Angiogenesis and Anti-Angiogenic Treatment in Prostate Cancer: Mechanisms of Action and Molecular Targets.

Prostate cancer (PC) is the most common cancer in men and the second leading cause of cancer-related death worldwide. Many therapeutic advances over the last two decades have led to an improvement in the survival of patients with metastatic PC, yet the majority of these patients still succumb to their disease. Antiagiogenic therapies have shown substantial benefits for many types of cancer but only a marginal benefit for PC. Ongoing clinical trials investigate antiangiogenic monotherapies or combination therapies. Despite the important role of angiogenesis in PC, clinical trials in refractory castration-resistant PC (CRPC) have demonstrated increased toxicity with no clinical benefit. A better understanding of the mechanism of angiogenesis may help to understand the failure of trials, possibly leading to the development of new targeted anti-angiogenic therapies in PC. These could include the identification of specific subsets of patients who might benefit from these therapeutic strategies. This paper provides a comprehensive review of the pathways involved in the angiogenesis, the chemotherapeutic agents with antiangiogenic activity, the available studies on anti-angiogenic agents and the potential mechanisms of resistance.

Validation of the Interagency Integrated Triage Tool in a resource-limited, urban emergency department in Papua New Guinea: a pilot study.

BACKGROUND: The Interagency Integrated Triage Tool (IITT) is a three-tier triage system designed for resource-limited emergency care (EC) settings. This study sought to assess the validity and reliability of a pilot version of the tool in an urban emergency department (ED) in Papua New Guinea. METHODS: A pragmatic observational study was conducted at Gerehu General Hospital in Port Moresby, commencing eight weeks after IITT implementation. All ED patients presenting within the subsequent two-month period were included. Triage assessments were performed by a variety of ED clinicians, including community health workers, nurses and doctors. The primary outcome was sensitivity for the detection of time-critical illness, defined by ten pre-specified diagnoses. The association between triage category and ED outcomes was examined using Cramer's V correlation coefficient. Reliability was assessed by inter-rater agreement between a local and an experienced, external triage officer. FINDINGS: Among 4512 presentations during the study period, 58 (1.3%) were classified as category one (emergency), 967 (21.6%) as category two (priority) and 3478 (77.1%) as category three (non-urgent). The tool's sensitivity for detecting the pre-specified set of time-sensitive conditions was 70.8% (95%CI 58.2-81.4%), with negative predictive values of 97.3% (95%CI 96.7 - 97.8%) for admission/transfer and 99.9% (95%CI 99.7 - 100.0%) for death. The admission/transfer rate was 44.8% (26/58) among emergency patients, 22.9% (223/976) among priority patients and 2.7% (94/3478) among non-urgent patients (Cramer's V=0.351, p=0.00). Four of 58 (6.9%) emergency patients, 19/976 (2.0%) priority patients and 3/3478 (0.1%) non-urgent patients died in the ED (Cramer's V=0.14, p=0.00). The under-triage rate was 2.7% (94/3477) and the over-triage rate 48.2% (28/58), both within pre-specified limits of acceptability. On average, it took staff 3 minutes 34 seconds (SD 1:06) to determine and document a triage category. Among 70 observed assessments, weighted κ was 0.84 (excellent agreement). INTERPRETATION: The pilot version of the IITT demonstrated acceptable performance characteristics, and validation in other EC settings is warranted. FUNDING: This project was funded through a Friendship Grant from the Australian Government Department of Foreign Affairs and Trade and an International Development Fund Grant from the Australasian College for Emergency Medicine Foundation.