Interferon regulatory factor-2 is required for the establishment of the gut intraepithelial T-cell compartment.

CD8αα+ intestinal intraepithelial lymphocytes (iIELs) are known for their unique role in keeping the integrity of the intestinal epithelial barrier, but factors affecting the development of these cells have not been thoroughly understood. Here, we found that the transcriptional regulator interferon regulatory factor-2 (IRF-2) plays a cell-intrinsic, indispensable role in establishing iIEL populations. CD8αα+, but not CD8αß+, iIELs bearing TCRαß or TCRγδ were severely reduced in numbers in mice lacking this factor (Irf2-/- mice). Moreover, the majority of residual CD8αα+TCRαß+ iIELs in these mice was immature as judged from their Thy1.2high phenotype and inefficient T-bet expression. Thymic IEL precursors isolated from Irf2-/- mice failed to efficiently generate CD8αα+TCRαß+ and TCRγδ+ IELs upon transfer in vivo and CD8αα+TCRαß+ cells in response to IL-15 in vitro. Double mutant mice lacking both interleukin-15 (IL-15) and IRF-2 showed an even more severe iIEL defect than in mice lacking IL-15 alone. Upon increasing agonistic TCR signal strength through OT-II TCR transgenesis, CD8αα+TCRαß+ iIELs became more abundant but remained immature on the Irf2-/- background. Our current observations, thus, revealed the unique bimodal role that IRF-2 plays in promoting not only generation of IEL progenitors in the thymus but also maturation of iIELs in the periphery in IL-15-dependent and -independent manners.

Circulating T cells and resident non-T cells restrict type 2 innate lymphoid cell expansion in the small intestine.

Interaction among various adaptive, circulating cells and tissue-resident cells including innate lymphocytes during the establishment and maintenance of the barrier-tissue immune system has only recently started to be explored. Here, we show that the cellular crosstalk with circulating T cells and other resident cells regulated the population size of type 2 innate lymphoid cells (ILC2s) in the small intestine lamina propria. Rag1-/- mice had excessive numbers of both ILC2s and ILC3s, and such an over-expansion was corrected by establishing parabiosis with wild type mice or by adoptively transferring wild type CD4+ T cells. In contrast, anti-CD3 antibody-mediated T cell depletion in wild type mice increased ILC2 but not ILC3 numbers. Unconventional CD4-CD8- αß T and γδ T cells could also restrict ILC2 expansion as the numbers of ILC2s were not altered even in mice treated with anti-CD4/anti-CD8 antibodies. ILC3 restriction seemed to be through the control of proliferation, but that for ILC2s did not. In addition, elevation in ILC2 numbers seen in mice lacking the transcription factors RORγt and STAT6 was found to be T cell-independent. Our current findings altogether uncovered the homeostatic 'quota' restriction imposed on intestinal ILC2s in the steady state by resident non-T cells via RORγt- and STAT6-dependent mechanisms as well as by conventional and nonconventional T cells.

Small-for-size syndrome in liver transplantation: Definition, pathophysiology and management.

BACKGROUND: Since the first success in an adult patient, living donor liver transplantation (LDLT) has become an universally used procedure. Small-for-size syndrome (SFSS) is a well-known complication after partial LT, especially in cases of adult-to-adult LDLT. The definition of SFSS slightly varies among transplant physicians. The use of a partial liver graft has risks of SFSS development. Persistent portal vein (PV) hypertension and PV hyper-perfusion after LT were identified as the main factors. Hence, various approaches were explored to modulate PV flow and decrease PV pressure in order to alleviate this syndrome. Herein, the definition, clinical symptoms, pathophysiology, basic research, as well as preventive and treatment strategies for SFSS are reviewed based on an extensive review of the literature and on our own experiences. DATA SOURCES: The articles were collected through PubMed using search terms "liver transplantation", "living donor liver transplantation", "living liver donation", "partial graft", "small-for-size graft", "small-for-size syndrome", "graft volume", "remnant liver", "standard liver volume", "graft to recipient body weight ratio", "sarcopenia", "porcine", "swine", and "rat". English publications published before March 31, 2020 were included in this review. RESULTS: Many transplant surgeons performed PV flow modulation, including portocaval shunt, splenic artery ligation and splenectomy. With these techniques, patient outcome has been improved even when using a "small" graft. Other factors, such as preoperative recipients' nutritional and skeletal muscle status, graft congestion, and donor factors, were also identified as risk factors which all have been addressed using various strategies. CONCLUSIONS: The surgical approach controlling PV flow and pressure could help to prevent SFSS especially in severely ill recipients. In the absence of efficacious medications to resolve SFSS, conservative treatments, including aggressive fluid balance correction for massive ascites, anti-microbiological therapy to prevent or control sepsis and intensive nutritional therapy, are all required if SFSS could not be prevented.

