Citations

As part of a multicenter trial, 70 individuals with insulin-dependent diabetes were randomized to either conventional insulin therapy (CIT) or continuous subcutaneous insulin infusion (CSII). In order to standardize patient selection in the six participating centers, one of the eligibility criteria was the demonstration that each patient had no residual endogenous insulin secretion as assessed by plasma C-peptide determinations. The patients were of average (± SEM) age of 33.0 ± 1.6 yr, had had diabetes for a mean (±SEM) duration of 17.4 ± 1.1 yr, and had both fasting and postglucagon stimulation C-peptide values of <0.1 pmol/ml, consistent with clinically insignificant endogenous insulin secretion. There was no change in C-peptide response at 4 or 8 mo compared with baseline values, whether or not the patient's glucose control remained unchanged (CIT group) or significantly improved to near-normoglycemia (CSII group). In a subgroup of 34 patients at three centers, the 24-h mean glucose concentration was significantly lower in the CSII group compared with the CIT group at 4 mo (126 ± 10 versus 176 ± 14 mg/dl) and at 8 mo (121 ± 5 versus 183 ± 15 mg/dl) (P < 0.005). Although the 24-h mean serum free immunoreactive insulin levels were shown to be no different at baseline (27.4 ± 3.8 versus 26.2 ± 3.1 μU/ml) or after 4 mo (22.5 ± 3.2 versus 25.6 ± 3.2) or 8 mo (26.5 ± 3.4 versus 28.8 ± 3.4) of CIT or CSII therapy, respectively, the mean increase of free insulin concentrations in relation to the main meals was greater in the CSII group (P < 0.05). The mean serum free insulin levels achieved with both CIT and CSII were significantly greater than the 24-h mean free insulin level obtained in 12 normal subjects (12.2 ± 1.4 μU/ml) (P < 0.001).

Background— Among patients with severe aortic stenosis (AS) and preserved ejection fraction, those with low gradient (LG) and reduced stroke volume may have an adverse prognosis. We investigated the prognostic impact of stroke volume using the recently proposed flow-gradient classification. Methods and Results— We examined 1704 consecutive patients with severe AS (aortic valve area <1.0 cm 2 ) and preserved ejection fraction (≥50%) using 2-dimensional and Doppler echocardiography. Patients were stratified by stroke volume index (<35 mL/m 2 [low flow, LF] versus ≥35 mL/m 2 [normal flow, NF]) and aortic gradient (<40 mm Hg [LG] versus ≥40 mm Hg [high gradient, HG]) into 4 groups: NF/HG, NF/LG, LF/HG, and LF/LG. NF/LG (n=352, 21%), was associated with favorable survival with medical management (2-year estimate, 82% versus 67% in NF/HG; P <0.0001). LF/LG severe AS (n=53, 3%) was characterized by lower ejection fraction, more prevalent atrial fibrillation and heart failure, reduced arterial compliance, and reduced survival (2-year estimate, 60% versus 82% in NF/HG; P <0.001). In multivariable analysis, the LF/LG pattern was the strongest predictor of mortality (hazard ratio, 3.26; 95% confidence interval, 1.71–6.22; P <0.001 versus NF/LG). Aortic valve replacement was associated with a 69% mortality reduction (hazard ratio, 0.31; 95% confidence interval, 0.25–0.39; P <0.0001) in LF/LG and NF/HG, with no survival benefit associated with aortic valve replacement in NF/LG and LF/HG. Conclusions— NF/LG severe AS with preserved ejection fraction exhibits favorable survival with medical management, and the impact of aortic valve replacement on survival was neutral. LF/LG severe AS is characterized by a high prevalence of atrial fibrillation, heart failure, and reduced survival, and aortic valve replacement was associated with improved survival. These findings have implications for the evaluation and subsequent management of AS severity.

