Triple targeting of RSK, AKT, and S6K as pivotal downstream effectors of PDPK1 by TAS0612 in B-cell lymphomas.

B-cell lymphomas (BCLs) are the most common disease entity among hematological malignancies and have various genetically and molecularly distinct subtypes. In this study, we revealed that the blockade of phosphoinositide-dependent kinase-1 (PDPK1), the master kinase of AGC kinases, induces a growth inhibition via cell cycle arrest and the induction of apoptosis in all eight BCL-derived cell lines examined, including those from activated B-cell-like diffuse large B-cell lymphoma (DLBCL), double expressor DLBCL, Burkitt lymphoma, and follicular lymphoma. We also demonstrated that, in these cell lines, RSK2, AKT, and S6K, but not PLK1, SGK, or PKC, are the major downstream therapeutic target molecules of PDPK1 and that RSK2 plays a central role and AKT and S6K play subsidiary functional roles as the downstream effectors of PDPK1 in cell survival and proliferation. Following these results, we confirmed the antilymphoma efficacy of TAS0612, a triple inhibitor for total RSK, including RSK2, AKT, and S6K, not only in these cell lines, regardless of disease subtypes, but also in all 25 patient-derived B lymphoma cells of various disease subtypes. At the molecular level, TAS0612 caused significant downregulation of MYC and mTOR target genes while inducing the tumor suppressor TP53INP1 protein in these cell lines. These results prove that the simultaneous blockade of RSK2, AKT, and S6K, which are the pivotal downstream substrates of PDPK1, is a novel therapeutic target for the various disease subtypes of BCLs and line up TAS0612 as an attractive candidate agent for BCLs for future clinical development.

Significance of localized expression of full-length growth differentiation factor-15 in cachexia of advanced non-small cell lung cancer.

PURPOSE: Growth differentiation factor-15 (GDF-15) is one of the key cachexia-inducing factors. Clinical trials on therapies targeting GDF-15 for cancer and cancer cachexia are underway. While the role of circulating GDF-15 in cachexia has been clarified, the effects of GDF-15 expression within cancer cells remain to be fully elucidated. Hence, the objective of this study was to investigate the expression of GDF-15 in advanced lung cancer tissues and to understand its role in cachexia. METHODS: We retrospectively examined the expression level of full-length GDF-15 in advanced non-small cell lung cancer tissues and analyzed the relationship between the staining intensity and clinical data in 53 samples. RESULTS: We found that 52.8% of the total samples were GDF-15 positive, and GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio (p = 0.008). It did not correlate with the existence of cancer cachexia and overall survival (p = 0.43). CONCLUSION: Our findings show that GDF-15 expression significantly correlated with improved C-reactive protein/albumin ratio, but not the existence of cancer cachexia in advanced NSCLC patients.

First Japanese case of disseminated blastomycosis imported from North America: A case report.

Blastomycosis is a fungal infectious disease that can occur in both immunocompromised and immunocompetent populations endemic in North America, with no previous reports in Japan. A 26-year-old Japanese female patient with no relevant medical history presented intermittent left back pain and an abnormal shadow in the left upper lung field eight months ago at a local clinic. She was referred to our hospital for further evaluation and treatment. The patient currently lives in Japan, but until two years ago had spent several years in New York, Vermont and California. Chest computed tomography revealed a 30 mm mass with a cavity in the left pulmonary apex. The specimens obtained by transbronchial biopsy showed periodic acid-Schiff stain (PAS)-positive and Grocott-positive yeast-like fungi scattered among the granulomas, with no malignant findings, and the initial pathology did not lead to a definitive diagnosis. She was empirically started on fluconazole because of onset of multiple subcutaneous abscesses and was referred to the Medical Mycology Research Center. Although antibody tests could not diagnose the disease, blastomycosis was suspected based on the pathology of the skin and lung tissue at the Medical Mycology Research Center, and Blastomyces dermatitidis was identified by ITS analysis of the rRNA region. Her symptoms and CT findings gradually improved with fluconazole. We reported the first Japanese case of blastomycosis with pulmonary and cutaneous involvement in Japan. As the number of overseas travelers is expected to continue increasing, we would like to emphasize the importance of travel history interviews and information of blastomycosis.

