Citations

Purpose Although it is well-established that fluorouracil- (FU-) based adjuvant therapy improves survival for patients with resected high-risk colon cancer, the magnitude of adjuvant therapy benefit across specific subgroups and for individual patients has been uncertain. Patients and Methods Using a pooled data set of 3,302 patients with stage II and III colon cancer from seven randomized trials comparing FU + leucovorin or FU + levamisole to surgery alone, we performed an analysis based on a Cox proportional hazards regression model. Treatment, age, sex, tumor location, T stage, nodal status, and grade were tested for both prognostic and predictive significance. Model derived estimates of 5-year disease-free survival and overall survival (OS) for surgery alone and surgery plus FU-based therapy were calculated for a range of patient subsets. Results Nodal status, T stage, and grade were the only prognostic factors independently significant for both disease-free survival and OS. Age was significant only for OS. In a multivariate analysis, adjuvant therapy showed a beneficial treatment effect across all subsets. Treatment benefits were consistent across sex, location, age, T-stage, and grade. A significant stage by treatment interaction was present, with treatment benefiting stage III patients to a greater degree than stage II patients. Conclusion Patients with high-risk resected colon cancer obtain benefit from FU-based therapy across subsets of age, sex, location, T stage, nodal status, and grade. Model estimates of survival stratified by T stage, nodal status, grade, and age are available at http://www.mayoclinic.com/calcs . This information may improve patients' and physicians' understanding of the potential benefits of adjuvant therapy.

Background— Hypercholesterolemia (HC) and atherosclerosis can elicit oxidative stress, coronary endothelial dysfunction, and myocardial ischemia, which may induce growth-factor expression and lead to myocardial neovascularization. We tested the hypothesis that chronic antioxidant intervention in HC would attenuate neovascularization and preserve the expression of hypoxia-inducible factor (HIF)-1α and vascular endothelial growth factor (VEGF). Methods and Results— Three groups of pigs (n=6 each) were studied after 12 weeks of normal or 2% HC diet or HC+antioxidant supplementation (100 IU/kg vitamin E and 1 g vitamin C daily). Myocardial samples were scanned ex vivo with a novel 3D micro-CT scanner, and the spatial density and tortuosity of myocardial microvessels were determined in situ. VEGF mRNA, protein levels of VEGF and VEGF receptor-1, HIF-1α, nitrotyrosine, and superoxide dismutase (SOD) were determined in myocardial tissue. The HC and HC+antioxidant groups had similar increases in serum cholesterol levels. HC animals showed an increase in subendocardial spatial density of microvessels compared with normal (160.5±11.8 versus 95.3±8.2 vessels/cm 2 , P <0.05), which was normalized in HC+antioxidant (92.5±20.5 vessels/cm 2 , P <0.05 versus HC), as was arteriolar tortuosity. In addition, HC induced upregulation of VEGF, HIF-1α, and nitrotyrosine expression and decreased SOD expression and activity, all of which were preserved by antioxidant intervention. Conclusions— Changes in myocardial microvascular architecture invoked by HC are accompanied by increases in HIF-1α and VEGF expression and attenuated by antioxidant intervention. This underscores a role of increased oxidative stress in modulating myocardial microvascular architecture in early atherogenesis.

Background Previous studies suggest that intraoperative anesthetic care may influence postoperative pain and recovery from surgery. The authors tested the hypothesis that the addition of intrathecal analgesia to general anesthesia would improve long-term functional status and decrease pain in patients undergoing radical retropubic prostatectomy. Methods One hundred patients received either general anesthesia supplemented with intravenous fentanyl or general anesthesia preceded by intrathecal administration of bupivacaine (15 mg), clonidine (75 microg), and morphine (0.2 mg). Patients and providers were masked to treatment assignment. All patients received multimodal pain management postoperatively. Primary outcomes included pain and functional status over the first 12 postoperative weeks. Results Patients receiving intrathecal analgesia required more intravenous fluids and vasopressors intraoperatively. Pain was well controlled throughout the study (mean numerical pain scores < 3 in both groups at all times studied). Intrathecal analgesia decreased pain and supplemental intravenous morphine use over the first postoperative day but increased the frequency of pruritus. Pain and functional status after discharge from the hospital did not differ between groups. Intrathecal analgesia significantly decreased the duration of hospital stay (from 2.8 +/- 2.0 to 2.1 +/- 0.5 days; P < 0.01) as a result of five patients in the control group who stayed in the hospital more than 3 days. Conclusions The benefits of improved immediate analgesia and decreased morphine requirements resulting from intrathecal analgesia must be weighed against factors such as pruritus, increased intraoperative requirement for fluids and vasopressors, and resources needed to implement this modality. Further studies are needed to determine the significance of the decrease in duration of hospital stay.

