Peripheral helper T cells, mavericks of peripheral immune responses.

Peripheral helper T (Tph) cells have been established, through intensive efforts to elucidate local immune responses in human rheumatoid arthritis (RA), as a CD4 subset intimately involved in acquired immunity in peripheral tissues. Initially, Tph cells were noted as a CD4 population that produces high levels of CXCL13 in RA synovial tissues, followed by a demonstration of their ability to help B cells. In contrast to follicular helper T (Tfh) cells, Tph cells do not express the transcription factor BCL6 but express molecules such as CXCL13, interleukin (IL)-21, and inducible T-cell costimulator (ICOS) to help B cells in peripheral tissues. Subsequent studies showed that Tph cells are associated with various diseases, including autoimmune diseases, infections, and malignancies, and with the development of early life immunity. This review summarizes the phenotype and function of Tph cells in RA and discusses their differentiation and diversity in various conditions.

Identification of anti-citrullinated osteopontin antibodies and increased inflammatory response by enhancement of osteopontin binding to fibroblast-like synoviocytes in rheumatoid arthritis.

BACKGROUND: Anti-citrullinated protein/peptide antibodies (ACPAs) are present in patients at onset and have important pathogenic roles during the course of rheumatoid arthritis (RA). The characteristics of several molecules recognized by ACPA have been studied in RA, but the positivity rate of autoantibodies against each antigen is not high, and the pathogenic mechanism of each antibody is not fully understood. We investigated the role of anti-citrullinated osteopontin (anti-cit-OPN) antibodies in RA pathogenesis. METHODS: Enzyme-linked immunosorbent assays on RA patients' sera were used to detect autoantibodies against OPN. Fibroblast-like synoviocytes (FLS) isolated from RA patients were used to test the binding activity and inflammatory response of OPN mediated by anti-cit-OPN antibodies, and their effect was tested using an inflammatory arthritis mouse model immunized with cit-OPN. Anti-cit-OPN antibody positivity and clinical characteristics were investigated in the patients as well. RESULTS: Using sera from 224 RA patients, anti-cit-OPN antibodies were positive in approximately 44% of RA patients, while approximately 78% of patients were positive for the cyclic citrullinated peptide (CCP2) assay. IgG from patients with anti-cit-OPN antibody increased the binding activity of OPN to FLSs, which further increased matrix metalloproteinase and interleukin-6 production in TNF-stimulated FLSs. Mice immunized with cit-OPN antibodies experienced severe arthritis. Anti-cit-OPN antibodies in RA patients decreased the drug survival rate of tumor necrosis factor (TNF) inhibitors, while it did not decrease that of CTLA4-Ig. CONCLUSIONS: Anti-cit-OPN antibodies were detected in patients with RA. IgG from patients with anti-cit-OPN antibodies aggravated RA, and anti-cit-OPN antibody was a marker of reduced the survival rate of TNF inhibitors in RA patients.

Knee Alignment Correction by High Tibial Osteotomy Reduces Symptoms and Synovial Inflammation in Knee Osteoarthritis Accompanied by Macrophage Phenotypic Change From M1 to M2.

OBJECTIVE: This study aimed to determine whether alignment correction by high tibial osteotomy (HTO) can change the biologic intraarticular microenvironment of osteoarthritic (OA) knees. METHODS: Synovial tissue (ST) and fluid (SF) were collected from the affected knees of 31 OA patients during initial HTO and plate removal surgeries. Changes in gene expression in ST were investigated by microarray and real-time polymerase chain reaction (PCR). ST specimens were also evaluated histologically using synovitis scores and immunofluorescence staining to determine macrophage polarity. Cytokines and chemokines in SF were analyzed by enzyme-linked immunosorbent assays. The mechanism of macrophage polarization was investigated in human peripheral blood mononuclear cell-derived macrophages and fibroblast-like synoviocytes (FLS) stimulated with cartilage fragments. We also evaluated Spearman correlations between Knee Injury and Osteoarthritis Outcome scores (KOOS) and macrophage-related gene expression. RESULTS: The microarray results indicated down-regulated inflammatory genes and pathways. Real-time PCR determined that genes expressing proinflammatory IL1B and IL6 were down-regulated and M2 macrophage-related IL1RA, IL10, CCL18, and CD206 were up-regulated. Histologic findings revealed attenuated synovitis scores and a shift from M1 to M2 macrophages. Interleukin-1ß (IL-1ß) concentrations in SF decreased after HTO. Cartilage fragments were responsible for M1 macrophage polarization and proinflammatory gene and protein expression in macrophages, whereas cartilage fragments up-regulated only IL-6 protein in FLS. Postoperative KOOS positively correlated with the expression of the M2-related genes CCL18 and CD206. CONCLUSION: Correction of lower limb alignment with HTO attenuated synovial inflammation and changed macrophage polarization from M1 to M2, suggesting an improved intraarticular environment in knee OA.