Spatially resolved immune microenvironmental profiling for follicular thyroid carcinoma with minimal capsular invasion.

Spatial profiles of the tumor-immune microenvironment are associated with disease progression and clinicopathological factors in various cancers. Follicular thyroid carcinoma (FTC) is the second most common thyroid cancer, where the presence of capsular invasion or angioinvasion determines the pathological diagnosis; however, little is known about the immune microenvironment profiles associated with the acquisition of invasive potential of FTC. In this study, we focused on FTC with minimal capsular invasion, and the spatially resolved immune microenvironment of FTC was studied in the discovery (n = 13) and validation cohorts (n = 40). CD8+ T cells, helper T cells, regulatory T cells, B cells, natural killer cells, tumor-associated macrophages, CD66+ granulocytes, mature dendritic cells, and mast cells were quantitatively evaluated in single tissue sections, via a 12-marker multiplex immunohistochemistry and image cytometry. Cell densities and compositions of immune cells were spatially stratified by six tissue regions including tumor center, subcapsular region, capsular invasion, adjacent stroma of capsular invasion, peritumoral stroma, and adjacent normal. Lymphoid cell lineages in the tumor center and subcapsular regions were significantly lower than those in adjacent normal and peritumoral stroma, potentially related to the lymphoid lineage exclusion from the intratumoral regions of FTC. Interestingly, immune cell composition profiles in the capsular invasive front were distinct from those of intratumoral region. The ratios of T cells to CD66b+ granulocytes with capsular invasion were significantly higher than those without capsular invasion, suggesting the presence of a unique immune microenvironment at the invasive front between tumor foci and stroma. In addition, tumor cells at the capsular invasive front showed significantly higher expression of tumor programmed cell death ligand 1 (PD-L1) than those at the tumor center. This study revealed spatial immune profiles associated with capsular invasion of FTC, providing new insights into the mechanisms underlying its development and initial invasion.

A clinicopathologic and molecular analysis of five cases of bronchiolar adenoma with rare mutations.

Bronchiolar adenoma (BA) is a rare benign lung tumor that shows proliferation of bland bronchiolar-type epithelium containing a continuous layer of basal cells. This tumor entity has been newly added to the recent World Health Organization (WHO) classification 5th edition. This entity encompasses a spectrum of lesions: the classic ciliated muconodular papillary tumor (CMPT) and the non-classic CMPT. Although BA is reported to have driver mutations including BRAF V600E, EGFR, and KRAS, the molecular profile of BA is still incompletely understood. Five resected BAs at our institutions were analyzed. The BA lesions were subdivided into two groups: three proximal-type BAs and two distal-type BAs. NRAS codon 12/13 mutation and EML4 exon 20-ALK exon 20 fusion were found in two of the three proximal-types. BRAF V600E mutation was found in one of the two distal-types. Two cases coexisted with lung adenocarcinoma, with EGFR exon 19 deletion and KRAS mutation, respectively. No recurrence was observed at a median of 12 months (range 2-84 months) of follow-up. BA has uncommon variants of mutation seen in lung adenocarcinoma. NRAS mutation and ALK fusion partner has not been reported previously. The present cases may reinforce the distinctive biology of BA from lung adenocarcinoma.

Mantle cell lymphoma with EBV-positive Hodgkin and Reed-Sternberg-like cells in a patient after autologous PBSCT: Phenotypically distinct but genetically related tumors.

