Giant pseudomeningocele causing urinary obstruction in a patient with Marfan syndrome.

Defective collagen biosynthesis in Marfan syndrome predisposes to dural defects such as dural ectasia, meningocele, and pseudomeningocele; thus, an increased index of suspicion for these conditions should be present in the clinical setting of Marfan syndrome. The authors describe a young woman with Marfan syndrome who was being treated with anticoagulants for a prosthetic heart valve and who presented with a spontaneous retroperitoneal hemorrhage requiring surgical evacuation. No CSF leak was encountered at surgery, but she developed progressively more severe positional headaches over the following year. She then experienced the sudden onset of acute urinary obstruction, at which time CT revealed a 17 × 15 × 13-cm presacral pseudomeningocele communicating with the thecal sac through a sacral bone defect. An anterior surgical approach was used for drainage of the pseudomeningocele as well as for primary closure of the dural defect with a bovine pericardial patch and autologous subcutaneous fat graft. After a short period of lumbar subarachnoid drainage of the CSF, the patient was able to resume normal activity without recurrent symptoms. To the authors' knowledge, such a pseudomeningocele in a patient with Marfan syndrome has been reported only twice, and this case features the largest pseudomeningocele to date. They also review the pertinent literature regarding presentation, diagnosis, and management of these lesions.

Pancreaticoduodenectomy in the setting of intestinal malrotation.

Malrotation is an intestinal gestational disorder which not only affects the positioning of the midgut, but also its vascular supply. While this is generally thought of as a pediatric surgical condition, it can have significant implications for adult surgeries as well. Herein we present a patient with asymptomatic nonrotation of the midgut with a concomitant pancreatic adenocarcinoma. The authors review the modifications necessary to perform a pancreaticoduodenectomy in a nonrotated patient. The review includes a caution and emphasis on an understanding of the vascular anatomic variants.

Case report and management of suspected acute appendicitis in pregnancy.

Suspected cases of acute appendicitis in pregnancy are considered surgical emergencies due to the potentially devastating outcomes for both mother and unborn child if the appendix perforates. Acute appendicitis is also the number one cause of non-traumatic acute abdomen in pregnancy, as well as the number one cause of fetal death. We present a case report with a typical presentation of suspected acute appendicitis in a pregnant woman. The work up and diagnostic tools available are discussed at length, as well as the finer points in treatment of this population.

Pharmacodynamic analysis of target inhibition and endothelial cell death in tumors treated with the vascular endothelial growth factor receptor antagonists SU5416 or SU6668.

PURPOSE: To determine the effects of small molecule inhibitors of vascular endothelial growth factor receptor (VEGFR)-2 (SU5416 and SU6668) on receptor phosphorylation in tumor xenografts and in paired tumor biopsies obtained in three clinical trials in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: The dose-dependent effects of SU6668 on angiogenesis and tumor growth were investigated in orthotopic L3.6pl pancreatic tumors. Excisional or 18G core biopsies were obtained from patients before and after therapy with SU5416 or SU6668. Laser scanning cytometry-mediated analysis was used to quantify levels of phosphorylated and total VEGFRs and platelet-derived growth factor receptors (PDGFR), tumor microvessel densities, vessel sizes, and endothelial and tumor cell apoptosis. RESULTS: Significant inhibition of tumor microvessel density and growth and increased apoptosis were observed at SU6668 maximum tolerated dose (100 mg/kg) in L3.6pl xenografts. At 6 hours post therapy, SU6668 reduced VEGFR and PDGFR phosphorylation in the tumors by 50% and 92%, respectively, but levels rebounded beyond the baselines by 24 hours. Levels of phosphorylated VEGFR-2 and PDGFR also decreased significantly ( approximately 50%) 6 hours after therapy in 1 of 6 primary human tumors treated with SU6668, but these effects were not associated with increased apoptosis. A significant increase in endothelial cell apoptosis was observed in one tumor exposed to SU5416 and was associated with an increase in vessel size, but these changes occurred without an increase in tumor cell death. CONCLUSIONS: SU5416 and SU6668 displayed biological activity in xenografts. However, neither drug produced marked biological activity in primary patient tumors.

Direct effects of recombinant human endostatin on tumor cell IL-8 production are associated with increased endothelial cell apoptosis in an orthotopic model of human pancreatic cancer.

PURPOSE: Recombinant human endostatin (rhES) is an antiangiogenic agent derived from collagen XVIII which inhibits tumor growth in subcutaneous models of various human malignancies. However, its effectiveness in an orthotopic xenograft model of an abdominal neoplasm has not been demonstrated. DESIGN: An orthotopic model of pancreatic cancer was established in 6-week-old male athymic mice from either of 2 human cell lines (L3.6pl or BxPC3). Established tumors were treated with 40 mg/kg rhES or vehicle controls for up to 3 weeks. Tumors were analyzed by immunohistochemistry for TUNEL/CD31, IL-8, VEGF, and bFGF. We also measured direct effects of rhES on tumor cell angiogenic factor production by ELISA in vitro. RESULTS: Overall tumor burden was not reduced with rhES treatment in mice inoculated with either cell line. Peritoneal carcinomatosis in the L3.6pl mice was greater in those treated with rhES than in those treated with normal saline or citrate buffer (p < 0.05). Treatment with rhES lowered IL-8 levels 32-47% in vivo (p < 0.001) and 40-65% in vitro (p < 0.05) in the fast-growing L3.6pl tumors but not in the slow-growing BxPC3 tumors (p < 0.05). rhES also increased the levels of endothelial cell apoptosis 16- to 24-fold in vivo in the L3.6pl mice, but not in the BxPC3 mice (p < 0.05). CONCLUSIONS: rhES downregulated IL-8 levels and induced endothelial cell apoptosis in the more aggressive cell line in a xenograft model of pancreatic cancer. Nonetheless, these effects were not sufficient to produce significant inhibition of tumor growth.

The proteasome inhibitor bortezomib enhances the activity of docetaxel in orthotopic human pancreatic tumor xenografts.

Bortezomib (Velcade, formerly known as PS-341) is a boronic acid dipeptide derivative, which is a selective and potent inhibitor of the proteasome. We examined the antitumor activity of combination therapy with bortezomib + docetaxel in two human pancreatic cancer cell lines (MiaPaCa-2 and L3.6pl) selected for their divergent responses to bortezomib alone. Bortezomib blocked docetaxel-induced apoptosis in the MiaPaCa-2 cells and failed to enhance docetaxel-induced apoptosis in L3.6pl cells in vitro but did interact positively with docetaxel to inhibit clonogenic survival. These effects were associated with decreased accumulation of cells in M phase, stabilization of the cyclin-dependent kinase inhibitors, p21 and p27, and inhibition of cdk2 and cdc2 activities. In orthotopic xenografts, combination therapy produced significant reductions in tumor weight and volume in both models associated with accumulation of p21, inhibition of proliferation, and increased apoptosis. Combination therapy also reduced tumor microvessel densities, effects that were associated with reductions in tumor cell production of vascular endothelial growth factor and increased levels of apoptosis in tumor-associated endothelial cells. Together, our results suggest that bortezomib enhances the antitumoral activity of taxanes by enforcing cell growth arrest and inhibiting angiogenesis.