Taku Kikuchi

Eight-year follow-up of patients with immune thrombocytopenic purpura related toH. pyloriinfection

Thrombocytopenia related to Helicobacter pylori infection is a definitive subset of chronic immune thrombocytopenic purpura (ITP) but its long-term prognosis has not been evaluated extensively. The possibility of recurrence of thrombocytopenia after re-infection of H. pylori is another concern. We evaluated 8-year follow-up data for 11 patients with ITP related to H. pylori infection in a single institution. In 2001, patients with chronic ITP were evaluated for H. pylori infection at the Tokyo Metropolitan Komagome Hospital using 13C urea breath test (UBIT). Nineteen patients turned out to be positive and were treated for H. pylori infection. Platelet count 6 months after treatment revealed complete response (CR) in 10 patients and response in one patient. Eight years later, 17 of these 19 patients were re-evaluated for H. pylori infection and platelet count. Platelet counts of the 11 previous responders remained to indicate CR. Two of 13 patients re-examined by UBIT showed positive results and one of these two patients continued to keep normal platelet count. Nonetheless, the prognosis of patients who responded to eradication was excellent.

Variable magnitude of drug interaction between oral voriconazole and cyclosporine A in recipients of allogeneic hematopoietic stem cell transplantation

Drug interaction between voriconazole and calcineurin inhibitors is often problematic after allogeneic hematopoietic stem cell transplantation (HSCT) or solid organ transplantation. We previously demonstrated an unpredictable inter‐individual variability in the magnitude of this drug interaction; however, the route of drug administration was not taken into account. In this study, the drug interaction between voriconazole and calcineurin inhibitors was further analyzed under the condition that both agents were administered orally. Twenty adult recipients of HSCT who had already been on a steady dose of oral cyclosporine A (CsA) and were started on oral voriconazole (400 mg/d) were eligible. The changes in the concentration/dose (C/D) ratio of CsA were evaluated by comparing the trough concentrations of CsA measured before and 7–10 d after initiating voriconazole. The median C/D ratio of CsA increased significantly from 64.1 to 114.3 (ng/mL)/(mg/kg) after initiating voriconazole (p < 0.01), and the median increase was 83.0% (range, 0.3–224.7%). The plasma concentration of voriconazole did not correlate significantly with the increase of the C/D ratio (ρ = −0.18, p = 0.45). These results indicate that the magnitude of drug interaction between oral voriconazole and CsA is widely variable, and it could not be explained by the difference in the blood levels of voriconazole. Further studies are required to elucidate the mechanism for this variability.

Disseminated mycobacterium marinum infection with a destructive nasal lesion mimicking extranodal NK/T cell lymphoma: A case report

AbstractMycobacterium marinum is a ubiquitous waterborne organism that mainly causes skin infection in immunocompetent patients, and its disseminated infection is rare. Extranodal NK/T cell lymphoma, nasal type (ENKL) usually localizes at the nasal and/or paranasal area, but occasionally disseminates into the skin/soft tissue and gastrointestinal tract. Compromised immunity is a risk factor for developing nontuberculous mycobacterial (NTM) infection and malignant lymphoma, and the 2 diseases may share similar clinical presentation; however, only a few reports have described NTM infection mimicking malignant lymphoma.A 43-year-old Japanese man presented to our hospital complaining of multiple progressive skin nodules and purulent nasal discharge for 3 weeks. He was diagnosed with Crohn disease with refractory enteropathic arthritis and has been treated with anti-tumor necrosis factor alpha agents for 25 years. Fiberoptic nasal examination revealed septal perforation with hemorrhagic mucus and purulent rhinorrhea. Histological examination of the nasal septum revealed the infiltration of atypical medium-to-large-sized cells with erosion. The cells were positive for cytoplasmic CD3, granzyme B, and Epstein–Barr virus-encoded small RNA. Histological examination of the skin nodules and auricle also showed infiltration of atypical lymphocytes. The patient was tentatively diagnosed with ENKL, and chemotherapy was considered. However, the skin lesions decreased in size after discontinuation of immunosuppressive agents and minocycline administration. Two weeks later, nasal septum and lavage fluid and left leg skin cultures were positive for M marinum, and minocycline was discontinued. The skin and the nasal lesions improved after 2 months.To the best of our knowledge, this is the first case of disseminated M marinum infection with a destructive nasal lesion mimicking ENKL. The differentiation between M marinum infection and ENKL is clinically important because misdirected treatment leads to a poor prognosis. NTM infections including M marinum should be considered in differential diagnosis of ENKL. Bacterial cultures, pathological analysis, and close monitoring are required for the differentiation of ENKL and disseminated M marinum infection; both are serious diseases and early diagnostic distinction between them and immediate appropriate treatment will improve the patients prognosis.

