Time since liver transplant and immunosuppression withdrawal outcomes: Systematic review and individual patient data meta-analysis.

BACKGROUND & AIMS: Successful immunosuppression withdrawal (ISW) is possible for a subfraction of liver transplant (LT) recipients but the factors that define the risk of ISW failure are largely unknown. One candidate prognostic factor for ISW success or operational tolerance (OT) is longer time between LT and ISW which we term "pre-withdrawal time". To clarify the impact of pre-withdrawal time span on subsequent ISW success or failure, we conducted a systematic review with meta-analysis. METHODS: We systematically interrogated the literature for LT recipient ISW studies reporting pre-withdrawal time. Eligible articles from Embase, Medline, and the Cochrane Central Register of Controlled Trials were used for backward and forward citation searching. Pre-withdrawal time individual patient data (IPD) was requested from authors. Pooled mean differences and time-response curves were calculated using random-effects meta-analyses. RESULTS: We included 17 studies with 691 patients, 15 of which (620 patients) with IPD. Study-level risk of bias was heterogeneous. Mean pre-withdrawal time was greater by 427 days [95% confidence interval (CI) 67-788] in OT compared to non-OT patients. This increase was potentiated to 799 days (95% CI 369-1229) or 1074 days (95% CI 685-1463) when restricting analysis to adult or European study participants. In time-response meta-analysis for adult or European ISW candidates, likelihood of OT increased by 7% (95% CI 4-10%) per year after LT (GRADE low- and moderate-certainty of evidence, respectively). CONCLUSIONS: Our data support the impact of pre-withdrawal time in ISW decision-making for adult and European LT recipients. PROSPERO REGISTRATION: CRD42021272995.

Advanced pancreatic cancer with long-term recurrence-free survival after radical pancreatic resection and subsequent resection of lung metastases twice: A case report.

INTRODUCTION AND IMPORTANCE: Reports on lung resection for recurrence with lung metastases after the surgical treatment of pancreatic cancer have been sporadic, and limited information is currently available on the long-term postoperative course. Furthermore, the significance of the surgical resection of recurrent/metastatic lesions after the resection of pancreatic cancer has not been sufficiently established. We herein present a long-term recurrence-free survivor after perioperative chemotherapy and pancreatic resection for primary pancreatic body cancer who underwent resection for isolated lung metastases twice. CASE PRESENTATION: A 66-year-old woman with locally advanced pancreatic cancer accompanied by invasion of the splenic artery underwent distal pancreatectomy with celiac axis resection following preoperative S1 + gemcitabine therapy. Recurrence with lung metastasis was detected 42 and 62 months after resection of the primary lesion, and lung resection was performed both times. As postoperative adjuvant therapies, S1 + gemcitabine therapy was performed after lung resection. The patient has survived free of recurrence for 11 years after resection of the primary lesion and 5 years and 9 months after the second lung resection. CLINICAL DISCUSSION: A long interval from resection of the primary lesion to the occurrence of lung metastases and the high responsiveness of the patient to chemotherapy may have contributed to her long-term survival. CONCLUSION: This case suggests that if lung metastasis occurring after radical resection of the primary lesion is resected without remnants, aggressive multidisciplinary treatment, including surgical resection with the appropriate selection of cases, may contribute to improvements in patient outcomes.

A case of mesenteric venous thrombosis complicating appendiceal diverticulitis.

BACKGROUND: Mesenteric venous thrombosis (MVT) and appendiceal diverticulitis are rare diseases. There has been no previous report on MVT complicating appendiceal diverticulitis. Herein, we report the first case of MVT complicating appendiceal diverticulitis. CASE PRESENTATION: A 70-year-old male patient with right lower abdominal pain presented to our hospital. Abdominal contrast-enhanced computed tomography (CT) suggested MVT complicating appendiceal diverticulitis. Initially, we started conservative treatment with antibacterial drugs, but on the 2nd hospital day his general condition deteriorated due to sepsis that seemed to be caused by appendiceal diverticulitis. Therefore, we performed laparoscopic appendectomy. Histopathological findings of the specimen showed appendiceal diverticulitis. After the operation, he gradually improved. He was discharged on the 30th hospital day. CONCLUSIONS: We report a successfully treated case of MVT complicating appendiceal diverticulitis by surgical intervention. This is the first case of MVT complicating appendiceal diverticulitis.

Laparoscopic approach to recurrence following multiple surgeries for external rectal prolapse: a case report.

