Efficacy and Safety of the Modified EPOCH Regimen (Etoposide, Vincristine, Doxorubicin, Carboplatin, and Prednisolone) for Adult T-cell Leukemia/Lymphoma: A Multicenter Retrospective Study.

BACKGROUND: We retrospectively analyzed patients with untreated aggressive adult T-cell leukemia/lymphoma who received the modified EPOCH (mEPOCH) regimen. PATIENTS AND METHODS: Patients received up to 6 mEPOCH cycles. Etoposide (50 mg/m2/day), doxorubicin (10 mg/m2/day), and vincristine (0.4 mg/m2/day) were each given as a continuous 96-hour infusion on days 1 to 4. Prednisolone (40 mg/m2/day) was given intravenously or orally on days 1 to 4 and then tapered and stopped on day 7, and carboplatin (dose calculated for each patient individually using Calvert's formula according to a target under the curve of 3 mg/mL/min) was given as a 2-hour intravenous infusion on day 6. RESULTS: In 103 patients, overall response rate and complete response rate were 58% and 25%, respectively. With a median follow-up of 8.9 months, the median survival time was 9.8 months (95% confidence interval, 7.2-13.9 months). The median progression-free survival (PFS) was 4.2 months (95% confidence interval, 3.4-5.7 months). Patients who completed ≥ 4 cycles experienced significantly better overall survival and PFS compared with those who completed < 4 cycles. Twenty-eight patients underwent allogeneic hematopoietic stem cell transplantation after mEPOCH and demonstrated significantly prolonged overall survival and PFS compared with those who did not undergo transplantation. CONCLUSION: The mEPOCH regimen is effective with tolerable adverse effects and may be an alternative treatment option for adult T-cell leukemia/lymphoma.

Schizophyllum commune sinusitis after allogeneic bone marrow transplantation for myelodysplastic syndrome: A case report and literature review.

Sinusitis is a serious infectious complication of allogeneic hematopoietic stem cell transplantation. Schizophyllum commune (S commune) is a common basidiomycete fungus that is rarely involved in human disease. We report herein a case of S commune sinusitis after allogeneic bone marrow transplantation. A 66-year-old man with myelodysplastic syndrome underwent allogeneic bone marrow transplantation and developed maxillary and ethmoid sinusitis. The sinusitis did not improve with liposomal amphotericin B after neutrophil engraftment, so we considered that surgical intervention was needed for the recovery of sinusitis. Endoscopic sinus surgery was performed. In the debridement tissue of paranasal mucosa, filamentous fungal elements were observed. Moreover, genetic analysis of the tissue revealed the presence of S commune. Schizophyllum commune should be recognized as a fungal pathogen that causes sinusitis after allogeneic hematopoietic stem cell transplantation. This case suggests the effectiveness of prompt surgical intervention with liposomal amphotericin B treatment for S commune sinusitis and the usefulness of genetic diagnosis for cases under antifungal treatment. (160 words).

Keratinocyte sheets prepared with temperature-responsive dishes show enhanced survival after in vivo grafting on acellular dermal matrices in a rat model of staged bi-layered skin reconstruction.

INTRODUCTION: Bi-layered skin reconstruction can be achieved by staged grafting of acellular dermal matrices (ADMs) and cultured epithelial keratinocyte sheets (KSs). Both KSs and ADMs have been used for long; yet, their combined use has shown poor effectiveness. This outcome has been related to the enzymatic treatment used in the preparation of KSs, which impairs their adhesion potential to ADMs and the formation of a basement membrane (BM). Temperature-responsive (TR) culture dishes allow for enzyme-free preparation of KSs with preservation of BMs and intercellular adhesion proteins; yet, their use has not been previously applied to staged bi-layered skin reconstruction. Using an in vivo rat model, we tested the hypothesis that TR cultures enhance KSs survival and BM preservation after sequential grafting on ADMs. METHODS: In nude rats (n = 9/group), a 9-cm [2] full-thickness dorsal skin defect was repaired with a commercial ADM. At 2 weeks after surgery, we grafted the ADM with KSs (circular, 25 mm diameter), prepared from human cells either by enzymatic Dispase treatment (DT control group) or a TR culture dish (TR experimental group). KSs survival and BMs preservation was assessed one week later by digital imaging, histology (hematoxylin & eosin), immunohistochemistry (collagen IV, pancytokeratins) and immunofluorescence (cytokeratin 1-5-6, laminin). RESULTS: The TR group showed a significantly higher KSs survival (120 ± 49 vs. 63 ± 42 mm2; p < 0.05) and epidermal thickness (165 ± 79 vs. 65 ± 54 µm; p < 0.01) compared with the control DT group, as well as higher epidermal maturation (cytokeratin) and a denser laminin and Collagen IV expression in the BMs in vitro and in vivo. CONCLUSION: These findings suggest that KSs prepared with TR culture dishes have significantly enhanced survival when grafted on ADMs; these outcomes could help improve current clinical strategies in wound care by skin reconstruction.

