Quality of life in peritoneal carcinomatosis: a prospective study in patients undergoing cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (HIPEC).

BACKGROUND/AIMS: Cytoreductive surgery and hyperthermic intraperitoneal chemoperfusion (HIPEC) can improve survival in selected patients with peritoneal carcinomatosis, but bear a significant risk of perioperative morbidity. The aim of this study was to prospectively evaluate the quality of life (QoL) following cytoreduction and HIPEC. METHODS: In this study including 40 patients (65% females) with different primary tumors, the EORTC QLQ-C30 questionnaire was applied prior to CS and HIPEC as well as 3, 9, and 18 months postoperatively. RESULTS: Global health status was not impaired significantly following HIPEC. Scales and symptom scores that deteriorated 3 months postoperatively (p < 0.05), that is, physical, role, and social functions as well as fatigue, pain, dyspnea, insomnia, and diarrhea, all returned to preoperative values within 9 months. CONCLUSIONS: Following cytoreductive surgery and HIPEC, QoL returns to preoperative levels within 9 months. Selected patients that are likely to benefit oncologically from HIPEC should not be denied this option for fear of reduced postoperative QoL.

Unlocking the enigma: Combined percutaneous-transhepatic and endoscopic strategies for retrieval of severed Dormia basket in choledocholithiasis. A case report and literature review.

Choledocholithiasis, characterized by the presence of stones in the common bile duct, poses significant challenges in clinical management, particularly when the stones are massive. While endoscopic methods are often effective in stone removal, complications such as the impaction of foreign bodies like Dormia baskets can occur. These complications may necessitate alternative approaches, including surgical intervention, highlighting the importance of exploring innovative interventional techniques. We report on an 89-year-old patient presenting with massive choledocholithiasis, involving complete filling of the intra- and extrahepatic bile duct system with large stones up to a maximum of 2 cm. The patient underwent interventional removal of a Dormia basket (3.5Fr. Boston Scientific, USA) impacted in the common bile duct. This procedure proved challenging due to the metallic end marker of the basket perforating through the wall of the distal common bile duct, rendering it fixed. Given the complexity of the case, a parallel approach combining percutaneous transhepatic cholangiography and drainage with simultaneous endoscopy was employed to successfully extract the fixed Dormia basket. In cases of severe choledocholithiasis complicated by the impaction of foreign bodies such as Dormia baskets, innovative interventional strategies are crucial for successful management. Our case highlights the effectiveness of a parallel approach involving percutaneous transhepatic cholangiography and drainage alongside simultaneous endoscopy in safely removing the fixed foreign body from the common bile duct. This multidisciplinary approach not only offers a viable alternative to surgical intervention but also underscores the importance of collaboration between interventional radiologists and endoscopists in optimizing patient outcomes in complex biliary interventions.

A case of an intraabdominal, but extrahepatic ruptured percutaneous transhepatic biliary drainage and its following rescue. A case report and literature review.

Percutaneous transhepatic biliary drainage is a well-established technique for the treatment of biliary obstruction in patients with failed endoscopic approaches. We report on an 82-year-old man with a history of cholangiocarcinoma treated with pancreaticoduodenectomy who presented with recurrent cholangitis and sepsis. Percutaneous transhepatic biliary drainage was performed after unsuccessful endoscopic retrograde cholangiography, which initially improved his condition. However, due to an accidental dislodgement, there was an intra-abdominal fracture of the drain which led to biliary peritonitis and clinical deterioration. The fractured intrahepatic drain was successfully extracted in our angio suite, and a novel subcutaneous fixation technique was introduced to prevent similar occurrences in the future. This case study signifies the role of interventional radiology in the management of percutaneous transhepatic biliary drainage complications and the importance of preventative measures to avoid dislodgement.

Surgery for metastasis to the pancreas: is it safe and effective?

