[Tailored surgery in the treatment of gastroesophageal cancer]. / Maßgeschneiderte Chirurgie in der Behandlung gastroösophagealer Tumoren.

The surgical options and particularly perioperative treatment, have significantly advanced in the case of gastroesophageal cancer. This progress enables a 5-year survival rate of nearly 50% to be achieved through curative multimodal treatment concepts for locally advanced cancer. Therefore, in tumor boards and surgical case discussions the question increasingly arises regarding the type of treatment that provides optimal oncological and functional outcomes for individual patients with pre-existing diseases. It is therefore essential to carefully assess whether organ-preserving treatment might also be considered in the future or in what way minimally invasive or robotic surgery can offer advantages. Simultaneously, the boundaries of surgical and oncological treatment are currently being shifted in order to enable curative forms of treatment for patients with pre-existing conditions or those with oligometastatic diseases. With the integration of artificial intelligence into decision-making processes, new possibilities for information processing are increasingly becoming available to incorporate even more data into making decisions in the future.

Imaged guided surgery during arteriovenous malformation of gastrointestinal stromal tumor using hyperspectral and indocyanine green visualization techniques: A case report.

BACKGROUND: This case report demonstrates the simultaneous development of a gastrointestinal stromal tumour (GIST) with arteriovenous malformations (AVMs) within the jejunal mesentery. A 74-year-old male presented to the department of surgery at our institution with a one-month history of abdominal pain. Contrast-enhanced computed tomography revealed an AVM. During exploratory laparotomy, hyperspectral imaging (HSI) and indocyanine green (ICG) fluorescence were used to evaluate the extent of the tumour and determine the resection margins. Intraoperative imaging confirmed AVM, while histopathological evaluation showed an epithelioid, partially spindle cell GIST. CASE SUMMARY: This is the first case reporting the use of HSI and ICG to image GIST intermingled with an AVM. The resection margins were planned using intraoperative analysis of additional optical data. Image-guided surgery enhances the clinician's knowledge of tissue composition and facilitates tissue differentiation. CONCLUSION: Since image-guided surgery is safe, this procedure should increase in popularity among the next generation of surgeons as it is associated with better postoperative outcomes.

The cathepsin-S/protease-activated receptor-(PAR)-2 axis drives chronic allograft vasculopathy and is a molecular target for therapeutic intervention.

BACKGROUND: Cathepsin S (CatS) and proteinase-activated receptor (PAR)-2 are involved in the remodelling of vascular walls and neointima formation as well as in alloantigen presentation and T-cell priming. Therefore, we hypothesized that CatS/PAR-2 inhibition/deficiency would attenuate chronic allograft vasculopathy. METHODS: Heterotopic aortic murine transplantation was performed from C57BL/6J donors to C57BL/6J recipients (syngeneic control group), Balb/c to C57BL/6J without treatment (allogenic control group), Balb/c to C57BL/6J with twice daily oral CatS inhibitor (allogenic treatment group) and Balb/c to Par2-/- C57BL/6J (allogenic knockout group). The recipients were sacrificed on day 28 and the grafts were harvested for histological analysis and RT-qPCR. RESULTS: After 28 days, mice of the allogenic control group exhibited significant neointima formation and massive CD8 T-cell infiltration into the neointima while the syngeneic control group showed negligible allograft vasculopathy. The mRNA expression level of CatS in allografts was 5-fold of those in syngeneic grafts. Neointima formation and therefore intima/media-ratio were significantly decreased in the treatment and knockout group in comparison to the allogenic control group. Mice in treatment group also displayed significantly fewer CD8 T cells in the neointima compared with allogeneic controls. Additionally, treatment with the CatS inhibitor and PAR2-deficiency decreased mRNA-levels of interleukins and cytokines. CONCLUSION: In conclusion, our data indicate that inhibiting CatS and PAR-2 deficiency led to a marked reduction of neointima formation and associated inflammation in a murine heterotopic model for allograft vasculopathy.