The case of 70-year-old man with mantle cell lymphoma (MCL) carrying t(11;14) translocation that relapsed as nodal lymphoma combining MCL and classic Hodgkin lymphoma (cHL) 9 years after autologous peripheral blood stem cell transplant (auto-PBSCT) is reported. Lymph nodes contained two separate areas of MCL and cHL-like components. Hodgkin and Reed-Sternberg (HRS)-like cells were accompanied by a prominent histiocyte background. HRS-like cells were CD5- , CD15+ , CD20- , CD30+ , PAX5+ , Bob.1- , Oct2- and EBER+ . The MCL component expressed cyclin D1 and SOX11, whereas cyclin D1 and SOX11 expressions were reduced and lost, respectively, in HRS-like cells. Polymerase chain reaction results showed a single clonal rearrangement of the IGH gene in MCL and cHL-like components. CCND1 break apart fluorescence in situ hybridization showed split signals in both MCL and HRS-like cells, suggesting that MCL and cHL-like components were clonally related. Acquisition of p53 expression and Epstein-Barr virus (EBV)-positivity was seen in HRS-like cells. The patient died of disease progression with elevated hepatobiliary enzymes. The autopsy showed both MCL and cHL-like components around the bile ducts, splenic white pulp and bone marrow. The two components were phenotypically distinct, but genetically related, suggesting that transformation of MCL to HRS-like cells during the course of MCL in association with EBV infection.

Prognostic significance of spatial immune profiles in human solid cancers.

Immune-based tumor characteristics in the context of tumor heterogeneity are associated with suppression as well as promotion of cancer progression in various tumor types. As immunity typically functions based on intercellular contacts and short-distance cytokine communications, the location and spatial relationships of the tumor immune microenvironment can provide a framework to understand the biology and potential predictive biomarkers related to disease outcomes. Immune spatial analysis is a newly emerging form of cancer research based on recent methodological advances in in situ single-cell analysis, where cell-cell interaction and the tissue architecture can be analyzed in relation to phenotyping the tumor immune heterogeneity. Spatial characteristics of tumors can be stratified into the tissue architecture level and the single-cell level. At the tissue architecture level, the prognostic significance of the density of immune cell lineages, particularly T cells, is leveraged by understanding longitudinal changes in cell distribution in the tissue architecture such as intra-tumoral and peri-tumoral regions, and invasive margins. At the single-cell level, the proximity of the tumor to the immune cells correlates with disease aggressiveness and therapeutic resistance, providing evidence to understand biological interactions and characteristics of the tumor immune microenvironment. In this review, we summarize recent findings regarding spatial information of the tumor immune microenvironment and review advances and challenges in spatial single-cell analysis toward developing tissue-based biomarkers rooted in the immune spatial landscape.

Diameter of the dilated main pulmonary artery in patients with pulmonary hypertension decreases after lung transplantation.

PURPOSE: The pulmonary artery (PA) in patients with pulmonary hypertension (PH) becomes dilated. We analyzed the postoperative changes of the main PA after lung transplantation (LuTx). METHODS: The subjects of this retrospective study were 68 LuTx recipients, divided into a PH group (n = 36) and a non-PH group (n = 32), based on preoperative right heart catheterization findings. The PA diameter was measured on chest computed tomography. We evaluated the correlation between the mean pulmonary arterial pressure (mPAP) and the main PA diameter and compared the main PA diameters before and 3 months after LuTx. RESULTS: The main PA diameter was significantly correlated with the mPAP (r = 0.423, P < 0.001). Preoperatively, the mean main PA diameter in the PH group was significantly greater than that in the non-PH group. However, by 3 months after LuTx, the main PA diameter in the PH group had decreased significantly from 32.4 ± 6.7 to 26.9 ± 4.8 mm (P < 0.001), while that in the non-PH group had decreased minimally from 28.3 ± 4.9 to 26.4 ± 4.6 mm (P < 0.001), resulting in no significant difference in postoperative main PA diameters between the two groups. CONCLUSIONS: The main PA diameter in recipients with PH was enlarged and correlated with the mPAP. The dilated main PA diameter in PH patients decreased shortly after LuTx.

A rare case of pulmonary typical carcinoid with prominent acinic cell differentiation, resembling acinic cell carcinoma.