BACKGROUND: Pancreatic metastases are rare and only sparse data exists on treatment options. After recent advances in pancreatic surgery, metastasectomies have become promising treatment alternatives. METHODS: Twenty-six patients underwent pancreatic metastasectomy between 1991 and 2010 at our institution. Data was evaluated retrospectively. RESULTS: Renal cell carcinoma was the most common origin of pancreatic metastases (n = 16; 62%). Other primaries include gall bladder carcinoma, leiomyosarcoma, colon cancer (all n = 2), and others. The median time interval between primary tumor and pancreatic resection was 5.3 years [0-24]. Eleven pancreatic head resections (42%), fourteen distal pancreatectomies (54%), and one total pancreatectomy were performed (4%). The estimated 3- and 5-year survival rates were 73.2% and 52.3%, respectively. The estimated median overall survival was 63 months (CI: 37.8-88.1 months). There' was no perioperative death. The complication rate and relaparotomy rate was 31% and 19%, respectively. Patients suffering from synchronous metastases at the time of pancreatic surgery had a statistically significant shorter median overall survival time (11 months vs. 64 months). CONCLUSIONS: Despite the operative risk involved, we believe that pancreatic resection should be considered in selected patients with good performance status, stable disease and isolated pancreatic metastases.

Impact of cyclosporine versus tacrolimus on the incidence of de novo malignancy following liver transplantation: a single center experience with 609 patients.

De novo malignancies are a major cause of late death after liver transplantation. Aim of the present study was to determine whether use of cyclosporine versus tacrolimus affects long-term tumor incidence considering potential confounders. De novo malignancies in 609 liver transplant recipients at Munich Transplant Centre between 1985 and 2007 were registered. In 1996, the standard immunosuppressive regimen was changed from cyclosporine to tacrolimus. Different effects of those drugs on long-term tumor incidence were analyzed in multivariate analysis. During 3765 patient years of follow-up (median 4.78 years), 87 de novo malignancies occurred in 71 patients (mean age 47.5 ± 13.3 years, mean time after liver transplantation 5.7 ± 3.7 years). The cumulative incidence of de novo malignancies was 34.7% for all tumor entities after 15 years as compared to 8.9% for a nontransplanted population. The most frequent tumors observed were nonmelanoma skin cancers (44.83%). Moreover, post-transplant lymphoid disease, oropharyngeal cancer (n = 6, 6.9%), upper gastrointestinal tract cancer (n = 4, 4.6%), lung cancer (n = 4, 4.6%), gynecological malignancies (n = 4, 4.6%), and kidney cancer (n = 3, 3.45%) were detected. Multivariate analysis revealed recipient age [hazards ratio (HR) 1.06], male gender (HR 1.73), and tacrolimus-based immunosuppression (HR 2.06) as significant risk factors. Based on those results, a tacrolimus-based immunosuppression should be discussed especially in older male patients. Whether reducing tacrolimus target levels may reduce the risk for de novo malignancies has yet to be determined in prospective trials.

Pancreaticobiliary Diseases with Severe Complications as a Rare Indication for Emergency Pancreaticoduodenectomy: A Single-Center Experience and Review of the Literature.

The pancreaticobiliary system is a complex and vulnerable anatomic region. Small changes can lead to severe complications. Pancreaticobiliary disorders leading to severe complications include malignancies, pancreatitis, duodenal ulcer, duodenal diverticula, vascular malformations, and iatrogenic or traumatic injuries. Different therapeutic strategies, such as conservative, interventional (e.g., embolization, stent graft applications, or biliary interventions), or surgical therapy, are available in early disease stages. Therapeutic options in patients with severe complications such as duodenal perforation, acute bleeding, or sepsis are limited. If less invasive procedures are exhausted, an emergency pancreaticoduodenectomy (EPD) can be the only option left. The aim of this study was to analyze a single-center experience of EPD performed for benign non-trauma indications and to review the literature concerning EPD. Between January 2015 and January 2022, 11 patients received EPD due to benign non-trauma indications at our institution. Data were analyzed regarding sex, age, indication, operative parameters, length of hospital stay, postoperative morbidity, and mortality. Furthermore, we performed a literature survey using the PubMed database and reviewed reported cases of EPD. Eleven EPD cases due to benign non-trauma indications were analyzed. Indications included peptic duodenal ulcer with penetration into the hepatopancreatic duct and the pancreas, duodenal ulcer with acute uncontrollable bleeding, and penetration into the pancreas, and a massive perforated duodenal diverticulum with peritonitis and sepsis. The mean operative time was 369 min, and the median length of hospital stay was 35.8 days. Postoperative complications occurred in 4 out of 11 patients (36.4%). Total 90-day postoperative mortality was 9.1% (1 patient). We reviewed 17 studies and 22 case reports revealing 269 cases of EPD. Only 20 cases of EPD performed for benign non-trauma indications are reported in the literature. EPD performed for benign non-trauma indications remains a rare event, with only 31 reported cases. The data analysis of all available cases from the literature revealed an increased postoperative mortality rate of 25.8%. If less invasive approaches are exhausted, EPD is still a life-saving procedure with acceptable results. Performed by surgeons with a high level of experience in hepatobiliary and pancreatic surgery, mortality rates below 10% can be achieved.