Peripheral Helper T Cell Responses in Human Diseases.

A series of rheumatoid arthritis (RA) studies established a PD-1hiCXCR5-CD4+ T-cell subset that was coined peripheral helper T (Tph) cells. CXCL13 production is a key feature of Tph cells and may contribute to the formation of tertiary lymphoid structures (TLS) in inflamed tissues. In addition, Tph cells provide help to B cells in situ as efficiently as follicular helper T (Tfh) cells, and these features would implicate Tph cells in the pathogenesis of RA. Subsequent studies have revealed that Tph cells are involved in various human diseases such as autoimmune diseases, infectious diseases, and cancers. Although the analysis of human immunity has various limitations, accumulating evidence demonstrated the expansion of B cells with low somatic hypermutation and a link between TLS and immune functions in these diseases. We discuss about the emerging roles of the Tph cell and its relevant immune responses in peripheral tissues including B-cell expansion with atypical features.

Dynamics of Type I and Type II Interferon Signature Determines Responsiveness to Anti-TNF Therapy in Rheumatoid Arthritis.

The factors influencing long-term responses to a tumor necrosis factor inhibitor (TNFi) in rheumatoid arthritis (RA) patients currently remain unknown. Therefore, we herein conducted a multi-omics analysis of TNFi responses in a Japanese RA cohort. Blood samples were collected from 27 biological disease-modifying antirheumatic drug (DMARD)-naive RA patients at the initiation of and after three months of treatment with TNFi. Treatment responses were evaluated at one year. Differences in gene expression levels in peripheral blood mononuclear cells (PBMCs), plasma protein levels, drug concentrations, and the presence/absence of anti-drug antibodies were investigated, and a cell phenotypic analysis of PBMCs was performed using flow cytometry. After one year of treatment, thirteen patients achieved clinical remission (responders), while the others did not or switched to other biologics (non-responders). Differentially expressed genes related to treatment responses were enriched for the interferon (IFN) pathway. The expression of type I IFN signaling-related genes was higher in non-responders than in responders before and after treatment (P = 0.03, 0.005, respectively). The expression of type II IFN signaling-related genes did not significantly differ before treatment; however, it increased in non-responders and decreased in responders, with a significant difference being observed after three months of treatment (P = 1.2×10-3). The total number of lymphocytes and C-X-C Motif Chemokine Ligand 10 (CXCL10) protein levels were associated with the type I IFN signature (P = 6.7×10-7, 6.4×10-3, respectively). Hepatocyte growth factor (HGF) protein levels before treatment predicted fold increases in type II IFN (P = 0.03). These IFN signature-related indices (the number of lymphocytes, CXCL10, and HGF) significantly differed between responders and non-responders (P = 0.01, 0.01, and 0.04, respectively). A single-cell analysis revealed that the type I IFN signature was more highly enriched in monocytes than in other cell types. A deconvolution analysis of bulk-RNA sequence data identified CD4+ and CD8+ T cells as the main sources of the type II IFN signature in non-responders. Collectively, the present results demonstrated that the dynamics of the type I and II IFN pathways affected long-term responses to TNFi, providing information on its biological background and potential for clinical applications.

CXCL13-producing CD4+ T cells accumulate in the early phase of tertiary lymphoid structures in ovarian cancer.

