T-cell depletion and graft survival induced by anti-human CD3 immunotoxins in human CD3epsilon transgenic mice

BACKGROUND: Anti-CD3 immunotoxins are broad-spectrum immunosuppressive agents in a wide range of organ transplantation animal models with potential use in eliciting antigen-specific tolerance. However, the anti-CD3 immunotoxins used in animal studies do not cross-react with human T cells, limiting extrapolation to humans and hindering clinical development. METHODS: Three anti-human CD3-directed immunotoxins, DT389-scFv(UCHT1), scFv(UCHT1)-PE38, and UCHT1-CRM9, were compared in vitro and in transgenic mice, tg(epsilon)600+/-, that have T cells expressing both human and murine CD3epsilon antigens. RESULTS: These immunotoxins were extraordinarily potent in vitro against human or transgenic mouse T cells, with IC50 values in cellular assays ranging from pM to fM. Systemic administration of these immunotoxins dose-dependently depleted >99% of tg(epsilon)600+/- lymph node and spleen T cells in vivo. Depletion was specific for T cells. The loss of the concanavalin A-induced, but not the lipopolysaccharide-induced, splenic proliferative response from immunotoxin-treated animals further demonstrated specific loss of T-cell function. Immunotoxin treatment prolonged fully allogeneic skin graft survival in tg(epsilon)600+/- recipients to 25 days from 10 days in untreated animals. T-cells recovered to approximately 50% of normal levels after approximately 22 days in animals with or without skin grafts; T-cell recovery correlated with skin graft rejection. All three immunotoxins elicited >100 day median survival of fully allogeneic heterotopic heart grafts. By 100 days, T cells recovered to normal numbers in these animals, but the grafts showed chronic rejection. CONCLUSION: These immunotoxins profoundly deplete T cells in vivo and effectively prolong allogeneic graft survival.     

Multicenter Randomized Comparison of Xenon and Isoflurane on Left Ventricular Function in Patients Undergoing Elective Surgery

Background: Volatile anesthetics are commonly used for general anesthesia. However, these can induce profound cardiovascular alterations. Xenon is a noble gas with potent anesthetic and analgesic properties. However, it is uncertain whether xenon alters myocardial function. The aim of this study was therefore to investigate left ventricular function during anesthesia with xenon compared with isoflurane.

Methods: The authors performed a randomized multicenter trial to compare xenon with isoflurane with respect to cardiovascular stability and adverse effects in patients without cardiac diseases scheduled for elective surgery. Two hundred fifty-nine patients were enrolled in this trial, of which 252 completed the study according to the protocol. Patients were anesthetized with xenon or isoflurane, respectively. Before administration of the study drugs and at four time points, the effects of both anesthetics on left ventricular function were investigated using transesophageal echocardiography.

Results: Global hemodynamic parameters were significantly altered using isoflurane (P < 0.05 vs. baseline), whereas xenon only decreased heart rate (P < 0.05 vs. baseline). In contrast to xenon, left ventricular end-systolic wall stress decreased significantly in the isoflurane group (P < 0.05 vs. baseline). Velocity of circumferential fiber shortening was decreased significantly in the xenon group but showed a more pronounced reduction during isoflurane administration (P < 0.05 vs. baseline). The contractile index (difference between expected and actually measured velocity of circumferential fiber shortening) as an independent parameter for left ventricular function was significantly decreased after isoflurane (P < 0.0001) but unchanged using xenon.     

Machine perfusion versus cold storage for preservation of kidneys from expanded criteria donors after brain death

The purpose of this study was to analyze the possible effects of machine perfusion (MP) versus cold storage (CS) on delayed graft function (DGF) and early graft survival in expanded criteria donor kidneys (ECD). As part of the previously reported international randomized controlled trial 91 consecutive heart‐beating deceased ECDs – defined according to the United Network of Organ Sharing definition – were included in the study. From each donor one kidney was randomized to MP and the contralateral kidney to CS. All recipients were followed for 1 year. The primary endpoint was DGF. Secondary endpoints included primary nonfunction and graft survival. DGF occurred in 27 patients in the CS group (29.7%) and in 20 patients in the MP group (22%). Using the logistic regression model MP significantly reduced the risk of DGF compared with CS (OR 0.460, P = 0.047). The incidence of nonfunction in the CS group (12%) was four times higher than in the MP group (3%) (P = 0.04). One‐year graft survival was significantly higher in machine perfused kidneys compared with cold stored kidneys (92.3% vs. 80.2%, P = 0.02). In the present study, MP preservation clearly reduced the risk of DGF and improved 1‐year graft survival and function in ECD kidneys. (Current Controlled Trials number: ISRCTN83876362).     

