Citations

Abstract Gastric emptying of solids and liquids was measured in 12 dogs with and without corporal or antral gastrojejunostomy. Both types of stoma hastened the onset but did not alter the time from onset to complete emptying of 40 small plastic spheres. Corporal gastrojejunostomy slowed the emptying of 400 ml. of 154 mM NaCl but not of 500 mM glucose, whereas antral gastrojejunostomy slowed the emptying of both.

Abstract Aberrant patterns of pre-mRNA processing are typical of human malignancies, yet the mechanisms responsible for these changes remain undefined. We have recently shown overexpression of a core splice regulatory protein, serine-arginine protein kinase 1 (SRPK1), in dysplastic and neoplastic pancreatic ductular cells. In the present study, we have established that SRPK1 levels are similarly up-regulated in breast and colonic tumors where its expression increases coordinately with tumor grade. Targeting SRPK1 for inhibition using small interfering RNA in breast and colonic tumor cell lines in vitro resulted in both increased apoptotic potential and enhanced cell killing after treatment with gemcitabine and cisplatin. Recent reports have described multifaceted interactions between the mitogen-activated protein kinase (MAPK) and AKT signaling networks and the splice regulatory machinery. Consequently, we have shown that targeted inhibition of SRPK1 in tumor cells results in reduced phosphorylation of MAPK3, MAPK1, and AKT. Alterations in the splice pattern and resulting expression of MAPK kinase are implicated in mediating the antitumoral effects resulting from SRPK1 down-regulation. The up-regulation of SRPK1 in multiple cancers and its ability to regulate multiple relevant signaling pathways provide support for developing agents to inhibit this kinase for possible broad application to treat epithelial cancers. [Cancer Res 2007;67(5):2072–80]

Abstract A policy of supportive treatment is frequently adopted for patients with metastatic disease to the adrenal glands. This study reports an experience with adrenalectomy for adrenal metastasis. Between 1983 and 1993, adrenalectomy was performed in 52 patients for metastasis to the adrenal glands. Survival was calculated by the Kaplan- Meier method and compared with the log rank test. Primary tumour sites included kidney (n = 15), lung (n = 11), colon (n = 7), unknown (n = 5), stomach (n = 3), melanoma (n = 3) and other (n = 8). Adenocarcinoma (69 per cent) was the most common histological cell type. Thirty-two patients were asymptomatic on initial evaluation. Symptomatic adrenal pain relief was achieved in 11 of 13 patients. Overall survival rates were 73 per cent at 1 year and 40 per cent at 2 years. Patients with potentially curative resection had better survival than those who had a palliative procedure. Patients with adrenal metastases due to adenocarcinoma had improved survival compared with that in those with other histological cell types. Although long-term survival is generally poor, highly selected patients with adrenal metastasis (symptomatic disease or adenocarcinoma) may benefit from surgical resection.

Background and Purpose— Thrombolysis for acute ischemic stroke saves societal costs, but hospitals that practice acute stroke care appear to shoulder the burden of the cost, which exceeds reimbursement. With creation of the diagnosis-related group (DRG) 559, the US Centers for Medicare and Medicaid Services pays hospitals approximately US $6000 more per case when thrombolysis is administered. We sought to determine the total cost of, and reimbursement for, acute stroke treatment with thrombolysis at a single stroke center and the economic impact of DRG 559. Methods— Between September 2001 and December 2004, we collected data on all patients with acute stroke who received thrombolysis. We identified all hospital costs and reimbursement per patient. Financial results were expressed as a cost-reimbursement ratio: average total cost to average total reimbursement per patient. We then reanalyzed data using the projected Medicare hospital reimbursement with DRG 559. Results— Sixty-seven patients with stroke (mean age, 72 years) were treated (mean length of stay, 4.4 days; mean stroke severity, National Institutes of Health Stroke Scale score of 15; and symptomatic intracranial hemorrhage rate, 7%). The cost-reimbursement ratio was 1.41 (95% CI=0.98 to 2.28) before DRG 559 and estimated to be 0.82 (95% CI=0.66 to 0.97) after DRG 559. Conclusions— Our hospital costs have traditionally exceeded Medicare reimbursement for the acute care of thrombolyzed patients with ischemic stroke, but with DRG 559, a new economically favorable cost-reimbursement ratio for hospitals will be established.

Background and Purpose— Genetic factors influence risk for ischemic stroke and likely do so at multiple steps in the pathogenic process. Variants in genes related to inflammation contribute to risk of stroke. The purpose of this study was to confirm our earlier finding of an association between allele 2 of a variable number tandem repeat of the IL-1 receptor antagonist gene ( IL1RN ) and cerebrovascular disease. Methods— An association study of the variable number tandem repeat genotype with ischemic stroke and stroke subtypes was performed on samples from a North American study of affected sibling pairs concordant for ischemic stroke and 2 North American cohorts of prospectively ascertained ischemic stroke cases and unrelated controls. DNA analysis was performed on cases and controls, stratified by race. Results— After adjustment for age, sex, and stroke risk factors, the odds ratio for association of allele 2 and ischemic stroke was 2.80 (95% confidence interval, 1.29 to 6.11; P =0.03) for the white participants. The effect of allele 2 of IL1RN on stroke risk most closely fits a recessive genetic model ( P =0.009). For the smaller sample of nonwhite participants, the results were not significant. Conclusions— Allele 2 of IL1RN , present in nearly one-quarter of stroke patients, may contribute to genetic risk for ischemic stroke and confirm the previously identified association with cerebrovascular disease. These results are driven by the association in the white participants. Further exploration in a larger nonwhite sample is warranted.