New-onset food allergy following cord blood transplantation in adult patients.

New-onset food allergy has been recognized as one of the complications after liver transplantation, especially in pediatric patients, which was closely associated with tacrolimus administration in several studies. One prospective study reported that 21% of pediatric patients receiving liver transplantation developed new-onset food allergy. In contrast to the extensive investigation of food allergy after liver transplantation, food allergy after hematopoietic stem cell transplantation has not been fully evaluated. In bone marrow or peripheral blood stem cell transplantation, allergic disease can be transferred from donors. However, cord blood donors are considered free from allergic disease, and the development of food allergy in cord blood transplantation (CBT) recipients is probably due to the dysregulated immune reconstitution. Recently, sporadic cases of newonset food allergy after CBT have been reported, including five pediatric and two adult patients. To elucidate its incidence and clinical features, we retrospectively evaluated patients who developed new-onset food allergy after CBT. This is a single-institutional retrospective study using the institutional database and medical records of adult patients who underwent CBT for hematological disorders between October 2001 and June 2014 at Keio University Hospital (Tokyo, Japan). This retrospective study was approved by the Ethical Committee of Keio University School of Medicine. After excluding three cases of graft rejection, one case of autologous bone marrow recovery and three cases of insufficient data, 51 patients (male, 31; female, 20) who achieved donor cell myeloid engraftment and survived longer than 30 days after CBT were selected and enrolled into the analysis. Median age of the patients at transplantation was 49 years (range, 18–64), and median follow-up time was 16.9 months (range, 1.4–149.7). Underlying diseases were hematological malignancies, except in one patient with aplastic anemia. The GvHD prophylaxis was cyclosporine A (CsA)-based in 25 patients and tacrolimus-based in 26. Raw foods were avoided during the neutropenic period after transplantation, and grapefruit was avoided until calcineurin inhibitors were discontinued. A diagnosis of food allergy was made on the basis of the clinical presentations repeatedly observed after the oral intake of a specific food, and on the basis of the positive results of the oral food challenge and/or radioallergosorbent tests for specific IgE against the allergens. The probability of food allergy was estimated on the basis of cumulative incidence curves to accommodate deaths due to any causes and the second hematopoietic stem cell transplantation as the competing event. Analyses were performed with EZR, a graphical user interface for R. Of the 51 patients, 3 patients developed food allergy at 5, 6 and 10 months after CBT, respectively. The medical histories of the three patients were not remarkable for any food allergies. The cumulative incidence of food allergy was estimated to be 6.6% (95% confidence interval, 1.7–16.4%) at 1 year after transplantation (Figure 1). The clinical characteristics of the three patients who developed food allergy are shown in Table 1. The patients were aged 19, 55 and 57 years at transplantation, and all developed food allergy within 1 year after CBT. All patients had repeated episodes of the same symptoms shortly after taking specific foods, which prompted the physicians to suspect food allergy. Together with such clinical presentations, the diagnosis of food allergy and incriminated allergens was confirmed by 0 50 100 150 0.0 0.2 0.4 0.6 0.8 1.0

Nephrotoxicity of concomitant use of tacrolimus and teicoplanin in allogeneic hematopoietic stem cell transplant recipients

