Assessment of the Clinical Impact of a Liver-Specific, BCAA-Enriched Diet in Major Liver Surgery.

BACKGROUND: The relationship between nutrition and liver disease is relevant for the outcome after surgery. Patients with liver cirrhosis characteristically show protein-energy malnutrition with decreased levels of branched-chain amino acids (BCAA) and increased levels of aromatic amino acids. MATERIALS AND METHODS: We conducted a prospective controlled clinical trial including 57 patients after liver transplantation or major liver resection surgery in order to test the effect of early postoperative nutrition on the outcome and nutrition profile of these patients. The test group received a dietetic program composed of ingredients naturally rich in BCAA (BCAA group), and the control group received standard hospital meals. Patient survival, liver function tests, subjective well-being, and a nutritional status including amino acid profiles were analyzed immediately and 14 days after major liver surgery (secondary end points). General health and well-being were assessed using the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (primary end point). RESULTS: In-depth analysis of amino acid profiles was performed for patients undergoing liver resection (n = 21) and liver transplantation (n = 36). Interestingly, amino acid profiles did not correlate with body mass index or the Model for End-Stage Liver Disease score. Patients scheduled for liver transplantation showed significantly lower levels of BCAA pretransplant compared to patients undergoing liver resection. Patients in the liver resection subgroup were more likely to benefit from the BCAA cuisine in terms of significantly higher food intake and subjective rating. The clinical liver function tests, however, did not show statistical difference between the BCAA group and the control group in the examination period of 14 days. CONCLUSION: Our specifically designed BCAA-enriched diet resulted in greater patient satisfaction and compliance with nutrition. A larger trial or longer-term follow-up may be required to identify an effect on survival, recovery, surgical complications, protein profiles, and amino acid profiles.

Open Management of the Renal Vein Is a Safe Modification in Right-Sided Laparoscopic Living Donor Nephrectomy to Maximize Graft Vein Length.

BACKGROUND: The primary objective in living donor kidney transplantation is donor safety. In laparoscopic living donor nephrectomy, most centers prefer the left kidney for donation given the shorter renal vein, higher rate of thromboses, and more difficult surgical procedure for right kidney retrieval. The goal of this study was to demonstrate the feasibility of a hybrid technique using a Satinsky clamp in right-sided living donor nephrectomy to obtain maximal renal vein and to compare the outcome with standard left-sided laparoscopic donor nephrectomies. MATERIAL AND METHODS: Between 2005 and 2013, 77 patients underwent a left (group L) and 54 a right (group R) living donor nephrectomy. In group R, after laparoscopic dissection and mobilization of the right kidney, two 12-mm trocar incisions in the right upper quadrant were connected in a 5-7 cm subcostal incision. The caval vein was partially clamped under direct vision prior to dissection of the renal vein. The venotomy was then closed with a running 4-0 Prolene suture. The two groups were compared with regard to surgical complications, graft function, and graft survival. RESULTS: Using this technique, no significant difference with regard to complications or graft function was observed. Serum creatinine at discharge in donor group L was 1.23 (±0.43) mg/dL and in donor group R 1.21 (±0.37) mg/dL (P = .71). Graft survival at one year was 100% in both groups. CONCLUSION: Open management of the renal vein is a safe alternative in laparoscopic right-sided donor nephrectomy and ensures maximal length of the vein.

History of Lung and Heart-Lung Transplantation, With Special Emphasis on German-Speaking Countries.

The first experimental lung transplants were performed in 1947 by the Russian surgeon V.P. Demikhov. Thereafter, various aspects associated with lung transplantation were studied by groups from Italy, France, and mainly the United States. The first clinical lung transplant took place in Jackson, Mississippi, in 1963 and was performed by D. Hardy. Until 1983, a total of 45 lung transplants were carried out at various centers, but only one patient transplanted in Ghent by F. Derom in 1968 survived for 10 months, whereas all other patients survived only hours to a few days. In 1983 at Toronto General Hospital, a single-lung transplant was performed that survived almost 7 years. From the same institution, the first long-term survivor after double-lung transplantation was reported in 1986. The first lobar transplant from a live donor was performed by V.A. Starnes at Stanford in 1990. The first heart-lung transplantation was performed in Houston by D.A. Cooley in 1968. Even though the girl who received this transplant survived only for 14 hours, this case showed that this kind of procedure can work. The first long-term survival was achieved by B. Reitz in 1981 in Stanford. In the German-speaking countries, successful lung and lung-heart transplants were reported between 1984 and 1993 and are described in detail.