Murine Cervical Aortic Transplantation Model using a Modified Non-Suture Cuff Technique.

With the introduction of powerful immunosuppressive protocols, distinct advances are possible in the prevention and therapy of acute rejection episodes. However, only minor improvement in the long-term results of transplanted solid organs could be observed over the past decades. In this context, chronic allograft vasculopathy (CAV) still represents the leading cause of late organ failure in cardiac, renal and pulmonary transplantation. Thus far, the underlying pathogenesis of CAV development remains unclear, explaining why effective treatment strategies are presently missing and emphasizing a need for relevant experimental models in order to study the underlying pathophysiology leading to CAV formation. The following protocol describes a murine heterotopic cervical aortic transplantation model using a modified non-suture cuff technique. In this technique, a segment of the thoracic aorta is interpositioned in the right common carotid artery. With the use of the non-suture cuff technique, an easy to learn and reproducible model can be established, minimizing the possible heterogeneity of sutured vascular micro anastomoses.

Multidisciplinary treatment of colorectal liver metastases.

INTRODUCTION: The therapy of patients with colorectal liver metastases (CRLM) has undergone significant changes. Extended survival has been observed to be associated with adoption of hepatic resection and improved chemotherapy. EVIDENCE ACQUISITION: This review summarizes standards, developments and controversies on the management of these patients. Literature search was performed with focus on work published within the last ten years. EVIDENCE SYNTHESIS: Patients with CRLM should undergo surgery whenever possible with careful and experienced patient selection as hepatic resection offers the best long-term prognosis. The multidisciplinary approach has markedly evolved and has increased the number of patients in whom curative-intended surgery is possible. Patients with resectable metastases can undergo upfront surgery or may receive perioperative chemotherapy in selected cases, a decision which is under debate and remains individual. Patients with non-resectable metastases that may become resectable upon conversion treatment should receive polychemotherapy with or without local ablative therapy as pretreatment with the main goal of achieving resectability. In patients with synchronous CRLM, the optimal sequence of treatment remains unclear. Depending on the hepatic tumor burden and its dynamics as well as the type and stage of the primary tumor, simultaneous resection or either the sequential "bowel-first" or reversed "liver-first" approach represent suitable options to achieve complete tumor clearance. CONCLUSIONS: The improvements in the management of CRLM due to multidisciplinary treatment and novel developments are a great example of successfully pushing the boundaries of cure in metastatic cancer. Surgery aiming at complete tumor clearance represents the central instrument to achieve long-term survival.

Modulation of Glutathione Hemostasis by Inhibition of 12/15-Lipoxygenase Prevents ROS-Mediated Cell Death after Hepatic Ischemia and Reperfusion.

BACKGROUND: Reactive oxygen species- (ROS-) mediated ischemia-reperfusion injury (IRI) detrimentally impacts liver transplantation and resection. 12/15-Lipoxygenase (12/15-LOX), an antagonistic protein of the glutathione peroxidase 4 (GPX4) signaling cascade, was proven to mediate cell death in postischemic cerebral and myocardial tissue. The aim of this study was to investigate the impact of 12/15-LOX inhibition on hepatic IRI. METHODS: Livers of C57BL/6 mice were exposed to 60 minutes of partial warm ischemia and 90 minutes of reperfusion after previous Baicalein administration, an inhibitor of 12/15-LOX. Tissue samples were analyzed by TUNEL assay, Western blot, and spectral photometry. RESULTS: TUNEL labeling showed a significant reduction of hepatic cell death following baicalein pretreatment. Western Blot analysis revealed a significant downregulation of Jun-amino-terminal-kinase (JNK), caspase-3, and poly-ADP-ribose-polymerase (PARP), besides considerably lowered p44/42-MAP-kinase (ERK1/2) expression after Baicalein administration. A significant elevation of glutathione oxidation was measured in Baicalein pretreated livers. CONCLUSION: Our data show that inhibition of 12/15-lipoxygenase causes significant cell death reduction after hepatic ischemia and reperfusion by enhancing glutathione metabolism. We conclude that GPX4-dependent cell death signaling cascade might play a major role in development of hepatic IRI, in which the investigated proteins JNK, caspase-3, ERK1/2, and PARP might contribute to tissue damage.