Successful heparin-perfusion therapy for complete thrombosis of the intra- and extrahepatic portal and mesenteric vein. A case report and literature review.

The initial treatment of acute and subacute portal vein thrombosis, which is the most common cause of portal vein occlusion, consists of intravenous anticoagulation with heparin, but there is still a huge uncertainty among physicians regarding the role of more invasive therapies. We report a 61-year-old male patient, who presented in our emergency room with a subacute complete thrombosis of the intra- and extrahepatic portal vein, mesenteric vein, with associated venous congestion of 20-30 cm length of the small intestine with a quick and complete remission of the portal vein thrombosis under sole i.v. heparin-perfusor therapy without any complications. Molecular genetic analysis found combined genetic mutations of the gene factor 2 (c.20210G>A, heterozygotic), SERPINE1 (-675 5G>4G, heterozygotic), and the MTHFR gene. Along with this interesting case, we also present the recent status of portal vein thrombosis and portal vein occlusion in the literature.

Arterial blood flow predicts graft survival in liver transplant patients.

Proper liver perfusion is essential for sufficient organ function after liver transplantation. The aim of this study was to determine the effects of portal and arterial blood flow on liver function and organ survival after liver transplantation. The arterial and portal venous blood flow was measured intraoperatively by transit time flow measurement after reperfusion for 290 consecutive liver transplants. The graft survival, hepatic cell damage (alanine aminotransferase and aspartate aminotransferase), and liver function (prothrombin ratio and bilirubin) were determined. Grafts were stratified into groups according to arterial blood flow measurements [<100 mL/minute for arterial blood flow group I (ART I), 100-240 mL/minute for ART II, and ≥ 240 mL/minute for ART III] and portal venous blood flow measurements (<1300 mL/minute for portal venous blood flow group I and ≥ 1300 mL/minute for portal venous blood flow group II). With multivariate analysis, the impact of blood flow on graft survival was determined, and potential confounders were considered. Decreased portal venous blood flow was associated with significantly less organ survival in univariate analysis but not in multivariate analysis. In contrast, the arterial blood flow was significantly correlated with organ survival after liver transplantation in univariate and multivariate analyses [hazard rate ratio = 2.5, confidence interval = 1.6-4.1, P < 0.001, median survival = 56.6 (ART I), 82.7 (ART II), or 100.7 months (ART III)]. Moreover, low arterial blood flow resulted in impaired postoperative organ function and higher rates of primary nonfunction. Biliary complications were not affected by blood flow. Other risk factors for graft failure that were identified by multivariate analysis included retransplantation, histidine tryptophan ketoglutarate solution versus University of Wisconsin solution, and donor treatment with epinephrine. Impaired arterial blood flow after reperfusion represents a significant predictor of primary graft nonfunction and is associated with impaired graft survival. Whether the intraoperative measurement of hepatic arterial flow is predictive of graft survival should be evaluated in a prospective trial.

Late reuse of liver allografts from brain-dead graft recipients: the Munich experience and a review of the literature.

The increasing donor organ shortage requires the consideration of any possible organ donor in order to meet the current demand. However, the growing number of long-term survivors of liver transplantation may create a situation in which former organ recipients may experience brain death with a functioning graft and therefore become organ donors themselves. Previous reports concerning this rare situation predominantly refer to the reuse of donor organs within the first 8 days after primary liver transplantation. So far, only a single case of late reuse of a donor liver has been published, with 2 additional cases mentioned in a summary of the United Network for Organ Sharing database. Here we report the case of a 43-year-old female donor who had received a liver graft for complications of Budd-Chiari syndrome 5 years before becoming an organ donor herself after cerebral infarction with consecutive brain death.

