Pilot study to determine the safety and feasibility of deceased donor liver natural killer cell infusion to liver transplant recipients with hepatocellular carcinoma.

Liver transplantation (LT) is a viable treatment option for cirrhosis patients with hepatocellular carcinoma (HCC). However, recurrence is the rate-limiting factor of long-term survival. To prevent this, we conducted the phase I study of the adoptive transfer of deceased donor liver-derived natural killer (NK) cells. Liver NK cells were extracted from donor liver graft perfusate and were stimulated in vitro with IL-2. The patient received an intravenous infusion of NK cells 3-5 days after LT. Eighteen LT recipients were treated. There were no severe cell infusion-related adverse events or acute rejection episodes. One patient withdrew from the study because the pathological observation revealed sarcoma instead of HCC. All patients who received this immunotherapy completed the follow-up for at least 2 years without evidence of HCC recurrence (median follow-up, 96 months [range, 17-121 months]). Considering that 9 (52.9%) of the 17 patients pathologically exceeded the Milan criteria, liver NK cell infusion is likely to be useful for preventing HCC recurrence after LT. This is the first-in-human immunotherapy study using deceased donor liver-derived NK cells to prevent HCC recurrence after LT. This treatment was well tolerated and resulted in no HCC recurrence after LT.Clinical trial registration www.clinicaltrials.gov ; NCT01147380; registration date: June 17, 2010.

New Frontier: Role of the Radiologist in Uterine Transplantation.

Uterine transplantation (UT) is a novel treatment for absolute uterine factor infertility (AUFI) that is currently being performed under experimental protocols in multiple medical centers worldwide. At the time of this publication, there have been at least 10 live births by women with a transplanted uterus. As successful outcomes from this innovative procedure increase, it is likely that more centers will perform UT. Imaging is performed in multiple steps of the UT process, including preoperative imaging of potential donors and recipients, posttransplant surveillance, and monitoring of pregnancy. Fetal imaging is performed by maternal-fetal medicine professionals, but most imaging examinations in UT are performed by radiologists. Given the significant role of imaging in this groundbreaking surgery, radiologists must be familiar with the causes of AUFI and the role of imaging in establishing this diagnosis. Radiologists working in medical centers where UT is performed should understand the role of imaging in preoperative planning and postoperative surveillance. While data regarding complications of UT are preliminary at best, radiologists must be aware of the risk of vascular compromise and graft failure and their imaging features. The authors provide a brief history of UT and define the radiologist's role in pre- and postoperative imaging assessments.©RSNA, 2019.

Abdominal transplantation for unresectable tumors in children: the zooming out principle.

PURPOSE: To present our experience in abdominal transplantations to manage unresectable abdominal neoplasms in children and to describe the role of extensive surgeries in such cases. METHODS: This is a retrospective study of 22 abdominal transplantations in 21 patients for abdominal tumors over 16 years. Transplantation techniques included liver transplant (LT), multivisceral transplant (MVTx), and intestinal autotransplant (IA). Follow-up intervals ranged from 0.3 to 168 months (median 20 months). RESULTS: LT alone was performed in 15 patients for primary malignant (11) and benign (4) liver tumors. Pathological classification included HB hepatoblastoma (6), HCC hepatocellular cancer (3), hepatic epithelioid hemangioendothelioma HEH (1), angiosarcoma (1), benign vascular tumors (3), and adenoma (1). IA was performed in four patients for lesions involving the root of the mesentery; tumors of the head of pancreas (3) and mesenteric hemangioma (1). MVTx was performed in 2 patients for malignancies; pancreaticoblastoma (1), recurrent hepatoblastoma (1), and in one patient as a rescue procedure after IA failure. Four of the eleven patients who underwent LT for malignant liver tumor had metastatic disease at presentation. Six of them died of recurrent neoplasm (3), transplant-related complications (2), and underlying disease (1). All LT patients who had benign tumors are alive with functioning grafts. All IA patients survived and are on an oral diet, with one patient requiring TPN supplementation. One of the three patients who underwent MVTx died of metastatic disease. CONCLUSIONS: Allo/auto transplantation for abdominal tumors is a valuable modality when conventional treatments fail or are not feasible.

