No augmentation of indoleamine 2,3-dioxygenase (IDO) activity through belatacept treatment in liver transplant recipients.

Belatacept is a second-generation cytotoxic T lymphocyte antigen (CTLA)-4 immunoglobulin (Ig) fusion protein approved for immunosuppression in renal transplant recipients. It was designed intentionally to interrupt co-stimulation via CD28 by binding to its ligands B7·1 and B7·2. Experimental evidence suggests a potential additional mechanism for CTLA-4 Ig compounds through binding to B7 molecules expressed on antigen-presenting cells (APCs) and up-regulation of indoleamine 2,3-dioxygenase (IDO), an immunomodulating enzyme that catalyzes the degradation of tryptophan to kynurenine and that down-regulates T cell immunity. So far it remains unknown whether belatacept up-regulates IDO in transplant recipients. We therefore investigated whether belatacept therapy enhances IDO activity in liver transplant recipients enrolled in a multi-centre, investigator-initiated substudy of the Phase II trial of belatacept in liver transplantation (IM103-045). Tryptophan and kynurenine serum levels were measured during the first 6 weeks post-transplant in liver transplant patients randomized to receive either belatacept or tacrolimus-based immunosuppression. There was no significant difference in IDO activity, as indicated by the kynurenine/tryptophan ratio, between belatacept and tacrolimus-treated patients in per-protocol and in intent-to-treat analyses. Moreover, no evidence was found that belatacept affects IDO in human dendritic cells (DC) in vitro. These data provide evidence that belatacept is not associated with detectable IDO induction in the clinical transplant setting compared to tacrolimus-treated patients.

Randomized clinical trial of platysma muscle suture versus no suture for wound closure after thyroid surgery.

BACKGROUND: Suturing the platysma muscle during wound closure after thyroid surgery is frequently described in the literature. There is no prospective evidence to support its use or benefit. The aim of this study was to evaluate how a platysma muscle suture influences initial postoperative pain following thyroid surgery. METHODS: Patients were assigned randomly to receive a platysma suture or no platysma suture in this prospective, patient-blinded trial. The duration of follow-up was 6 months. The primary endpoint was wound-specific pain 24 h after thyroid resection. Secondary endpoints were intraoperative and perioperative analgesia requirement, postoperative pain and complications until postoperative day 14, and Patient and Observer Scar Assessment Score (POSAS) 6 months after surgery. RESULTS: Forty-one patients were randomized to each group. Visual analogue scale scores for wound-specific pain were lower in patients without a platysma suture 24 h after surgery (mean(s.d.) 3·15(1·46) versus 2·17(1·41) in groups with and without suture respectively; P = 0·002). There were no differences in the perioperative and postoperative need for analgesics, postoperative wound complications or cervical scar cosmesis 6 months after surgery (mean(s.d.) POSAS 23·99(9·53) versus 26·51(8·69); P = 0·148). CONCLUSION: Omitting the platysma muscle suture after thyroid surgery resulted in less wound-specific pain initially, with no difference in postoperative wound complications or cosmetic results. Registration number: NCT02951000 (http://www.clinicaltrials.gov).

Spontaneous hepatic rupture in amyloidosis - report of a case.

In systemic amyloidosis spontaneous rupture of the liver is a rare complication. Here we report on a patient with unrecognized systemic amyloidosis who presented to an outside hospital with unspecific abdominal pain. Under the signs of a hemorrhagic shock, distended abdomen and intraabdominal bleeding a laparotomy was performed. Due to uncontrollable hemorrhage of the ruptured right liver lobe a packing was performed. After being transferred to the reporting institution a CT scan was performed showing a grade IV laceration of the right liver. Therefore a transarterial embolization of the right hepatic artery was carried out. The following day an infection of the abdominal cavity and the abdominal wall with gas-producing bacteria was noticed and a relaparotomy, necrectomy and repacking due to diffuse bleeding were performed. The situation deteriorated and at the second relaparotomy the following day an almost completely necrotic liver was found. The patient deceased the following day. Life-threatening spontaneous liver rupture due to systemic amyloidosis might only successfully be cured by high urgency liver transplantation as presented in the literature. However, in two published cases interventional therapy by embolization of bleeding vessels has saved patients' life.

Intestinal lipid absorption increases cold ischemia of the small bowel in rats.