We herein describe a rare case of low-grade endobronchial tumor that exhibited two distinct features of typical carcinoid and acinic cell carcinoma (ACC) by immunohistochemical and ultrastructure study. ACC was suspected on transbronchial biopsy. The resected specimen showed that the tumor surface comprised an acinic cell component (40% of the tumor), and the central area comprised typical carcinoid (60% of the tumor). The acinic cell component was positive for chromogranin A, synaptophysin and alpha-1-antichymotrypsin. Additionally, this component showed focal apical membranous staining for DOG1 and weak positivity for BCL10 and SOX10. Conversely, the carcinoid component was negative for all proteins except for chromogranin A and synaptophysin. Electron microscopy indicated zymogen-type granules (600-800 nm in diameter) in the acinic cell component, whereas neuroendocrine-type granules (200-300 nm in diameter) were observed in the carcinoid component. Nuclear NR4A3 immunostaining, which is highly specific for ACC of the salivary gland, was negative in this case. We conclude that the pulmonary carcinoid tumor with true zymogen-type granules could be seen but showed superficial similarities to ACC based on negative nuclear staining for NR4A3. Pulmonary carcinoids encompass a wide morphological spectrum and may exhibit prominent acinic cell differentiation.

Pulmonary endothelial chimerism after hematopoietic stem cell transplantation.

PURPOSE: Few studies have investigated pulmonary endothelial chimerism after hematopoietic stem cell transplantation. In the present study, we investigated pulmonary endothelial chimerism using the ABH histo-blood group antigen as an identifying marker in cases of ABO-incompatible hematopoietic stem cell transplantation. METHODS: Sixteen lung samples were analyzed. Of these, seven were explanted lungs from lung transplant recipients with severe pulmonary chronic graft-versus-host disease (GVHD). The remaining nine were autopsy samples from patients who died from various causes, and six of these nine cases had a diagnosis of pulmonary chronic GVHD. The ABH histo-blood group antigen was used to differentiate donor cells from recipient cells immunohistochemically. We estimated the percentage of vessels positive for donor blood group antigens in comparison with the total number of vessels. RESULTS: Donor blood group antigens were expressed in the endothelium of 13 samples, all of which were pathologically diagnosed with pulmonary chronic GVHD. The proportion of vessels with donor group antigens ranged from 0.1 to 17.5%. In contrast, no chimeric vessels were observed in the three samples without pulmonary chronic GVHD. CONCLUSIONS: Our results demonstrate that circulating stem cells engraft into the endothelium to a considerable extent in pulmonary chronic GVHD.

Loss of Hep Par 1 immunoreactivity in the livers of patients with carbamoyl phosphate synthetase 1 deficiency.

The hepatocyte paraffin 1 (Hep Par 1) antibody is widely used as a hepatocyte marker, recognizing carbamoyl phosphate synthetase 1 (CPS1), an essential component of the urea cycle. Various missense, nonsense, and frameshift mutations occur in the CPS1 gene. In neonatal patients with homozygous CPS1 deficiency (CPS1D), urea cycle defects with resulting severe hyperammonemia can be fatal, though liver transplantation provides a complete cure for CPS1D. We performed Hep Par 1 immunostaining in the explanted livers of 10 liver transplant patients with CPS1D. Seven were negative for Hep Par 1 in the hepatocytes and the other three showed normal diffuse granular cytoplasmic staining. As expected, all three Hep Par 1-positive patients had at least one missense mutation, and all four patients who had only nonsense or frameshift mutations were Hep Par 1-negative. The other three patients were unexpectedly negative for Hep Par 1, even though each had one missense mutation. These results suggest that CPS1D can be related to the loss of Hep Par 1 reactivity due to the loss of protein production, a one amino acid substitution resulting in an abortive protein product, or both. Hep Par 1 immunohistochemistry can be used as a simple method to confirm CPS1D.

Pleuroparenchymal fibroelastosis and non-specific interstitial pneumonia: frequent pulmonary sequelae of haematopoietic stem cell transplantation.

