A Preliminary Study on the Postoperative Survival of Patients Given Aspirin After Resection for Squamous Cell Carcinoma of the Esophagus or Adenocarcinoma of the Cardia

Background  We examined the effect of aspirin on survival following resection for squamous cell carcinoma (SCC) of the esophagus or adenocarcinoma of the gastric cardia. Methods  Patients who underwent esophagectomy for these cancers between May 2000 and December 2002 were allocated to one of three groups and given daily either a low dose of aspirin, placebo, or no tablets. Results  The 5-year survival for all patients on aspirin (445) was 51.2%, placebo (658) 41%, and no tablet (495) 42.3% (P = 0.04 for difference between treatments). The 5-year survival for all SCC patients on aspirin (267) was 49.8%, placebo (433) 42.2%, and no tablet (343) 41.2% (P = 0.26). There was a significant improvement in survival for patients with adenocarcinoma of the cardia on aspirin compared with the two control groups combined (P = 0.029). Survival for T2N0M0 SCC patients was significantly improved with aspirin (71) compared with placebo (167) or no tablet (134) (P = 0.0004). However, there was no significant difference between the survival curves for T2N0M0 adenocarcinoma patients on aspirin (21) and the two control groups combined (65) (P = 0.29). Conclusions  The results of this preliminary study support further investigation of aspirin as adjuvant therapy to improve survival in subsets of postesophagectomy patients.     

Intersecting Guidelines: Administering Erythropoiesis-Stimulating Agents to Chronic Kidney Disease Patients with Cancer

There has been a dramatic sea change in the use of erythropoiesis-stimulating agents (ESAs) for anemic persons with chronic kidney disease (CKD) or cancer patients undergoing chemotherapy. An important area that has not been addressed previously is a CKD patient who also has a malignancy. Clinical guidelines exist that outline recommended treatments for each disease, but the intersection of the two disease processes presents difficult decisions for patients and physicians. Herein, we review the background underlying recent revisions in clinical alerts and guidelines for ESAs, and provide guidance for treating anemia among CKD patients who are receiving no therapy, chemotherapy with curative intent, or chemotherapy with palliative intent. The guiding principle is that comprehensive assessment of risks and benefits in the relevant clinical setting is imperative.     

Thoracoscopic talc poudrage decreases T-lymphocytes in the peripheral blood

BACKGROUND: Thoracoscopic talc poudrage induces peripheral blood granulocytosis and lymphopenia. The aim of this study is to investigate the type of lymphopenia in patients undergoing thoracoscopic talc poudrage. METHODS: We have measured peripheral blood lymphocyte subsets in 11 patients undergoing thoracoscopic talc poudrage, before (baseline), at 24 and 48 h after the procedure. Lymphocyte numbers were analysed by flow cytometry for the evaluation of the CD3+, CD4+, CD8+ cells (total T-lymphocytes, helper T-lymphocytes, cytotoxic T-lymphocytes, respectively), the CD19+ cells (B-lymphocytes), and the CD16+, CD56+ and CD57+ cells (NK-cells). No anti-inflammatory medication was permitted before, during or after the procedure. RESULTS: Absolute peripheral blood lymphocyte count significantly decreased following thoracoscopic talc poudrage compared to baseline values (p=0.007). Similarly, peripheral blood CD3+, CD4+ and CD8+ lymphocyte counts significantly decreased compared to baseline (p=0.005, 0.02 and 0.03, respectively) with a more prominent reduction of CD3/CD45RO memory cells. No significant difference was found in the absolute number of CD19+, CD16+, CD56+, and CD57+ cells before and after thoracoscopic talc poudrage. CONCLUSION: Patients undergoing thoracoscopic talc poudrage display peripheral blood T-lymphopenia following the procedure.     