Multiparametric Functional MRI: A Tool to Uncover Subtle Changes following Allogeneic Renal Transplantation.

PURPOSE: To investigate multiparametric functional MRI to characterize acute rejection in a murine allogeneic renal transplant model and evaluate the effect of novel therapeutics. MATERIAL AND METHODS: We performed allogeneic and syngeneic orthotopic transplantations (Balb/c to C57Bl/6 and C57Bl/6 to C57Bl/6). Allogeneic Groups (n = 5) were either treated with the anti-CCL2-Spiegelmer (mNOX-E36) in monotherapy or in combination with low doses of Ciclosporin-A (10mg/kgBW/d) for 10 days. Controls received equivalent doses of a non-functional spiegelmer (revmNOX-E36) or low dose Ciclosporin-A. Diffusion-weighted (DWI) and Dynamic-contrast-enhanced (DCE-) MRI-scans were performed using a clinical 3T-scanner. DWI analysis (b-values from 0-800 s/mm2) was performed mono- and biexponentially, while DCE-MRI was assessed with deconvolution analysis. Therapy effects were assessed ex vivo with histopathology, immunohistochemistry and RT-PCR. Statistical analysis was performed with unpaired t-tests and Spearman´s correlation coefficient. RESULTS: DWI showed a significant diffusion restriction in allogeneic compared to syngeneic transplants (ADC: 0.63±0.08 vs. 1.29±0.12 mm2/s*103) with decreasing diffusion restriction under therapy. DCE-MRI showed restored organ perfusion under Ciclosporin A alone and combination therapy (Plasma Flow: 43.43±12.49; 38.75±7.53ml/100ml/min) compared to syngeneic controls (51.03±12.49ml/100ml/min). Ex vivo analysis showed reduced monocytic infiltrates, attenuated levels of inflammatory cytokines under mNOX-E36 monotherapy with an additive effect of low dose Ciclosporin A. There was a significant (p<0.05) negative correlation between ADC and interstitial inflammation (r = -0.73) or macrophage infiltration (r = -0.81) and between organ perfusion and intimal arteritis (r = -0.63). CONCLUSION: Multiparametric functional MRI is suited to detect renal allograft rejection in an experimental murine model and allows to characterize effects of immunosuppressive therapy alleviating acute rejection processes in allogeneic transplantation.

Time-dependent impact of age and comorbidities on long-term overall survival after liver resection.

BACKGROUND & AIMS: Advanced age and comorbidities are known to be associated with increased perioperative risks after liver resection. However, the precise impact of these variables on long-term overall survival (OS) remains unclear. Thus, the aim of this study was to evaluate the confounder-adjusted, time-dependent effect of age and comorbidities on OS following hepatectomy for primary and secondary malignancies. METHODS: From a prospective database of 1.143 liver resections, 763 patients treated for primary and secondary malignancies were included. For time-varying OS calculations, a Cox-Aalen model was fitted. The confounder-adjusted hazard was compared with mortality tables of the German population. RESULTS: Overall, age (P = 0.003) and comorbidities (P = 0.001) were associated with shortened OS. However, time-dependent analysis indicated that age and comorbidities had no impact on OS within 39 and 55 months after resection respectively. From this time on, a significant decline in OS was shown. Subgroup analysis indicated an earlier increase of the effect of age in patients with hepatocellular carcinoma (17 months) than in those with colorectal metastases (70 months). The confounder-adjusted hazard of 70-year-old patients was increased post-operatively but dropped 66 months after surgery, and the risk of death was comparable to the general population 78 months after resection. At this time, one-third of patients aged 70 years and older were still alive. CONCLUSIONS: With regard to long-term outcome, liver resection for both primary and secondary malignancies should not be categorically denied due to age and comorbidities. This information should be considered for the patient selection process and informed consent.

