoprotein involved in compaction of early mouse embryo. Antibodies, either monoclonal or polyclonal, raised against a purified tryptic fragment of uvomorulin recognize, in a detergent lysate of embryonal carcinoma cells metabolically labeled with 35S, three molecules (120, 100, and 88 kDa) that are not related, as judged by peptide mapping. Only the 120-kDa form is related to the tryptic fragment of uvomorulin and, thus, is considered as the native form of uvomorulin. Although all three products are apparently detectable at the cell surface, only the 120-kDa form is glycosylated. Coimmunoprecipitation of the three different polypeptides is probably due to shared epitopes rather than to their presence in a multimeric complex.     

Ultrasound Measures of Brain Pulsatility Correlate with Subcortical Brain Volumes in Healthy Young Adults

Increasing evidence suggests that brain pulsatility is involved in the pathophysiology of various neurological and psychiatric disorders. However, it remains unclear whether high brain pulsatility is damaging to or protective of the brain in normal conditions, and this could depend on the age of the individual and the methods used to measure brain pulsatility. The goal of our study was to investigate associations between subcortical volumes and brain pulsatility as assessed with ultrasound in healthy young adults using both a conventional method (transcranial Doppler pulsatility index [TCD-PI]) and the innovative method of tissue pulsatility imaging (TPI), which allows a high level of detection of small brain movements (micrometers). Twenty-five females aged 18–55 with no history of significant medical disorder underwent magnetic resonance imaging and ultrasound assessment. The volumes of six subcortical regions known to be particularly sensitive to change in cerebral blood flow were measured and compared with brain pulsatility as assessed with TCD-PI and TPI. TCD-PI and TPI measures positively correlated with all subcortical regions, with the caudate nucleus having the strongest association. Linear regressions found that TCD-PI and TPI measures of brain pulsatility explained 16% to 67% of the variance of the subcortical volumes. Our results suggest that a greater pulsatility as assessed with ultrasound in healthy young adults may constitute a protective factor for brain structure. Ultrasound measures of brain pulsatility may be appropriate to provide costless, non-invasive, portable and highly sensitive markers of cerebral blood flow pulsatility related to brain structure.     

Follicular dendritic cells (FDC) in retroviral infection: host/pathogen perspectives

Summary: Follicular dendritic cells (FDC) are found in the follicles of virtually all secondary lymphoid tissues. In health, these cells trap and retain antigens (Ag) in the form of immune complexes and preserve them for months in their native conformation. FDC thus serve as a long-term repository of extracellular Ag important for induction and maintenance of memory responses. In retroviral infection. FDC trap and retain large numbers of retroviral particles with profound effects on FDC. FDC-trapped retrovirus induces follicular hyperplasia, and conventional Ag trapped prior to infection are lost and new Ag cannot be trapped. Concomitantly, antibody-forming cells (AFC) specific for Ag lost from FDC decrease follow I by loss of specific serum antibody (Ab). Eventually, FDC die and follicular lysis occurs. From the pathogen perspective, binding to FDC is remarkably beneficial, bringing together virus and activated target cells that are highly susceptible to infection. Furthermore, FDC permit HIV to infect surrounding cells even in the presence of a vast excess of neutralizing Ab. Preliminary data suggest that FDC maintain virus infectivity - even when the virus cannot replicate. Thus retrovirus infection monopolizes FDC networks, thereby transforming the FDC Ag repository into a highly infectious retroviral reservoir.     

Characteristics and outcome of 1755 operable breast cancers in women over 70 years of age

From 1981 to 1995, 1755 patients aged 70 years or over who had nonmetastatic unilateral breast carcinoma received curative local or regional treatment in our institute. Median follow-up was 8 years. The median age of these patients was 75 years (range: 70-94), and 86% were under 81 years of age. Tumors were classed as T3-4 in 24% of them; 18% had N1b/N2 tumors, and in 12% grade 3 disease was present. Only 19% were both ER and PR negative. The S phase fraction was <5% in 79% of patients. In 1046 patients (60%) modified radical mastectomy was performed, while 20% underwent lumpectomy and in 20% radiotherapy was the only treatment administered. Adjuvant endocrine therapy was given in 463 (26%) cases, and only 3% of patients received chemotherapy. The median overall survival time was 121 months. The overall cancer-related death rate was 49%. The 10-year disease-free survival (DFS) rate was 64%, and the 10-year local relapse rate was 14%. Prognostic factors determined on univariate analysis were tumor size, clinical nodal status (ER and PR), and grade. No significant difference in outcome was observed between mastectomy and conservative treatment. Parameters for which correlations with DFS were found on multivariate analysis were clinical nodal status (P < 0.0001), tumor size (P < 0.0001), ER (P < 0.0001), and PR (P = 0.04). Breast cancer in elderly women is frequently hormone-dependent (81%) with a low proliferation index. Prognostic factors are the same as in younger postmenopausal patients. More than 50% of these patients died from a cause other than their breast cancer.