UNLABELLED: The short cold ischemic tolerance of the gut is a major problem in small bowel transplantation. We have shown that intestinal lipid administration is beneficial during systemic inflammation like sepsis. METHODS: Rats were intestinally infused with either water or 1% olive oil for 12 hours. The small bowel was removed and stored in HTK solution on ice. At t = 0, t = 60, t = 120, t = 180, t = 240, t = 300, t = 360, t = 420, and t = 480 minutes, a tissue sample of the gut was fixed, stained, and analyzed by three independent observers. Damage score was calculated (0 = no damage, 1 = minor damage, 2 = major damage, 3 = loss of structure) for integrity of the mucosa, integrity of the basal membrane of the mucosa, and integrity of villy. The damage score was allocated when all three observers agreed on the same or a higher damage score. RESULTS: In all control animals minor damage for the integrity of the basal membrane occurred within 60 minutes, but in only 50% of the lipid-treated rats. In all control rats, major damage for both integrity of mucosa and villi occurred within 300 minutes or less, but only in 50% of the lipid-treated rats. In all control rats, the structure of the villi was completely lost within 480 minutes or less, whereas only 50% of the lipid treated animals reached maximal damage scores for either mucosa or villi. CONCLUSION: Intestinal lipid administration before cold storage clearly decreases histologic damage of the small bowel and might increase the tolerance for cold ischemia. Lipids or their metabolites stored in enterocytes may act as an antiinflammatory. Intestinal lipid administration in organ donors might be useful to increase cold ischemic tolerance of the small bowel.

Abdominal Wall Morbidity Following Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy.

BACKGROUND: Incisional hernia formation has been reported as high as 20% within 1 year following midline laparotomy. Since hyperthermic intraperitoneal chemotherapy is likely to impair wound healing, we sought to investigate the incidence of incisional hernia formation and abdominal wall rupture following cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. METHODS: Consecutive patients with radiographic evidence of peritoneal metastases were scheduled for cytoreductive surgery and hyperthermic intraperitoneal chemotherapy at the Comprehensive Cancer Center, University Hospital Tuebingen, Germany. Clinical data were retrospectively analyzed. RESULTS: Between May 2005 and May 2014, 271 patients underwent cytoreductive surgery and hyperthermic intraperitoneal chemotherapy. Within follow-up, 19 (7%) incisional hernias and 11 (4%) abdominal wall ruptures were observed. Age ⩾70 years, cardio-pulmonary comorbidity, the presence of pseudomyxoma peritonei or mesothelioma, and postoperative abdominal wall rupture were detected as risk factors for hernia formation. However, Cox multivariate analysis only confirmed the presence of pseudomyxoma peritonei or mesothelioma and postoperative abdominal wall rupture as independent risk factors. CONCLUSION: Our data do not suggest that cytoreductive surgery and hyperthermic intraperitoneal chemotherapy is necessarily associated with a higher incidence of incisional hernia formation. However, patients suffering from pseudomyxoma peritonei or mesothelioma and patients with postoperative abdominal wall rupture seem to be at risk for developing incisional herniation.

Simultaneous pancreas-kidney transplantation in a large multicenter study: surgical complications.

UNLABELLED: Simultaneous pancreas-kidney (SPK) transplantation has evolved as an effective treatment modality for patients with end-stage nephropathy owing to type 1 diabetes mellitus. This kidney-pancreas transplant procedure includes a number of risks, one of them being surgical complications, which were analyzed in this large prospective multicenter study. PATIENTS AND METHODS: The analysis included 205 patients randomly assigned to tacrolimus (n = 103) or cyclosporine ME (n = 102) in the Euro-SPK001 study. Surgical complications were defined as any intervention in the postoperative course related to the transplant procedure. RESULTS: The number of patients undergoing relaparotomy was significantly lower among the tacrolimus group (26.2%) as compared to the cyclosporine ME group (43.1%, P = .0109). Relaparotomy was performed earlier in the cyclosporine ME group (day 14 +/- 17) compared to patients in the tacrolimus group (day 26 +/- 26, P = .0506). Graft vessel thrombosis, intra-abdominal hemorrhage, and enteric or ureteral leakage within the first 3 months occurred significantly more frequently in cyclosporine ME-treated patients. Donor age above 45 years showed a negative impact on surgical complications. Relaparotomy had no impact on patient survival but significantly affected pancreas and kidney graft survival in both groups. CONCLUSION: This prospective, randomized, multicenter trial in patients undergoing primary SPK demonstrated a benefit of tacrolimus over cyclosporine ME with regard to the incidence of surgical complications and, consecutively, to kidney and pancreas graft survival.

Infectious complications limit the outcome of liver transplantation in medical urgency code 2 patients.