Effects of malnutrition on complication rates, length of hospital stay, and revenue in elective surgical patients in the G-DRG-system.

OBJECTIVE: Malnutrition is known to independently affect patient outcomes. The aim of this study was to investigate the prevalence of patients at risk for malnutrition in an elective surgery patient cohort and to analyze the effects of malnutrition on morbidity, mortality, and hospital length of hospital (LOS). Furthermore, we aimed to evaluate the economic effect of a diligent coding of malnutrition, as a side diagnosis, in a simulation of the German Diagnosis-Related Group system. METHODS: The nutritional status of 1244 patients undergoing elective surgery was standardized on the day of admission by the Nutritional Risk Screening (NRS) 2002. To quantify the influence of malnutrition on revenue, the real DRGs of all patients were grouped. In simulation, an appropriate International Classification of Diseases code was used as a secondary diagnosis for all malnourished patients based on the NRS rating. A multivariate logistic regression analysis and a Cox regression were performed to identify potential confounders and to determine the adjusted effect of nutritional status on the occurrence of complications and hospital LOS. RESULTS: The prevalence of patients at risk for malnutrition (NRS ≥3) was 24.1% (300 of 1244). These patients showed a significant increase in hospital LOS (13 versus 7 d). Additionally, postoperative complications were significantly higher in this group (7.23% versus 6.91%). Including malnutrition in the Diagnosis-Related Group coding system resulted in a reimbursement of €1979.67 per patient at risk for malnutrition and a total reimbursement of €79,186.73 for all patients at risk for malnutrition in the present study. CONCLUSION: Establishment of a structured, comprehensive assessment of the nutritional status of hospitalized patients can repetitiously identify patients at risk for malnutrition. Additionally, the diligent codification of malnutrition can lead to cost compensation in the German Diagnosis-Related Group system.

Genetic engineering of mesenchymal stromal cells for cancer therapy: turning partners in crime into Trojan horses.

Mesenchymal stromal cells (MSCs) are adult progenitor cells with a high migratory and differentiation potential, which influence a broad range of biological functions in almost every tissue of the body. Among other mechanisms, MSCs do so by the secretion of molecular cues, differentiation toward more specialized cell types, or influence on the immune system. Expanding tumors also depend on the contribution of MSCs to building a supporting stroma, but the effects of MSCs appear to go beyond the mere supply of connective tissues. MSCs show targeted "homing" toward growing tumors, which is then followed by exerting direct and indirect effects on cancer cells. Several research groups have developed novel strategies that make use of the tumor tropism of MSCs by engineering them to express a transgene that enables an attack on cancer growth. This review aims to familiarize the reader with the current knowledge about MSC biology, the existing evidence for MSC contribution to tumor growth with its underlying mechanisms, and the strategies that have been developed using MSCs to deploy an anticancer therapy.

SDF-1/CXCR4/CXCR7 is pivotal for vascular smooth muscle cell proliferation and chronic allograft vasculopathy.

