Animal models of fulminant hepatic failure

The six requirements for a satisfactory animal model of fulminant hepatic failure are reversibility, reproducibility, death from liver failure, a therapeutic window, a large animal model, and minimal hazard to personnel. Different models may be required to evaluate the various types of liver failure seen in man. The available models include surgical anhepatic and devascularization procedures, as well as hepatotoxic drug administration using agents such as carbon tetrachloride, acetaminophen, or galactosamine. Currently combined surgical and drug models appear to provide the best model but the search for the ideal models continues.Presented at the Proceedings of the International Meeting on Normal and Neoplastic Growth in Hepatology, Bari, Italy, June 1989.     

Impact of MammaPrint on Clinical Decision‐Making in South African Patients with Early‐Stage Breast Cancer

The aim of the study was to evaluate the impact of MammaPrint on treatment decision‐making in patients with breast cancer. Clinicopathologic information of all breast cancer patients referred for MammaPrint testing in South Africa was collected from 2007 until 2014. A total of 107 patients (109 tumors) with estrogen receptor/progesterone receptor positive and human epidermal growth factor receptor‐2 negative tumors were selected with tumors ≥10 mm, or when 1–3 nodes were involved without extra‐nodal extension. None of the clinical indicators correlated significantly with the MammaPrint risk classification, which changed the decision for adjuvant chemotherapy in 52% of patients. Of 60 patients who were clinically high risk, 62% had a low‐risk MammaPrint result and of the 47 clinically low ‐risk patients 40% had a high‐risk MammaPrint result. This study indicates that MammaPrint could reduce the need for adjuvant chemotherapy by 17% using the selection criteria stipulated. The significant impact on treatment decisions confirmed the clinical utility of MammaPrint independent of standard clinicopathologic risk factors as supported by long‐term clinical outcome studies.     

Mapping FACT-P and EORTC QLQ-C30 to Patient Health Status Measured by EQ-5D in Metastatic Hormone-Refractory Prostate Cancer Patients

OBJECTIVES: To construct and validate a prediction model of preference-adjusted health status (EQ-5D) for metastatic hormone-refractory prostate cancer (HRPCA) patients using cancer-specific health-related quality of life (HRQoL) measures. METHODS: Data were obtained from a multicenter, multinational observational study of metastatic HRPCA patients conducted during 2002 to 2004. In addition to clinical and resource utilization, preference-adjusted health status (EQ-5D) and HRQoL (Functional Assessment of Cancer Therapy-Prostate [FACT-P] and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire [EORTC QLQ-C30]) data were collected. Predictive validity of ordinary least square (OLS) and median regressions of various model specifications were tested using cross-validation samples. The selected specification was then further refined and tested for alternative model specifications and restrictions. RESULTS: OLS regression with both HRQoL measures as individual components and patient demographics was the best-performing model. It explained 58.2% of the observed EQ-5D variation in the validation sample. A model including only the prostate cancer-specific HRQoL measure, FACT-P, explained 53.5% of the observed EQ-5D variation. CONCLUSIONS: The models developed have good predictive validity. These algorithms enable researchers to translate cancer-specific HRQoL measures to preference-adjusted health status in metastatic HRPCA patients. The findings will help perform health status adjustments in cost-utility analyses.     

Anastomotic strictures and delayed gastric emptying after esophagectomy: incidence,risk factors and management

The aim of this study was to report the incidence, risk factors, and management of gastric conduit dysfunction after esophagectomy in 177 patients over a 3‐year period in a single center. Patients with anastomotic strictures or delayed gastric emptying (DGE) were identified from a prospective database. Anastomotic strictures occurred in 48 patients (27%). Eighty‐three percent of early anastomotic strictures (<1 year) were benign, and all late strictures (>1 year) were malignant. Dilatation was effective in 98% of benign and 64% of malignant strictures. DGE occurred in 21 patients (12%), and was associated with both anastomotic leak (P = 0.001) and anastomotic stricture (P = 0.001). 4/8 patients with late DGE (>3 months postesophagectomy) were tumor‐related. Pyloric dilatation was effective in 92% of early and 63% of late DGE. Pyloric stents were inserted in 3 patients with tumor‐related DGE. After esophagectomy, early anastomotic strictures (within 1 year) and early delayed gastric emptying (within 3 months) are usually benign and respond to dilatation. However, patients presenting later with tumor‐related obstruction are unlikely to respond to anastomotic or pyloric dilatation and should be stented.     

