The mitogen-activated protein kinase pathway is thought to be essential in cellular growth and differentiation. Here we report the discovery of a highly potent and selective inhibitor of the upstream kinase MEK that is orally active. Tumor growth was inhibited as much as 80% in mice with colon carcinomas of both mouse and human origin after treatment with this inhibitor. Efficacy was achieved with a wide range of doses with no signs of toxicity, and correlated with a reduction in the levels of activated mitogen-activated protein kinase in excised tumors. These data indicate that MEK inhibitors represent a promising, noncytotoxic approach to the clinical management of colon cancer.

Abstract. Polyoma virus (PV) can cause interstitial nephritis and lead to graft failure in renal transplant recipients. The clinical course of patients with polyoma virus nephritis (PVN) is not well understood, partially due to its relatively low incidence. This study is a retrospective analysis of our experience over 4 yr. The specific purpose is to outline the clinical course and outcome of patients with PVN and to study the relationship between immunosuppression and the disease process. Between

Mycophenolate mofetil (MMF) is widely used for maintenance immunosuppression in solid organ transplantation. Gastrointestinal toxicity, usually manifested as diarrhea, is the most common side effect of MMF. We evaluated colonic biopsies from 20 renal transplant patients with MMF-related diarrhea. The latter was defined by the absence of any other demonstrable etiology and improvement or resolution of symptoms by the discontinuation or reduction of the dose of MMF alone. These biopsies were compared with colon biopsies from patients with the following: acute graft-versus-host disease (GVHD, n=10), inflammatory bowel disease (IBD) or infectious colitis (n=10), and colon biopsies from renal transplant patients not receiving MMF (n=8). Normal colonic segments from surgical specimens served as normal controls (n=5). Colonic biopsies from patients with MMF-related diarrhea showed prominent crypt cell apoptosis and reactive/reparative changes including enterocyte cytologic atypia, increased neuroendocrine cells, and glandular architectural distortion. The changes were similar, although of milder degree to the ones seen in patients with acute intestinal GVHD. This pattern of injury was not seen in controls or in biopsies from transplant patients not receiving MMF, and it was markedly different from the one seen in idiopathic inflammatory or infectious colitis. The severity of histologic changes correlated significantly with the endoscopic degree of "colitis." There was no statistically significant correlation between histologic damage and the dose of MMF (corrected for body weight and renal function). MMF-related colitis is a distinct entity that displays histologic features remarkably similar to the ones associated with intestinal GVHD. This form of injury could be related to either direct toxicity or an "innocent by-stander" phenomenon secondary to the alteration of the immunologic microenvironment of the colon caused by the MMF.

A positive cross-match is not necessarily a contraindication to LD transplantation, especially for patients with low donor-specific alloantibody titers.

Everolimus (EVR) in heart and renal transplant (RTx) recipients may be associated with a decreased incidence of cytomegalovirus (CMV). A detailed analysis of the association between EVR versus mycophenolic acid (MPA) and CMV events has not been reported. CMV data from 2004 de novo RTx recipients from threerandomized, prospective, EVR studies A2309 (N = 833), B201 (N = 588) and B251 (N = 583) were retrospectively analyzed to identify differences between two EVR dosing groups and MPA. EVR groups received 1.5 mg/day, or 3 mg/day with either standard (SD-CsA) or reduced dose cyclosporine (RD-CsA). Controls received MPA with SD-CsA. CMV prophylaxis was as per center practice. CMV incidence (infection/syndrome, disease, viremia) was captured per local center evaluations. Kaplan-Meier analyses demonstrated that freedom from CMV viremia and infection/syndrome was significantly greater for EVR versus MPA for recipients without CMV prophylaxis. Among recipients who received prophylaxis, freedom from viremia was greater for EVR 3.0 mg; freedom from infection/syndrome was greater for EVR 3.0 and 1.5 mg. Although freedom from organ involvement was numerically greater for EVR, it was not statistically significant. This analysis documents significant reductions in the incidence of CMV infection/syndrome and viremia in EVR-treated de novo RTx recipients, especially those who did not receive CMV prophylaxis versus MPA.