Abstract Primary aldosteronism (PA) is a common form of endocrine hypertension previously believed to account for less than 1% of hypertensive patients. Hypokalemia was considered a prerequisite for pursuing diagnostic tests for PA. Recent studies applying the plasma aldosterone/plasma renin activity ratio (ARR) as a screening test have reported a higher prevalence. This study is a retrospective evaluation of the diagnosis of PA from clinical centers in five continents before and after the widespread use of the ARR as a screening test. The application of this strategy to a greater number of hypertensives led to a 5- to 15-fold increase in the identification of patients affected by PA. Only a small proportion of patients (between 9 and 37%) were hypokalemic. The annual detection rate of aldosterone-producing adenoma (APA) increased in all centers (by 1.3–6.3 times) after the wide application of ARR. Aldosterone-producing adenomas constituted a much higher proportion of patients with PA in the four centers that employed adrenal venous sampling (28–50%) than in the center that did not (9%). In conclusion, the wide use of the ARR as a screening test in hypertensive patients led to a marked increase in the detection rate of PA.

Acute injury to the intestinal mucosa is a major dose-limiting complication of abdominal radiation therapy. We studied the role of the transcription factor NF-κB in protection against radiation-induced apoptosis in the intestinal epithelium in vivo . We use mice in which NF-κB signaling through IκB-kinase (IKK)-β is selectively ablated in intestinal epithelial cells to show that failure to activate epithelial cell NF-κB in vivo results in a significant increase in radiation-induced epithelial cell apoptosis. Furthermore, bacterial lipopolysaccharide, which is normally a radioprotective agent, is radiosensitizing in IKKβ-deficient intestinal epithelial cells. Increased apoptosis in IKKβ-deficient intestinal epithelial cells was accompanied by increased expression and activation of the tumor suppressor p53 and decreased expression of antiapoptotic Bcl-2 family proteins. These results demonstrate the physiological importance of the NF-κB system in protection against radiation-induced death in the intestinal epithelium in vivo and identify IKKβ as a key molecular target for radioprotection in the intestine. Selective preactivation of NF-κB through IKKβ in intestinal epithelial cells could provide a therapeutic modality that allows higher doses of radiation to be tolerated during cancer radiotherapy.

Pregnancy-associated plasma protein A (PAPPA) is a metzincin superfamily metalloproteinase in the insulin-like growth factor (IGF) system. PAPPA increases IGF bioavailability and mitogenic effectiveness in vitro through regulated cleavage of IGF-binding protein 4 (IGFBP4). To determine its function in vivo, we generated PAPPA-null mice by gene targeting. Mice homozygous for targeted disruption of the PAPPA gene were viable but 60% the size of wild-type littermates at birth. The impact of the mutation was exerted during the early embryonic period prior to organogenesis, resulting in proportional dwarfism. PAPPA, IGF2 and IGFBP4 transcripts co-localized in wild-type embryos, and expression of IGF2 and IGFBP4 mRNA was not altered in PAPPA-deficient embryos. However,IGFBP4 proteolytic activity was completely lacking in fibroblasts derived from PAPPA-deficient embryos, and IGFBP4 effectively inhibited IGF-stimulated mitogenesis in these cells. These results provide the first direct evidence that PAPPA is an essential growth regulatory factor in vivo, and suggest a novel mechanism for regulated IGF bioavailability during early fetal development.

A polymorphism in the gene encoding the β2-adrenergic receptor (arginine or glycine at amino acid position 16) is associated with altered vasodilator responses to β2-agonists, which may modulate the pressor response to endogenous catecholamines during stress. To test the hypothesis that the Arg16/Gly polymorphism is associated with differences in acute pressor responses to sympathoexcitation, we measured mean arterial pressure (MAP, Finapres) and heart rate (HR, ECG) during mental stress (MS), cold pressor test (CPT), and handgrip (HG) to fatigue in 31 healthy, nonobese, normotensive adults (mean age ± SE: 31 ± 1; 16 females). Subjects were homozygous for Gly16 ( n = 16) or Arg16 ( n = 15). Both groups had similar baseline MAP (Arg16, 86 ± 3 mmHg; Gly16, 89 ± 2 mmHg; P = 0.4) and HR (Arg16, 68 ± 2 beats/min; Gly16, 65 ± 3 beats/min; P = 0.3). For MS and CPT, MAP and HR did not differ between genotype groups. Handgrip also produced similar increases in MAP; however, the change in HR was greater in the Gly16 homozygotes ( PANOVA= 0.001, genotype-by-time interaction). During HG, peak HR at fatigue was 100 ± 4 beats/min for Gly16 (54% increase from rest) vs. 93 ± 3 beats/min for Arg16 (37% increase). We conclude that the cardiovascular responses to MS and CPT do not differ between Gly16 and Arg16 homozygotes. However, the greater HR response to exercise in the Gly16 homozygotes may serve to maintain the pressor response (increased cardiac output) in the face of augmented peripheral vasodilation (decreased total peripheral resistance) in this group.