The Organ shortage has caused an accumulation of acutely decompensated patients listed as medical urgency code 2 (MUC 2) (United network for Organ Sharing 2) while awaiting liver transplantation. Between June 1997 and June 2003, 22 of 360 liver transplantation patients (6%) were listed as MUC 2. Prophylactic immunosuppression consisted of calcineurin inhibitor-based drug therapy, using antithymocyte globulin or interleukin-2 receptor antagonist induction in 64%. The overall perioperative infection rate was 50%, and the rejection rate was 23%. We observed 7 episodes of oral or genital herpes simplex virus lesions; 2 patients (both with cytomegalovirus-mismatched transplants) developed cytomegalovirus disease, and another 5 patients received ganciclovir for preemptive therapy or prophylaxis. Two patients developed pneumonia: 5, sepsis that originated in 4 cases from a contaminated central venous line; and 1 methicillin-resistant endocarditis, which resulted in Staphylococcus aureus lethal outcome. After a median follow up of 3 years, 1 patient underwent a repeat transplantation procedure and 6 patients had died, 4 of them from infectious complications. Liver transplantation of MUC 2-listed patients may result in acceptable results similar to those of MUC 3 and MUC 4 categories.

Assessment of relapse in patients with peritoneal carcinomatosis after cytoreductive surgery and hyperthermic intraperitoneal chemotherapy using F-18-FDG-PET/CT.

PURPOSE: In patients with peritoneal carcinomatosis (PC), cytoreductive surgery combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is an evolving therapeutic approach with curative intention. The differentiation between posttherapeutic findings after HIPEC and relapse of PC is challenging. We evaluated the diagnostic value of F-18-FDG-PET/CT in patients with relapse of PC after HIPEC. MATERIALS AND METHODS: 36 patients with recurring PC after HIPEC were examined on a whole-body PET/CT system (44 examinations). The examination included 3 D F-18-FDG-PET and contrast-enhanced CT. Images were assessed by two experienced readers regarding the presence and the extent of PC using the peritoneal carcinomatosis index (PCI). Imaging results were correlated with surgical findings or follow-up. RESULTS: Relapse was suspected in 40 of 44 examinations. Relapse was missed by F-18-FDG PET/CT in 4 patients and significantly underestimated in 8 patients. The diagnostic accuracy for the detection of PC on a patient basis was 91 %, the sensitivity was 91 % and the positive predictive value was 100 %. The mean PCI was 11.4 ±â€Š11.9 for PET/CT, 8.4 ±â€Š10.3 for CT and 16.6 ±â€Š15.0 in the case of surgical exploration. The extent of PC was underestimated by PET/CT and even more by CT alone (p < 0.05). CONCLUSION: The diagnostic value of F-18-FDG PET/CT after cytoreductive surgery and HIPEC in the detection of recurring PC is superior to contrast-enhanced CT. However, the quantification of the extent of PC is limited due to post-therapeutic tissue alterations. KEY POINTS: • Imaging of recurrent PC after HIPEC is challenging due to posttherapeutic tissue alterations.• The extent of recurrent PC after HIPEC is systematically underestimated by F-18-FDG PET/CT.• F-18-FDG PET/CT provides improved sensitivity for recurrent PC compared to contrast-enhanced CT.• The correlation of the extent of recurrent PC depicted by F-18-FDG PET/CT and surgical exploration is better than that of contrast-enhanced CT and surgical exploration.

Correlation of preoperative magnetic resonance imaging of peritoneal carcinomatosis and clinical outcome after peritonectomy and HIPEC after 3 years of follow-up: preliminary results.

PURPOSE: In patients with peritoneal carcinomatosis, cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) is an evolving approach with curative intention. Previous studies indicate a correlation between preoperative magnetic resonance imaging (MRI) and surgical findings regarding the extent of peritoneal carcinomatosis. The aim of this study was to assess retrospectively whether preoperative MRI can predict the outcome and is therefore a suitable tool for patient selection. MATERIALS AND METHODS: Fifteen patients with laparoscopically proven peritoneal carcinomatosis were preoperatively examined using a 1.5-T whole-body MRI system. Results were correlated with surgical exploration. Follow-up was done by contrast-enhanced abdominal computed tomography and, if suspicious for recurring disease, laparoscopy or laparotomy. Survival time and interval to recurring disease were correlated with the preoperative peritoneal carcinomatosis index (PCI) on MRI (Spearman's rank correlation). RESULTS: In five patients radical resection could not be achieved (PCI 34 ± 6.9); survival time was 78.2 ± 54.1 days. In seven patients recurring disease was found 430 ± 261.2 days after initial complete cytoreduction (PCI 11.6 ± 6.9); survival time was 765.9 ± 355 days. Two patients are still alive after 3 years. Two patients with initially complete cytoreduction are without recurring disease after 3 years (PCI 5 and 12). One patient was lost for follow-up. CONCLUSIONS: Results of the preoperative MRI correlate well with the surgical PCI, postoperative resection status, and survival time. MRI might be a suitable technique for patient selection when considering peritonectomy and HIPEC. In our patients the outcome seems to correlate well with the extent of peritoneal carcinomatosis found by the preoperative MRI.