Tertiary lymphoid structures (TLS) are transient ectopic lymphoid aggregates whose formation might be caused by chronic inflammation states, such as cancer. However, how TLS are induced in the tumor microenvironment (TME) and how they affect patient survival are not well understood. We investigated TLS distribution in relation to tumor infiltrating lymphocytes (TILs) and related gene expression in high-grade serous ovarian cancer (HGSC) specimens. CXCL13 gene expression correlated with TLS presence and the infiltration of T cells and B cells, and it was a favorable prognostic factor for patients with HGSC. Coexistence of CD8+ T cells and B cell lineages in the TME significantly improved the prognosis of HGSC and was correlated with the presence of TLS. CXCL13 expression was predominantly coincident with CD4+ T cells in TLS and CD8+ T cells in TILs, and it shifted from CD4+ T cells to CD21+ follicular DCs as TLS matured. In a mouse ovarian cancer model, recombinant CXCL13 induced TLS and enhanced survival by the infiltration of CD8+ T cells. These results suggest that TLS formation was associated with CXCL13-producing CD4+ T cells and that TLS facilitated the coordinated antitumor response of cellular and humoral immunity in ovarian cancer.

Role of Lysine-Specific Demethylase 1 in Metabolically Integrating Osteoclast Differentiation and Inflammatory Bone Resorption Through Hypoxia-Inducible Factor 1α and E2F1.

OBJECTIVE: Hypoxia occurs in tumors, infections, and sites of inflammation, such as in the affected joints of patients with rheumatoid arthritis (RA). It alleviates inflammatory responses and increases bone resorption in inflammatory arthritis by enhancing osteoclastogenesis. The mechanism by which the hypoxia response is linked to osteoclastogenesis and inflammatory bone resorption is unclear. This study was undertaken to evaluate whether the protein lysine-specific demethylase 1 (LSD1) metabolically integrates inflammatory osteoclastogenesis and bone resorption in a state of inflammatory arthritis. METHODS: LSD1-specific inhibitors and gene silencing with small interfering RNAs were used to inhibit the expression of LSD1 in human osteoclast precursor cells derived from CD14-positive monocytes, with subsequent assessment by RNA-sequencing analysis. In experimental mouse models of arthritis, inflammatory osteolysis, or osteoporosis, features of accelerated bone loss and inflammatory osteolysis were analyzed. Furthermore, in blood samples from patients with RA, cis-acting expression quantitative trait loci (cis-eQTL) were analyzed for association with the expression of hypoxia-inducible factor 1α (HIF-1α), and associations between HIF-1α allelic variants and extent of bone erosion were evaluated. RESULTS: In human osteoclast precursor cells, RANKL induced the expression of LSD1 in a mechanistic target of rapamycin-dependent manner. Expression of LSD1 was higher in synovium from RA patients than in synovium from osteoarthritis patients. Inhibition of LSD1 in human osteoclast precursors suppressed osteoclast differentiation. Results of transcriptome analysis identified several LSD1-mediated hypoxia and cell-cycle pathways as key genetic pathways involved in human osteoclastogenesis. Furthermore, HIF-1α protein, which is rapidly degraded by the proteasome in a normoxic environment, was found to be expressed in RANKL-stimulated osteoclast precursor cells. Induction of LSD1 by RANKL stabilized the expression of HIF-1α protein, thereby promoting glycolysis, in conjunction with up-regulation of the transcription factor E2F1. Analyses of cis-eQTL revealed that higher HIF-1α expression was associated with increased bone erosion in patients with RA. Inhibition of LSD1 decreased pathologic bone resorption in mice, both in models of accelerated osteoporosis and models of arthritis and inflammatory osteolysis. CONCLUSION: LSD1 metabolically regulates osteoclastogenesis in an energy-demanding inflammatory environment. These findings provide potential new therapeutic strategies targeting osteoclasts in the management of inflammatory arthritis, including in patients with RA.

Induction and expansion of human PRRX1+ limb-bud-like mesenchymal cells from pluripotent stem cells.

Current protocols for the differentiation of human pluripotent stem cells (hPSCs) into chondrocytes do not allow for the expansion of intermediate progenitors so as to prospectively assess their chondrogenic potential. Here we report a protocol that leverages PRRX1-tdTomato reporter hPSCs for the selective induction of expandable and ontogenetically defined PRRX1+ limb-bud-like mesenchymal cells under defined xeno-free conditions, and the prospective assessment of the cells' chondrogenic potential via the cell-surface markers CD90, CD140B and CD82. The cells, which proliferated stably and exhibited the potential to undergo chondrogenic differentiation, formed hyaline cartilaginous-like tissue commensurate to their PRRX1-expression levels. Moreover, we show that limb-bud-like mesenchymal cells derived from patient-derived induced hPSCs can be used to identify therapeutic candidates for type II collagenopathy and we developed a method to generate uniformly sized hyaline cartilaginous-like particles by plating the cells on culture dishes coated with spots of a zwitterionic polymer. PRRX1+ limb-bud-like mesenchymal cells could facilitate the mass production of chondrocytes and cartilaginous tissues for applications in drug screening and tissue engineering.