Both tacrolimus and glycopeptide antibiotics are known to be nephrotoxic, and are often concomitantly given after hematopoietic stem cell transplantation (HSCT) or solid organ transplantation. The aim of this study is to evaluate the nephrotoxicity of concomitant use of tacrolimus and glycopeptide antibiotics in HSCT recipients. We retrospectively evaluated 67 patients who received intravenous tacrolimus and teicoplanin concomitantly for >4 days after allogeneic HSCT for hematologic diseases. Therapeutic drug monitoring (TDM) was performed in all patients for both tacrolimus and teicoplanin. The median age of the patients was 48 years (range: 16–62), and the median duration of the co‐administration of tacrolimus and teicoplanin was 11 days (range: 4–40). The mean serum creatinine (sCr) level tended to be elevated after the co‐administration (from 0.69 ± 0.26 to 0.75 ± 0.30 mg/dL; P = 0.08); however, a 2‐fold or greater increase in sCr was observed only in 2 (3.0%) patients. Increased sCr was reversible, and no patient required hemodialysis. These results suggest that the incidence of clinically significant nephrotoxicity can be minimized if the TDM of each drug is properly applied.

Persistent parvovirus B19 infection resulting in red cell aplasia after allogeneic hematopoietic stem cell transplantation

Persistent parvovirus B19 (PVB) infection has been reported sporadically in immunocompromised patients including hematopoietic stem cell and solid organ transplant recipients. However, the pathogenesis of persistent infection has yet to be fully elucidated. We report here a patient with multiple myeloma developing red cell aplasia during the hematopoietic recovery after allogeneic hematopoietic stem cell transplantation (HSCT) caused by PVB. The patient had already had PVB viremia before transplantation and remained asymptomatic. The route of PVB transmission was considered to be direct contact with the patients family member with primary PVB infection 1 month before transplantation. Treatment with intravenous immunoglobulin resulted in prompt resolution of anemia. These findings suggest that monitoring of PVB DNA is recommended for patients undergoing HSCT and having contact with individuals with documented PVB infection, even if they are asymptomatic.

Long‐term follow‐up of reduced‐intensity allogeneic hematopoietic stem cell transplantation for refractory or relapsed follicular lymphoma

Although allogeneic hematopoietic stem cell transplantation (HSCT) is considered the only curative treatment for refractory or relapsed follicular lymphoma (FL), transplant-related mortality (TRM) greatly interferes with the success. A variety of reduced-intensity conditionings (RICs) have been used to reduce TRM, but an optimal conditioning for FL has not been fully established. We retrospectively evaluated the outcome of allogeneic HSCT for FL with RIC consisting of fludarabine and melphalan. Nineteen adult patients with relapsed or refractory FL were conditioned with fludarabine (125 mg/m2) and melphalan (140 mg/m2), and received grafts from an HLA-identical sibling (n = 6) or an unrelated donor (n = 13). For the prophylaxis of graft-versus-host disease (GVHD), cyclosporine A or tacrolimus with short-term methotrexate was given. There were no early deaths before engraftment, and all patients achieved engraftment. Three patients died of extensive-type chronic GVHD (n = 2) or bacterial infection (n = 1) without disease progression. With a median follow-up period of 75.2 months (range: 33.3–111.9 months), 16 patients were alive without disease progression. Both the 5-year overall and progression-free survival rates were 84.2% (95% CI: 67.7–100%). These results strongly suggest that allogeneic HSCT with RIC using fludarabine and melphalan could be a promising treatment choice for refractory or relapsed FL.

Successful treatment of tafro syndrome with tocilizumab, prednisone, and cyclophosphamide

TAFRO syndrome is a rare systemic inflammatory disease characterized by thrombocytopenia, pleural effusion, fever, renal dysfunction, reticulin fibrosis of the bone marrow, and organomegaly. The clinical course varies significantly among patients. However, the prognosis is usually dismal in patients with severe TAFRO syndrome, and no optimal treatment has yet been established. We herein describe the first case of TAFRO syndrome, which was successfully treated with combination therapy consisting of tocilizumab, prednisone, and cyclophosphamide.