Employing vasopressin as an adjunct vasopressor in uncontrolled traumatic hemorrhagic shock. Three cases and a brief analysis of the literature.

Resuscitation of patients in hemorrhagic shock remains one of the most challenging aspects of trauma care. We showed in experimental studies that vasopressin, but not fluid resuscitation, enabled short-term and long-term survival in a porcine model of uncontrolled hemorrhagic shock after penetrating liver trauma. In this case report, we present two cases with temporarily successful cardiopulmonary resuscitation (CPR) using vasopressin and catecholamines in uncontrolled hemorrhagic shock with subsequent cardiac arrest that was refractory to catecholamines and fluid replacement. In a third patient, an infusion of vasopressin was started before cardiac arrest occurred; in this case, we were able to stabilize blood pressure thus allowing further therapy. The patient underwent multiple surgical procedures, developed multi-organ failure, but was finally discharged from the critical care unit without neurological damage.

Experience with 100 combined pancreatic renal transplantations in a single center.

Compared to the still increasing number of kidney, liver and heart transplants performed worldwide, pancreas transplantation remains a rare occurrence. At our center a pancreas transplant program was began in late 1979. Since then a total of 113 pancreas transplants were performed in 106 patients, 100 of them also received a kidney from the same donor. The first group consisted of 5 patients with immediate duct occlusion (IDO). In the second group (n = 8) the pancreatic juice of the segmental graft was diverted into a Roux-Y loop of jejunum. Because of two fatal technique-associated complications, delayed duct occlusion was introduced and applied in 15 patients. Because of a prolonged hospitalization period due to local complications, the surgical technique was changed again. From 1987, 72 segmental pancreatic transplants with bladder drainage were performed and finally one whole organ with a duodenal segment was transplanted. Immunosuppression consisted of cyclosporine A, azathioprine and prednisolone from 1984 on. Rejection episodes were treated with a high-dose methylprednisolone on 3 consecutive days and steroid-resistant rejections with ATG. The overall patient survival at 6 years was 80%, renal allograft survival 72% and pancreas graft survival 63% for the entire group. In the delayed duct occlusion group, 1-year patient and kidney graft survival of 93% each and 79% for the pancreas was calculated. One-year survival in the most recent and largest group with bladder drainage was 89% for patients, 86% for the kidney and 75% for the pancreas. Excellent metabolic control was achieved in the majority of patients with mean C-peptide levels and HbA1C levels at 6 months of 1.46 pmol/ml and 5.6%, respectively. Successful pancreas transplants with normalization of carbohydrate metabolism seem to have a beneficial effect on secondary complications of diabetes, contributing to the high degree of rehabilitation of these patients.

Atrial natriuretic peptide (ANP), aldosterone, angiotensin II and renin in the 'low T3 syndrome' in organ donors.

The present prospective study was conducted in order to investigate the effect of an acute decrease in serum T3 levels on ANP, aldosterone, angiotensin II, renin and ADH. All patients showed a pathologic TRH stimulation test prior to organ harvesting. Our patients developed secondary T3 hypothyroidism of different severity dependent on intensive care unit (ICU) stay. T3 values in group 1 (ICU stay > or = 77 h) were smaller than 70 ng/dl, those of group 2 (ICU stay < or = 53 h) were greater than 70 ng/dl. In both groups a severe elevation of plasma renin activity was measured, with almost high-normal values for ANP in group 1 and slightly elevated values in group 2 [not significant (n.s.)]. Results demonstrate that, contrary to patients who are not critically ill, brain-dead patients develop a dissociation of the renin-angiotensin-aldosterone mechanism. No statistical significant difference was found between the groups in serum levels of ADH and aldosterone. This endocrine dissociation, however, seems to have no clinical significance with regard to organ function after transplantation in kidney recipients.