Improving graft survival for patients undergoing liver transplantation

Dickson RC, Pungpapong S, Keaveny AP, Taner BC, Ghabril M, Aranda‐Michel J, Satyanarayana R, Bonatti H, Kramer DJ, Nguyen JH. Improving graft survival for patients undergoing liver transplantation.
Clin Transplant 2011: 25: E345–E355. © 2011 John Wiley & Sons A/S. Abstract: Liver transplant (LT) outcomes are reported to be improving in non‐HCV recipients but not for those infected with HCV. Our aim was to evaluate graft survival and predictors of outcome in HCV and non‐HCV patients before and after 2003. Patients with primary LT between February 1, 1998, and December 31, 2005, were included. Patients were divided into Era 1 (1998–2002) and Era 2 (2003–2005) with follow‐up through May 31, 2009. Graft survival was compared for HCV, non‐HCV, and all patients. There was significant improvement in graft survival in Era 2 for HCV patients. Graft survival in Era 2 of HCV patients was equivalent to non‐HCV patients. The most significant improvement between eras was in outcomes of grafts from donors ≥60 yr with three‐yr graft survival 58.6 (51.3–65.9) vs. 75.4 (68.9–81.9), p = 0.002. The use of donors ≥60 did not change between eras: 31% vs. 34%; however, utilization in HCV recipients decreased from 36% to 3% (p < 0.001). In conclusion, graft survival of HCV patients has improved significantly since 2003 and was comparable to non‐HCV patients up to three yr. The change in management of donor organs into HCV and non‐HCV patients likely contributed to this outcome.     

Serum estradiol concentration as a predictor of death in critically ill and injured adults

BACKGROUND: Whereas animal models of sepsis demonstrate survival benefits for the pro-estrus state, human observational studies have failed to demonstrate a consistent survival advantage among female patients. Estrogen biosynthesis differs substantially in primate and non-primate animals, and estrogens have diverse immunologic actions. Estrogen concentrations are elevated in response to critical illness and injury (regardless of sex), and elevated concentrations of serum estradiol are associated with a higher mortality rate. Our objective was to determine the predictive ability and test characteristics of the serum estradiol concentration at 48 h in critically ill patients. METHODS: A prospective cohort study of surgical and trauma adult intensive care unit patients at two academic tertiary-care centers. Sex hormones (estradiol, progesterone, testosterone, prolactin, and dehydroepiandrosterone) and cytokines were assayed at 48 h, and the 28-day all-cause mortality rate was assessed. RESULTS: There was no difference in mortality rates between the sexes (survivors being male in 75.2% of cases vs. 76.0% in non-survivors; p = 0.43). The serum estradiol concentration was significantly elevated in non-survivors regardless of sex (median 18.7 pg/mL [interquartile range {IRQ} 9.99-43.6] in survivors and 40.7 pg/mL [IQR 9.99-94.8] in non-survivors; p < 0.001). The area under the receiver-operating characteristic (ROC) curve for serum estradiol was 0.64 (95% confidence interval [CI] 0.55, 0.72). The parameter with the largest ROC curve was the Acute Physiology and Chronic Health Evaluation (APACHE) II score (0.75; 95% CI 0.68, 0.82). A serum estradiol cut-point of 50 pg/mL was 48% sensitive and 80% specific in predicting death and classified the outcome of 76% of patients correctly. CONCLUSIONS: Serum estradiol concentration is a valuable prognostic tool and potential contributor to adverse outcomes of critically ill or injured surgical patients.     

Assessment of Depth of Anesthesia and Postoperative Respiratory Recovery after Remifentanil-versus Alfentanil-based Total Intravenous Anesthesia in Patients Undergoing Ear-Nose-Throat Surgery

Background: The authors investigated whether total intravenous anesthesia (TIVA) with precalculated equipotent infusion schemes for remifentanil and alfentanil would ensure appropriate analgesia and that remifentanil would result in better recovery characteristics.

