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Total pancreatectomy with islet autotransplantation (TPIAT) is a reliable therapy to retain endocrine function, to alleviate pain and improve quality of life in adult and pediatric patients suffering from refractory chronic pancreatitis and recurrent acute pancreatitis. Recently, an expansion of indications to include benign and malignant pancreatic disease has been suggested. Improved methods for evaluating the functional quality of islets and predicting transplant outcome have been discussed. Furthermore, this review will discuss the recent advances in the procedure, anti-inflammatory strategies and outcomes of TPIAT.New assays to measure posttransplant islet damage and improved methods to assess islet quality by monitoring the oxygen consumption rate have shown great promise. Anti-inflammatory strategies such as an interleukin-1 receptor antagonist, α-1 antitrypsin, tumor necrosis factor α inhibitor and an inhibitor of CXCR1/2 have been widely investigated under clinical trials.The primary objective of TPIAT, which is to relieve pain and reduce narcotic usage, has been shown to have long-term success. However, achieving long-term insulin independence is still a challenge that needs to be addressed. The mechanism that leads to chronic graft failure in TPIAT needs to be delineated.