The liver graft as Trojan horse-multilineage donor-derived hematopoiesis after liver transplantation: case report.

Hematopoietic macrochimerism, which is rarely seen after orthotopic liver transplantation (OLT), has been linked to the development of graft versus host disease (GvHD). We report on a patient with GvHD after OLT in whom full engraftment of donor-derived, multilineage hematopoiesis occurred, indicating that the liver contains pluripotent hematopoietic progenitor cells (HPC) capable to restore hematopoiesis in recipients. Although preventing graft rejection, standard immunosuppressive therapy may be under certain immunological conditions not sufficient to prevent GvHD. Age-, disease-, and treatment-related variables might be critical determinants for the development of an effective alloreactive T-cell response leading to the establishment of full hematopoietic chimerism.

Donor pretreatment with tetrahydrobiopterin saves pancreatic isografts from ischemia reperfusion injury in a mouse model.

Depletion of the nitric oxide synthase cofactor tetrahydrobiopterin (H4B) during ischemia and reperfusion is associated with severe graft pancreatitis. Since clinically feasible approaches to prevent ischemia reperfusion injury (IRI) by H4B-substitution are missing we investigated its therapeutic potential in a murine pancreas transplantation model using different treatment regimens. Grafts were subjected to 16 h cold ischemia time (CIT) and different treatment regimens: no treatment, 160 µM H4B to perfusion solution, H4B 50 mg/kg prior to reperfusion and H4B 50 mg/kg before recovery of organs. Nontransplanted animals served as controls. Recipient survival and endocrine graft function were assessed. Graft microcirculation was analyzed 2 h after reperfusion by intravital fluorescence microscopy. Parenchymal damage was assessed by histology and nitrotyrosine immunohistochemistry, H4B tissue levels by high pressure liquid chromatography (HPLC). Compared to nontransplanted controls prolonged CIT resulted in significant microcirculatory deterioration. Different efficacy according to route and timing of administration could be observed. Only donor pretreatment with H4B resulted in almost completely abrogated IRI-related damage showing graft microcirculation comparable to nontransplanted controls and restored intragraft H4B levels, resulting in significant reduction of parenchymal damage (p < 0.002) and improved survival and endocrine function (p = 0.0002 each). H4B donor pretreatment abrogates ischemia-induced parenchymal damage and represents a promising strategy to prevent IRI following pancreas transplantation.

Pancreatic graft survival despite partial vascular graft thrombosis due to splenocephalic anastomoses.

Thrombotic complications following pancreas transplantation are still the most common cause of nonimmunologic graft loss. The aim of this study was to analyze pancreatic graft function after partial arterial graft thrombosis and the investigation of the pancreatic arterial anatomy with regard to intraparenchymal anastomoses. We retrospectively analyzed the data for 175 consecutive pancreas transplants performed between January 2002 and October 2007. Selective Y-graft angiography was performed in 10 and rubber-milk injection in 5 fresh pancreas specimens. Thrombosis of one leg of the Y-graft was diagnosed in 18 (10.3%) patients. Only one of these patients with thrombosis of the splenic artery required exogenous insulin. Sufficient graft perfusion was demonstrated in all of the remaining grafts. One graft was lost due to acute rejection. In all specimens angiography showed an excellent perfusion of the pancreaticoduodenal arcade, even after selective cannulation of the splenic artery. Arterial collaterals between the gastroduodenal, splenic artery and the superior mesenteric artery were demonstrated. Our results demonstrate that global perfusion of the pancreatic graft and sufficient graft function is sustained after the thrombotic occlusion of one branch of the Y-graft by a complex system of intraparenchymal anastomoses. These anatomical findings may have consequences for resection strategies in pancreas surgery.

Molecular markers and targeted therapy of skin rejection in composite tissue allotransplantation.