Abstract Bcl family members Bcl-2, Bcl-xL, and Mcl-1, are frequently expressed and implicated in the survival of myeloma cells. Obatoclax (GX015-070) is a novel, small-molecule antagonist of the BH3-binding groove of the Bcl family of proteins. We show that GX015-070 inhibits the binding of Bak to Mcl-1, up-regulates Bim, induces cytochrome c release, and activates capase-3 in human myeloma cell lines (HMCLs), confirming the predicted mechanism of action. Consequently, GX015-070 potently inhibited the viability of 15 of 16 HMCLs (mean IC50 of 246 nM), including those resistant to melphalan and dexamethasone. In combination studies, GX015-070 enhanced the antimyeloma activity induced by melphalan, dexamethasone, or bortezomib. Sensitivity to GX015-070 correlated with the absence or near absence of Bcl-xL. Coculture with interleukin-6 or adherence to bone marrow stroma conferred modest resistance; however, it did not overcome GX015-070–induced cytotoxicity. Of importance, GX015-070 as a single agent induced potent cytotoxic responses against patient-derived tumor cells. GX015-070 inhibited normal bone marrow–derived colony formation; however, cytotoxicity to human blood lymphocytes was not observed. Taken together, these studies describe a novel BH3 mimic with selectivity for Mcl-1, and support the therapeutic application of GX015-070 for diverse neoplasias including multiple myeloma.

Abstract The surgical management of locally recurrent rectal cancer may involve major procedures and is not for the faint-hearted. Nevertheless, such treatment is preferable to chemotherapy and radiotherapy; the latter will fail over a period of months during which the patient is likely to experience intractable pain. Radical surgery offers good palliation and a better quality of life. Survival is prolonged by such operations which may be curative in up to one-third of patients. Nevertheless, surgeons must be realistic in their assessment of and discussions with patients.

BACKGROUND: The application of vascularized rib grafts in spine surgery has been limited to the treatment of kyphosis with anterior placement of the rib graft to facilitate anterior spine arthrodesis. The outcomes following use of vascularized rib grafts in complex spinal reconstruction have not been adequately evaluated. The purpose of this study was to determine the results, including the time to osseous union and complications, following anterior or posterior placement of pedicled vascularized rib grafts for complex spinal reconstruction. METHODS: The medical records and images of all patients in whom a vascularized rib graft had been used for a multisegmental spine reconstruction at a single institution between 1994 and 2004 were retrospectively reviewed. Eighteen patients (mean age, 45.3 years) who had been followed for an average of 31.8 months were identified. Details regarding indications, the levels that were spanned, the graft length, the time to union, and complications were evaluated. RESULTS: The preoperative diagnoses included metastatic or primary tumor (thirteen patients) and progressive kyphosis secondary to chronic osteomyelitis (two), injury (one), congenital anomalies (one), or implant failure (one). On the average, 4.4 levels were fused and 1.9 vertebral bodies were excised. All eighteen arthrodeses included various forms of allograft and/or autograft material, and instrumentation was used, in addition to the vascularized rib graft, in twelve patients. The mean rib length was 16.1 cm, and a rib between the fifth and eleventh ribs, inclusive, was used, depending on the location of the spinal reconstruction. The average time to union was 6.8 months, and all rib grafts united. There were no complications specific to the rib-harvesting procedure. CONCLUSIONS: The use of a vascularized rib graft in complex spinal reconstruction adds little time to the overall procedure, is associated with low morbidity, and appears to offer substantial benefits to the patient.

Abstract Pregnancy-associated plasma protein A (PAPP-A), a metalloproteinase that regulates IGF bioavailability in vitro through cleavage of inhibitory IGF-binding protein-4 (IGFBP-4), has been implicated in skeletal development and injury repair responses. However, direct in vivo data are lacking. In this study, we used PAPP-A knock-out (KO) mice to determine the role of PAPP-A in fracture repair. Stabilized mid-shaft fractures were produced in femurs of 3-month-old mice. At 14 days post-fracture, complete bony bridging of the fracture callus was seen radiographically in wild-type but not in PAPP-A KO mice. Histological examination 5 to 28 days post-fracture showed reductions in the amount of intramembranous bone formation, cartilage production, endochondral ossification and remodeling in PAPP-A KO compared with wild-type mice. However, fracture healing appeared similar in both groups at 42 days post-fracture when analyzed by histology. A similar degree of healing strength in wild-type and PAPP-A KO femurs was demonstrated by mechanical testing at 28 and 42 days post-fracture. Untreated cultures of day 5 fracture calluses from wild-type mice showed robust IGFBP-4 protease activity and IGF receptor phosphorylation, whereas fracture calluses from PAPP-A KO mice had no IGFBP-4 protease activity and reduced IGF receptor phosphorylation. These data demonstrate a marked delay in fracture healing in PAPP-A KO compared with wild-type mice, and suggest that PAPP-A is necessary in the early phases of the process for expeditious fracture repair. The ability of PAPP-A to enhance local IGF action may be an important mechanism for optimizing the fracture repair response.