Shared and distinct roles of T peripheral helper and T follicular helper cells in human diseases.

The interactions of CD4+ T cells and B cells are fundamental for the generation of protective antibody responses, as well as for the development of harmful autoimmune diseases. Recent studies of human tissues and blood samples have established a new subset of CD4+ B helper T cells named peripheral helper T (Tph) cells. Unlike T follicular helper (Tfh) cells, which interact with B cells within lymphoid organs, Tph cells provide help to B cells within inflamed tissues. Tph cells share many B helper-associated functions with Tfh cells and induce B cell differentiation toward antibody-producing cells. The differentiation mechanism is also partly shared between Tph and Tfh cells in humans, and both Tfh and Tph cells can be found within the same tissues, including cancer tissues. However, Tph cells display features distinct from those of Tfh cells, such as the expression of chemokine receptors associated with Tph cell localization within inflamed tissues and a low Bcl-6/Blimp1 ratio. Unlike that of Tfh cells, current evidence shows that the target of Tph cells is limited to memory B cells. In this review, we first summarize recent findings on human Tph cells and discuss how Tph and Tfh cells play shared and distinct roles in human diseases.

A VCP modulator, KUS121, as a promising therapeutic agent for post-traumatic osteoarthritis.

Post-traumatic osteoarthritis (PTOA) is a major cause which hinders patients from the recovery after intra-articular injuries or surgeries. Currently, no effective treatment is available. In this study, we showed that inhibition of the acute stage chondrocyte death is a promising strategy to mitigate the development of PTOA. Namely, we examined efficacies of Kyoto University Substance (KUS) 121, a valosin-containing protein modulator, for PTOA as well as its therapeutic mechanisms. In vivo, in a rat PTOA model by cyclic compressive loading, intra-articular treatments of KUS121 significantly improved the modified Mankin scores and reduced damaged-cartilage volumes, as compared to vehicle treatment. Moreover, KUS121 markedly reduced the numbers of TUNEL-, CHOP-, MMP-13-, and ADAMTS-5-positive chondrocytes in the damaged knees. In vitro, KUS121 rescued human articular chondrocytes from tunicamycin-induced cell death, in both monolayer culture and cartilage explants. It also significantly downregulated the protein or gene expression of ER stress markers, proinflammatory cytokines, and extracellular-matrix-degrading enzymes induced by tunicamycin or IL-1ß. Collectively, these results demonstrated that KUS121 protected chondrocytes from cell death through the inhibition of excessive ER stress. Therefore, KUS121 would be a new, promising therapeutic agent with a protective effect on the progression of PTOA.

Complete atrioventricular block and torsade de pointes due to dose-dense epirubicin and cyclophosphamide therapy.

The dose-dense epirubicin and cyclophosphamide (EC) therapy for breast cancer decreases the risk of cancer recurrence and death. However, epirubicin and cyclophosphamide also cause cardiotoxicity, and cardiomyopathy is the most well-known related adverse effect. A 58-year-old woman presented to our hospital with palpitations 2 weeks after her final dose-dense EC therapy for breast cancer. Holter electrocardiogram (ECG) showed transitory complete atrioventricular block (CAVB) and torsade de pointes. A 12-lead ECG showed QT prolongation in addition to CAVB. Patients receiving dose-dense EC therapy should be monitored more carefully with ECG due to their risk of fatal arrhythmias.

CXCL13-producing PD-1hiCXCR5- helper T cells in chronic inflammation.

CXCL13-producing PD-1hiCXCR5-CD4+ T cells were discovered in synovial tissues of rheumatoid arthritis (RA). Further intensive analysis of RA samples led to the proposal of PD-1hiCXCR5-CD4+ T cells as a pathogenic CD4 subset, peripheral helper T (Tph) cells. Tph cells are upregulated also in the peripheral blood of seropositive RA patient and exert B-cell helper activities. Furthermore, Tph cells are associated with other inflammatory conditions including systemic lupus erythematosus, IgG4-related diseases, type 1 diabetes, inflammatory bowel diseases, and malignant tumors. In this review, molecular feature and pathogenic and beneficial functions of Tph cells in inflammatory conditions are discussed.