INTRODUCTION: The optimal procedure for recurrent external rectal prolapse remains unclear, particularly in laparoscopic approach. In addition, pelvic organ prolapse (POP) is sometimes concomitant with rectal prolapse. We present a case who underwent laparoscopic procedure for the recurrence of full-thickness external rectal prolapse coexisting POP. CASE PRESENTATION: An 81-year-old parous female had a 10-cm full-thickness external rectal prolapse following the two operations: the first was perineal recto-sigmoidectomy and the second was laparoscopic posterior mesh rectopexy. Imaging study revealed that the recurrent rectal prolapse was concomitant with both cystocele and exposed vagina, what we call POP. We planned and successfully performed laparoscopic ventral mesh rectopexy (LVMR) with laparoscopic sacrocolpopexy (LSC) using self-cut meshes without any perioperative complication. CONCLUSION: This is the first report of LVMR and LSC for recurrent rectal prolapse with POP following the perineal recto-sigmoidectomy and laparoscopic posterior mesh rectopexy. Even for recurrent rectal prolapse with POP, our experience suggests that LVMR and LSC could be utilized.

Proposal for a Safe and Functional Pancreaticojejunostomy Technique from a Histopathological Perspective.

BACKGROUND: To prevent leakage of pancreatic juice from the main pancreatic duct (MPD), complete external drainage appears to be the most effective technique. However, because this requires a pancreatic stent tube to be ligated with MPD, duct-to-mucosa pancreaticojejunostomy (PJ) is difficult. From our histopathological examination, a large amount of pancreatic juice is drained from the ducts other than MPD. This study aimed to evaluate our new conceptual technique of PJ after pancreaticoduodenectomy (PD). METHODS: We considered it important to drain pancreatic juice from the branch pancreatic ducts to the intestinal tract and to perform duct-to-mucosa PJ, while pancreatic juice from MPD is completely drained out of the body. We designed a technique that could simultaneously achieve these points. In our technique, which is based on conventional "two-row" anastomosis, a stent tube is fixed with MPD and its surrounding tissue by purse-string suture at the cut surface of the pancreas, and duct-to-mucosa PJ is concomitantly performed. RESULTS: Of 45 patients undergoing PD, 12 of soft pancreas underwent surgery with this technique. According to the classification of the International Study Group on Pancreatic Fistula, a Grade A PF was observed in four patients, whereas no patient had a Grade B or C PF. CONCLUSIONS: We propose our anastomotic technique that could simultaneously prevent PF and keep the pancreatic duct patent.

Utility of CD127 combined with FOXP3 for identification of operational tolerance after liver transplantation.

Loss of cell surface expression of CD127 on CD4(+)CD25(++) regulatory T-cells (Tregs) may be a useful marker to efficiently isolate Tregs. As FOXP3 was specifically used to identify Tregs, combining these two markers could give better identification for patient with operational tolerance (OT) after liver transplantation. To testify this mixed lymphocyte reaction (MLR), the function of circulating CD4(+)CD25(++)CD127(dim) cells (CD127(dim) cells) was examined in immunosuppression (IS)-free pediatric recipients after liver transplantation (LTx) (group operational tolerance: OT) (Gr-tol n=25) compared to recipients who could not stop IS due to clinically overt rejection (group intolerance) (Gr-intol n=18), recipients who were weaning IS (Gr-weaning n=11) and age-matched healthy volunteers (Gr-vol n=11). In addition, the frequencies of CD127(dim) cells vs CD4(+)CD25(++)CD127(dim)FOXP3(+) (CD127(dim)FOXP3(+)) cells were compared in these four groups by FACS analyses. Our results showed that The proliferation of CD4 cells to donor antigens was reduced compared to third-party antigens only in Gr-tol (P=0.022) but not in other groups (P=NS). Depletion of CD127(dim) cells resulted in a donor antigen-specific abrogation of this MLR hyporesponsiveness in Gr-tol (P<0.001) but not other groups (P=NS). This implied that CD127 efficiently isolated donor antigen-specific Tregs. The frequencies of CD127(dim) cells were significantly lower in Gr-intol (5.2%±1.9%) compared to those in Gr-tol (7.8%±1.8%) (P<0.001) as were the frequencies of CD127(dim) FOXP3(+) cells (Gr-tol: 5.4%±1.7% vs Gr-intol: 2.9%±1.0%, P<0.001). Of interest, there were fewer CD127(dim)FOXP3(+) cells in Gr-intol (2.9%±1%) than in Gr-weaning (5.1%±1.8%) (P=0.002), but no difference in CD127(dim) cells (Gr-intol: 5.2%±1.9% vs Gr-weaning: 6.7%±2.0%) (NS). Thus, combining FOXP3 with CD127 for phenotype analysis demonstrated an unequivocal difference between Gr-intol and Gr-weaning that was not detected by CD127 alone. In conclusion CD127 was a useful surface marker to isolate donor-antigen-specific-Tregs in OT after LTx. The additive effect of its combination with FOXP3 is important in phenotypical Treg analyses of OT patients.