Successful treatment with bendamustine and rituximab for paraneoplastic pemphigus

Dear Editor, Paraneoplastic pemphigus (PNP) is an autoimmune mucocutaneous disease associated with neoplasms, particularly lymphoid malignancies [1, 2]. PNP is characterized by painful stomatitis, polymorphous skin eruption, and the presence of antibodies against desmogleins (Dsg) 1 and 3, envoplakin, and periplakin [1, 2]. Various treatments have been applied to PNP, including corticosteroid, cyclophosphamide, plasmapheresis, and rituximab, but their efficacy has been limited and an optimal treatment remains to be established. We herein report a case of follicular lymphoma developing PNP that was successfully treated with bendamustine and rituximab. A 74-year-old woman noticed rapidly progressing left axillary lymphadenopathy. She had a 23-year history of follicular lymphoma (histological grade 2) and had been receiving a series of treatments including CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone), MACOP-B (methotrexate, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomicin), rituximab alone, and local radiation therapy. The adenopathy was histologically diagnosed as a recurrence of follicular lymphoma. The lesion was treated with local radiation therapy (total 36 Gy) delivered against the lesion. Two months after the initiation of radiation therapy, blisters developed at the radiation site (from the left shoulder to the back) along with eruptions and blisters at the oral, vaginal, and anal mucosa (Fig. 1a, b). Prednisolone (0.5 mg/kg/ day) was initiated but the lesions remained unchanged. The patient was referred to our hospital’s dermatology service. The histopathological studies of the skin and oral mucosa lesions showed suprabasal blister, acantholysis, and basal cell layer degeneration. Immunoblot analysis of the serum revealed the presence of antibodies against envoplakin, periplakin, Dsg1, and Dsg3. The anti-Dsg3 antibody value was 47.5 U/mL (normal range, less than 20.0 U/mL). On the basis of these findings, a diagnosis of PNP was made. Prednisolone was increased to 1.0 mg/kg/day, but there was no improvement. Bendamustine (90 mg/m on days 1, 2) in combination with rituximab (375 mg/m on day 1), BR, was initiated. After 2 weeks, the skin lesions and oral eruption had begun to improve and were almost resolved at 4 weeks (Fig. 1c, d). During the treatment, cytomegalovirus reactivation and neutropenia developed and were successfully treated with an antiviral agent and granulocyte colony-stimulating factor. After two courses of BR, anti-Dsg3 antibodywas undetectable. At 1 year after the initiation of BR treatment, prednisolone administration was successfully tapered to 6 mg/day without recurrence of PNP or follicular lymphoma. Although corticosteroid has been used for the treatment of PNP, it has not been effective for mucosal lesions of PNP [1–5]. Recently, the efficacy of rituximab against PNP associated with malignant lymphoma has been reported [6]. Bendamustine has been used as both a firstand second-line therapy for follicular lymphoma [7, 8]. Although there was a case of PNP developing after BR chemotherapy for follicular lymphoma [9], we observed that BR dramatically improved PNP lesions. The inconsistency between these findings suggests that the pathogenesis and clinical features of PNP associated with malignant lymphoma are diverse. * Taku Kikuchi taku_k_1123@mac.com

Sinusitis caused by Exserohilum rostratum after cord blood transplantation for myelodysplastic syndrome: A case report and literature review

Invasive fungal disease is a serious infectious complication of allogeneic hematopoietic stem cell transplantation (HSCT). Exserohilum rostratum is a species causing phaeohyphomycosis, which rarely causes invasive disease in humans. We treated a case of sinusitis caused by E. rostratum after cord blood transplantation (CBT). A 60‐year‐old man with myelodysplastic syndrome, who had a medical history of an operation to correct deviation of the nasal septum, developed sinusitis caused by E. rostratum under prolonged profound neutropenia after a second CBT because of the graft rejection of the first transplantation. Liposomal amphotericin B improved the sinusitis. A literature review revealed nine reported cases of sinusitis caused by E. rostratum, including our case. Although five cases had severe neutropenia at onset (HSCT recipients, n = 2; aplastic anemia, n = 3), the remaining four had no preexisting immunosuppressive conditions. However, three of the four patients had preexisting nasal diseases with or without a history of surgery, as in our case. Excluding our case, the outcome was fatal in five neutropenic patients, whereas the four patients without neutropenia recovered. Although sinusitis caused by E. rostratum is rare, E. rostratum should be recognized as a possible pathogen causing sinusitis in highly immunosuppressed patients such as HSCT recipients. Preexisting nasal disease and/or nasal surgery could be risks for this infection.