Successful outcome after resection of pancreatic cancer with a solitary hepatic metastasis

The presence of hepatic metastasis in pancreatic cancer has generally been considered to be a contraindication for surgery. However, the present case survived seven years after concomitant resection of pancreatic cancer and hepatic metastasis. This shows that hepatic metastasis may be a strong predictor of poor survival, but not a determinant of noncurability. Surgical resection may be an option for highly selected patients with pancreatic cancer complicated with hepatic metastasis.     

Acute renal infarction caused by Behçet's disease

A case of acute renal infarction due to Behçet's disease is described. Selective renal arteriography revealed multiple microaneurysms of both kidneys and arterial obstruction distal to an aneurysm in the left kidney. Bilateral microaneurysms were no longer seen on the follow-up angiogram 5 years later. Behçet's disease should be considered in the differential diagnosis of acute renal infarction in young adults.     

Role of the Thymus in Transplantation Tolerance in Miniature Swine. I. Requirement of the Thymus for Rapid and Stable Induction of ?Tolerance to Class I–mismatched Renal Allografts

The almost uniform failure in transplant patients of tolerance-inducing regimens that have been found to be effective in rodents, has made it necessary to examine large animal models before testing of new approaches clinically. Miniature swine have been shown to share many relevant immunologic parameters with humans, and because of their reproducible genetics, have proved extremely useful in providing such a large animal model. We have previously shown that indefinite systemic tolerance to renal allografts in miniature swine is induced in 100% of cases across a two-haplotype class I plus minor histocompatibility antigen disparity by a 12-d course of Cyclosporine A (CyA), in contrast to irreversible rejection observed uniformly without CyA treatment. In the present study, we have examined the role of the thymus during the induction of tolerance by performing a complete thymectomy 21 d before renal transplantation. This analysis demonstrated a striking difference between thymectomized and nonthymectomized animals. Thymectomized swine developed acute cellular rejection characterized by a T cell (CD25⁺) infiltrate, tubulitis, endothelialitis and glomerulitis, and anti–donor CTL reactivity in vitro. Nonthymectomized and sham thymectomized animals had a mild T cell infiltrate with few CD25⁺ cells and no anti–donor CTL response in vitro. These results indicate that the thymus is required for rapid and stable induction of tolerance.Many methods by which transplantation tolerance can be induced in rodents have failed when applied to large animals or to patients (1–4), making testing in large animals a necessary step before applying new techniques clinically. Miniature swine provide the only large animal model in which one can reproducibly study the effects of selective matching within the MHC on parameters of transplantation (5–7). We have therefore used MHC inbred and recombinant lines of miniature swine extensively for preclinical studies of transplantation tolerance (8–12). Previous studies from this laboratory have demonstrated that tolerance to renal allografts in miniature swine occurs spontaneously in about one-third of animals selectively matched for class II antigens and mismatched for a single class I MHC locus plus minor antigens (8, 13). The induction of spontaneous long-term tolerance was associated with a transient antidonor class I humoral response which has been shown to be almost entirely of the IgM class. Rejector animals developed antidonor class I IgG and promptly rejected their allografts. The failure to switch from IgM to IgG in spontaneous acceptors, suggested that the pathway to tolerance involved a deficiency of T cell help. Studies in miniature swine mismatched for two class I haplotypes were consistent with this hypothesis. Such animals reject renal allografts in 100% of cases without immunosuppression, but when T cell help was limited by the administration of a 12-d course of Cyclosporine A (CyA)¹, 100% of animals developed long-term tolerance (9). Subsequent studies demonstrated that transplants of second renal allografts, MHC-matched to the original donors, were accepted without further immunosuppression if grafted at the time of the transplant nephrectomy (14). These results indicate that long-term graft acceptance is associated with the induction of systemic tolerance.The role of the thymus has been shown to be critical for systemic central tolerance to self antigens in which potentially autoreactive T cells are deleted or anergized by exposure to the appropriate self antigens presented by either bone marrow–derived cells or thymic stromal cells (15–19). Similar intrathymic mechanisms may also be important in inducing donor-specific tolerance to alloantigens, and there are recent reports of studies in which donor alloantigens directly injected into the thymus resulted in donor-specific tolerance to the alloantigens in vivo or in vitro (20–23). To determine if the thymus is involved in the induction of tolerance in our two haplotype class I–mismatched renal allograft model, the effect of thymectomy 21 d before renal transplantation was examined. The data from this study demonstrate that the thymus is essential for rapid and stable tolerance induction. However, one graft was accepted by a thymectomized animal, indicating that allograft tolerance may also be achieved by peripheral mechanisms.     