Association of anti-human leukocyte antigen and anti-angiotensin II type 1 receptor antibodies with liver allograft fibrosis after immunosuppression withdrawal.

BACKGROUND: Many pediatric patients who receive a living-donor liver transplant undergo withdrawal of immunosuppression (IS). For them, the high incidence of long-term progressive graft fibrosis is of particular concern. METHODS: We conducted a cross-sectional study including 81 pediatric patients who underwent IS withdrawal after living-donor liver transplant at Kyoto University Hospital and whose serum samples and pathological data could be obtained during the analysis period. We examined the association of donor-specific anti-human leukocyte antigen (HLA) antibody (DSA) and angiotensin II type 1 receptor antibody (anti-AT1R Ab) with posttransplant graft fibrosis. Normalized mean fluorescence intensity (MFI) 5,000 or higher and anti-AT1R Ab concentrations 17 U/mL or higher were both considered high level. The patients were classified into an advanced fibrosis group (AFG) (Ishak score ≥ 3) and a control group (CG) (Ishak score ≤ 2). RESULTS: Only one patient demonstrated DSA class I. Among those who demonstrated DSA class II, more AFG patients than CG patients demonstrated high-level mean fluorescence intensity, although the difference was not significant (64% vs. 39%; P=0.053). The incidence of high-level DSA-DRB1, however, was significantly higher in the AFG than that in the CG (40% vs. 4%; P<0.001), but there was no significant difference in DSA-DQB1 or DSA-DRB345. High-level anti-AT1R Ab was significantly more frequent in the AFG than in the CG (65% vs. 36%; P=0.02). All patients with both high-level DSA-DRB1 and high-level anti-AT1R Ab were found to have advanced fibrosis (P<0.001). CONCLUSION: Anti-AT1R Ab and DSA-DRB1 may be candidates as biomarkers of graft fibrosis; both HLA and non-HLA immunity may be involved in graft fibrosis after IS withdrawal.

Intragraft Vδ1 γδ T cells with a unique T-cell receptor are closely associated with pediatric semiallogeneic liver transplant tolerance.

BACKGROUND: T-cell receptor Vδ2 γδ T cells (Vδ2 cells) participate in host defense, whereas Vδ1 γδ T cells (Vδ1 cells) may regulate immune responses. Vδ1 cells appear to play a role in fetomaternal tolerance and our aim was to examine their role in liver transplant tolerance. METHODS: To determine whether Vδ1 cells increase within accepted grafts after semiallogeneic pediatric liver transplantation, the Vδ1/Vδ2 ratio was assessed at the transcriptional level and the complementarity-determining region 3 loop of the δ chain of Vδ1 cells was sequenced in biopsies from immunosuppression-free (n=6) or almost free (n=3) liver transplant recipients, referred to as group tolerance (Gr-Tol; n=9). The results were compared with biopsies from grafts of recipients on maintenance immunosuppression due to concern of rejection (Gr-IS; n=11). Chronically rejected grafts (Gr-CR; n=6) and normal livers (Gr-NL; n=8) were also examined. RESULTS: The Vδ1/Vδ2 ratio was the highest in Gr-Tol (0.07±0.06) compared with Gr-IS (0.03±0.02; P=0.04), Gr-CR (0.01±0.02; P=0.008), and Gr-NL (0.02±0.04; P=0.01). There was an identical complementarity-determining region 3 sequence (100% homologous) among all recipients in Gr-Tol, which was dominant in six of nine recipients. This sequence was not seen in Gr-IS or Gr-CR, although it was observed in five of six normal livers. CONCLUSIONS: A unique Vδ1-bearing T-cell clone accumulates within accepted human liver grafts. It might be useful as a biomarker of tolerance and the identification of its ligand might aid in the development of a novel strategy for tolerance induction.

Factors affecting operational tolerance after pediatric living-donor liver transplantation: impact of early post-transplant events and HLA match.