Intestinal Behçet's Disease with Primary Myelofibrosis Involving Trisomy 8.

Behçet's disease (BD) is a disorder characterized by systemic inflammation of multiple organs, including the intestines. Several studies have reported a relationship between myelodysplastic syndrome and BD, and trisomy 8 was frequently seen, especially in intestinal BD. However, the association of BD with primary myelofibrosis (PMF) has not been well documented. A 58-year-old Japanese female was diagnosed with PMF in 2014. The symptoms of PMF resolved with ruxolitinib. However, she developed fever and intestinal perforation due to multiple ulcers in the terminal ileum in 2017. Intestinal perforation recurred 1 month later, and the dose of ruxolitinib was tapered. After discontinuation of ruxolitinib, she presented with recurrent oral aphthous ulcers and uveitis. Subsequently, intestinal perforation recurred, and she was diagnosed with intestinal BD. Trisomy 8 was identified in her peripheral blood. She underwent steroid therapy, azathioprine, and infliximab. This case suggests relationships between PMF, trisomy 8, and BD.

Transformation of follicular lymphoma to double-hit lymphoma during adjuvant chemotherapy for concurrent ovarian carcinoma.

The frequency of multiple primary malignant neoplasms (MPMN) is increasing due to population aging. Since consensus guidelines for the treatment of MPMN are lacking, treatment strategies are determined by disease status on a per-patient basis. In this report, we describe a case of MPMN with follicular lymphoma (FL) grade 1 that transformed to double-hit lymphoma during adjuvant chemotherapy for concurrent ovarian carcinoma. A 64-year-old woman was diagnosed with MPMN of FL and endometrioid carcinoma by staging laparotomy and lymph node biopsy. She received four cycles of adjuvant chemotherapy (carboplatin and paclitaxel) for endometrioid carcinoma, but during chemotherapy, the FL grade 1 transformed to double-hit lymphoma. We speculate that adjuvant chemotherapy for endometrioid carcinoma may have triggered the transformation of FL in the present case.

Methotrexate-associated lymphoproliferative disorders with angioimmunoblastic T-cell lymphoma-like features accompanied by gamma-heavy chain disease in a patient with rheumatoid arthritis.

Although gamma heavy chain disease (γ-HCD) lesions occasionally morphologically resemble angioimmunoblastic T-cell lymphoma (AITL), no association has been described in detail due to the rarity of the disease. In this report, we present a rare manifestation of methotrexate (MTX)-associated lymphoproliferative disorders (LPDs) with AITL-like features accompanied by γ-HCD in a 75-year-old man with rheumatoid arthritis (RA). A biopsy specimen was evaluated using immunohistochemistry, clonal analyses of immunoglobulin VH and T-cell receptor γ gene rearrangements by polymerase chain reaction, and Sanger sequencing for confirmation of the structure of deleted γ-HCD clones. The histological features characterized by proliferation of CD4- and PD-1-positive medium-sized T cells and arborizing high endothelial venules together with numbers of small lymphocytes, eosinophils, plasma cells, and histiocytes in the background mimicked those of AITL, but did not completely fulfill the diagnostic criteria. Clonal analysis demonstrated that the specimen contained multiple LPDs of both B-cell and T-cell lineages. Sequence analysis confirmed the co-existence of a clone responsible for production of the abnormal heavy chain. This report provides new insights into the pathology of γ-HCD. Multiple host-derived factors (e.g., RA and/or use of MTX) may be responsible for the occurrence of LPDs of multiple lineages within a single lymph node.