Skin rejection remains a major hurdle in reconstructive transplantation. We investigated molecular markers of skin rejection with particular attention to lymphocyte trafficking. Skin biopsies (n = 174) from five human hand transplant recipients were analyzed for rejection, characteristics of the infiltrate and lymphocytic adhesion markers. The cellular infiltrate predominantly comprised CD3+ T cells. CD68, Foxp3 and indoleamine 2, 3-dioxygenase expression and the CD4/CD8 increased with severity of rejection. Lymphocyte adhesion markers were upregulated upon rejection, intercellular adhesion molecule-1 and E-selectin correlated best with severity of rejection. Guided by the findings, a specific E- and P-selectin inhibitor was investigated for its effect on skin rejection in a rat hind limb allotransplant model. While efomycine M (weekly s.c. injection into the graft) alone had no effect, long-term allograft survival was achieved when combined with antithymocyte globulin and tacrolimus (control group without efomycine M rejected at postoperative day [POD] 61 +/- 1). Upregulation of lymphocyte trafficking markers correlates with severity of skin rejection and time after transplantation in human hand transplantation. Blocking E- and P-selectin in the skin holds potential to significantly prolong limb allograft survival.

Group Milleri Streptococci in perianal infections.

BACKGROUND: Anal abscesses are commonly associated with fistulas-in-ano and are usually polymicrobial in nature, with gram-negative rods and anaerobes being the most prevalent isolates. Group Milleri Streptococci (GMS) comprise a heterogeneous group of cocci, which are capable of causing severe purulent infection with a high recurrence rate. METHOD: All anorectal infections caused by GMS, which were identified at our centre during a 4-year period were retrospectively analysed. The 18 patients with GMS-positive anorectal abscesses were matched with 36 GMS-negative anorectal abscesses to identify outcome characteristics of this clinical entity. RESULTS: During the study period, 358 patients underwent surgical treatment for anal infections; GMS were isolated in 46 individuals (13%) including 18 perianal abscesses, 11 pilonidal sinuses, eight fistulae in and nine miscellaneous infections. Seventy-two per cent of perianal GMS infections were polymicrobial with E. coli and Bacteroides fragilis being the predominant second bacteria. Nine patients (20%) developed recurrent abscesses and fistulae-in-ano and underwent additional surgical interventions with resolution at follow-up. Additional antibiotic treatment was administered in 10 patients with complex anal infections. Matched pair analysis revealed that GMS-positive perianal abscesses were more commonly polymicrobial, and that the recurrence rate was higher (55.6% GMS-positive and 22.2% GMS-negative patients, P = 0.017). CONCLUSIONS: Our data confirm the propensity of GMS to form deep and recurrent abscesses with a higher recurrence rate than non-GMS infections. First-line treatment includes surgical drainage, and antibiotic treatment may be useful in selected patients.

Vascular considerations for stapled haemorrhoidopexy.

OBJECTIVE: Modern haemorrhoidectomy techniques aim to interrupt arterial blood supply to the hypertrophied piles. The aim of this study was to investigate morphological and physiological alterations in the terminal branches of the superior rectal artery (SRA) in patients with haemorrhoidal disease treated by stapled haemorrhoidopexy (SH) using noninvasive transperineal ultrasound. METHOD: Thirty-seven consecutive patients (14 women, 23 men; median age 52, range 30-77 years) who underwent SH for treatment of grade III haemorrhoids were scanned by transperineal colour Doppler ultrasound at baseline, 4 weeks and 3 months postoperatively. Seventeen healthy volunteers served as the control group (nine women, eight men; median age 24, range 18-72 years). Calibre and arterial flow velocity (AFV) of the terminal branches of the SRA were measured. RESULTS: Baseline measurements significantly differed between patients and the control group (median calibre 2, range 0.9-3.6 mm, vs 1, range 0.6-1.2 mm, and median AFV 24, range 10-65 cm/s, vs 12, range 5-21 cm/s, P < 0.0001). Postoperative follow-up showed no significant alterations in the physiological parameters. Patients with a higher recurrence rate of haemorrhoidal disease had higher baseline AFV values. CONCLUSION: Stapled haemorrhoidopexy does not reduce arterial inflow in the feeding vessels of the anorectal vascular plexus. Preoperative ultrasound may serve as a tool for assessing vascularization status in haemorrhoidal disease and is useful in deciding whether patients should undergo SH or, for individuals with high AFV, whether conventional haemorrhoidectomy might be the better choice.