Spontaneous diabetes in hemizygous human amylin transgenic mice that developed neither islet amyloid nor peripheral insulin resistance

OBJECTIVES—We sought to 1) Determine whether soluble-misfolded amylin or insoluble-fibrillar amylin may cause or result from diabetes in human amylin transgenic mice and 2) determine the role, if any, that insulin resistance might play in these processes.RESEARCH DESIGN AND METHODS—We characterized the phenotypes of independent transgenic mouse lines that display pancreas-specific expression of human amylin or a nonaggregating homolog, [^25,28,29Pro]human amylin, in an FVB/n background.RESULTS—Diabetes occurred in hemizygous human amylin transgenic mice from 6 weeks after birth. Glucose tolerance was impaired during the mid- and end-diabetic phases, in which progressive β-cell loss paralleled decreasing pancreatic and plasma insulin and amylin. Peripheral insulin resistance was absent because glucose uptake rates were equivalent in isolated soleus muscles from transgenic and control animals. Even in advanced diabetes, islets lacked amyloid deposits. In islets from nontransgenic mice, glucagon and somatostatin cells were present mainly at the periphery and insulin cells were mainly in the core; in contrast, all three cell types were distributed throughout the islet in transgenic animals. [^25,28,29Pro]human amylin transgenic mice developed neither β-cell degeneration nor glucose intolerance.CONCLUSIONS—Overexpression of fibrillogenic human amylin in these human amylin transgenic mice caused β-cell degeneration and diabetes through mechanisms independent from both peripheral insulin resistance and islet amyloid. These findings are consistent with β-cell death evoked by misfolded but soluble cytotoxic species, such as those formed by human amylin in vitro.Increasing evidence indicates that decreased β-cell mass contributes to the impaired insulin secretion characteristic of type 2 diabetes (1–3). Amylin, also referred to as islet amyloid polypeptide, is a 37-amino acid polypeptide (4,5) secreted from pancreatic islet β-cells whose aggregation results in islet amyloid formation in type 2 diabetes (6). Islet amyloid has been reported in 40–90% of pancreases from type 2 diabetic subjects studied post mortem (7–11) and has been linked to both decreased β-cell mass and β-cell dysfunction (12,13). In vitro, human amylin causes apoptosis of islet β-cells, and there is growing evidence that this pathogenic process may contribute to the β-cell deficit in type 2 diabetes (1,2,14,15). However, it remains unresolved whether islet amyloid contributes to the etiopathogenesis of type 2 diabetes or, by contrast, occurs only as a consequence of the disease.Several independent lines of human amylin transgenic mice have been developed to investigate the role of amylin and islet amyloid in the pathogenesis of type 2 diabetes (16–19). The findings and conclusions from phenotypic characterization studies are wide ranging and sometimes at variance. Transgenic animals developed by several research groups did not develop spontaneous diabetes or insulin resistance or exhibit evidence of islet amyloid formation, suggesting that overexpression of human amylin alone was not sufficient to contribute to diabetes development and islet amyloid formation in those models (16–18). In contrast, Janson et al. (19) showed development of spontaneous diabetes in the absence of islet amyloid in homozygous individuals from a further transgenic mouse model, consistent with the view that overexpression of human amylin is sufficient for diabetes development but not islet amyloid formation in that model. It was previously thought that overexpression of human amylin might be sufficient for islet amyloid formation, but some studies have suggested that insulin resistance might also be necessary (20–22).Evidence concerning the role of human amylin in the processes that lead to or cause diabetes remains conflicting, and a clear role for human amylin–mediated β-cell death has not been established at this time, at least in part due to conflicting evidence from the different lines of human amylin transgenic mice. Previous reports have described the noticeable lack of correlation between amyloid deposition and hyperglycemia in other transgenic models of amylin-induced diabetes (21,23). Islets from homozygous individuals from the FVB/n-based line reported by Janson et al. (19) demonstrated a pattern of β-cell loss that closely reflects that in islets from human type 2 diabetic patients (1,3,9), but hemizygous animals from that line reportedly do not develop diabetes.Here, we report a transgenic human amylin mouse model (L13) in which hemizygous individuals developed early-onset diabetes without peripheral insulin resistance and islet amyloid formation. We demonstrate that the disappearance of functional β-cells during the progression of diabetes in this model contributes to the pathogenesis of diabetes. The absence of islet amyloid in the pancreas of transgenic mice before diabetes onset and during its progression, despite the high secretion rates of human amylin, shows that islet amyloid is not required for islet β-cell degeneration and loss of physiological insulin secretion. These findings are consistent with the reports of Janson et al. (19) and provide strong support for continuing exploration of the mechanism by which human amylin evokes β-cell death and contributes to the failure of insulin secretion in type 2 diabetes.