Chronic rejection remains a major obstacle in transplant medicine. Recent studies suggest a crucial role of the chemokine SDF-1 on neointima formation after injury. Here, we investigate the potential therapeutic effect of inhibiting the SDF-1/CXCR4/CXCR7 axis with an anti-SDF-1 Spiegelmer (NOX-A12) on the development of chronic allograft vasculopathy. Heterotopic heart transplants from H-2bm12 to B6 mice and aortic transplants from Balb/c to B6 were performed. Mice were treated with NOX-A12. Control animals received a nonfunctional Spiegelmer (revNOX-A12). Samples were retrieved at different time points and analysed by histology, RT-PCR and proliferation assay. Blockade of SDF-1 caused a significant decrease in neointima formation as measured by intima/media ratio (1.0 ± 0.1 vs. 1.8 ± 0.1, P < 0.001 AoTx; 0.35 ± 0.05 vs. 1.13 ± 0.27, P < 0.05 HTx). In vitro treatment of primary vascular smooth muscle cells with NOX-A12 showed a significant reduction in proliferation (0.42 ± 0.04 vs. 0.24 ± 0.03, P < 0.05). TGF-ß, TNF-α and IL-6 levels were significantly reduced under SDF-1 inhibition (3.42 ± 0.37 vs. 1.67 ± 0.33, P < 0.05; 2.18 ± 0.37 vs. 1.0 ± 0.39, P < 0.05; 2.18 ± 0.26 vs. 1.6 ± 0.1, P < 0.05). SDF-1/CXCR4/CXCR7 plays a critical role in the development of chronic allograft vasculopathy (CAV). Therefore, pharmacological inhibition of SDF-1 with NOX-A12 may represent a therapeutic option to ameliorate chronic rejection changes.

Treatment of advanced gastrointestinal tumors with genetically modified autologous mesenchymal stromal cells (TREAT-ME1): study protocol of a phase I/II clinical trial.

BACKGROUND: Adenocarcinoma originating from the digestive system is a major contributor to cancer-related deaths worldwide. Tumor recurrence, advanced local growth and metastasis are key factors that frequently prevent these tumors from curative surgical treatment. Preclinical research has demonstrated that the dependency of these tumors on supporting mesenchymal stroma results in susceptibility to cell-based therapies targeting this stroma. METHODS/DESIGN: TREAT-ME1 is a prospective, uncontrolled, single-arm phase I/II study assessing the safety and efficacy of genetically modified autologous mesenchymal stromal cells (MSC) as delivery vehicles for a cell-based gene therapy for advanced, recurrent or metastatic gastrointestinal or hepatopancreatobiliary adenocarcinoma. Autologous bone marrow will be drawn from each eligible patient after consent for bone marrow donation has been obtained (under a separate EC-approved protocol). In the following ~10 weeks the investigational medicinal product (IMP) is developed for each patient. To this end, the patient's MSCs are stably transfected with a gamma-retroviral, replication-incompetent and self-inactivating (SIN) vector system containing a therapeutic promoter - gene construct that allows for tumor-specific expression of the therapeutic gene. After release of the IMP the patients are enrolled after given informed consent for participation in the TREAT-ME 1 trial. In the phase I part of the study, the safety of the IMP is tested in six patients by three treatment cycles consisting of re-transfusion of MSCs at different concentrations followed by administration of the prodrug Ganciclovir. In the phase II part of the study, sixteen patients will be enrolled receiving IMP treatment. A subgroup of patients that qualifies for surgery will be treated preoperatively with the IMP to verify homing of the MSCs to tumors as to be confirmed in the surgical specimen. DISCUSSION: The TREAT-ME1 clinical study involves a highly innovative therapeutic strategy combining cell and gene therapy and is conducted at a high level of pharmaceutical quality ensuring patient safety. This patient-tailored approach represents the first clinical study worldwide utilizing genetically engineered MSCs in humans. TRIAL REGISTRATION: EU Clinical Trials Register/European Union Drug Regulating Authorities Clinical Trials Database number: 2012-003741-15.

A German survey of the abdominal transplantation surgical work force.