Influence of portosystemic shunt on liver regeneration after hepatic resection in pigs.

OBJECTIVE: The minimal amount of liver mass necessary for regeneration is still a matter of debate. The aim of the study was to analyze liver regeneration factors after extended resection with or without portosystemic shunt. METHODS: An extended left hemihepatectomy was performed in 25 domestic pigs, in 15 cases after a portosystemic H-shunt. The expression of Ki-67, VEGF, TGF-alpha, FGF, and CK-7 was analyzed in paraffin-embedded tissue sections. RESULTS: The volume of the remnant liver increased about 2.5-fold at the end of the first week after resection. With 19 cells/10 Glisson fields versus 4/10, Ki-67-expression was significantly higher in the H-shunt group. VEGF- and CK-7-expressions were significantly higher in the control group. No significant change was found in FGF-expression. The expression of TGF-alpha was higher, but not significantly, in the control group. CONCLUSIONS: The expression of Ki-67, and therefore hepatocyte regeneration, was increased in the shunt group. The expression of CK-7 on biliary epithelium and the expression of VEGF, however, were stronger in the control group.

[Immunosuppression in hand transplantation: state of the art and future perspectives]. / Immunosuppression bei Handtransplantation: State of the Art, Zukunftsperspektiven.

Avoidance or minimization of maintenance immunosuppression represents the key step for promoting wider applicability of reconstructive transplantation. Understanding the mechanisms of composite tissue allograft rejection is of essence in working towards this goal. We herein review the current knowledge on acute rejection in reconstructive transplantation and discuss findings in the light of novel immunosuppressive and immunomodulatory strategies.

[Musculosceletal reconstruction in bilateral forearm transplantation]. / Muskuloskelettale Rekonstruktion bei bilateraler Unterarmtransplantation.

BACKGROUND: Improvement of motor function of the upper extremity was investigated in a patient following bilateral forearm transplantation. PATIENTS AND METHODS: Following an electric shock injury with amputation of both forearms at the proximal level a bilateral allotransplantation was performed 2003 in a 41-year-old male patient. Missing and insufficient muscles were replaced by donor units. For use of myoprothesis in case of transplant failure remnants of BR, ECRL, ECRB and ECU remained at the recipient. 3.5 mm DCP plating was used without bone grafting to stabilize the forearm bones. PT, FCR, FDS, PL of the donor was fixed to the medial epicondyle of the humerus, ECU and EDC to the periosteum of the ulna. FCU, BR, ECRL; ECRB of the donor were sutured to the corresponding fascia of the recipient muscles. For motor function NIA; NIP and the motor branches of the median nerve for PT, FCR, FDS, PL were coapted. The ulnar nerve was coapted distally to the motor branch for the FCU. Following induction therapy today IS consist of tacrolimus (trough level 8 ng/ml), everolimus (trough level 6 ng/ml) und Prednisone (5 mg/day). RESULTS: Both grafts are vital at FU of 6 years and 1 month. During the first 3 years episodes of graft rejection, opportunistic infection and transient metabolic disorder occurred which could be treated successfully by systemic, topical agents and change of IS. Bone healing appeared normal. TRM of the upper extremity improved from 32.7% before surgery to 74.6% of normal, with gain of wrist motion/forearm rotation of 8.7% and finger motion of 33, and 2%. The moderate muscle power (M4/5) of the deep flexors, the extensors and the intrinsic muscles is considered to be due to the long distance of reinnervation, a pre-existing electric damage to the nerv and repeated rejection episodes. CONCLUSION: Range of motion of the upper extremity improved primarily by extrinsic muscle function. Muscle strength and grip are moderate. The patient described the following to be most beneficial: the better range of motion, the possibility to perform tasks without visual control, the availability of his range of motion 24 h a day and a new sense of body integrity.

Immunosuppression and rejection in human hand transplantation.

