Personalized medicine: caught between hope, hype and the real world.

Genomic and personalized medicine have become buzz phrases that pervade all fields of medicine. Rapid advances in "-omics" fields of research (chief of which are genomics, proteinomics, and epigenomics) over the last few years have allowed us to dissect the molecular signatures and functional pathways that underlie disease initiation and progression and to identify molecular profiles that help the classification of tumor subtypes and determine their natural course, prognosis, and responsiveness to therapies. Genomic medicine implements the use of traditional genetic information, as well as modern pangenomic information, with the aim of individualizing risk assessment, prevention, diagnosis, and treatment of cancers and other diseases. It is of note that personalizing medical treatment based on genetic information is not the revolution of the 21st century. Indeed, the use of genetic information, such as human leukocyte antigen-matching for solid organ transplantation or blood transfusion based on ABO blood group antigens, has been standard of care for several decades. However, in recent years rapid technical advances have allowed us to perform high-throughput, high-density molecular analyses to depict the genomic, proteinomic, and epigenomic make-up of an individual at a reasonable cost. Hence, the so-called genomic revolution is more or less the logical evolution from years of bench-based research and bench-to-bedside translational medicine.

Personalized medicine: caught between hope, hype and the real world

Genomic and personalized medicine have become buzz phrases that pervade all fields of medicine. Rapid advances in "-omics" fields of research (chief of which are genomics, proteinomics, and epigenomics) over the last few years have allowed us to dissect the molecular signatures and functional pathways that underlie disease initiation and progression and to identify molecular profiles that help the classification of tumor subtypes and determine their natural course, prognosis, and responsiveness to therapies. Genomic medicine implements the use of traditional genetic information, as well as modern pangenomic information, with the aim of individualizing risk assessment, prevention, diagnosis, and treatment of cancers and other diseases. It is of note that personalizing medical treatment based on genetic information is not the revolution of the 21st century. Indeed, the use of genetic information, such as human leukocyte antigen-matching for solid organ transplantation or blood transfusion based on ABO blood group antigens, has been standard of care for several decades. However, in recent years rapid technical advances have allowed us to perform high-throughput, high-density molecular analyses to depict the genomic, proteinomic, and epigenomic make-up of an individual at a reasonable cost. Hence, the so-called genomic revolution is more or less the logical evolution from years of bench-based research and bench-to-bedside translational medicine.

Aquaporin 5 gene promoter--1364A/C polymorphism associated with 30-day survival in severe sepsis.

BACKGROUND: Because the aquaporin (AQP) 5 promoter -1364A/C polymorphism is associated with altered AQP5 expression, this association could have an impact on key mechanisms in sepsis, such as cell migration, activity of the rennin-angiotensin- aldosterone system (RAAS), and water transport across biologic membranes. Therefore, we tested the hypothesis that the AQP5 promoter -1364A/C polymorphism is associated with increased 30-day survival in severe sepsis. METHODS: In a prospective study, adults with severe sepsis (N = 154) were genotyped for the AQP5 promoter -1364A/C polymorphism. The clinical endpoint was 30-day survival. Kaplan-Meier plots and multivariate proportional hazard analyses were used to evaluate the relationship between genotypes and clinical outcomes. RESULTS: Thirty-day survival was significantly associated with AQP5 -1364A/C genotypes (P = 0.001). Survival rates were 57% for AA genotypes (n = 90) but 83% for combined AC/CC genotypes (56 vs. 8, respectively). Multivariate proportional hazard analysis including sex, age, Simplified Acute Physiology Score II, Sequential Organ Failure Assessment score, body mass index, necessity for continuous hemofiltration/dialysis, concentrations of plasma angiotensin II, serum aldosterone, C-reactive protein, and interleukin 6 as covariates revealed the AQP5 -1364A/C polymorphism as a strong and independent prognostic factor for 30-day survival. In this analysis, homozygous AA subjects were at high risk for death within 30 days (hazard ratio, 3.59; 95% CI, 1.47-8.80; P = 0.005) compared with AC/CC genotypes. CONCLUSION: The C-allele of the AQP5 -1364A/C polymorphism is associated with increased 30-day survival in patients with severe sepsis. This finding suggests the importance of variations in expression of AQP5 channels in severe sepsis.

Neurologic complications in adult living donor liver transplant patients: an underestimated factor?

Liver transplantation is the only curative treatment in patients with end-stage liver disease. Neurological complications (NC) are increasingly reported to occur in patients after cadaveric liver transplantation. This retrospective cohort study aims to evaluate the incidence and causes of NC in living donor liver transplant (LDLT) patients in our transplant center. Between August 1998 and December 2005, 121 adult LDLT patients were recruited into our study. 17% of patients experienced NC, and it occurred significantly more frequently in patients with alcoholic cirrhosis (42%) and autoimmune hepatitis (43%) as compared with patients with hepatitis B or C (9/10%, P = 0.013). The most common NC was encephalopathy (47.6%) followed by seizures (9.5%). The choice of immunosuppression by calcineurin inhibitor (Tacrolimus or Cyclosporin A) showed no significant difference in the incidence of NC (19 vs. 17%). The occurrence of NC did not influence the clinical outcome, since mortality rate, median ICU stay and length of hospital stay were similar between the two groups. Most patients who survived showed a nearly complete recovery of their NC. NCs occur in approximately 1 in 6 patients after LDLT and seem to be predominantly transient in nature, without major impact on clinical outcome.

Neurological complications after cadaveric and living donor liver transplantation.

Problems related to the central nervous system have a major impact on survival and quality of life. The aim of this retrospective study was to evaluate the incidence of neurological complications after liver transplantation (LT), including both cadaveric and living donor liver transplantation. Between April 2001 and March 2004 174 patients (120 cadaveric liver transplantations, 54 living donor transplantations) were admitted to our intensive care after liver transplantation. Of the transplanted patients 24.7% developed neurological complications. These patients' stay in the intensive care (14.2 +/- 17.2 days) was much longer than that of all admitted patients (8.4 +/- 10.5 days, p < 0.05). The most common neurological complications were encephalopathy (72.1%) and seizures (11.6 %). The incidence of neurological complications in living donor liver transplanted patients was significantly lower than in cadaveric transplantation patients (20.4% vs 26.7 %). The cold ischemia time in living donor transplanted patients was significantly shorter in comparison with cadaveric transplanted patients (215 +/- 119.3 vs. 383.7 +/- 214.7). The survival rate after liver transplantation of patients with neurological complications was lower than that of patients without, but not significantly different (79.1 % vs. 82.4%, p > 0.05). The incidence of neurological symptoms was found to be similar between the patients treated with cyclosporine (25%) and tacrolimus (23.8 %) in this study. In conclusion, there was a high incidence of neurological complications after LT, prolonging the patients' stay in intensive care significantly. The major neurological manifestation in our patients was encephalopathy followed by seizures. Living donor liver transplantation was associated with a significantly lower incidence of neurological complications compared with patients who had received a cadaveric graft. This might be due to the good quality of the organ and the much shorter cold ischemia time of the graft when the donor was alive.