When and why portal vein thrombosis matters in liver transplantation: a critical audit of 174 cases.

OBJECTIVE: To identify complications associated with different techniques utilized to treat portal vein thrombosis (PVT) during primary liver transplantation and their impact on survival. BACKGROUND: PVT remains an intricate problem in liver transplantation, and the long-term outcomes of patients with PVT who undergo transplantation are not well defined. METHODS: We performed a retrospective cohort analysis of all consecutive adult patients who underwent primary isolated liver transplantation from 1998 to 2009 (median follow-up period, 89 months). The outcomes of patients with PVT were compared with those without PVT. RESULTS: Among 1379 recipients, 174 (12.6%) had PVT at the time of transplantation [83 (48%) complete and 91 (52%) partial]. Among PVT patients with reestablished physiological portal inflow (PVT: physiological group; n = 149), 123 underwent thrombectomies, 16 received interpositional vein grafts, and 10 received mesoportal jump grafts. In 25 patients, physiological portomesenteric venous circulation was not reconstituted (PVT: nonphysiological group; 18 underwent cavoportal hemitranspositions, 6 renoportal anastomoses, and 1 arterialization). The PVT: nonphysiological group suffered a significantly increased incidence of rethrombosis of the portomesenteric veins and gastrointestinal bleeding, with a marginal 10-year overall survival rate of 42% (no PVT, 61%; P = 0.002 and PVT: physiological, 55%; P = 0.043). The PVT: physiological and no PVT groups exhibited comparable survival rates (P = 0.13). No significant differences in survival were observed between complete and partial PVT as long as physiological portal flow was reestablished. CONCLUSIONS: The subset of PVT patients requiring nonphysiological portal vein reconstruction was associated with higher complication rates and suffered diminished long-term prognoses. For the most severe PVT cases, a comprehensive approach is critical to further improve outcomes.

Excessive immunosuppression as a potential cause of poor survival in simultaneous liver/kidney transplantation for hepatitis C.

Appropriate recipient selection of simultaneous liver/kidney transplantation (SLKT) remains controversial. In particular, data on liver graft survival in hepatitis C virus-infected (HCV+) SLKT recipients are lacking. We conducted a single-center, retrospective study of HCV+ SLKT recipients (N = 25) in comparison with HCV- SLKT (N = 26) and HCV+ liver transplantation alone (LTA, N = 296). Despite backgrounds of HCV+ and HCV- SLKT being similar, HCV+ SLKT demonstrated significantly impaired 5-year liver graft survival of 35% (HCV- SLKT, 79%, P = 0.004). Compared with HCV+ LTA, induction immunosuppression was more frequently used in HCV+ SLKT. Five-year liver graft survival rate for HCV+ SLKT was significantly lower than that for LTA (35% vs. 74%, respectively, P < 0.001). Adjusted hazard ratio of liver graft loss in HCV+ SLKT was 4.9 (95% confidence interval 2.0-12.1, P = 0.001). HCV+ SLKT recipients were more likely to succumb to recurrent HCV and sepsis compared with LTA (32% vs. 8.8%, P < 0.001 and 24% vs. 8.8%, P = 0.030, respectively). Ten HCV+ SLKT recipients underwent anti-HCV therapy for recurrent HCV; only 1 achieved sustained virological response. HCV+ SLKT is associated with significantly decreased long-term prognosis compared with HCV- SLKT and HCV+ LTA.

Long-term deleterious effects of aortohepatic conduits in primary liver transplantation: proceed with caution.

