Abdominal vascular trauma.

Abdominal vascular trauma, primarily due to penetrating mechanisms, is uncommon. However, when it does occur, it can be quite lethal, with mortality ranging from 20% to 60%. Increased early mortality has been associated with shock, acidosis, hypothermia, coagulopathy, free intraperitoneal bleeding and advanced American Association for the Surgery of Trauma Organ Injury Scale grade. These patients often arrive at medical centers in extremis and require rapid surgical control of bleeding and aggressive resuscitation including massive transfusion protocols. The most important factor in survival is surgical control of hemorrhage and restoration of appropriate perfusion to the abdominal contents and lower extremities. These surgical approaches and the techniques of definitive vascular repair can be quite challenging, particularly to the inexperienced surgeon. This review hopes to describe the most common abdominal vascular injuries, their presentation, outcomes, and surgical techniques to control and repair such injuries.

A phase I study of interleukin 12 with trastuzumab in patients with human epidermal growth factor receptor-2-overexpressing malignancies: analysis of sustained interferon gamma production in a subset of patients.

PURPOSE: On the basis of preclinical studies, we hypothesized that interleukin (IL)12 would potentiate the antitumor actions of an antihuman epidermal growth factor receptor-2 (HER2) monoclonal antibody (trastuzumab). We conducted a Phase I trial to determine the safety and optimal biological dose of IL-12 when given in combination with trastuzumab. PATIENTS AND METHODS: Patients with metastatic HER2-positive malignancies received trastuzumab on day 1 of each weekly cycle. Beginning in week 3, patients also received intravenous injections of IL-12 on days 2 and 5. The IL-12 component was dose-escalated within cohorts of 3 patients (30, 100, 300, or 500 ng/kg). Correlative assays were conducted using serum samples and peripheral blood cells obtained during the course of therapy. RESULTS: Fifteen patients were treated, including 12 with HER2 2+ or 3+ breast cancer. The regimen was well tolerated with IL-12-induced grade 1 nausea and grade 2 fatigue predominating. Evaluation of dose-limiting toxicity and biological end points suggested that the 300 ng/kg dose was both the maximally tolerated dose and the optimal biological dose of IL-12 for use in combination with trastuzumab. Two patients with HER2 3+ breast cancer within the 500 ng/kg dose level experienced grade 1 asymptomatic decreases in left ventricular ejection fraction of 12% and 19% after 3 and 10 months of therapy, respectively. There was one complete response in a patient with HER2 3+ breast cancer metastatic to the axillary, mediastinal, and supraclavicular nodes, and 2 patients with stabilization of bone disease lasting 10 months and >12 months, respectively. Correlative assays showed sustained production of interferon (IFN)gamma by natural killer cells only in those patients experiencing a clinical response or stabilization of disease. Elevated serum levels of macrophage inflammatory protein-1alpha, tumor necrosis factor-alpha, and the antiangiogenic factors IFN-gamma inducible protein-10 and monokine induced by gamma were also observed in these patients. Patient genotyping suggested that a specific IFN-gamma gene polymorphism might have been associated with increased IFN-gamma production. The ability of patient peripheral blood cells to conduct antibody-dependent cellular cytotoxicity against tumor targets in vitro did not correlate with clinical response or dose of IL-12. CONCLUSIONS: The addition of IL-12 to trastuzumab therapy did not appear to enhance the efficacy of this antibody treatment. Sustained production of IFN-gamma and other cytokines were observed in three patients: One who exhibited a complete response and two others who had stabilization of disease lasting over 6 months. Given the small sample size and heterogeneity of the patient population, the effects of IL-12 on the innate immune response to trastuzumab therapy should be further explored in the context of a larger clinical trial.

IFN-gamma gene polymorphisms associate with development of EBV+ lymphoproliferative disease in hu PBL-SCID mice.

Posttransplantation lymphoproliferative disorder (PTLD) is a devastating post-transplantation complication often associated with Epstein-Barr virus (EBV). Although the type and length of immunosuppression are risk factors, a patient's inherent immune capacity also likely contributes to this disorder. This report uses severe-combined immunodeficient mice given injections of human peripheral blood leukocytes (hu PBL-SCID [Severe Combined Immunodeficient] mice) to test the hypothesis that cytokine genotype associates with the development of EBV-associated lymphoproliferative disease (LPD). We observed that the A/A (adenosine/adenosine) genotype for base + 874 of the interferon gamma (IFN-gamma) gene was significantly more prevalent in PBLs producing rapid, high-penetrance LPD in hu PBL-SCID mice, compared to PBLs producing late, low-penetrance LPD or no LPD. In examining the relationship between genotype and cytolytic T-lymphocyte (CTL) function, transforming growth factor beta (TGF-beta) inhibited restimulation of CTLs in PBLs with adenosine at IFNG base + 874, but not in PBLs homozygous for thymidine. Importantly, neutralization of TGF-beta in hu PBL-SCID mice injected with A/A genotype PBLs resulted in reduced LPD development and expanded human CD8(+) cells. Thus, our data show that TGF-beta may promote tumor development by inhibiting CTL restimulation and expansion. Further, our data indicate that IFNG genotype may provide valuable information for both identifying transplant recipients at greater risk for PTLD and developing preventive and curative strategies.