Regulation of Immune Responses and Chronic Inflammation by Fibroblast-Like Synoviocytes.

Synovial tissue is a membranous non-immune organ lining joint cavities where it supports local immune responses, and functions directly and indirectly in joint destruction due to chronic inflammatory diseases such as rheumatoid arthritis (RA). Fibroblast-like synoviocytes (FLS), the dominant non-immune cells of synovial tissues, mainly contribute to joint destruction via multiple mechanisms. In RA, FLS respond to endogenous ligands of pattern recognition receptors (PRRs) and inflammatory cytokines as non-immune cells. In addition, FLS aid in the activation of immune responses by interacting with immune cells and by supporting ectopic lymphoid-like structure (ELS) formation in synovial tissues. Moreover, FLS directly cause the pathogenicity of RA i.e., joint deformities. Here, we describe new findings and review the mechanisms underlying the regulation of immune reactions by non-immune FLS and their roles in inflammatory diseases such as RA.

In vitro bone-like nodules generated from patient-derived iPSCs recapitulate pathological bone phenotypes.

The recapitulation of bone formation via the in vitro generation of bone-like nodules is frequently used to understand bone development. However, current bone-induction techniques are slow and difficult to reproduce. Here, we report the formation of bone-like nodules within ten days, via the use of retinoic acid (RA) to induce the osteogenic differentiation of human induced pluripotent stem cells (hiPSCs) into osteoblast-like and osteocyte-like cells that create human bone tissue when implanted in calvarial defects in mice. We also show that the induction of bone formation depends on cell signalling through the RA receptors RARα and RARß, which simultaneously activate the BMP (bone morphogenetic protein) and Wnt signalling pathways. Moreover, by using patient-derived hiPSCs, the bone-like nodules recapitulated the osteogenesis-imperfecta phenotype, which was rescued via the correction of disease-causing mutations and partially by an mTOR (mechanistic target of rapamycin) inhibitor. The method of inducing bone nodules may serve as a fast and reproducible model for the study of the formation of both healthy and pathological bone.

Factors influencing spinal sagittal balance, bone mineral density, and Oswestry Disability Index outcome measures in patients with rheumatoid arthritis.

PURPOSE: To identify the factors influencing spinal sagittal alignment, bone mineral density (BMD), and Oswestry Disability Index (ODI) outcome measures in patients with rheumatoid arthritis (RA). METHODS: We enrolled 272 RA patients to identify the factors influencing sagittal vertical axis (SVA). Out of this, 220 had evaluation of bone mineral density (BMD) and vertebral deformity (VD) on the sagittal plane; 183 completed the ODI questionnaire. We collected data regarding RA-associated clinical parameters and standing lateral X-ray images via an ODI questionnaire from April to December 2012 at a single center. Patients with a history of spinal surgery or any missing clinical data were excluded. Clinical parameters included age, sex, body mass index, RA disease duration, disease activity score 28 erythrocyte sedimentation rate (DAS28-ESR), serum anti-cyclic citrullinated peptide antibody, serum rheumatoid factor, serum matrix metalloproteinase-3, BMD and treatment type at survey, such as methotrexate (MTX), biological disease-modifying anti-rheumatic drugs, and glucocorticoids. We measured radiological parameters including pelvic incidence (PI), lumbar lordosis (LL), and SVA. We statistically identified the factors influencing SVA, BMD, VD, and ODI using multivariate regression analysis. RESULTS: Multivariate regression analysis showed that larger SVA correlated with older age, higher DAS28-ESR, MTX nonuse, and glucocorticoid use. Lower BMD was associated with female, older age, higher DAS28-ESR, and MTX nonuse. VD was associated with older age, longer disease duration, lower BMD, and glucocorticoid use. Worse ODI correlated with older age, larger PI-LL mismatch or larger SVA, higher DAS28-ESR, and glucocorticoid use. CONCLUSIONS: In managing low back pain and spinal sagittal alignment in RA patients, RA-related clinical factors and the treatment type should be taken into consideration.

Constitutive Activation of Integrin α9 Augments Self-Directed Hyperplastic and Proinflammatory Properties of Fibroblast-like Synoviocytes of Rheumatoid Arthritis.