Acquired hemophilia A associated with autoimmune pancreatitis with serum IgG4 elevation.

A case of acquired hemophilia A (AHA) that developed in a patient with autoimmune pancreatitis (AIP) is presented. A 64-year-old woman was diagnosed with AIP in 2007. The symptoms resolved with prednisolone (PSL). Although the dose of PSL was tapered to 7.5 mg/day for maintenance, serum IgG4 levels remained high. She suddenly presented with subcutaneous bleeding in 2015. Her activated partial thromboplastin time was prolonged (80.0 s). A mixing test showed an inhibitor pattern, factor VIII (FVIII) activity was less than 1%, and FVIII inhibitor was 290 BU/mL. She was diagnosed with AHA. Her serum IgG4 was elevated to 133 mg/dL. She was treated first with PSL alone, but she developed bladder tamponade. Cyclophosphamide and activated prothrombin complex concentrate were combined with PSL. She then achieved hemostasis, and FVIII inhibitor disappeared. FVIII inhibitor had been detected since PSL was tapered and AHA recurred two months later. An enzyme-linked immunosorbent assay showed that the inhibitor was mainly IgG4 and IgG1. This case suggests that elevation of IgG4 may be associated with the development of both AHA and AIP.

Fatal Disseminated Tuberculosis during Treatment with Ruxolitinib Plus Prednisolone in a Patient with Primary Myelofibrosis: A Case Report and Review of the Literature.

A 73-year-old man with primary myelofibrosis (PMF) was being treated with hydroxyurea, which was changed to ruxolitinib treatment because of worsening constitutional symptoms. Although ruxolitinib rapidly induced relief, he developed a high-grade fever. A comprehensive fever work-up found no apparent cause of the fever, except for PMF. Therefore, we increased the dose of ruxolitinib and added prednisolone, which was gradually withdrawn with resolution of the fever. However, the patient subsequently developed disseminated tuberculosis and died eight months after initiation of ruxolitinib. Our case highlights the importance of assessing and monitoring the immune status of patients receiving ruxolitinib.

Achievement of disease control with donor-derived EB virus-specific cytotoxic T cells after allogeneic peripheral blood stem cell transplantation for aggressive NK-cell leukemia.

Aggressive NK-cell leukemia (ANKL) is characterized by systemic infiltration of Epstein-Barr virus (EBV)-associated natural killer cells and poor prognosis. We report a case of ANKL in which EBV-specific cytotoxic T lymphocytes (CTLs) were induced. A 41-year-old male suffered from fever, pancytopenia, and hepatosplenomegaly. The number of abnormal large granular lymphocytes in the bone marrow was increased and the cells were positive for CD56 and EBV-encoded small nuclear RNAs. The patient was diagnosed with ANKL and achieved a complete response following intensive chemotherapy. He then underwent allogeneic peripheral blood stem cell transplantation from his sister. Conditioning therapy consisted of total body irradiation and cyclophosphamide. Graft-versus-host disease prophylaxis consisted of cyclosporine and methotrexate. On day 31, complete donor chimerism was achieved and no acute graft-versus-host disease developed. The ANKL relapsed on day 80, and cyclosporine was rapidly tapered and chemotherapy was started. During hematopoietic recovery, the number of atypical lymphocytes increased, but they were donor-derived EBV-specific CTLs. The patient achieved a partial response and EBV viral load decreased to normal range. Unfortunately, ANKL worsen again when the CTLs disappeared from his blood. This is the first case report of ANKL in which induced EBV-specific CTLs may have contributed to disease control.

Danazol-induced peliosis hepatis accompanied by disseminated intravascular coagulation in a patient with myelodysplastic syndrome transformed from aplastic anemia.

