Quality of life: A critical outcome for all surgical treatments of gastric cancer.

Surgery represents the main curative therapeutic modality for gastric cancer, and it is occasionally considered for palliation as well as prophylaxis. Most frequently, surgical outcomes are conveyed in terms of oncological outcomes such as recurrence and survival. However, quality of life (QoL) is also important and should be considered when making treatment decisions - including the extent of and approach to surgery. Measurement of QoL usually involves the application of questionnaires. While there are multiple QoL questionnaires validated for use in oncology patients, there are very few that have been validated for use in those with gastric cancer. In this review, we discuss and compare the current status of QoL questionnaires in gastric cancer. More importantly, the impact of surgery for treatment, palliation and prophylaxis of gastric cancer on QoL will be described. These data should inform the surgeon on the optimal approach to treating gastric cancer, taking into account oncological outcomes. Knowledge gaps are also identified, providing a roadmap for future studies.

Caspase inhibitor IDN6556 facilitates marginal mass islet engraftment in a porcine islet autotransplant model.

BACKGROUND: Large numbers of islets are lost in the early phase after clinical islet transplantation, through apoptosis, necrosis, or innate inflammatory injury. We previously demonstrated the efficacy of a series of caspase inhibitors in mouse models on islet engraftment through reduction in early posttransplant apoptosis. We studied IDN6556, a caspase inhibitor with a first-pass effect, in a large animal (pig) intraportal marginal mass islet autotransplant model. METHODS: Total pancreatectomy and marginal mass islet autotransplantation were carried out in Yucatan miniature swine to explore the effects of IDN6556 on islet engraftment. Pigs were treated with IDN6556 at a dose of 20 mg/kg orally twice daily (n=7) or phosphate-buffered saline control (n=6) orally for 7 days, and blood glucose was monitored for 1 month. Glucose tolerance and acute insulin release were determined at 1 month. RESULTS: There were no differences in islet procurement, isolation, or islet functional parameters between the two groups. Pigs receiving IDN6556 had lower fasting blood glucose level after transplantation and a higher percentage (100% vs. 33.3%) showed fasting blood glucose levels less than 11 mM. This translated into an enhanced metabolic reserve and acute insulin release for pigs in the treatment group. CONCLUSIONS: IDN6556 led to enhanced islet engraftment in this large animal islet transplant model. Although this study has limitations including a short interval of study (1 month) and the use of unpurified islets, the results justify early clinical trials of IDN6556 in islet transplantation.

Sirolimus drug-eluting, hydrogel-impregnated polypropylene mesh reduces intra-abdominal adhesion formation in a mouse model.

BACKGROUND: Prosthetic mesh is used frequently in abdominal wall hernia reconstruction but is prone to postoperative adhesion formation. Complications resulting from intra-abdominal adhesions represent a considerable clinical and cost burden. We, herein, investigate the antiproliferative and antiadhesiogenic properties of sirolimus and hydrogel-impregnated, drug-eluting mesh to decrease such complications in a mouse model of abdominal wall hernia repair. METHODS: A 1 × 1cm(2) polypropylene mesh from 1 of 3 groups (group 1, plain control; group 2, hydrogel [2% agarose]; and group 3, hydrogel + 10 mcg sirolimus) was implanted operatively into the peritoneal cavity of BALB/c mice and followed for up to 4 weeks. Adhesions were scored by percent surface area of mesh (range, 0-100%), severity (range, 0-3), and tenacity (range, 0-4). Representative samples were assessed by scanning electron microscopy. RESULTS: Mesh impregnated with the combination of hydrogel and sirolimus led to a significant decrease in adhesion formation. The percent surface area of adhesional attachment to mesh was decreased from 100.0 ± 0% in the plain mesh control group versus 18 ± 8% (P < .001) in the combined impregnated mesh group. Similarly, adhesion severity scores were decreased from a score of 2.9 ± 0.1 (plain mesh) versus 1.4 ± 0.1 (sirolimus/hydrogel-impregnated mesh) (P < .001). Scores for tenacity were also decreased markedly from 3.5 ± 0.2 (plain mesh) versus 1.5 ± 0.1 (sirolimus/hydrogel-impregnated mesh (P < .001). CONCLUSION: Creation of a sirolimus drug-eluting and hydrogel-impregnated polypropylene mesh resulted in marked decrease of adhesion formation in this mouse model, was well tolerated without side effects, and has potential for clinical application.

Resveratrol fails to improve marginal mass engraftment of transplanted islets of Langerhans in mice.

One limitation of current islet transplantation protocols is the loss of up to 70% of the transplanted islet mass. Inflammatory events play a major role in islet loss including the cytokines TNFα and IL-1. Resveratrol, a compound with anti-inflammatory and anti-oxidant properties, has the potential to mitigate islet loss. Using a syngeneic marginal  after mouse islet transplantation model we tested the ability of resveratrol to enhance islet engraftment. We failed to show a difference in diabetes reversal between mice treated with vehicle and those treated with either 10 mg/kg (47.1% for resveratrol vs. 35.3% for control) or 50 mg/kg (20% for resveratrol vs. 22.2% for control) of resveratrol daily for three weeks. In addition, at one month there was no difference in glucose tolerance or graft survival (10 mg/kg: 552.6 ng/ml resveratrol group vs. 576.6 ng/ml control group; 50 mg/kg: 463 ng/ml resveratrol group vs. 444.1 ng/ml control group). In summary, over a wide range of doses, resveratrol did not exert a benefit on mouse islet engraftment. Further studies should be conducted with human islets before deeming resveratrol ineffective in islet engraftment and survival.

Histopaque provides optimal mouse islet purification kinetics: comparison study with Ficoll, iodixanol and dextran.

Islet transplantation has become a very promising treatment for type 1 diabetes. To facilitate further clinical improvements in this exciting field, rodent islets are used to evaluate new strategies and modifications. One method to purify islets is on a density gradient, although the optimal gradient component can be debated. N=6 separate mouse islet isolations were used and the resulting islets were separated and purified on either a Ficoll, Histopaque, Dextran or Iodixanol gradient. Islets were assessed for recovery, viability, purity and in vitro functionality. Aliquots were transplanted into diabetic mice to assess in vivo functionality and survival. There was no difference in the number of islets recovered across groups nor in the size of recovered islets. Use of a Ficoll or Histopaque gradient led to the most pure and viable islets in comparison to Dextran and Iodixanol. Functionally, islets isolated on a Ficoll gradient had the highest glucose-stimulated insulin release in vitro while performing equally to Histopaque and Dextran gradients in vivo. Using a Ficoll gradient, however, comes at a higher monetary cost. We recommend using a Histopaque gradient, which led to the isolation of viable and functional islets with a reduced cost as compared to a Ficoll gradient.

Are stem cells a cure for diabetes?

With the already heightened demand placed on organ donation, stem cell therapy has become a tantalizing idea to provide glucose-responsive insulin-producing cells to Type 1 diabetic patients as an alternative to islet transplantation. Multiple groups have developed varied approaches to create a population of cells with the appropriate characteristics. Both adult and embryonic stem cells have received an enormous amount of attention as possible sources of insulin-producing cells. Although adult stem cells lack the pluripotent nature of their embryonic counterparts, they appear to avoid the ethical debate that has centred around the latter. This may limit the eventual application of embryonic stem cells, which have already shown promise in early mouse models. One must also consider the potential of stem cells to form teratomas, a complication which would prove devastating in an immunologically compromised transplant recipient. The present review looks at the progress to date in both the adult and embryonic stem cells fields as potential treatments for diabetes. We also consider some of the limitations of stem cell therapy and the potential complications that may develop with their use.