AIMS: Pulmonary sequelae, reported as chronic graft-versus-host disease (cGVHD), of haematopoietic stem cell transplantation (HSCT) include constrictive bronchiolitis obliterans (CBO), lymphocytic bronchiolitis (LB), and veno-occlusive disease (VOD); recently, pleuroparenchymal fibroelastosis (PPFE) has also been described in bone marrow transplant recipients. The histological features of pulmonary HSCT sequelae have not been described systematically. The aim of the study was to review and identify the histological features of PPFE after bone marrow transplant. METHODS AND RESULTS: A retrospective review of 20 patients who underwent lung transplantation for pulmonary disease following HSCT between 2004 and 2013 was conducted. The patient age at transplantation ranged from 8 years to 57 years (median, 27.5 years). Fifteen patients had cGVHD in other organs (skin, nine; liver, six; salivary gland, six). Lung transplantation was performed at a median of 4.6 years (range, 1.2-14.8 years) post-HSCT. Histologically, all cases had CBO, with concurrent LB in 10, and VOD in three. PPFE was identified in 15 cases (75%), with subpleural (15), paraseptal (11) and centrilobular (13) distributions; and non-specific interstitial pneumonia (NSIP) was identified in 15 cases (75%), with fibrotic (nine) and cellular (six) patterns. PPFE was distributed in all lobes, with a predominance in the upper lobe. NSIP was mostly focal, with two cases having diffuse involvement. CONCLUSIONS: PPFE and NSIP were frequently seen in HSCT patients. Possible causes may include reactions to drugs or radiation, or cGVHD.

Regorafenib suppresses sinusoidal obstruction syndrome in rats.

BACKGROUND: Sinusoidal obstruction syndrome (SOS), a form of drug-induced liver injury related to oxaliplatin treatment, is associated with postoperative morbidity after hepatectomy. This study aimed to examine the impact of regorafenib, the first small-molecule kinase inhibitor to show efficacy against metastatic colorectal cancer, on a rat model of SOS. METHODS: Rats with monocrotaline (MCT)-induced SOS were divided into two groups according to treatment with either regorafenib (6 mg/kg) or vehicle alone, which were administered at 12 and 36 h, respectively, before MCT administration. Histopathologic examination and serum biochemistry tests were performed 48 h after MCT administration. Sinusoidal endothelial cells were evaluated by immunohistochemistry and electron microscopy. To examine whether regorafenib preserved remnant liver function, a 30% hepatectomy was performed in each group. RESULTS: The rats in the vehicle group displayed typical SOS features, whereas these features were suppressed in the regorafenib group. The total SOS scores were significantly lower in the regorafenib group than in the vehicle group. Immunohistochemistry and electron microscopy showed that regorafenib had a protective effect on sinusoidal endothelial cells. The postoperative survival rate after 7 d was significantly better in the regorafenib group than that in the vehicle group (26.7% versus 6.7%, P < 0.05). Regorafenib reduced the phosphorylation of extracellular signal-regulated kinase, which induced matrix metalloproteinase-9 (MMP-9) activation and decreased the activity of MMP-9, one of the crucial mediators of SOS development. CONCLUSIONS: Regorafenib suppressed MCT-induced SOS, concomitant with attenuating extracellular signal-regulated kinase phosphorylation, and MMP-9 activation, suggesting that regorafenib may be a favorable agent for use in combination with oxaliplatin-based chemotherapy.

CD8⁺ tumor-infiltrating lymphocytes at primary sites as a possible prognostic factor of cutaneous angiosarcoma.