Avoidance or at least minimization of maintenance immunosuppression represents the key step for promoting wider applicability of reconstructive transplantation. Understanding the mechanisms of composite tissue allograft rejection is essential in working toward that goal. We herein review the current knowledge on acute rejection in reconstructive transplantation and discuss findings in the light of novel immunosuppressive and immunomodulatory strategies.

The Innsbruck hand transplant program: update at 8 years after the first transplant.

We herein provide an update on two bilateral hand and one bilateral forearm transplants with emphasis on immunosuppression (IS), function, morphology, and graft vascular changes at 8 years and 2 years after bilateral hand and 5 years after bilateral forearm transplantation. Between March 2000 and May 2006, three patients underwent bilateral hand or forearm transplantation at our institution. Following induction therapy with antithymocyte globulin (ATG) (n = 2) or alemtuzumab (n = 1), tacrolimus, prednisolone +/- mycophenolate mofetil (MMF) were given for maintenance IS. Later, tacrolimus (n = 1) or MMF (n = 1) was replaced by sirolimus/everolimus for long-term IS. Clinical follow-ups with evaluation of hand function, skin biopsies, X-ray, ultrasound, angiography, computed tomography angiography, electrophysiological studies, and somatosensory evoked potentials were performed at regular intervals. Three, six, and three rejection episodes were successfully treated with bolused steroids, anti-CD25 or anti-CD52 antibodies. Subsequently, skin histology remained normal without any evidence of chronic rejection. Hand function continuously improved during the first 3 years and since then remained stable with minor improvements. Investigation of hand arteries revealed no signs of occlusion or stenosis. Motor and intrinsic hand muscle function continues to improve in all patients. Protective sensation was observed in all patients; however, discriminative sensation was only accomplished after hand but not forearm transplantation. No life-threatening adverse events occurred. Despite immunologic challenging postoperative courses, patients are now free of rejection with moderate levels of IS and good functional results. No signs indicating chronic rejection have been encountered.

Alemtuzumab: key for minimization of maintenance immunosuppression in reconstructive transplantation?

Minimization of immunosuppression has become the key effort in solid organ transplantation. Alemtuzumab, the humanized CD-52 monoclonal antibody, is an effective depleting agent increasingly used in transplantation trials. In this article, we summarize the current experience with alemtuzumab use in hand transplantation and discuss its role in current and future approaches toward minimization of maintenance immunosuppression in reconstructive transplantation.

Indoleamine 2,3-dioxygenase and foxp3 expression in skin rejection of human hand allografts.

Human hand transplantation is complicated by skin rejection. To better define the characteristics of infiltrating cells, biopsies from human hand transplants have been investigated for expression of Foxp3 and indoleamine 2,3-dioxygenase (IDO), a key regulatory enzyme to induce T-lymphocyte unresponsiveness. A total of 104 skin biopsies taken from three bilateral hand transplant recipients over 6 years posttransplant were assessed by hematoxylin-eosin histology (graded 1-4b) and immunohistochemistry for IDO and Foxp3 according to a three-grade classification and correlated with the grade of rejection as well as time after transplantation. Overall, rejection ranged between grades 0 and 4a with an average score of 0.94. IDO was expressed in the endothelium independent of rejection. Upon rejection, IDO staining within the cellular infiltrate was significantly increased. Foxp3 in regulatory T cells was mainly found in samples undergoing severe rejection. Expression of IDO and Foxp3 compared well to each other, although the overall expression of Foxp3 was lower when compared to IDO. An increased expression of IDO as well as Foxp3 during rejection late after transplantation was observed. Characteristics of the cellular infiltrate indicate tolerogenic properties of a proportion of the cells and therefore a tendency toward self-limitation of the alloimmune response during skin rejection after hand transplantation.

Infectious complications in three double hand recipients: experience from a single center.