Pediatric recipients of living-donor liver transplants (LDLT) can often discontinue immunosuppression (IS). We examined factors affecting development of operational tolerance (OT), defined as off IS for >1 year, in this population. A historic cohort analysis was conducted in 134 pediatric primary semi-allogeneic LDLT. Multivariate logistic regression analysis was used. The frequency of peripheral regulatory T cells (Tregs) was determined at >10 years post-Tx by FACS analysis. IS was successfully discontinued in 84 tolerant patients (Gr-tol), but not in 50 intolerant patients (Gr-intol). The Gr-intol consisted of 24 patients with rejection (Gr-rej) and 26 with fibrosis of grafts (Gr-fib). The absence of early rejection [odds ratio (OR) 2.79, 95% CI 1.11-7.02, P = 0.03], was a positive independent predictor, whereas HLA-A mismatch (0.18, 0.03-0.91, P = 0.04) was a negative predictor. HLA-DR mismatches did not affect OT. The Treg frequency was significantly decreased in Gr-intol (4.9%) compared with Gr-tol (7.6%) (P = 0.003). There were increased levels of tacrolimus in the first week in Gr-Tol (P = 0.02). Although HLA-B mismatch (8.73, 1.09-70.0, P = 0.04) was a positive independent predictor of OT, its clinical significance remains doubtful. In this large cohort of pediatric LDLT recipients, absence of early rejection, HLA-A match and the later predominance of Tregs are factors associated with OT.

Factors affecting graft survival within 1-year post-transplantation in heart and lung transplant: an analysis of the OPTN/UNOS registry.

Today, a main focus of the transplant community is the long-term outcomes of lung and heart allograft recipients. However, even early post-transplant survival (within the first post-transplant year) needs improvement, as early graft failure still accounts for many allograft losses. In this chapter, we review the experience of heart and lung transplantation as reported to the Organ Procurement Transplant Network/United Network of Organ Sharing registry and investigate the factors responsible for causing failure in the first post-transplant year. Trends indicate that sicker patients are increasingly being transplanted, thereby limiting improvements in early post-transplant survival. More lung and heart transplant patients are coming to transplant on dialysis. In heart transplant, there is an increase in the number of heart retransplant patients and an increase in patients on extracorporeal membrane oxygenation. For lung transplant, more patients are on a ventilator prior to transplant than in the past 25 years. Given that sicker/riskier patients are now receiving more heart and lung transplants, future studies need to take place to better understand these patients so that they can have the same survival as patients entering transplant with less severe illnesses.

Factors affecting outcomes of liver transplantation: an analysis of OPTN/UNOS database.

This was a historic cohort analysis based on 110,521 patients who underwent liver transplant between 1987 and July 2011 in the United States and were reported to the UNOS registry. In addition to univariate Kaplan-Meier survival analyses, we used cox proportional hazard analysis and multiple logistic regression analysis to evaluate hazard ratios adjusted for clinical factors. The overall 5- and 10-year patient survival rates were 81% and 72%, respectively, for 4,412 recipients of living donor livers and 73% and 59%, respectively, for 106,109 recipients of deceased donor livers. Multivariate analyses suggest that these differences are due to demographics, including patient age rather than differences due to the donor organs. Recipients of zero HLA-mismatched livers had significantly worst graft survival (HR 1.29, p = 0.02) compared with those given an HLA mismatched graft. This appears to be due in part to graft versus host disease. Among recipients who experienced GVHD, multivariate analysis revealed that zero mismatch of HLA-A (HR 2.75), zero mismatch of HLA-B (HR 4.79), recipient age > 65 (HR 2.57) and Asian recipient (HR 2.70) were significant risk factors for GVHD respectively.

The generation of donor-specific CD4+CD25++CD45RA+ naive regulatory T cells in operationally tolerant patients after pediatric living-donor liver transplantation.