Safety and efficacy of noncardiac surgical procedures in the management of patients with trisomy 13: A single institution-based detailed clinical observation.

Intensive treatment including surgery for patients with trisomy 13 (T13) remains controversial. This study aimed to evaluate the safety and efficacy of noncardiac surgical intervention for T13 patients. Medical records of patients with karyotypically confirmed T13 treated in the neonatal intensive care unit in Nagano Children's Hospital from January 2000 to October 2016 were retrospectively reviewed, and data from patients who underwent noncardiac surgery were analyzed. Of the 20 patients with T13, 15 (75%) underwent a total of 31 surgical procedures comprising 15 types, including tracheostomy in 10 patients and gastrostomy in 4. Operative time, anesthesia time, and amount of bleeding are described for the first time in a group of children with T13. All the procedures were completed safely with no anesthetic complications or surgery-related death. The overall rate of postoperative complications was 19.3%. Patients receiving tracheostomy had stable or improved respiratory condition. Six of them were discharged home and were alive at the time of this study. These results suggest at least short-term safety and efficacy of major noncardiac surgical procedures, and long-term efficacy of tracheostomy on survival or respiratory stabilization for home medical care of children with T13. Noncardiac surgical intervention is a reasonable choice for patients with T13.

Extraosseous Ewing sarcoma in the mesentery: the first report of cases in children.

Extraosseous ewing sarcoma (EES) is a rare soft-tissue tumor usually found in the extremities or paraspinal region. We describe the case of a 4-year-old boy with a large cystic mass in the mesentery diagnosed as mesenteric lymphangioma preoperatively and as EES after partial resection and histopathological examination. EES in the mesentery is extremely rare, with only 2 reports described in the English literature. This represents the first report of EES in a child.

Long-term Catch-up Growth and Risk Factors for Short Adult Height After Pediatric Liver Transplantation: A Retrospective Study.

BACKGROUND: Children requiring liver transplantation generally have severe growth retardation. Recipients experience posttransplantation catch-up growth, although some show short adult heights. We aimed to determine decades-long catch-up growth trends and risk factors for short adult height following liver transplantation. METHODS: We analyzed long-term height Z scores and risk factors for short adult height in a single-center retrospective cohort of 117 pediatric liver transplantation recipients who survived >5 y, with 75 of them reaching adult height. RESULTS: Median age at transplantation was 1.3 y, and the most common primary diagnosis was biliary atresia (76.9%). Mean height Z scores pretransplantation and 1, 3, and 8 y after transplantation were -2.26, -1.59, -0.91, and -0.59, respectively. The data then plateaued until 20 y posttransplantation when mean adult height Z score became -0.88, with a median follow-up of 18.6 y. Nineteen recipients did not show any catch-up growth, and one quarter of recipients had short adult height (<5th percentile of the healthy population). Multivariate analysis identified old age (odds ratio, 1.22 by 1 y; P = 0.002), low height Z scores at transplantation (odds ratio, 0.46 by 1 point; P < 0.001), and posttransplantation hospital stay ≥60 d (odds ratio, 4.95; P = 0.015) as risk factors for short adult height. In contrast, prolonged steroid use after transplantation was not considered a significant risk factor. CONCLUSIONS: Although tremendous posttransplantation catch-up growth was observed, final adult height remained inadequate. For healthy physical growth, liver transplantation should be performed as early as possible, before growth retardation becomes severe.

Primary leiomyosarcoma of the inferior vena cava in a pediatric case: a case report and literature review.