Aortohepatic conduits provide a vital alternative for graft arterialization during liver transplantation. Conflicting results exist with respect to the rates of comorbidities, and long-term survival data on primary grafts are lacking. To identify the complications associated with aortohepatic conduits in primary liver transplantation and their impact on survival, we conducted a single-center, retrospective cohort analysis of all consecutive adult (n = 1379) and pediatric primary liver transplants (n = 188) from 1998 to 2009. The outcomes of aortohepatic conduits were compared to those of standard arterial revascularization. Adults with a conduit (n = 267) demonstrated, in comparison with adults with standard arterialization (n = 1112), an increased incidence of late (>1 month after transplantation) hepatic artery thrombosis (HAT; 4.1% versus 0.7%, P < 0.001) and ischemic cholangiopathy (7.5% versus 2.7%, P < 0.001) and a lower 5-year graft survival rate (61% versus 70%, P = 0.01). The adjusted hazard ratio (HR) for graft loss in the conduit group was 1.38 [95% confidence interval (CI) = 1.03-1.85, P = 0.03]. Notably, the use of conduits (HR = 4.91, 95% CI = 1.92-12.58) and a warm ischemia time > 60 minutes (HR = 11.12, 95% CI = 3.06-40.45) were independent risk factors for late HAT. Among children, the complication profiles were similar for the conduit group (n = 81) and the standard group (n = 107). In the pediatric cohort, although the 5-year graft survival rate for the conduit group (69%) was significantly impaired in comparison with the rate for the standard group (81%, P = 0.03), the use of aortohepatic conduits did not emerge as an independent predictor of diminished graft survival via a multivariate analysis. In conclusion, in adult primary liver transplantation, the placement of an aortohepatic conduit should be strictly limited because of the greater complication rates (notably late HAT) and impaired graft survival; for children, its judicious use may be acceptable.

Liver natural killer cell inoculum for liver transplantation with hepatocellular carcinoma.

PURPOSE OF REVIEW: Natural killer (NK) cells are innate immune lymphocytes. NK cells contribute to host antimicrobial and antitumor immunity. Liver transplantation in patients with hepatocellular carcinoma (HCC) has increased recently. The possibility of NK cell immunotherapy for liver cancer has been studied. RECENT FINDINGS: Adoptive transfer of interleukin-2 (IL-2)-stimulated NK cells extracted from donor liver perfusate could increase an antitumor response without causing toxicity against 1-haplotype identical recipient intact tissues in patients with live donor liver transplant. Donor liver NK cells showed the most vigorous cytotoxicity against an HCC after in-vitro IL-2 stimulation, compared with donor and recipient peripheral blood NK cells and recipient liver NK cells. IL-2 stimulation led to an increased expression of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) on liver NK cells. T-cell contamination and risk of graft-versus-host disease can be minimized with a T-cell depleting agent such as anti-CD3 antibody. SUMMARY: Allogeneic NK cells might have an advantage for adoptive immunotherapy. Liver NK cells from a deceased donor liver can be used safely as adoptive immunotherapy under current good manufacturing practice conditions for the treatment of liver transplantation with HCC. IL-2-stimulated liver NK cells have strong cytotoxicity, express TRAIL and secret interferon-γ.

Uterus Transplantation: Revisiting the Question of Deceased Donors versus Living Donors for Organ Procurement.

Uterus transplantation is a surgical treatment for women with congenital or acquired uterine factor infertility. While uterus transplantation is a life-enhancing transplant that is commonly categorized as a vascular composite allograft (e.g., face or hand), it is similar to many solid organ transplants (e.g., kidney) in that both living donors (LDs) and deceased donors (DDs) can be utilized for organ procurement. While many endpoints appear to be similar for LD and DD transplants (including graft survival, time to menses, livebirth rates), there are key medical, technical, ethical, and logistical differences between these modalities. Primary considerations in favor of a LD model include thorough screening of donors, enhanced logistics, and greater donor availability. The primary consideration in favor of a DD model is the lack of physical or psychological harm to a living donor. Other important factors, that may not clearly favor one approach over the other, are important to include in discussions of LD vs. DD models. We favor a stepwise approach to uterus transplantation, one in which programs first begin with DD procurement before attempting LD procurement to maximize successful organ recovery and to minimize potential harms to a living donor.