Peliosis hepatis (PH) is a condition involving benign tumors pathologically characterized by multiple blood-filled cavities, mostly affecting the liver and spleen. Androgenic-steroids are widely used in patients with bone marrow failure syndromes (e.g.: aplastic anemia) and these patients are at increased risk of developing PH. Although patients with PH are generally asymptomatic, PH can progress to liver failure and even fatal spontaneous intraabdominal hemorrhage. Therefore, early diagnosis is critical in order to prevent life-threatening complications of PH. We herein report a patient with PH which had been treated with danazol, who presented with liver dysfunction and multiple hepatic lesions on imaging studies at the time of diagnosis. Although the patient presented with disseminated intravascular coagulation (DIC), a bone marrow biopsy revealed no evidence of leukemic transformation. The patient was diagnosed as having danazol-induced PH, and these abnormalities spontaneously resolved after the discontinuation of danazol. PH is one of the most important complications of long-term administration of androgenic-steroids. Although the mechanisms remain unclear, the multiple blood-filled cavities characteristic of PH may be responsible for the development of DIC. Therefore, monitoring of coagulation markers might also be a key strategy for early diagnosis of PH.

Spontaneous splenic rupture in a patient with light-chain deposition disease undergoing autologous peripheral blood stem cell transplantation.

Light-chain deposition disease (LCDD) is a rare plasma cell neoplasm that secretes an abnormal immunoglobulin light chain, which is deposited in tissues, leading to organ dysfunction. Spontaneous splenic rupture is a rare and life-threatening complication of treatment with granulocyte colony-stimulating factor (G-CSF). Herein, we describe spontaneous splenic rupture after the administration of lenograstim to a patient with LCDD undergoing autologous stem cell transplantation (ASCT). The patient was successfully treated by transcatheter embolization of the splenic artery, and long-term stringent complete remission was attained. Plasma cell neoplasms, including multiple myeloma with amyloidosis, are among the most commonly reported conditions associated with spontaneous splenic rupture in patients undergoing ASCT. This finding suggests that, in addition to the effect of G-CSF on the spleen, a combination of factors, including tissue vulnerability induced by the infiltration of abnormal immunoglobulins, may be involved in the pathogenesis of spontaneous splenic rupture. Notably, splenomegaly is not always evident in these patients. Surgical treatment may not be an option, because of severe myelosuppression, and thus less invasive treatment using transcatheter embolization may be feasible.

Orally Administered Salacia reticulata Extract Reduces H1N1 Influenza Clinical Symptoms in Murine Lung Tissues Putatively Due to Enhanced Natural Killer Cell Activity.

Influenza is a major cause of respiratory tract infection. Although most cases do not require further hospitalization, influenza periodically causes epidemics in humans that can potentially infect and kill millions of people. To countermeasure this threat, new vaccines need to be developed annually to match emerging influenza viral strains with increased resistance to existing vaccines. Thus, there is a need for finding and developing new anti-influenza viral agents as alternatives to current treatments. Here, we tested the antiviral effects of an extract from the stems and roots of Salacia reticulata (SSRE), a plant rich in phytochemicals, such as salacinol, kotalanol, and catechins, on H1N1 influenza virus-infected mice. Following oral administration of 0.6 mg/day of SSRE, the incidence of coughing decreased in 80% of mice, and only one case of severe pulmonary inflammation was detected. Moreover, when compared with mice given Lactobacillus casei JCM1134, a strain previously shown to help increase in vitro natural killer (NK) cell activity, SSRE-administered mice showed greater and equal NK cell activity in splenocytes and pulmonary cells, respectively, at high effector cell:target cell ratios. Next, to test whether or not SSRE would exert protective effects against influenza in the absence of gut microbiota, mice were given antibiotics before being inoculated influenza virus and subsequently administered SSRE. SSRE administration induced an increase in NK cell activity in splenocytes and pulmonary cells at levels similar to those detected in mice not treated with antibiotics. Based on our results, it can be concluded that phytochemicals in the SSRE exerted protective effects against influenza infection putatively via modulation of the immune response, including enhancement of NK cell activity, although some protective effects were not necessarily through modulation of gut microbiota. Further investigation is necessary to elucidate the molecular mechanisms underlying the protective effects of SSRE against influenza infection.

SC1, an immunoglobulin-superfamily cell adhesion molecule, is involved in the brain metastatic activity of lung cancer cells.