BACKGROUND: Composite tissue allograft (CTA) recipients require high level of immunosuppression and, therefore, are at significant risk to acquire opportunistic infections. PATIENTS AND METHODS: A review of all serious infectious complications in the 3 CTA recipients from the Innsbruck Medical University was performed. RESULTS: The most common infection was cytomegalovirus (CMV)-associated disease, which developed in all 3 individuals. The CMV match was CMV-positive donor/CMV-negative recipient in the first case and CMV-positive donor/CMV-positive recipient in the other 2. The first 2 patients developed complicated CMV infections despite ganciclovir (GCV) prophylaxis and required treatment with anti-CMV hyperimmunoglobulin, foscarnet, and cidofovir to control infection. The third patient had a mild course of CMV disease after withdrawel of prophylaxis, which was successfully treated with ValGCV. Whereas no major additional infections were observed in the first and third case, the second patient, who experienced multiple steroid-resistent rejections, experienced a variaty of additional infections, including 1 episode of Clostridium difficile-associated colitis (CDAC), a soft tissue infection with Alternaria alternata and an infection with human papilloma virus (HPV), which extensively involved both transplanted forearms. CDAC was successfully treated with metronidazole, Alternaria alternata with liposomal amphotericin B, and itraconazole and HPV lesions with topical cidofovir. CONCLUSION: Rare and difficult to treat infections must be expected in CTA recipients, in particular when donor-derived viruses are introduced in naïve recipients and when excessive immunosuppression is required. Meticulous infectious screening and prophylaxis are warranted in these high-risk patients.

TROP2 expression as prognostic marker for gastric carcinoma.

BACKGROUND: In gastric cancer the recurrence rate is unacceptably high, even after R0 resection and (neo)adjuvant chemotherapy. Therefore, there is an urgent need for identification of predictive and/or prognostic biomarkers to select high-risk patients who might benefit from additional therapies. Expression of TROP2 has been shown to be associated with tumour aggressiveness and poor prognosis in patients with various epithelial cancers. AIMS: To investigate TROP2 expression in gastric cancer and its correlation with clinicopathological features and disease outcome. METHODS: Expression of TROP2 was investigated by immunohistochemistry of tumour specimens from 104 patients who underwent resection for gastric cancer. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. RESULTS: TROP2 was found to be overexpressed in 58 (56%) tumour samples. Significantly higher expression of TROP2 could be detected in intestinal-type carcinomas (p = 0.03). In intestinal-type gastric cancer, TROP2 overexpression was significantly correlated with shorter disease-free survival (DFS) (p = 0.03). Among the total group, TROP2 overexpression was predictive for poor disease-free (p<0.01) and overall (p = 0.03) survival in lymph node positive patients. Multivariate Cox regression analysis revealed TROP2 overexpression to be an independent prognostic marker for poor DFS in the subgroup of patients with intestinal-type gastric cancer irrespective of lymph node involvement. CONCLUSION: Results show that TROP2 is an independent prognostic marker for disease recurrence in intestinal type gastric cancer. Due to its wide distribution TROP2 may become an attractive therapeutic target in a subgroup of patients with gastric cancer.

High expression of TROP2 correlates with poor prognosis in pancreatic cancer.

Pancreatic cancer is one of the most devastating human malignancies. Despite considerable research efforts, it remains resistant to almost all available treatment regimens. The human trophoblast cell-surface antigen, TROP2, was found to be strongly expressed in a variety of human epithelial cancers, correlating with aggressiveness and poor prognosis. TROP2 antigen expression was investigated retrospectively by immunohistochemistry in paraffin-embedded primary tumour tissue samples from a series (n=197) of consecutive patients with pancreatic adenocarcinoma. Survival was calculated using Kaplan-Meier curves. Parameters found to be of prognostic significance in univariate analysis were verified in a multivariate Cox regression model. TROP2 overexpression was observed in 109 (55%) of 197 pancreatic cancer patients and was significantly associated with decreased overall survival (P<0.01). By univariate analysis, TROP2 overexpression was found to correlate with the presence of lymph node metastasis (P=0.04) and tumour grade (P=0.01). Furthermore, in the subgroup of patients treated surgically with curative intent, TROP2 overexpression significantly correlated with poor progression-free survival (P<0.01). Multivariate analyses revealed TROP2 to be an independent prognosticator. These findings suggest for the first time that TROP2 could be a novel prognostic biomarker for pancreatic cancer. Targeting TROP2 might be a useful treatment approach for patients with pancreatic cancer overexpressing this cell-surface marker.