This manuscript reports the results of a nationwide survey of transplant surgeons in Germany, including the demographics, training, position, individual case loads, center volumes, program structure, professional practice, grade of specialization, workload, work hours, salary, and career expectations. We contacted all 32 German transplant centers that perform liver, kidney, and pancreas transplantation. Surgeons engaged in transplantation were asked to reply to the survey. Eighty-five surgeons responded, with a mean age of 44 ± 8 years, 13% of whom were female. The median transplant frequency per active transplant surgeon was relatively low, with 16 liver transplants, 15 kidney transplants, and three pancreas transplants. The median reported center volumes were 45 liver transplants, 90 kidney transplants, and five pancreas transplants per year. Most of the surgeons reported a primary focus on hepato-pancreato-biliary surgery, and only 10% of effective work time was actually dedicated to perform transplant surgeries. The majority of respondents estimated their weekly work hours to be between 55 and 66 h. When asked about their career satisfaction and expectations, most respondents characterized their salaries as inappropriately low and their career prospects as inadequate. This survey provides a first impression of the transplant surgery work force in Germany.

Intraoperative simulation of remnant liver function during anatomic liver resection with indocyanine green clearance (LiMON) measurements.

OBJECTIVE: Post-hepatectomy liver failure (PHLF) is the major cause of death following liver resection. The aim of this study was to evaluate the feasibility of an intraoperative simulation of post-resection liver function. METHODS: Intraoperative liver function was measured by indocyanine green (ICG) clearance using the LiMON technology. In 20 patients undergoing anatomic liver resection, ICG plasma disappearance rate (PDR (%/min) and ICG retention at 15 min (R15 ) (%) were measured immediately after the induction of anaesthesia (t0 ), after selective arterial and portovenous inflow trial clamping (TC) of the resected liver segments (t1 ), after the completion of resection (t2 ) and before the closure of the abdominal cavity (t3 ). RESULTS: The median baseline (t0 ) PDR was 16.5%/min. Trial clamping of the inflow (t1 ) resulted in a significant reduction in PDR to 10.5%/min. Results under TC were similar to those obtained after resection (t2 ) (median PDR: 10.5%/min). Linear regression modelling showed that post-resection liver volume could be accurately predicted by TC of liver inflow (P < 0.0001), but not by determining the resected liver volume. Simulated post-resection liver function under TC correlated well with PHLF and length of hospital stay. CONCLUSIONS: Intraoperative ICG clearance measurements allow real-time monitoring of intraoperative liver function during surgery. Trial clamping of arterial and portovenous inflow accurately predicts immediate post-resection liver function. The intraoperative measurement of liver function and simulation of post-resection liver function may help to avoid PHLF.

Management of acute upside-down stomach.

BACKGROUND: Upside-down stomach (UDS) is characterized by herniation of the entire stomach or most gastric portions into the posterior mediastinum. Symptoms may vary heavily as they are related to reflux and mechanically impaired gastric emptying. UDS is associated with a risk of incarceration and volvulus development which both might be complicated by acute gastric outlet obstruction, advanced ischemia, gastric bleeding and perforation. CASE PRESENTATION: A 32-year-old male presented with acute intolerant epigastralgia and anterior chest pain associated with acute onset of nausea and vomiting. He reported on a previous surgical intervention due to a hiatal hernia. Chest radiography and computer tomography showed an incarcerated UDS. After immediate esophago-gastroscopy, urgent laparoscopic reduction, repair with a 360° floppy Nissen fundoplication and insertion of a gradually absorbable GORE® BIO-A®-mesh was performed. CONCLUSION: Given the high risk of life-threatening complications of an incarcerated UDS as ischemia, gastric perforation or severe bleeding, emergent surgery is indicated. In stable patients with acute presentation of large paraesophageal hernia or UDS exhibiting acute mechanical gastric outlet obstruction, after esophago-gastroscopy laparoscopic reduction and hernia repair followed by an anti-reflux procedure is suggested. However, in cases of unstable patients open repair is the surgical method of choice. Here, we present an exceptionally challenging case of a young patient with a giant recurrent hiatal hernia becoming clinically manifest in an incarcerated UDS.

Rectal prolapse.