A prospective randomised, open-labeled, trial comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing liver transplantation for hepatocellular carcinoma.

BACKGROUND: The potential anti-cancer effects of mammalian target of rapamycin (mTOR) inhibitors are being intensively studied. To date, however, few randomised clinical trials (RCT) have been performed to demonstrate anti-neoplastic effects in the pure oncology setting, and at present, no oncology endpoint-directed RCT has been reported in the high-malignancy risk population of immunosuppressed transplant recipients. Interestingly, since mTOR inhibitors have both immunosuppressive and anti-cancer effects, they have the potential to simultaneously protect against immunologic graft loss and tumour development. Therefore, we designed a prospective RCT to determine if the mTOR inhibitor sirolimus can improve hepatocellular carcinoma (HCC)-free patient survival in liver transplant (LT) recipients with a pre-transplant diagnosis of HCC. METHODS/DESIGN: The study is an open-labelled, randomised, RCT comparing sirolimus-containing versus mTOR-inhibitor-free immunosuppression in patients undergoing LT for HCC. Patients with a histologically confirmed HCC diagnosis are randomised into 2 groups within 4-6 weeks after LT; one arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol and the second arm is maintained on a centre-specific mTOR-inhibitor-free immunosuppressive protocol for the first 4-6 weeks, at which time sirolimus is initiated. A 21/2 -year recruitment phase is planned with a 5-year follow-up, testing HCC-free survival as the primary endpoint. Our hypothesis is that sirolimus use in the second arm of the study will improve HCC-free survival. The study is a non-commercial investigator-initiated trial (IIT) sponsored by the University Hospital Regensburg and is endorsed by the European Liver and Intestine Transplant Association; 13 countries within Europe, Canada and Australia are participating. DISCUSSION: If our hypothesis is correct that mTOR inhibition can reduce HCC tumour growth while simultaneously providing immunosuppression to protect the liver allograft from rejection, patients should experience less post-transplant problems with HCC recurrence, and therefore could expect a longer and better quality of life. A positive outcome will likely change the standard of posttransplant immunosuppressive care for LT patients with HCC. TRIAL REGISTER: Trial registered at http://www.clinicaltrials.gov: NCT00355862(EudraCT Number: 2005-005362-36).

Atrial resection for lung cancer: morbidity, mortality, and long-term follow-up.

BACKGROUND: The purpose of this study was to examine our results of combined resection of the atrium and non-small-cell lung cancer using a concurrent and continuously updated database. METHODS: A total of 35 patients underwent extended pulmonary resection with partial resection of the atrium. The main focus of the study was to define subgroups of patients who can potentially benefit from surgery. RESULTS: Pneumonectomy was performed in 31 cases, and the other 4 patients underwent a lesser resection. Postoperative morbidity was 20%, and the mortality rate was 9%. The median intensive care unit stay was 2 days and the hospital stay 13 days. The survival rates were 80% at 1 year, 21% at 3 years, and 16% at 5 years. The median survival of patients with low-grade tumors (G1/2) was 27 months, contrasted by only 15 months' survival for patients with high-grade tumors (P = 0.026). Multivariate analysis indicated that completeness of resection had a significant impact on survival (P = 0.042). CONCLUSIONS: Combined resection of lung and atrium is a complex surgical procedure, but it can be performed with fair morbidity and mortality rates, even in patients with an increased number of preoperative risk factors. Patients suffering from low-grade tumors benefit significantly from radical surgery. Future studies must define whether a multimodal therapeutic approach that includes induction therapy can prolong patient survival.

Esophageal leiomyomatosis combined with intrathoracic stomach and gastric volvulus.