Despite advances in the treatment of rheumatoid arthritis (RA), currently approved medications can have significant side effects due to their direct immunosuppressive activities. Additionally, current therapies do not address residual synovial inflammation. In this study, we evaluated the role of integrin α9 and its ligand, tenascin-C (Tn-C), on the proliferative and inflammatory response of fibroblast-like synoviocytes (FLSs) from RA patients grown in three-dimensional (3D)-micromass culture. FLSs from osteoarthritis patients, when grown in the 3D-culture system, formed self-directed lining-like structures, whereas FLSs from RA tissues (RA-FLSs) developed an abnormal structure of condensed cellular accumulation reflective of the pathogenic features of RA synovial tissues. Additionally, RA-FLSs grown in 3D culture showed autonomous production of proinflammatory mediators. Predominant expression of α9 and Tn-C was observed in the condensed lining, and knockdown of these molecules abrogated the abnormal lining-like structure formation and suppressed the spontaneous expression of matrix metalloproteinases, IL-6, TNFSF11/RANKL, and cadherin-11. Disruption of α9 also inhibited expression of Tn-C, suggesting existence of a positive feedback loop in which the engagement of α9 with Tn-C self-amplifies its own signaling and promotes progression of synovial hyperplasia. Depletion of α9 also suppressed the platelet-derived growth factor-induced hyperplastic response of RA-FLSs and blunted the TNF-α-induced expression of matrix metalloproteinases and IL-6. Finally, α9-blocking Ab also suppressed the formation of the condensed cellular lining by RA-FLSs in 3D cultures in a concentration-related manner. This study demonstrates the central role of α9 in pathogenic behaviors of RA-FLSs and highlights the potential of α9-blocking agents as a nonimmunosuppressive treatment for RA-associated synovitis.

Nardilysin is involved in autoimmune arthritis via the regulation of tumour necrosis factor alpha secretion.

OBJECTIVE: Tumour necrosis factor alpha (TNF-α) plays an important role in rheumatoid arthritis (RA). TNF-α is synthesised as a membrane-anchored precursor and is fully activated by a disintegrin and metalloproteinase 17 (ADAM17)-mediated ectodomain shedding. Nardilysin (NRDC) facilitates ectodomain shedding via activation of ADAM17. This study was undertaken to elucidate the role of NRDC in RA. METHODS: NRDC-deficient (Nrdc-/- ) mice and macrophage-specific NRDC-deficient (NrdcdelM ) mice were examined in murine RA models, collagen antibody-induced arthritis (CAIA) and K/BxN serum transfer arthritis (K/BxN STA). We evaluated the effect of gene deletion or silencing of Nrdc on ectodomain shedding of TNF-α in macrophages or monocytes. NRDC concentration in synovial fluid from patients with RA and osteoarthritis (OA) were measured. We also examined whether local gene silencing of Nrdc ameliorated CAIA. RESULTS: CAIA and K/BxN STA were significantly attenuated in Nrdc-/- mice and NrdcdelM mice. Gene deletion or silencing of Nrdc in macrophages or THP-1 cells resulted in the reduction of TNF-α shedding. The level of NRDC is higher in synovial fluid from RA patients compared with that from OA patients. Intra-articular injection of anti-Nrdcsmall interfering RNA ameliorated CAIA. CONCLUSION: These data indicate that NRDC plays crucial roles in the pathogenesis of autoimmune arthritis and could be a new therapeutic target for RA treatment.

Portal vein thrombosis after reconstruction in 270 consecutive patients with portal vein resections in hepatopancreatobiliary (HPB) surgery.

BACKGROUNDS: This study was aimed to evaluate the occurrence of portal vein thrombosis after portal vein reconstruction. METHODS: The portal veins were repaired with venorrhaphy, end-to-end, patch graft, and segmental graft in consecutive 270 patients undergoing hepato-pancreto-biliary (HPB) surgery. RESULTS: Portal vein thrombosis was encountered in 20 of 163 of end-to-end, 2 of 56 of venorrhaphy, and 2 of 5 of patch graft groups, as compared with 0 of 46 of segmental graft group (p < 0.05, N.S., p < 0001, respectively). Portal vein thrombosis occurred more frequently after hepatectomy than after pancreatectomy (p < 0.0001). The restoration of portal vein blood flow was more sufficiently achieved in the early re-operation within 3 days after surgery than in the late re-operation over 5 days after surgery (p < 0.05). CONCLUSIONS: The segmental graft might have to be more preferred in the portal vein reconstruction. The revision surgery for portal vein thrombosis should be performed within 3 days after surgery.