CASE REPORT: A 56-year-old male presented to the emergency department with a feeling of heaviness and a protruding mass at the anal verge associated with pruritus in this area. The patient did not feel any pain and did not report experiencing faecal incontinence. Physical examination resulted in the visual diagnosis of a total rectal prolapse. Immediate manual repositioning through gentle pressure succeeded and the patient was scheduled for an elective laparoscopic ventral rectopexy. DISCUSSION: Total rectal prolapse, or full-thickness rectal prolapse (procidentia), is defined as protrusion of the rectum beyond the anus. The entire rectal wall can be palpated in the externalized tissue exhibiting circular plication. Thus, a less distinct rectal prolapse can be distinguished visually from an anal mucosal prolapse as the latter shows stellate plication. Symptomatic patients having difficulties in reduction, substantial incontinence or obstructed defecation are to be referred for consideration of surgery.

Laparoscopic anterior hemifundoplication and hiatoplasty for the treatment of upside-down stomach: mid- and long-term results after 40 patients.

BACKGROUND: Treatment of type 4 hiatal hernia using a minimally invasive approach is challenging and requires good familiarity with this technique. METHODS: From October 1992 to August 2010, 40 patients with a median age of 68 years underwent laparoscopic anterior hemifundoplication surgery for upside-down stomach and were included in our prospective study. The median symptoms duration was 5 years. The leading clinical symptoms were postprandial, epigastric, or retrosternal pain (80%), heartburn (78%), regurgitation (80%), dysphagia (53%), and anemia (48%). Preoperative evaluation included blood test, chest X-ray, upper endoscopy, and barium swallow. In some patients an esophageal 24-h pH study and esophageal manometry were performed. The median follow-up was 46 months using a standardized questionnaire, including Smiley score, modified Visick score, gastrointestinal quality-of-life index (GQLI), and specific reflux symptoms score. RESULTS: Surgery was finished laparoscopically in 39 patients (97%). One patient had to be converted to an open procedure because of severe adhesions. Mesh hiatoplasty had to be performed in one patient due to a large hiatal defect. Median operative time was 160 min (range=90-275) and median blood loss was 5 ml (range=0-300). Seven patients (18%) presented with acute symptoms. Intraoperative technical complications occurred in four patients (10%) and nontechnical complications in two cases (5%). Median postoperative hospital stay was 5 days (range=2-17). Postoperative complications occurred in two patients (5%): one pleural effusion and one surgical emphysema. There was no mortality or symptomatic recurrence. All scores showed significant improvement and patient satisfaction. CONCLUSION: Laparoscopic treatment of type 4 hiatal hernia is safe. With respect to the quality of life, anterior hemifundoplication is highly effective.

Heme oxygenase-1, carbon monoxide, and bilirubin induce tolerance in recipients toward islet allografts by modulating T regulatory cells.

Heme oxygenase-1 (HO-1) induction in, or carbon monoxide (CO), or bilirubin administration to, donors and/or recipients frequently lead to long-term survival (>100 days) of DBA/2 islets into B6AF1 recipients. We tested here whether similar treatments show value in a stronger immunogenetic combination, i.e., BALB/c to C57BL/6, and attempted to elucidate the mechanism accounting for tolerance. Induction of HO-1, administering CO or bilirubin to the donor, the islets or the recipient, prolonged islet allograft survival to different extents. Combining all the above treatments (the "combined" protocol) led to survival for >100 days and antigen-specific tolerance to 60% of the transplanted grafts. A high level of forkhead box P3 (Foxp3) and transforming growth factor beta (TGF-beta) expression was detected in the long-term surviving grafts. With the combined protocol, significantly more T regulatory cells (Tregs) were observed surrounding islets 7 days following transplantation. No prolongation of graft survival was observed using the combined protocol when CD4+ CD25+ T cells were predepleted from the recipients before transplantation. In conclusion, our combined protocol led to long-term survival and tolerance to islets in the BALB/c to C57BL/6 combination by promoting Foxp3+ Tregs; these cells played a critical role in the induction and maintenance of tolerance in the recipient.