Is surgical resection superior to transplantation in the treatment of hepatocellular carcinoma?

OBJECTIVE: To compare outcomes for patients with hepatocellular carcinoma (HCC) treated with either liver resection or transplantation. METHODS: A retrospective, single-institution analysis of 413 HCC patients from 1999 to 2009. RESULTS: A total of 413 patients with HCC underwent surgical resection (n = 106) and transplantation (n = 270) or were listed without receiving transplantation (n = 37). Excluding transplanted patients with incidental tumors (n = 50), 257 patients with suspected HCC were listed with the intent to transplant (ITT). The median diameter of the largest tumor by radiography was 6.0 cm in resected, 3.0 cm in transplanted, and 3.4 cm in the listed-but-not-transplanted patients. Median time to transplant was 48 days. Recurrence rates were 19.8% for resection and 12.1% for all ITT patients. Overall, patient survival for resection versus ITT patients was similar (5-year survival of 53.0% vs 52.0%, not significant). However, for HCC patients with model end-stage liver disease (MELD) scores less than 10 and who radiologically met Milan or UCSF (University of California, San Francisco) criteria, 1-year and 5-year survival rates were significantly improved in resected patients. For patients with MELD score less than 10 and who met Milan criteria, 1-year and 5-year survival were 92.0% and 63.0% for resection (n = 26) versus 83.0% and 41.0% for ITT (n = 73, P = 0.036). For those with MELD score less than 10 and met UCSF criteria, 1-year and 5-year survival was 94.0% and 62.0% for resection (n = 33) versus 81.0% and 40.0% for ITT (n = 78, P = 0.027). CONCLUSIONS: Among known HCC patients with preserved liver function, resection was associated with superior patient survival versus transplantation. These results suggest that surgical resection should remain the first line therapy for patients with HCC and compensated liver function who are candidates for resection.

Liver transplantation using elderly donors: a risk factor analysis.

Survival after liver transplantation is negatively impacted by use of elderly deceased donors, but excluding them would increase waiting times and waiting list mortality. We reviewed our experience with liver transplantation (LT) utilizing livers from deceased donors 65 yr of age and older to identify those factors that impact graft survival. All adult patients (≥ 18 yr old) who underwent primary LT using deceased donor livers from donors aged ≥ 65 yr between February 1995 and November 2003 were included. With multivariate analysis we found four unfavorable characteristics significantly associated with higher post-transplant graft failure rate. These characteristics are hepatitis C as an etiology of liver disease, Model for End-Stage Liver Disease score >20, serum glucose level of donor > 200 mg/dL at the time of liver recovery, and skin incision to aortic cross-clamp time > 40 minutes in the donor surgery. The five-yr estimated graft survival rates having 0, 1, 2, 3, and 4 unfavorable characteristics were 100%, 82.0%, 81.7%, 39.3%, and 25.0%, respectively (p < 0.05). Our data demonstrated good graft survival can be achieved in LT using elderly donor liver allografts with appropriate patient selection, donor blood glucose management and efficient liver recovery with minimal manipulation of the liver during donor surgery.

Characteristic immune, apoptosis and inflammatory gene profiles associated with intestinal acute cellular rejection in formalin-fixed paraffin-embedded mucosal biopsies.