CASE REPORT: A 42-year-old female presented with long-standing symptoms suggestive of gastroesophageal reflux disease improved after proton pump inhibitor treatment. An upper endoscopy revealed an intrathoracic position of the stomach (type 4 hiatal hernia) with no mucosal abnormality. Barium swallow demonstrated gastric herniation with gastric volvulus without stenosis. A computed tomographic scan confirmed the intrathoracic location of the stomach associated with thickening and edema of the gastric wall due to gastric volvulus, but no evidence of malignancy. The patient was scheduled for laparoscopic gastric repositioning with anterior hemifundoplication. Due to the incidental intraoperative finding of a large distal esophageal tumor (frozen section: esophageal leiomyomatosis), the operation was converted to conventional distal esophagectomy and proximal gastrectomy with reconstruction using a Merendino procedure. Final histology revealed extensive circumferential leiomyomatosis of the distal esophagus with a diameter of 10 cm. Esophageal leiomyomatosis is an extremely rare pathological finding with <100 cases reported in the literature. CONCLUSION: Any surgeon performing laparoscopic fundoplication has to be ready to deal with such unexpected findings, ie, converting the procedure and doing reconstruction with minimal morbidity. The Merendino procedure is a well-established reconstructive surgical option in cases of tumor formation at the gastroesophageal region with fewer postoperative morbidities like reflux symptoms.

Liver resection or combined chemoembolization and radiofrequency ablation improve survival in patients with hepatocellular carcinoma.

BACKGROUND/AIMS: To evaluate the long-term outcome of surgical and non-surgical local treatments of patients with hepatocellular carcinoma (HCC). METHODS: We stratified a cohort of 278 HCC patients using six independent predictors of survival according to the Vienna survival model for HCC (VISUM-HCC). RESULTS: Prior to therapy, 224 HCC patients presented with VISUM stage 1 (median survival 18 months) while 29 patients were classified as VISUM stage 2 (median survival 4 months) and 25 patients as VISUM stage 3 (median survival 3 months). A highly significant (p < 0.001) improved survival time was observed in VISUM stage 1 patients treated with liver resection (n = 52; median survival 37 months) or chemoembolization (TACE) and subsequent radiofrequency ablation (RFA) (n = 44; median survival 45 months) as compared to patients receiving chemoembolization alone (n = 107; median survival 13 months) or patients treated by tamoxifen only (n = 21; median survival 6 months). Chemoembolization alone significantly (p < or = 0.004) improved survival time in VISUM stage 1-2 patients but not (p = 0.341) in VISUM stage 3 patients in comparison to those treated by tamoxifen. CONCLUSION: Both liver resection or combined chemoembolization and RFA improve markedly the survival of patients with HCC.

Sirolimus Use in Liver Transplant Recipients With Hepatocellular Carcinoma: A Randomized, Multicenter, Open-Label Phase 3 Trial.

BACKGROUND: We investigated whether sirolimus-based immunosuppression improves outcomes in liver transplantation (LTx) candidates with hepatocellular carcinoma (HCC). METHODS: In a prospective-randomized open-label international trial, 525 LTx recipients with HCC initially receiving mammalian target of rapamycin inhibitor-free immunosuppression were randomized 4 to 6 weeks after transplantation into a group on mammalian target of rapamycin inhibitor-free immunosuppression (group A: 264 patients) or a group incorporating sirolimus (group B: 261). The primary endpoint was recurrence-free survival (RFS); intention-to-treat (ITT) analysis was conducted after 8 years. Overall survival (OS) was a secondary endpoint. RESULTS: Recurrence-free survival was 64.5% in group A and 70.2% in group B at study end, this difference was not significant (P = 0.28; hazard ratio [HR], 0.84; 95% confidence interval [95% CI], 0.62; 1.15). In a planned analysis of RFS rates at yearly intervals, group B showed better outcomes 3 years after transplantation (HR, 0.7; 95% CI, 0.48-1.00). Similarly, OS (P = 0.21; HR, 0.81; 95% CI, 0.58-1.13) was not statistically better in group B at study end, but yearly analyses showed improvement out to 5 years (HR, 0.7; 95% CI, 0.49-1.00). Interestingly, subgroup (Milan Criteria-based) analyses revealed that low-risk, rather than high-risk, patients benefited most from sirolimus; furthermore, younger recipients (age ≤60) also benefited, as well sirolimus monotherapy patients. Serious adverse event numbers were alike in groups A (860) and B (874). CONCLUSIONS: Sirolimus in LTx recipients with HCC does not improve long-term RFS beyond 5 years. However, a RFS and OS benefit is evident in the first 3 to 5 years, especially in low-risk patients. This trial provides the first high-level evidence base for selecting immunosuppression in LTx recipients with HCC.

mTOR inhibition and its effect on cancer in transplantation.