BACKGROUND: Leiomyosarcoma is classified as a soft tissue sarcoma. In adults, leiomyosarcoma is the most common malignancy affecting the vascular system; however, vascular leiomyosarcoma in children is extremely rare as most pediatric soft tissue tumors are rhabdomyosarcomas. The survival rate is very low, and incomplete resection is a poor prognostic factor. There is also a high rate of distant recurrence, with the lungs and liver being the most common sites of metastasis. There is no established effective chemotherapy, and complete surgical resection is the only potentially curative treatment for leiomyosarcoma. CASE PRESENTATION: A 15-year-old female patient with no significant medical history presented with severe upper abdominal pain and was admitted. Abdominal contrast-enhanced computed tomography and magnetic resonance imaging showed a large retroperitoneal tumor protruding into the lumen of the inferior vena cava behind the liver and multiple small nodules, and metastasis to the liver was suspected. The tumor was 6 × 4 × 5 cm in diameter, located just behind the hepatic hilar structures, and was suspected to infiltrate into the right portal vein. The tumor was diagnosed as a leiomyosarcoma through an open tumor biopsy. As the multiple liver metastases were located only in the right lobe of the liver on imaging, we performed tumor resection with right hepatectomy and replacement of the inferior vena cava (IVC). The postoperative course was uneventful; however, on postoperative day 51, distant metastatic recurrences were found in the remaining liver and right lung. The patient was immediately started on chemotherapy and trabectedin proved to be the most effective drug in the treatment regimen; however, severe side effects, such as hepatotoxicity, prevented timely administration, and the patient passed away 19 months after surgery. CONCLUSIONS: IVC resection and reconstruction combined with right hepatectomy were able to be safely performed even in a pediatric case. To improve the prognosis of leiomyosarcoma with multiple metastases, an effective treatment strategy combining surgical treatment and chemotherapy, including molecularly targeted drugs, should be established as early as possible.

Antibody titer after administration of mRNA-based vaccine against severe acute respiratory syndrome coronavirus 2 in liver transplant recipients.

Introduction: The mRNA-based vaccine was released as a COVID-19 prophylactic; however, its efficacy in organ transplant recipients is unknown. This study aimed to clarify this in liver transplant recipients. Methods: Herein, liver transplant recipients from two hospitals who received vaccines were included. Immunoglobulin-G antibodies against the spike and nucleocapsid proteins were measured chronologically after the second, third, and fourth vaccine doses. Results: Antibody levels in 125 liver transplant recipients and 20 healthy volunteers were analyzed. The median age at transplant was 35 (interquartile range 1, 53) years, and the period between transplant and the first dose was 15.2 ± 7.7 years. After the second and third doses, 89.1% and 100% of recipients displayed a positive humoral response, respectively. Anti-spike antibodies after the second dose were significantly reduced at 3 and 6 months, compared to that at 1 month (26.0 [5.4, 59.5], 14.7 [6.5, 31.4] vs. 59.7 [18.3, 164.0] AU/mL, respectively, p < 0.0001). However, a booster vaccine significantly elevated anti-spike antibodies in LT recipients (p < 0.0001) as well as in healthy controls (p < 0.0001). Additionally, the decay rate was comparable between the transplant recipients and controls (2.1 [0.8, 4.5] vs. 2.7 [1.1, 4.1] AU/mL/day, p = 0.9359). Only 4.0% of vaccinated transplant recipients were positive for anti-nucleocapsid antibodies. Conclusion: Liver transplant recipients can acquire immunity similar to that of healthy people through vaccination against SARS-CoV-2. The antibody decay rate is the same, and booster vaccinations should be administered similarly to that in healthy individuals.

Late-onset Chronic Kidney Disease Over 2 Decades After Pediatric Liver Transplantation: A Single-center, Retrospective Study.

BACKGROUND: Although chronic kidney disease (CKD) after liver transplantation (LTx) is a common complication in adults, its long-term significance after pediatric LTx remains unclear. We examined the decades-long transition of renal function and revealed the risk factors for late-onset CKD after pediatric LTx in a single-center retrospective cohort of 117 pediatric LTx recipients who survived >5 y. METHODS: The estimated glomerular filtration rate (eGFR) and CKD stages were calculated using serum creatinine. Risk factor analysis for late-onset CKD was performed in 41 patients whose eGFR could be evaluated at >20 y after LTx. RESULTS: The median age at LTx was 1.3 y, and most primary diagnoses were biliary atresia (77%). The mean pre-LTx and 1, 5, 10, 20, and >20 y post-LTx eGFRs were 180, 135, 131, 121, 106, and 95 mL/min/1.73 m 2 , respectively, with a median renal follow-up period of 15 y. The eGFR declined by 47% at >20 y after LTx ( P < 0.001). CKD was observed in 8%, 19%, and 39% of cases at 10, 20, and >20 y after LTx, respectively. In patients receiving cyclosporine, trough levels were 1.5 times higher in those with CKD up to 10 y after LTx. The multivariate analysis showed that older age at LTx (odds ratio, 1.3 by 1 y; P = 0.008) and episodes of repeated/refractory rejection (odds ratio, 16.2; P = 0.002) were independent risk factors of CKD >20 y after LTx. CONCLUSIONS: In conclusion, renal function deteriorates slowly yet steadily after pediatric LTx. Long-term careful surveillance is essential after pediatric LTx, especially in repeated/refractory rejection or long-term high trough-level use of cyclosporine cases.