Small bowel transplantation (SBT) is becoming a preferred treatment for patients with irreversible intestinal failure. Despite continuous improvement of immunosuppression, SBT is plagued by a high incidence of acute cellular rejection (ACR) that is frequently intractable. Therefore, there is a need for reliable detection markers and novel immunosuppressive strategies that can achieve better control of ACR. We hypothesized that particular transcriptomes provide critical regulation of the intragraft immune response. The aim of our study was to detect potential molecular biomarkers for identifying ACR in minute mucosal biopsies. We examined 30 intestinal mucosal biopsies (AR/NR; 17/13) obtained from recipients after SBT or multivisceral transplantation. We utilized TaqMan® Gene Signature Arrays (immune, inflammation and apoptosis) and investigated the expression of 280 genes. As one of our validations, we performed immunohistochemistry for selected targets. We detected 252 mRNAs in total, 92 of which were found with significantly different expression levels between the AR and NR groups. Immunohistochemistry showed significantly increased staining for IL1R2, ICAM1, GZMB, and CCL3 (P < 0.05) during ACR. For the first time, we characterize the potential molecular changes that are associated with modulation of histological appearances of intestinal ACR. These differences in transcriptome patterns can be used to identify robust biomarkers and potential novel therapeutic targets for immunosuppressive agents.

Effect of liver transplantation on spleen size, collateral veins, and platelet counts.

BACKGROUND: The aim of this study was to evaluate the effect of liver transplantation on the spleen size, spontaneous splenorenal shunt (SRS) function, and platelet counts in patients with hypersplenism. METHODS: Between December 2001 and February 2007, 462 adult patients underwent orthotopic liver transplantations (OLTX) at our institution. Of these patients, CT or MRI information was reviewed retrospectively in 55 patients. Volume measurements of the spleen and liver, spleen/liver volume ratio (S/L ratio), presence and size of SRS, and platelet counts were evaluated before and after OLTX. RESULTS: Mean spleen volume decreased from 827 +/- 463 ml to 662 +/- 376 ml after OLTX (p < 0.01). Five (11%) patients returned to normal-range spleen size after OLTX. SRS was observed in 19 patients before OLTX (35%). The diameter of SRS also significantly decreased from 1.0 +/- 0.5 cm before OLTX to 0.7 +/- 0.5 cm after OLTX (p < 0.05). SRS disappeared in 16% of patients (3/19). S/L ratio significantly decreased from 0.65 +/- 0.33 to 0.38 +/- 0.17 (p < 0.01) after OLTX. Platelet counts significantly increased after OLTX (p < 0.01). Improvement of the platelet count in the group with postoperative S/L ratio >0.35 was not as good as that in the group with S/L ratio <0.35 (p < 0.01). CONCLUSIONS: Spleen size and SRS size became significantly smaller after OLTX. However, patients with postoperative S/L ratio >0.35 tend to have lower platelet counts after OLTX.

Differential transcriptome patterns for acute cellular rejection in recipients with recurrent hepatitis C after liver transplantation.

Histopathological evaluation of the liver via biopsy remains the standard procedure for the diagnosis of both acute cellular rejection (ACR) and recurrent hepatitis C (RHC) after liver transplantation. Nevertheless, it is often difficult to diagnose ACR in hepatitis C virus-positive recipients because of changes in common and overlapping with RHC. The aim of this study was to identify potential target genes for ACR in recipients with RHC. We analyzed 22 liver biopsy samples obtained from 21 hepatitis C virus-positive recipients. The clinicopathological diagnosis based on biopsy examination was ACR-predominant with superimposed RHC in 9 samples (ACR group) and RHC without ACR (non-ACR group) in 13. Using oligonucleotide microarrays, we compared the transcriptional changes in the 2 groups and selected 2206 genes that were significantly modulated in ACR. We analyzed the regulatory networks in ACR with Ingenuity Pathway Analysis software, and we confirmed with quantitative real-time polymerase chain reaction the reproducibility of caspase 8, apoptosis-related cysteine peptidase and bone morphogenetic protein 2 up-regulation in another group of validation samples, representing 2 genes from the core network as the target genes for ACR. Our results demonstrated novel transcriptome patterns for ACR with concurrent RHC that were distinct from those of recipients with only RHC, suggesting that gene expression profiling may be useful in the diagnosis of ACR in recipients with hepatitis C.

Small bowel transplantation: technical advances/updates.