A considerable amount of data indicates that transplanted patients are at increased risk for de novo and recurrent cancer. Treatment of this population is difficult. It remains unclear if the immunosuppressive therapy should be continued, tapered or even stopped or if immunosuppressive drugs with antiproliferative properties have beneficial effects in this situation. In various models, mTOR-inhibitors were shown to have immunosuppressive and anti-tumor effects. Here, we have reviewed the current literature trying to clarify if mTOR-inhibition brings advantages for the transplanted patients suffering from tumors.

Pro- and anti-cancer effects of immunosuppressive agents used in organ transplantation.

Development of cancer is a feared, and increasingly apparent, complication of long-term immunosuppressive therapy in transplant recipients. In addition to the need to reduce cancer occurrence in these patients, therapeutic protocols are lacking to simultaneously attack the malignancy and protect the allograft when neoplasms do occur. In this overview, we present the current literature regarding the pro- and anti-neoplastic effects of immunosuppressive agents on cancer growth and development. Recent experimental findings are paving the way for new therapeutic strategies aimed at both protecting an allograft from immunologic rejection and addressing the problem of cancer in this high-risk population.

The antineoplastic drug Paclitaxel has immunosuppressive properties that can effectively promote allograft survival in a rat heart transplant model.

INTRODUCTION: Recurrent and de novo neoplasms are ominous risk factors for transplant patients. In particular, when organ transplantation is attempted to cure isolated cancers, conventional immunosuppression likely promotes cancer reestablishment. Therefore, drugs with both immunosuppressive and antineoplastic activity are needed. We show that the anticancer agent paclitaxel may fulfill these diverse expectations. METHODS: Heterotopic heart transplantation was performed in the ACI-to-Lewis or Lewis-to-ACI rat-strain combination and paclitaxel was injected i.p. daily (days 0-14) at doses from 0.75-1.5 mg/kg. Serum cytotoxic antidonor antibody levels were measured using a complement-mediated cell cytotoxicity assay. In vitro, the effect of paclitaxel on Lewis lymphocyte viability and apoptosis was determined. Also, Lewis lymphocytes preconditioned with irradiated ACI cells+/-paclitaxel, were restimulated with ACI cells and tested for cytotoxic T cell (CTL) activity and interleukin-2 (IL-2) production. RESULTS: Paclitaxel promoted heart allograft survival in a dose-dependent manner in both high- and low-responder transplant combinations. Furthermore, low-doses of paclitaxel (0.75-1.0 mg/kg) and cyclosporine (1 mg/kg) in combination synergistically increased transplant survival. Immunologically, paclitaxel markedly reduced the antidonor cytotoxic antibody response. In vitro, nearly 90% of prestimulated lymphocytes were killed by paclitaxel and cells became positive for the apoptosis marker, annexin-V. Furthermore, paclitaxel reduced CTL activity and IL-2 production after alloantigen rechallenge. CONCLUSION: Paclitaxel, a clinically proven antineoplastic agent, also has potent immunosuppressive properties in rodent organ transplantation. This drug could be extremely valuable in transplant situations where de novo cancer develops, or when organ transplantation is performed to treat isolated, but typically recurrent, neoplasms.

Rapamycin protects allografts from rejection while simultaneously attacking tumors in immunosuppressed mice.