Novel Causative RET Mutation in a Japanese Family with Hirschsprung's Disease: Case Report and Factors Impacting Disease Severity.

RET gene variances confer susceptibility to Hirschsprung's disease (HSCR) with pathogenetic mutations being identified in half of familial cases. This investigation of familial HSCR was aimed to clarify the relationship between genetic mutations and clinical phenotype using next-generation sequencing. A novel c2313C > G(D771E) RET mutation was identified in all three affected family members. The mutation involved the kinase domain, which is believe to impair RET activity and intestinal function. A second RET mutation, c1465G > A(D489N), was found only in the extensive aganglionosis case. We conclude that the novel c2313C > A(D771E) mutation in RET may be pathogenic for HSCR, while the c1465C > G(D489N) mutation may be related to phenotype severity.

Fatal disseminated mucormycosis due to Cunninghamella bertholletiae infection after ABO-incompatible living donor liver transplantation: a case report.

BACKGROUND: Fungal infection may develop because of immunosuppression after organ transplantation, in which invasive types, such as Aspergillus and Mucorales, fungi cause morbidity. We present a case of disseminated mucormycosis due to Cunninghamella bertholletiae after ABO-incompatible living donor liver transplantation (LDLT). CASE PRESENTATION: A 47-year-old man with decompensated liver cirrhosis and hepatocellular carcinoma underwent an ABO-incompatible LDLT using a graft procured from his son, who had a different blood type. Rituximab and mycophenolate mofetil were administered 3 weeks before LDLT as immunosuppressive therapy. Although liver graft function improved, mass-like infiltrates appeared in the lungs following intubation for > 1 week due to impaired consciousness. The brain magnetic resonance imaging findings were normal. Decreased ejection fraction and ST elevation were detected on echocardiography and electrocardiography, respectively. There was no dominant stenosis on coronary arteriography. The recipient underwent segmentectomy of the right lung 20 days after LDLT. C. bertholletiae was identified from a specimen using polymerase chain reaction, thus establishing a diagnosis of mucormycosis. Multiple infarctions in the brain, heart, and kidney developed within 2 weeks. Treatment with amphotericin B was ineffective. The patient developed circulatory collapse, and a temporary pacemaker and percutaneous coronary intervention were required for cardiac infarction. The recipient died of cardiac failure 27 days after the LDLT. Autopsy revealed disseminated mucormycosis involving the brain, thyroid, heart, lung, liver, gastrointestinal tract, and both kidneys. In addition, fungal endocarditis may have been responsible for septic emboli in multiple organs, resulting in multiple organ invasion. Hypothrombocytopenia was present since the pre-transplant period, and the recipient was diagnosed posthumously with myelodysplastic syndrome due to hereditary abnormalities. Multiple factors such as organ transplantation, bone marrow dysfunction, immunosuppression, and inadequate administration of antifungal reagents might have promoted mucormycosis development in our patient. CONCLUSIONS: Mucormycosis by C. bertholletiae is a fatal complication; thus, early diagnosis and treatment are warranted before multiple organ invasion.

Segmental Hepatic Steatosis Due to Portal Vein Stricture After Pediatric Living Donor Liver Transplantation: A Case Report.

BACKGROUND AND OBJECTIVE: Liver transplantation (LT) is the gold-standard treatment for end-stage liver disease; however, late-onset complications such as fatty liver can occur in the absence of metabolic comorbidities. We report a unique case of post-transplant hepatic steatosis developing in only a part of the liver graft. CASE REPORT: A 1-year-old boy underwent ABO-incompatible living donor liver transplantation (LDLT) with a left lateral liver graft donated from his mother for biliary atresia. The biliary tract was reconstructed by hepaticojejunostomy using the previous Roux-en-Y limb. Liver function tests increased by up to 2-fold of the upper normal limit after the second year. He developed segmental steatosis in a part of the liver graft 2 years after LDLT. Venous blood drained into the area of the liver graft from veins in the Roux-en-Y limb of the jejunum. Pathologic findings from a liver biopsy showed fatty depositions without steatohepatitis, acute rejection, or tumors. Portal vein stricture (PVS) subsequently became apparent, which was complicated by the symptoms of portal hypertension, such as gastrointestinal varices. We treated PVS with 2 sessions of percutaneous transhepatic portal vein angioplasty (PTPA), after which the segmental steatosis disappeared. We hypothesize that PVS caused local hemodynamic anomalies, leading to fatty deposition in a part of the liver graft. CONCLUSION: We experienced a case of post-LT with segmental steatosis that was successfully treated by portal vein flow modification with PTPA. Steatosis of the graft might indicate a vascular abnormality, and further examinations should be performed after LT.