Acute Liver Failure (ALF) still presents high mortality rates, and liver transplant is the only treatment with proven efficacy. However transplant is not always possible and systems for Extracorporeal Liver Support (ELS) are being developed which can treat patients with ALF, for whom a transplant is not available, or is delayed. They can also treat patients with chronic liver disease who develop ALF. There are two types of ELS: artificial systems (hemoperfusion, plasmaperfusion, therapeutic plasma exchange, continuous hemodialysis and high volume continuous hemofiltration) and bioartificial systems. These are based on a biological component (animal or human hepatocytes) inserted into a bioreactor, whose main function is to perform the metabolic activity and synthesis that the liver can no longer perform. The results obtained in clinical trials have so far shown that the best results in terms of compensating for lost metabolic function and detoxification are obtained inserting artificial components in the bioartificial circuit.
Whereas clinical trials of cancer drugs have methodological standards and conventional primary endpoints, these are not necessarily applicable to the clinical development of loco-regional treatments and new medical devices. The current challenge is to generate high-level clinical evidence for loco-regional treatments to define the benefits for patients. In this article, we argue that, to generate convincing evidence of clinical efficacy and safety, the collective coherence of the entire data package is often more important than the primary endpoint of one clinical trial. We also propose that, when a comprehensive clinical data package is not feasible, limited clinical data can be supplemented with other types of evidence. Emerging life science companies often define the "valley of death" after securing initial investment to translate an early medical device concept to a development stage that is attractive to funders. Unfortunately for this industry, there is a second "valley of death" if the focus and goal is only regulatory approval, to the neglect of clinical acceptance and reimbursement. For the emerging specialism of interventional oncology, it is critical to plan a clear line of sight for each new medical device to avoid the valleys of death and to demonstrate the clinical benefit. Increased international guidance to establish realistic yet convincing standards in this area may avoid attrition of potentially beneficial devices and therapeutic procedures in the valleys of death.
OpinionJ Liver Res Disord Ther 2017, 3(2): 00050 and Interventional Oncology (IO) is the discipline that deals with them. The lesion is reached, normally by interventional radiologists, using sophisticated medical devices, through percutaneous or trans-arterial access; some form of necrotising agent (chemotherapy, beta-emission, thermal energy, etc) is then released in or in the immediate proximity of the lesion, thus maximising local efficacy, and in the same time minimising systemic toxicity.The growth of this discipline as a valid option to be considered in the treatment of liver cancer is, however, negatively influenced by the limited number of referrals from medical oncologists; this is mainly due to the relative lack of solidity of clinical evidence, for two main reasons: (1) the challenges in applying to IO clinical trials the standards established by clinical trials of chemotherapy; and (2) the regulatory framework for medical devices, often not conducive to the set up of adequate clinical trials.
In their excellent review (JPEN 11:72-80, 1988) Kirby, Fiorenza, and Craig stressed the limited number of papers about the safety of amino acid solutions used for iv nutritional support during pregnancy.In the little existing literature, placental transfer and immature or leaky blood brain barrier (BBB) influence on neurotoxicity of some amino acids; glutamic and aspartic acids (putative neurotransmitters) were carefully examined about 10 years ago in a Mario Negri Institute Monograph edited by Filer et all More recently, interesting experimental results have been achieved on placental amino acid transfer' together with toxicological data on phenylalanine and sulfur amino acid administration in newborn babies.3-s Considering the still unclear amino acid transfer properties of the healthy human placenta and the existence of brain areas without a BBB, a detailed analysis of amino acid solutions is needed before a long-term intravenous administration, especially in the last 3 months of pregnancy.In our opinion potentially neurotoxic amino acids (glutamic acid, aspartic acid, phenylalanine, methionine, glycine etc.) must meet the minimum requirements for the best long-term protein synthesis, while probably other amino acids (tyrosine, cysteine, taurine, etc.) have to be added to routine formulations for the same purpose.Recent clinical literature reported that, unlike standard formulations, updated pediatric amino acid solutions are nutritionally satisfactory for the newborn baby, avoiding abnormal SGOT, SGPT, gamma GT, bilirubin serum values.' Other authors suggest pediatric solutions also for very depleted and for acute uremic patients submitted to CAVH or other intensive dialytic treatment. lO, m Further experimental and clinical studies on the use of amino acid solutions in normal and difficult pregnancies are needed; however we believe that updated crystalline amino acid solutions, which claim to meet the specific amino acid needs of infants, have to be preferred for a better parenteral nutrition of the pregnant woman and to protect the growing fetus.
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