Cancer is an increasingly recognized problem associated with immunosuppression. Recent reports, however, suggest that the immunosuppressive agent rapamycin has anti-cancer properties that could address this problem. Thus far, rapamycin's effects on immunity and cancer have been studied separately. Here we tested the effects of rapamycin, versus cyclosporine A (CsA), on established tumors in mice simultaneously bearing a heart allograft. In one tumor-transplant model, BALB/c mice received subcutaneous syngenic CT26 colon adenocarcinoma cells 7 days before C3H ear-heart transplantation. Rapamycin or CsA treatment was initiated with transplantation. In a second model system, a B16 melanoma was established in C57BL/6 mice that received a primary vascularized C3H heart allograft. In vitro angiogenic effects of rapamycin and CsA were tested in an aortic ring assay. Results show that CT26 tumors grew for 2 weeks before tumor complications occurred. However, rapamycin protected allografts, inhibited tumor growth, and permitted animal survival. In contrast, CsA-treated mice succumbed to advancing tumors, albeit with a functioning allograft. Rapamycin's antitumor effect also functioned in severe combined immunodeficient BALB/c mice. Similar effects of the drugs occurred with B16 melanomas and primary vascularized C3H allografts in C57BL/6 mice. Furthermore, in this model, rapamycin inhibited the tumor growth-enhancing effects of CsA. Moreover, in vitro experiments showed that CsA promotes angiogenesis by a transforming growth factor-beta-related mechanism, and that this effect is abrogated by rapamycin. This study demonstrates that rapamycin simultaneously protects allografts from rejection and attacks tumors in a complex transplant-tumor situation. Notably, CsA protects allografts from rejection, but cancer progression is promoted in transplant recipients.

Hepatocyte expression of soluble donor MHC class I antigen via gene transfer inhibits multiple aspects of the antidonor immune response in fully sensitized rat transplant recipients.

Sensitized organ transplant recipients face an increased risk of hyperacute rejection (HAR) due to donor major histocompatibility complex (MHC) class I antigen (Ag) preexposure. We recently reported a novel donor-specific strategy to address this problem, whereby soluble donor MHC class I Ag gene therapy prevented HAR of heart allografts in passively sensitized rats. Here, we tested this same approach in presensitized rat recipients with a fully preactivated humoral and cellular immune response. Our gene therapy method involved liposomal transfection of cultured recipient (Lewis-RT1.A(1)) hepatocytes with DNA encoding secretable donor MHC class I Ag, RT1.A(a). Control-transfected or RT1.A(a)-transfected hepatocytes were implanted intrasplenically into Lewis rats presensitized with three skin transplants. Subsequently, antidonor antibody, cytotoxic T lymphocyte (CTL), and helper T lymphocyte (HTL) assays were performed. Additionally, the effectiveness of our gene therapy on the prevention of ACI (RT1(a)) heart HAR was evaluated. Results indicated that soluble MHC not only decreased cytotoxic antibody levels, but also suppressed antidonor CTL and HTL responses; furthermore, HAR of heart allografts was prevented in all recipients. Therefore, soluble donor MHC class I gene therapy can inhibit multiple aspects of the primed antidonor immune response in actively presensitized rats. Development of this strategy in presensitized humans could improve organ transplant outcome.

Use of an adenoviral vector to express soluble donor-major histocompatibility complex molecules capable of suppressing the immune response in rat transplant recipients.

There is an accumulating body of evidence indicating that soluble major histocompatibility complex (sMHC) molecules have donor-specific immunosuppressive properties. One classic, but still unproven, theory is that production of sMHC by liver transplants induces a potent immunosuppressive effect. To mimic this possible effect, we have developed a replication deficient adenovirus (Ad-RQ) to express high levels of donor sMHC class I molecules (sRT1.A(a)) in the liver. Ad-RQ produced sRT1.A(a) was measured by enzyme-linked immunosorbent assay (ELISA) after in vitro infection of Lewis (RT1(l)) hepatocytes, and in vivo following intravenous virus injection into Lewis rats. Results indicated high sRT1.A(a) expression in Lewis hepatocyte cultures and, in vivo, high expression was also demonstrated and maintained for at least 1 week. A strong immunosuppressive potential of sMHC in vivo was revealed by prolongation of cardiac (ACI, RT1(a)) heart allograft survival in high-responder Lewis rat recipients treated with Ad-RQ alone. Furthermore, limiting dilution cytotoxic T-lymphocyte precursor (CTLp) analysis of lymphocytes from Ad-RQ-treated Lewis recipients receiving an ACI heart transplant indicated a marked decrease in antidonor CTLp frequency. In conclusion, our results demonstrate that viral vectors can be used effectively to express high levels of sMHC molecules, and their immunosuppressive effect, without concurrent immunosuppression, is sufficiently potent to prolong heart transplant survival.