Report of the xenotransplantation advisory committee of the international society for heart and lung transplantation:: The present status of xenotransplantation and its potential role in the treatment of end-stage cardiac and pulmonary diseases

An urgent and steadily increasing need exists world-wide for a greater supply of donor thoracic organs. Xenotransplantation offers the possibility of an unlimited supply of hearts and lungs that could be available electively when required. However, anti-body- mediated mechanisms cause the rejection of pig organs transplanted into non-human primates, and these mechanisms provide major immunologic barriers that have not yet been overcome. Having reviewed the literature on xenotransplantation, we present a number of conclusions on its present status with regard to thoracic organs, and we make a number of recommendations relating to eventual clinical trials. Although pig hearts have functioned in heterotopic sites in non-human primates for periods of several weeks, median survival of orthotopically transplanted hearts is currently ,1 month. No transplanted pig lung has functioned for even 24 hours. Current experimental results indicate that a clinical trial would be premature. A potential risk exists, hitherto undetermined, of transferring infectious organisms along with the donor pig organ to the recipient, and possibly to other members of the community. A clinical trial of xeno-transplantation should not be undertaken until experts in microbiology and the relevant regulatory authorities consider this risk to be minimal. A clinical trial should be considered when approximately 60% survival of life-supporting pig organs in non-human primates has been achieved for a minimum of 3 months, with at least 10 animals surviving for this minimum period. Furthermore, evidence should suggest that longer survival (.6 months) can be achieved. These results should be achieved in the absence of life-threatening complications caused by the immunosuppressive regimen used. The relationship between the presence of anti-HLA antibody and anti-pig antibody and their cross-reactivity, and the outcome of pig-organ xenotransplantation in recipients previously sensitized to HLA antigens require further investigation. We recommend that the patients who initially enter into a clinical trial of cardiac xenotransplantation be unacceptable for allotransplantation, or acceptable for allotransplantation but unlikely to survive until a human cadaveric organ becomes available, and in whom mechanical assist-device bridging is not possible. National bodies that have wide-reaching government-backed control over all aspects of the trials should regulate the initial clinical trial and all subsequent clinical xenotransplantation procedures for the foreseeable future. We recommend coordination and monitoring of these trials through an international body, such as the International Society for Heart and Lung Transplantation, and setting up a registry to record and widely disperse the results of these trials. Xenotransplantation has the potential to solve the problem of donor-organ supply, and therefore research in this field should be actively encouraged and supported.     

Cellular/extracellular matrix cross‐talk in scar evolution and control

The principles of scar evolution and control are recognized and defined. Further clarity has been shed on these principles with the elucidation and elaboration of the sequence of events occurring at a molecular level. Cellular cross‐talk among structures in the cell cytosol, in the cellular nucleus, and outside the cell within in the extracellular matrix is continuous and controlling in nature. This interaction or “dynamic reciprocity” takes place via a series of signals, ionic messenger shifts, protein activation, and receptor transactions. The described principles are now able to be defined in terms of cellular/extracellular matrix interactions and the identification of the cross‐talk involved in scar evolution and maturation presents the possibility of influencing the “wording” of this cross‐talk to improve scar outcome. The principles of mechanostimulation and scar support, hydration occlusion, controlled inflammation, and collagen/extracellular remodeling are discussed with possible interventions in each category.