Tumor-infiltrating lymphocytes (TILs) have been reported as a prognostic factor in various cancers and are a promising target for immunotherapy. To investigate whether TILs have any impact on the prognosis of angiosarcoma patients, 55 non-treated patients (40 patients at stage 1 with cutaneous localized tumors, 4 patients at stage 2 with lymph node metastases and 11 patients at stage 3 with distant metastases) with angiosarcoma were evaluated retrospectively by immunohistochemistry stained CD4, CD8, FOXP3 and Ki67. The Kaplan-Meier method was used to estimate overall survival with patients at stage 1. Survival differences were analyzed by the log-rank test. Patients with higher numbers of CD8(+) TILs in their primary tumors survived significantly longer compared with patients with lower values. Moreover, the number of CD8 in TILs was positively correlated with a distant metastasis-free period. The total number of primary TILs (CD4 plus CD8) and CD8(+) primary TILs of stage 3 patients with distant metastases was positively correlated with their overall survival. To evaluate whether CD8(+) effector T cells are activated or differentiated, flow cytometric analysis of peripheral blood mononuclear cells (PBMC) was performed. The percentages of CD8(+) T cells producing IFN-γ in PBMC were significantly higher in patients with angiosarcoma (n = 10) compared not only with that of healthy controls (n = 20) but also patients with advanced melanoma (n = 11). These results suggest that anti-tumor immunity is clinically relevant in angiosarcoma.

Application of complement component 4d immunohistochemistry to ABO-compatible and ABO-incompatible liver transplantation.

Antibody-mediated rejection (AMR) is difficult to diagnose after ABO-compatible or ABO-identical (ABO-C) liver transplantation. To determine whether complement component 4d (C4d) immunostaining would be useful for diagnosing AMR, we compared the results of C4d immunohistochemistry for allograft biopsy samples with assays for anti-donor antibodies performed at the time of biopsy. One hundred fourteen patients with ABO-C grafts and 29 patients with ABO-incompatible (ABO-I) grafts were included. Linear C4d endothelial staining (identifiable with a 4× objective lens) or staining seen in 50% or more of the portal tracts was considered positive. Five of the 114 patients (4%) with ABO-C grafts and 15 of the 29 patients (52%) with ABO-I grafts showed C4d positivity. In the ABO-C cases, C4d positivity in late biopsy samples (≥30 days after transplantation) was associated with stage 2 or higher fibrosis (METAVIR score; P = 0.01) and with the presence of donor-specific anti-human leukocyte antigen DR antibodies (HLA-DR DSAs) with a mean fluorescence intensity > 5000 according to the Luminex single-antigen bead assay (P = 0.04). Conversely, the presence of HLA-DR DSAs was associated with the presence of stage 2 or higher fibrosis, acute cellular rejection, and C4d positivity. During the 2-year follow-up, neither C4d positivity nor HLA-DR DSAs were related to graft loss. Among ABO-I patients, C4d positivity was not associated with allograft dysfunction or fibrosis. Only 3 of the 15 C4d-positive patients (20%) showed periportal hemorrhagic edema, which could be a histological sign of AMR in ABO-I grafts, and they were the only cases associated with elevations in anti-donor A/B antibody titers. In conclusion, C4d endothelial positivity among ABO-C patients is an uncommon event that could be associated with chronic graft damage with or without clinical AMR. C4d positivity is common among ABO-I patients and may not be associated with allograft dysfunction if alloantibody titers are not elevated.

Soluble thrombomodulin attenuates sinusoidal obstruction syndrome in rat through suppression of high mobility group box 1.

BACKGROUND: Sinusoidal obstruction syndrome (SOS) is a drug-induced liver injury caused by anticancer treatment such as oxaliplatin-based chemotherapy in patients with hepatic colorectal metastases. SOS is also associated with postoperative morbidity after hepatectomy. AIMS: The aim of this study was to investigate the effects of recombinant human soluble thrombomodulin (rTM) in a monocrotaline (MCT)-induced SOS model in rats. METHODS: Rats were administered rTM by intravenous injection (3 mg/kg) and subcutaneous injection (3 mg/kg) concurrently with MCT administration. Other rats received the same volume of normal saline (NS) and MCT. Liver tissue and blood were collected 48 h after MCT administration to evaluate SOS. Survival after 30% partial hepatectomy was also investigated in both groups. Electron microscopy and immunohistochemistry were used to examine sinusoidal endothelial cells (SECs). Serum concentrations of high mobility group box 1 (HMGB1) and neutrophil accumulation were also measured. RESULTS: In the NS group, liver histology showed SOS phenotypes. In the rTM group, these changes were suppressed, total SOS scores were significantly lower, and serum transaminase levels were significantly reduced compared with the NS group. Survival after 30% hepatectomy was significantly higher in the rTM group (57% vs. 22%, P = 0.0070). Electron microscopy and immunohistochemistry showed a protective effect of rTM on SECs. rTM also attenuated the serum HMGB1 level (9.2 vs. 19.6 ng/ml, P = 0.0086), active neutrophil recruitment and myeloperoxidase activity. CONCLUSION: rTM preserved SECs and attenuated MCT-induced SOS in rats through suppression of circulatory HMGB1 and neutrophil accumulation, resulting in improved survival after hepatectomy.