Fluid resuscitation with hemoglobin vesicles in a rabbit model of acute hemorrhagic shock

Several hemoglobin (Hb)-based oxygen carriers are available for use in clinical situations, but their use risks inducing cardiovascular dysfunction as a result of Hb interacting with nitric oxide. Hb vesicles (HbV) are liposome-encapsulated purified human Hb with polyethylene glycol chains at the surface. This study evaluated the effects of HbV on hemodynamics, tissue and systemic oxygenation, and osmotic pressure after fluid resuscitation in an acute hemorrhagic shock model. Hemorrhagic shock was induced in 24 anesthetized mechanically ventilated male rabbits by withdrawing blood to a mean arterial blood pressure (MAP) of 30 to 35 mmHg over 15 min and maintaining this state for 30 min. The animals were resuscitated by replacing the blood with equal volumes of HbV in recombinant human albumin solution (HbV/rHSA), rHSA alone, or Ringer lactated solution (RL), or with three times the withdrawn volume of RL and observed for 2 h. Fluid resuscitation restored MAP, central venous pressure, and cardiac index values, but these fell again within 2 h in rabbits treated with RL. Fluid resuscitation using HbV/rHSA immediately increased MAP and cardiac index but not systemic vascular resistance, maintained a high level of oxygen consumption, and reduced the blood glucose level, which increased after hemorrhage. Fluid resuscitation using HbV/rHSA did not disturb microoxygenation in the brain, kidneys, liver, or muscle; allowed an immediate recovery of tissue oxygenation without decreasing cardiac output or increasing systemic vascular resistance, and increased the oxygen consumption. HbV solution offers the advantages of systemic oxygenation without impairing microcirculation in the treatment of hemorrhagic shock.     

Treatment results by uneven fractionated irradiation, low-dose rate telecobalt therapy as a boost, and intraoperative irradiation for malignant glioma.

The prognosis of malignant glioma is extremely poor. We applied conventionally fractionated irradiation combined with 1-(4-amino-2-methyl-5-pyrimidinyl)methyl-3-(2-chloroethyl)-3-nitrosourea (ACNU), uneven fractionated irradiation with ACNU, low dose rate telecobalt therapy as a boost, and intraoperative irradiation against 110 malignant gliomas to investigate the efficacy of these methods as alternative treatments for malignant glioma. Although local tumor control by uneven fractionated irradiation was better than that by the other methods, no significant improvement was obtained in survival rates. As a result of multiple regression analysis, age and histology were major factors for survival rates, and the difference of treatment methods was not important. Both low-dose rate telecobalt therapy as a boost and intraoperative irradiation showed little advantage because of the high risk of brain necrosis associated with them.     

Molecular targeted therapy in lung cancer

Lung cancer continues to be the leading cause of cancer death worldwide, and nonsmall cell lung cancer(NSCLC) is the most common type of lung cancer. Despite many clinical trials of platinum-based chemotherapy in combination with various drugs, the median survival time of NSCLC patients remains poor. The overall 5-year survival rate is approximately 15%, and has improved only marginally over the last few decades despite the introduction of new therapeutic agents. A recent milestone in this field has been the development of molecular-targeting drugs, among which gefitinib and erlotinib targeting the epidermal growth factor receptor (EGFR) have improved the efficacy of therapy for NSCLC. Anti-angiogenetic drug, such as bevacizumab, had become clinical use in the treatment for NSCLC. Moreover, discovery of EML4-ALK made the marvelous progress in cancer research in NSCLC. In this review, we discuss about the development of molecular-targeting drugs, such as EGFR-TKI, anti-angiogenetic drug, and EMLA-ALK inhibitors.