PURPOSE OF REVIEW: The field of intestinal transplantation continues to grow, both in terms of overall transplants performed each year and number of centers adopting this procedure. Numerous advances in technical and management procedures have resulted in improvements of patient and graft survival. This review focuses on the technical advances that have emerged over the last year. RECENT FINDINGS: Multiple variations of the original technique of intestinal transplantation are now utilized according to the patients' original diagnoses and/or degree of liver dysfunction. Multivisceral grafts can include both donor spleen and large intestine; preservation of the native spleen and pancreas is possible in some cases. Living donor intestinal transplantation is being described as alternative technique to minimize death on the waitlist. SUMMARY: Constant evolution in the surgical aspects of intestinal transplantation parallels the improvements that have taken place in the medical management and immunosuppression. The transplant surgeon with full knowledge of all variations of intestinal transplant techniques will be able to tailor the type of surgery to each individual patient.

Analysis of acute and chronic rejection in multiple organ allografts from retransplantation and autopsy cases of multivisceral transplantation.

BACKGROUND: Small intestinal allografts in multivisceral transplantation are felt to be more susceptible to acute cellular rejection (ACR) and chronic rejection (CR) when compared with other allografts although there is little direct evidence for this impression. METHODS: A total of 48 cases of multiple allograft specimens (37 autopsy and 11 explanted allograft cases) from 41 patients were evaluated in this study. Histopathologic assessments were performed with special concern to ACR and CR in allografts. The numbers of allografts available for evaluation were liver 37, small intestine 47, stomach 41, pancreas 45, and large intestine 25. RESULTS: Among 48 cases, 15 cases showed ACR (ACR case) and 12 showed CR (CR case) in at least one organ. In ACR cases, there was a statistically significant difference of organ-specific susceptibility to ACR among multivisceral allografts with the small intestinal allograft being the most susceptible (P<0.05). Severe ACR were observed only in small and large intestinal allografts. In CR cases, there was no statistically significant difference of organ-specific susceptibility to CR among multivisceral allografts with a tendency for the pancreas allograft to be the most susceptible (P=0.35). CONCLUSIONS: Our study clearly indicated variation in organ susceptibility to ACR and CR. Small intestinal allografts were the most susceptible organ to ACR in frequency and severity. Pancreatic allografts may be more susceptible to CR in comparison with ACR.

Fecal calprotectin level measurements in small bowel allograft monitoring: a pilot study.

BACKGROUND: Protocol endoscopy with biopsy is currently the gold standard of small bowel transplantation (SBTx) monitoring, however it is invasive, costly, needs skilled operator, may require anesthesia and may cause complications. We investigated fecal calprotectin level (FCL) as a candidate noninvasive marker for monitoring patients after SBTx. METHODS: A pilot study was performed to test the use of FCL measurement in following up SBTx patients. Ileostomy effluents were collected at various postoperative days before endoscopy and biopsy. FCLs were measured by enzyme-linked immunosorbent assay and a cut-off level of 100 ng/mg was considered positive. The results were retrospectively evaluated in combination with clinical, endoscopic, and histopathological findings. FCLs are presented as median nanogram per milligram. RESULTS: FCLs were measured in 122 samples that were obtained from 29 patients after SBTx. Only 1 of 69 positive FCL did not accompany abnormal findings. Retrospective evaluation showed that 11 samples from six patients (FCL: 217) coincided with rejection episodes, six samples from three patients (FCL: 125) coincided with viral enteritis, 51 samples from 21 patients (FCL: 207) coincided with nonspecific inflammation, 11 samples from two patients (FCL: 998) coincided with chronic intestinal ulceration, and finally 50 samples from 19 patients (FCL: 43) coincided with normal findings. No significant FCL difference was found between rejection, infection, and inflammation. FCL evolution in individuals showed that FCL can predict rejection days before histopathological diagnosis. CONCLUSION: FCL is a sensitive test for ongoing organic intestinal allograft pathologies. It might be useful as prescreening marker to avoid unnecessary endoscopies.