SC1 is a cell adhesion molecule that belongs to the immunoglobulin superfamily; this molecule was initially purified from the chick embryonic nervous system and was reported to exhibit homophilic adhesion activity. SC1 is transiently expressed in various organs during development and has been identified in numerous neoplastic tissues, including lung cancer and colorectal carcinomas. The present study focused on the encephalic metastasis of lung cancer cells with respect to the potential function of SC1, as this molecule is known to be consistently expressed in the central nervous system as well as lung cancers. SC1 complementary DNA was introduced into A549 cells, a human lung cancer-derived cell line. The stable overexpression of the SC1 protein in A549 cells was demonstrated to enhance the self-aggregation of the cells. In addition, the SC1 transfectants enhanced the metastatic and invasive potential to the encephalic parenchyma following implantation into nude mice. In conclusion, the results of the present study demonstrated that cell adhesion due interactions between SC1 on brain tissue and SC1 on lung cancer cells was involved in the malignant aspects of lung cancer, including invasion and metastasis to the brain.

Antibodies against swine influenza virus neutralize the pandemic influenza virus A/H1N1.

The most effective method for the prevention of influenza infection would be prophylaxis with a safe and effective vaccine and anti-viral materials. After vaccination, neutralizing antibodies are generated by plasma cells following various immune responses, thus resulting in protection against an infectious agent expressing the same antigens. However, in the case of novel or unknown pathogens, the onset of immune responses is occasionally delayed, thus resulting in considerable morbidity and mortality. Antibodies are therefore considered to play an important role in preventing infectious diseases. Furthermore, antibodies are used for additional purposes, including diagnosis and immunotherapy. In the beginning of spring 2009, an outbreak of influenza in North America was caused by a novel strain of influenza virus, designated pandemic influenza A/H1N1 2009. Initially, most people had low immunity against this pathogen, resulting in the worldwide spread of the infection to produce a so-called 'pandemic'. We herein report the generation of 'immunoglobulin yolk (IgY)' neutralizing antibodies against the pandemic influenza virus A/H1N1 from ostrich eggs immunized with a swine influenza virus vaccine strain. Using this simple method, a large amount of specific antibody against the influenza virus was produced by one female ostrich. An enzyme-linked immunosorbant assay and immunocytochemistry indicated that the IgY from the immunized ostrich eggs possessed strong cross-reactivity to the pandemic influenza virus A/H1N1 2009, as well as to the swine influenza virus. Moreover, the hemaggregation activities of the erythrocytes induced by pandemic influenza A/H1N1 virus were inhibited by the ostrich antibodies generated by swine virus immunization. In addition, the cytopathological effects on MDCK cells of infection with pandemic virus were clearly inhibited in co-cultures with the antibodies, indicating the neutralizing of viral infectivity in the cells. In conclusion, we have succeeded in the mass production of neutralizing antibodies against pandemic influenza virus A/H1N1 2009 using ostrich eggs immunized with swine influenza virus antigens. This enables the cost-effective production of effective antibodies, which could be applied to facial masks and air-conditioning filters in order to prevent populations from acquiring pandemic influenza virus A/H1N1.

Protection from avian influenza H5N1 virus infection with antibody-impregnated filters.

There is worldwide concern over the possibility of a new influenza pandemic originating from the highly pathogenic avian H5N1 influenza viruses. We herein demonstrate that functional air filters impregnated with ostrich antibodies against the hemagglutinin of the H5N1 virus protect chickens from death by H5N1 transmission. These results suggest that the use of ostrich antibody-impregnated filters might be a powerful way to prevent the transmission of H5N1.

Expression of SC1, a cell adhesion molecule, promotes the metastatic activities of the Gallus gallus lymphoblastoid cell line MDCC-MSB1 derived from Marek's disease.

SC1 is an immunoglobulin superfamily cell adhesion molecule purified from the Gallus gallus spinal cord. SC1 is present in embryonic tissues and plays a role in chick development through its cell adhesive property. Interestingly, increased SC1 expression is observed in some sporadic tumours of the chicken, including Marek's disease-induced lymphomas and in nephroblastomas. To elucidate the possible functions of SC1 in tumour progression in the chicken, SC1 cDNA was introduced into the endogenous SC1-negative Marek's disease-derived chicken lymphoblastoid cell line MDCC-MSB1, and subsequently the metastatic potentials of these cell lines were analysed. The in vitro analyses revealed that the SC1-transfected MDCC-MSB1 cells were enhanced in their adhesive and migratory activities in the presence of the SC1 proteins. In addition, the metastatic potential of the SC1-transfected MDCC-MSB1 cells to the lung was enhanced after intravenous implantation into chickens. These findings suggest that the expression of SC1 contributes to the malignancy and metastatic properties of chicken Marek's disease-induced lymphomas.