Redo living-donor lobar lung transplantation for bronchiolitis obliterans associated with antibody-mediated rejection.

Living-donor lobar lung transplantation (LDLLT) is an established therapy for patients with end-stage lung disease, but living-donor lobar lung retransplantation (re-LDLLT) is rarely reported. We previously reported a case of unilateral antibody-mediated rejection after LDLLT in the presence of newly formed donor-specific antibodies against a right-lobe donor. The same patient developed contralateral bronchiolitis obliterans, resulting in bilateral bronchiolitis obliterans, but re-LDLLT was successful. Pathological findings of the explanted lungs were consistent with the clinical course of the patient. One year after re-LDLLT, the patient is doing well without any anti-human leukocyte antigen antibodies. Four lobes from four different donors were transplanted in this patient. The first two lobes were rejected eventually, but the two lobes implanted later presented no signs of rejection at least for 1 year after the transplant. Herein, we report this rare case and compare the clinical course and pathological findings.

Plasma cell hepatitis induced by the termination of antiviral therapy for recurrent hepatitis C after living donor liver transplantation.

Plasma cell hepatitis (PCH) is an idiopathic disorder characterized by plasma cell infiltration in the allografts of patients who have undergone liver transplantation. Although an increasing number of cases of PCH have been reported in liver transplant recipients with hepatitis C recurrence treated with interferon, it is unclear whether PCH is induced by interferon itself. Here, we describe the cases of two patients who developed PCH just after the termination of antiviral therapy for recurrent hepatitis C after living donor liver transplantation. Liver dysfunction appeared at 1 month in one patient and 2 months in the other patient after pegylated interferon plus ribavirin therapy, and liver histology showed interface hepatitis with plasma cell-rich lymphoid aggregates. Both patients recovered after steroid therapy and achieved sustained virological response. These cases suggest that PCH could be induced by the alteration of the immune condition resulting from the termination of antiviral therapy. PCH should be considered when the transaminase levels increase after antiviral therapy, and it should be carefully distinguished from hepatitis C relapse.

Deciphering the association between biopsy-confirmed systemic small vessel vasculitis and Epstein-Barr virus-positive polymorphic B-cell lymphoproliferation.

The Epstein-Barr virus (EBV) is associated with various lymphoproliferative disorders (LPD). Additionally, EBV infection has correlated with diverse autoimmune diseases. However, the association between EBV and systemic small vessel vasculitis (SVV) remains controversial. Here, we report a case of SVV with pauci-immune glomerulonephritis accompanied by an EBV-positive polymorphic B-cell LPD, not otherwise specified. The intricate distinction between EBV-positive B-cell LPD and SVV was difficult, as both diseases demonstrated similar clinical presentations. Lymph node and kidney biopsies facilitated the accurate diagnosis of these two conditions. The administration of high-dose prednisolone, combined with rituximab, proved efficacious, with no instances of relapse over the subsequent 2-year period. This case indicates an association between EBV-positive B-cell LPD and SVV. The diligent execution of biopsies is a crucial diagnostic and interpretive strategy, generating precise comprehension of this condition and guiding its appropriate therapeutic management.