Methods: Forty consenting patients (classified as American Society of Anesthesiologists physical status I-III) scheduled for microlaryngoscopy were randomized to receive, in a double-blind manner, either remifentanil (loading dose 1 [mu]g/kg; maintenance infusion, 0.25 [mu]g [middle dot] kg-1 [middle dot] min-1) or alfentanil (loading dose, 50 [mu]g/kg; maintenance infusion, 1 [mu]g [middle dot] kg-1 [middle dot] min-1) as the analgesic component of TIVA. They were combined with propofol (loading dose, 2 mg/kg; maintenance infusion, 100 [mu]g [middle dot] kg-1 [middle dot] min-1). To insure an equal state of anesthesia, the opioids were titrated to maintain heart rate and mean arterial pressure within 20% of baseline, and propofol was titrated to keep the bispectral index (BIS) less than 60. Neuromuscular blockade was achieved with succinylcholine. Drug dosages and the times from cessation of anesthesia to extubation, verbal response, recovery of ventilation, and neuropsychological testing, orientation, and discharge readiness were recorded.

Results: Demographics, duration of surgery, and anesthesia were similar between the two groups. Both groups received similar propofol doses. There were no difference in BIS values preoperatively (mean, 96), intraoperatively (mean, 55), and postoperatively (mean, 96). Recovery of BIS and times for verbal response did not differ. At 20, 30, and 40 min after terminating the opioid infusion, the peripheral oxygen saturation and respiratory rate were significantly higher in the remifentanil group compared with the alfentanil group.     

Prostate cancer distribution in patients diagnosed by transperineal template-guided saturation biopsy

OBJECTIVES: To determine the prostate cancer incidence, anatomic distribution, Gleason score profile, and tumor burden in patients diagnosed by transperineal template-guided saturation biopsy (TTSB). MATERIALS AND METHODS: One hundred and two patients underwent TTSB; all but one patient had undergone at least one prior negative TRUS biopsy. Criteria for inclusion included an elevated PSA and/or the diagnosis of ASAP or high-grade PIN on prior biopsy. The prostate gland was divided into 24 regional biopsy locations. The median number of biopsy cores was 50. Multiple clinical parameters were evaluated as predictors for prostate cancer diagnosis. RESULTS: The mean patient age was 64.8 yr with a mean PSA of 9.1 ng/ml and a prostate volume of 78.6 cm(3). On average, patients had undergone 2.1 prior negative TRUS biopsies with a mean of 22.4 core biopsies. Prostate cancer was diagnosed in 43 patients (42.2%) with a Gleason score distribution of 6-9. No anatomic region of the prostate gland was spared of cancer. In patients with prostate cancer, an average of 9.9 cores were involved. In multivariate analysis, prostate volume was the best predictor for prostate cancer diagnosis. CONCLUSIONS: TTBS diagnosed prostate cancer in 42.2% of patients. Considerable anatomic variability in prostate cancer distribution was documented. On the basis of this and other reports, cancer eradication will depend on treatment of the entire prostate gland.     

Technical Considerations in Laparoscopic Fundoplication

Gastroesophageal reflux disease (GERD) is a common disease and can be successfully treated by laparoscopic fundoplication. This article describes the technique of laparoscopic surgery for GERD with a focus on operative pitfalls.     

Management in patients with liver cirrhosis and an umbilical hernia

BACKGROUND: Optimal management in patients with umbilical hernias and liver cirrhosis with ascites is still under debate. The objective of this study was to compare the outcome in our series of operative versus conservative treatment of these patients. METHODS: In the period between 1990 and 2004, 34 patients with an umbilical hernia combined with liver cirrhosis and ascites were identified from our hospital database. In 17 patients, treatment consisted of elective hernia repair, and 13 were managed conservatively. Four patients underwent hernia repair during liver transplantation. RESULTS: Elective hernia repair was successful without complications and recurrence in 12 out of 17 patients. Complications occurred in 3 of these 17 patients, consisting of wound-related problems and recurrence in 4 out 17. Success rate of the initial conservative management was only 23%; hospital admittance for incarcerations occurred in 10 of 13 patients, of which 6 required hernia repair in an emergency setting. Two patients of the initially conservative managed group died from complications of the umbilical hernia. In the 4 patients that underwent hernia correction during liver transplantation, no complications occurred and 1 patient had a recurrence. CONCLUSIONS: Conservative management of umbilical hernias in patients with liver cirrhosis and ascites leads to a high rate of incarcerations with subsequent hernia repair in an emergency setting, whereas elective repair can be performed with less morbidity and is therefore advocated.