Ostrich produce cross-reactive neutralization antibodies against pandemic influenza virus A/H1N1 following immunization with a seasonal influenza vaccine.

An outbreak of influenza in 2009 was found to be caused by a novel strain of influenza virus designated as pandemic influenza A/H1N1 2009. Vaccination with recent seasonal influenza vaccines induced little or no cross-reactive antibody response to the pandemic influenza virus A/H1N1 2009 in any age group in human populations. Accordingly, most people had low immunity against this pathogen, thus resulting in the worldwide spread of the infection to produce a so-called 'pandemic'. This report presents the important finding that ostrich eggs generate cross-reactive antibodies to the pandemic influenza virus A/H1N1 following immunization of female ostrich with a seasonal influenza vaccine. This simple method produced a large amount of antibodies against influenza viruses by one female ostrich. An enzyme-linked immunosorbent assay (ELISA) and immunocytochemistry indicated that the ostrich antibodies possessed strong cross-reactivity to the pandemic A/H1N1 as well as to the seasonal A/H1N1, A/H3N2 and B viruses. The hemaggregation activities of erythrocytes induced by this pandemic strain were also inhibited by the ostrich antibodies. In addition, the cytopathological effects of infection with a pandemic virus on MDCK cells were clearly inhibited in co-cultures with the ostrich antibodies, thereby indicating the neutralization of viral infectivity in the cells. In conclusion, cross-reactive neutralization antibodies against pandemic influenza virus A/H1N1 2009 were successfully generated in ostrich eggs produced by females immunized with seasonal influenza viral vaccine.

Involvement of gicerin, a cell adhesion molecule, in the portal metastasis of rat colorectal adenocarcinoma cells.

Gicerin, an Ig-superfamily cell adhesion molecule, has homophilic adhesion activity, thus leading to the formation of gicerin aggregates. Gicerin is highly expressed in various embryonic tissues, and it contributes to development through its adhesive activities. In contrast, the expression of the protein is limited to the muscular tissues and endothelial cells in the mature animals. In the liver, gicerin is constitutively expressed in sinusoidal endothelial cells. Interestingly, an overexpression of gicerin is found in a variety of tumors and may play a role in tumorigenesis. Previously, up-regulated expression of the gicerin protein was found in some sporadic cases of chicken colorectal adenocarcinomas and their hepatic metastasized lesions. In the present study, gicerin cDNA was introduced into endogenous gicerin negative ACL-15 cells, a rat colon adenocarcinoma cell line. The cells were subsequently evaluated for changes in their metastatic potentials in order to elucidate the possible role of gicerin in the hepatic metastasis of colorectal adenocarcinomas. The stable overexpression of gicerin in the cells enhanced the self-aggregation and migratory activities on the protein compared with the mock-transfectants. In addition, the gicerin- transfectants had enhanced metastatic potential to the liver compared with mock-transfected cells after implantation into the ileocolic vein of the cognate rats. These results suggest that gicerin might promote the interaction of tumor cells with a hepatic endothelium, thus leading to the hepatic metastasis of colon adenocarcinomas.

Involvement of gicerin, a cell adhesion molecule, in a dermal autograft chicken model.

Gicerin is a cell adhesion molecule in the immunoglobulin superfamily. This molecule has homophilic and heterophilic adhesive activities, binding to the neurite out-growth factor (NOF). We have previously reported that gicerin plays an important role in the development and regeneration as well as in the metastasis of tumors through its adhesive activities, mediating cell-cell and/or cell-extracellular matrix interactions. In this study, we investigated the involvement of gicerin in a dermal autograft chicken model. Gicerin and NOF were transiently present in the regenerating epithelia after the dermal graft transplantation. The treatment with an anti-gicerin polyclonal antibody, by placing drops onto the wounds, inhibited the adhesiveness of the grafts to the marginal skin. The chimeric protein of gicerin-IgG, gicerin-Fc, and NOF proteins promoted the regeneration of the grafts. These findings suggest the potential function of gicerin in dermal autografts, and gicerin and NOF proteins could help clinical improvement after transplantations.