BACKGROUND: CD4+CD25++CD45RA+ cells (naïve regulatory T cells [naïve-Tregs]) have been identified as a functionally premature form of CD4+CD25+++CD45RA(-) cells (conventional-Tregs). However, their contribution to transplant tolerance remains to be elucidated. METHOD: We examined the frequency and the function of conventional and naive-Tregs in the peripheral blood derived from operationally tolerant patients after pediatric living-donor liver transplant (Gr-tol). The data were compared with those of patients who were unable to be weaned off immunosuppression due to rejection (group-intolerance [Gr-intol]), patients in the process of weaning immunosuppression (Gr-weaning) and healthy volunteers (group-healthy volunteers [Gr-vol]). RESULTS: In Gr-tol, the frequency of conventional-Tregs was significantly higher than that in Gr-vol and tended to be higher than that in Gr-intol. The frequency of naive-Tregs was significantly decreased in Gr-intol versus those in Gr-tol, -weaning, and -vol. In mixed lymphocyte reactions, donor-specific hyporesponsiveness of CD4+ cells was observed only in Gr-tol but not in the other groups. Depletion of conventional or naive-Tregs from CD4+ cells demonstrated that the suppressive properties of donor antigen-reactive conventional and naïve-Tregs were upregulated compared with those of third-party antigen-reactive conventional and naïve-Tregs in Gr-tol only. CONCLUSIONS: This is the first report providing detailed evidence that donor-specific naïve-Tregs were generated and their suppressive properties were upregulated in the peripheral blood of tolerant patients, whereas their frequency was downregulated in intolerant patients. Therefore, we speculate that not only conventional-Tregs play a role in Tx tolerance but also the role of naïve-Tregs is critical.

Requirement of protocol biopsy before and after complete cessation of immunosuppression after liver transplantation.

BACKGROUND: Operational tolerance is defined as long-term acceptance of a transplanted organ after complete cessation of immunosuppression (IS), but may not always protect against antigen-dependent changes in graft morphology. METHOD: IS free patients after living-donor liver transplantation (LDLT) underwent protocol biopsy (tolerance group [Gr-Tol]) and were evaluated for rejection and fibrosis. The degree of fibrosis was compared with those in the patients on maintenance IS group (Gr-IS) and the base line normal liver group (Gr-BS). When bridging fibrosis or progression of fibrosis was observed, IS was reintroduced or increased in Gr-Tol or in the patients in the weaning process. RESULTS: Neither acute nor chronic rejection was observed. The degree of fibrosis, however, was significantly greater in Gr-Tol than those in Gr-IS and Gr-BS. In Gr-Tol, the number of graft infiltrating FOXP3 cells was significantly increased, the interval between LDLT and biopsy plus the donor age was significantly longer, and recipient age at LDLT was significantly younger, compared with those in Gr-IS. However, none of these three parameters correlated with the degree of fibrosis. In 7 of 11 patients in whom IS was reintroduced or increased, the improvement of fibrosis was observed by the subsequent biopsy. CONCLUSION: Grafts of operationally tolerant patients after LDLT did not exhibit acute or chronic rejection, but they exhibited fibrosis. It remains elusive whether fibrosis observed in tolerant grafts is antigen dependent. The finding that after [corrected] the reintroduction or the increase of IS fibrosis was improved supported the possibility that fibrosis in operationally tolerant patients was antigen dependent.

Value of FOXP3 expression in peripheral blood as rejection marker after miniature swine lung transplantation.

BACKGROUND: Outcome for highly immunogenic lung transplantation remains unsatisfactory despite the development of potent immunosuppressants. The poor outcome may be the result of a lack of minimally invasive methods to detect early rejection. There is emerging clinical evidence that, paradoxically, expression of forkhead box P3 (FOXP3, a specific marker for the regulatory T cells) is upregulated within rejecting grafts. METHODS: Orthotopic lung transplantation was performed using miniature swine without immunosuppression. Rejection was monitored by chest radiography and open lung biopsy. Expressions levels of FOXP3, perforin, Fas-L and IP-10 mRNA were quantified in the peripheral blood. In addition, rescue immunosuppressive therapy (steroid plus tacrolimus) was administered on post-operative day (POD) 4 or 6. RESULTS: Early rejection was detected by open lung biopsy, but misdiagnosed by chest radiography on POD 4. Expression of FOXP3 in the peripheral blood reached its highest value as early as POD 4, followed by a decline. Such an increase of FOXP3 was not observed in recipients given high-dose tacrolimus. Neither perforin, Fas-L or IP-10 in the peripheral blood exhibited significant fluctuations in the early phase of rejection. Rescue immunosuppressive therapy from POD 4, when peak FOXP3 was seen, prolonged graft survival (27.2 days, versus 9.1 days without immunosuppression, p < 0.001), in contrast to POD 6, when rejection was suspected by chest radiography (11.5 days, p = not statistically significant [NS]). CONCLUSIONS: In a miniature swine lung transplantation model, the FOXP3 mRNA level in the peripheral blood was upregulated at an early phase of rejection. The clinical implication of this finding remains to be elucidated.