Objective: To summarize the pharmacology, development, and clinical application of sorafenib, a specific tyrosine kinase and vascular growth factor inhibitor, for the treatment of renal cell carcinoma (RCC). Data Sources: Clinical literature, including both primary studies and review articles, was obtained by searching MEDLINE (1966–May 2006), using the search terms BAY 43-9006, sorafenib, renal cell carcinoma, and tyrosine kinase inhibitor. Additional information was supplied by the manufacturer, Bayer HealthCare Pharmaceuticals. Study Selection and Data Extraction: Review articles, abstracts, and clinical studies related to sorafenib were analyzed. An evaluation of the research exploring sorafenib as a potential therapy for RCC was conducted. Relevant information was then selected and is reviewed in this article. Data Synthesis: Knowledge of the cellular abnormalities that can cause solid tumors has led to the development of medications that block these pathways. Sorafenib is an oral tyrosine kinase inhibitor that both blocks the Raf kinase pathway and inhibits vascular growth factors. Phase I and II trials have demonstrated that sorafenib has activity against RCC. Dermatologic reactions (rash, desquamation), fatigue, and hypertension have been the most commonly seen treatment-related adverse events. Sorafenib received FDA approval in December 2005 for treatment of advanced RCC. Conclusions: Sorafenib is a novel oral tyrosine kinase inhibitor effective in the treatment of RCC.

Objective: To report a case in which a young woman receiving medroxyprogesterone acetate injections developed deep vein thrombosis (DVT) after prolonged travel. Case Summary: An obese 27-year-old African American woman who had been receiving medroxyprogesterone acetate injections 150 mg intramuscularly every 3 months for 6 years experienced DVT after a 56-hour car ride. The patient's known risk factors for DVT included immobility, obesity (140 kg), and medroxyprogesterone acetate therapy. Family and personal history for thrombotic events were denied. Tests were performed after detection of the DVT to assess the patient for anticoagulation defects; results revealed an unidentified underlying protein S deficiency. All other test results were within normal limits. Discussion: Based on the Naranjo probability scale, it is possible that the DVT experienced by our patient was due to medroxyprogesterone acetate. Although she did have other risk factors for DVT, her underlying protein S deficiency was diagnosed after the thrombosis. Literature describing the relationship between the injectable form of contraception and thrombosis is limited. Therefore, this report reviews protein S deficiency, the relationship between oral contraceptives (OCs) and thrombosis, the influence of immobility on thrombosis development, and the clinical implications of evaluating patients for underlying inherited clotting abnormalities before initiating OCs. Conclusions: When considering whether to prescribe contraceptives, clinicians should assess the patient's risk factors for thrombosis, such as family or personal history. Although generally not recommended, prescreening tests may be considered if there is a positive family or personal history.

Abstract Physical activity may be associated with reduced risk of gastric cancer. We performed a systematic review and meta-analysis to evaluate the magnitude of the association and the quality of supporting evidence. After a comprehensive search of bibliographic databases and conference proceedings through February 2013 for observational studies that examined associations between recreational and/or occupational physical activity and gastric cancer risk, we identified 16 studies (seven cohort, nine case control) reporting 11,111 cases of gastric cancer among 1,606,760 patients. Summary adjusted-OR estimates with 95% confidence intervals (CI) were estimated using the random-effects model. Meta-analysis demonstrated that the risk of gastric cancer was 21% lower among the most physically active people as compared with the least physically active people (OR = 0.79; 95% CI, 0.71–0.87) with moderate heterogeneity among studies (I2 = 55%). This protective effect was seen for gastric cancers in the cardia (four studies; OR = 0.80; 95% CI, 0.63–1.00) and distal stomach (five studies; OR = 0.63; 95% CI, 0.52–0.76). The effect size was significantly smaller in high-quality studies (six studies; OR = 0.86; 95% CI, 0.75–0.99), as compared with low-quality studies (10 studies; OR = 0.74; 95% CI, 0.69–0.81). The results were consistent across sex, study quality, study design, and geographic location. In conclusion, meta-analysis of published observational studies indicates that physical activity is associated with reduced risk of gastric cancer. Lifestyle interventions focusing on increasing physical activity may decrease the global burden of gastric cancer, in addition to a myriad of other health benefits. Cancer Prev Res; 7(1); 12–22. ©2013 AACR.

Accumulation of visceral fat, more so than subcutaneous fat, is strongly associated with severe metabolic complications. However, the factors regulating depot-specific adipogenesis are poorly understood. In this study, we show differential expression of pregnancy-associated plasma protein-A (PAPP-A), a secreted regulator of local insulin-like growth factor (IGF) action, in adipose tissue of mice. PAPP-A mRNA expression was fivefold higher in visceral (mesenteric) fat compared with subcutaneous (inguinal, subscapular), perirenal, and brown fat of mice. To investigate the possible role of depot-specific PAPP-A expression in fat accumulation, wild-type (WT) and PAPP-A knockout (KO) mice were fed a high-fat diet (HFD) for up to 20 wk. Adipocyte size increased in subcutaneous and perirenal depots similarly in WT and PAPP-A KO mice. However, fat cell size and in vivo lipid uptake were significantly reduced in mesenteric fat of PAPP-A KO compared with WT mice. After 20 wk on HFD, phosphorylation of AKT, a downstream signaling intermediate of IGF-I and insulin receptor activation, was significantly decreased by 50% in mesenteric compared with subcutaneous fat in WT mice, but was significantly increased threefold in mesenteric compared with subcutaneous fat in PAPP-A KO mice. This appeared to be because of enhanced insulin-stimulated signaling in mesenteric fat of PAPP-A KO mice. These data establish fat depot-specific expression of PAPP-A and indicate preferential impact of PAPP-A deficiency on visceral fat in the mouse that is associated with enhanced insulin receptor signaling. Thus, PAPP-A may be a potential target for treatment and/or prevention strategies for visceral obesity and related morbidities.

AbstractBackground: It is widely accepted that chronic inflammation plays a role in the etiology of colorectal cancer. Using a two-stage design, we examined the associations between colorectal cancer and common variation in 37 key genes in the inflammation and innate immunity pathways.Methods: In the discovery stage, 2,322 discordant sibships (2,535 cases, 3,915 sibling controls) from the Colorectal Cancer Family Registry were genotyped for more than 600 tagSNPs and 99 single-nucleotide polymorphisms (SNP) were selected for further examination based on strength of association. In the second stage, 351 SNPs tagging gene regions covered by the 99 SNPs were tested in 4,783 Multiethnic Cohort subjects (2,153 cases, 2,630 controls).Results: The association between rs9858822 in the PPARG gene and colorectal cancer was statistically significant at the end of the second stage (OR per allele = 1.36, Bonferroni-adjusted P = 0.045), based on the “effective” number of markers in stage II (n = 306). The risk allele C was common (frequency 0.3) in African Americans but rare (frequency &lt; 0.03) in whites, Japanese Americans, Latinos, and Native Hawaiians. No statistically significant heterogeneity of effects across race/ethnicity, body mass index (BMI) levels, regular aspirin use, or pack-years of smoking was detected for this SNP. Suggestive associations were also observed for several SNPs in close vicinity to rs9858822.Conclusions: Our results provide new evidence of association between PPARG variants and colorectal cancer risk.Impact: Further replication in independent samples is warranted. Cancer Epidemiol Biomarkers Prev; 22(11); 2094–101. ©2013 AACR.

The use of charged-particle radiation therapy (CPRT) is an increasingly important development in the treatment of cancer. One of the most pressing controversies about the use of this technology is whether randomised controlled trials are required before this form of treatment can be considered to be the treatment of choice for a wide range of indications. Equipoise is the key ethical concept in determining which research studies are justified. However, there is a good deal of disagreement about how this concept is best understood and applied in the specific case of CPRT. This report is a position statement on these controversies that arises out of a workshop held at Wolfson College, Oxford in August 2011. The workshop brought together international leaders in the relevant fields (radiation oncology, medical physics, radiobiology, research ethics and methodology), including proponents on both sides of the debate, in order to make significant progress on the ethical issues associated with CPRT research. This position statement provides an ethical platform for future research and should enable further work to be done in developing international coordinated programmes of research.