Disseminated Infection by Scedosporium/Lomentospora During Induction Therapy for Acute Myeloid Leukemia Complicated by Nontuberculous Mycobacteria.

Scedosporium/Lomentospora infections are rare and are associated with a high mortality rate in immunocompromised patients. A 69-year-old man with nontuberculous mycobacteria (NTM) died during induction chemotherapy for acute myeloid leukemia because of multiple organ failure due to pneumonia. During an autopsy, Lomentospora prolificans was detected using a fungal gene analysis of the blood, lungs, spleen, kidneys, and intestines, and Scedosporium aurantiacum was detected in the lungs. NTM disease may predispose patients to Scedosporium/Lomentospora infections. Physicians should consider Scedosporium/Lomentospora spp. as an invasive fungal infection that occurs during myelosuppression, particularly when NTM is a complication.

[Perforated upper gastrointestinal ulcers potentially attributable to mycophenolate mofetil after allogeneic hematopoietic stem cell transplantation].

A 46-year-old man with myelodysplastic syndrome/myeloproliferative neoplasm-unclassifiable underwent myeloablative bone marrow transplantation from an HLA-DR-1-antigen-mismatched related donor while receiving tacrolimus and mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis. However, grade III acute GVHD of the gut occurred on day 20 and was treated with prednisolone (PSL) and oral beclomethasone dipropionate while continuing MMF. Subsequently, he presented with progressive epigastric pain. Endoscopy demonstrated multiple stomach and duodenal deep ulcers. The ulcers were suspected to be GVHD; thus, the PSL dose was increased and infliximab was administered; however, the ulcers exacerbated, resulting in repeated perforations and hemorrhagic shock. Furthemore, MMF was suspected as the cause of refractory ulcers and was discontinued on day 156, which resolved the ulcers after 6 months. MMF-induced gastrointestinal (GI) injury resembles anti-inflammatory drug-related ulcers and upper and lower GI tract GVHD, respectively. MMF-induced GI injury has been reportedly resolved after discontinuing or reducing the MMF dose. Several reports suggested that refractory upper GI ulcers and rectal sparing colitis were associated with MMF toxicities rather than GVHD in hematopoietic stem cell transplantations. Physicians should be aware that MMF can induce severe GI injury.

Clinical Characteristics of Posttransplant Lymphoproliferative Disorder After Cord Blood Transplantation Without Antithymocyte Globulin.

BACKGROUND: CBT with ATG use is a well-known PTLD risk factor. However, little is known regarding the clinical features of PTLD after ATG-free CBT. PATIENTS AND METHODS: We analyzed the incidence, risk factors and prognosis of PTLD in 183 adults undergoing ATG-free CBT. RESULTS: Fifteen patients (diffuse large B-cell lymphoma, n = 9, mucosa-associated lymphoid tissue lymphoma, n = 2 nondestructive PTLD, n = 1, T-cell lymphoma, n = 3) developed PTLD. The 2-year CuI of PTLD was 8.0% (95% CI: 4.6-12.7). Pathologically, all 12 B-cell PTLD patients had Epstein-Barr virus (EBV), compared with 1 of 3 T-cell PTLD patients. All patients, excluding one with nondestructive PTLD, showed extranodal involvement. In the univariate analysis, the 2-year CuI of PTLD was significantly higher in patients who received mycophenolate mofetil to prevent graft-versus-host disease than in nonrecipients (11.2%/2.9%, P = .0457). However, multivariate analysis revealed no independent PTLD risk factors. All 11 PTLD patients who received specific therapy achieved complete remission. The 1-year overall survival of PTLD patients was 70.9%. CONCLUSION: Although we found a higher CuI of PTLD than previously reported, the prognosis was generally good. In CBT recipients, many factors, including MMF use, may be associated with the clinical features of PTLD.

Rapid Improvement in Jaundice Using Transdermal Isosorbide Tape as a Nitric Oxide Donor in Two Adult Patients with Transplantation-associated Microangiopathy Related to Graft-versus-host Disease.

Two adult patients with acute leukemia developed transplantation-associated microangiopathy (TAM) related to graft-versus-host disease (GVHD). Both patients were resistant to standard therapy for TAM and GVHD, which led to markedly elevated serum total bilirubin levels of 47.5 and 10.6 mg/dL, respectively. Transdermal isosorbide tape as a nitric oxide donor was applied to Patients 1 and 2 on post-transplantation days 60 and 66, respectively, which rapidly improved their jaundice after 1 day. This is the first report to describe the efficacy of transdermal isosorbide tape for adult patients with jaundice associated with TAM related to GVHD.

Clinical characteristics and incidence of toxoplasmosis after autologous hematopoietic stem cell transplantation: A retrospective study and literature review.

BACKGROUND: Toxoplasmosis is a rare but life-threatening infection occurring in immunocompromised hosts, including allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients. However, thus far, the clinical features and incidence of toxoplasmosis in autologous HSCT (auto-HSCT) recipients remain unknown. This retrospective survey aimed to analyze 152 patients who received auto-HSCT between 1998 and 2017. METHODS: Serological tests for Toxoplasma gondii-specific IgG were performed on 109 (71.7%) recipients, and 12 pre-HSCT recipients (11%) were Toxoplasma seropositive. Among the 12 recipients, three who did not receive trimethoprim-sulfamethoxazole (TMP/SMX) prophylaxis developed cerebral, pulmonary or disseminated toxoplasmosis due to reactivation after auto-HSCT and died despite treatment. RESULTS: The incidences of toxoplasmosis were 2% and 25% among 152 auto-HSCT recipients (five recipients received auto-HSCT two times) and 12 pre-HSCT Toxoplasma seropositive recipients, respectively. Further, we conducted a literature review and identified 21 cases of toxoplasmosis following auto-HSCT. In these previous cases, the mortality rate was high, especially for pulmonary and disseminated toxoplasmosis. Our findings suggest that, similar to toxoplasmosis after allo-HSCT, toxoplasmosis after auto-HSCT is a fatal complication. CONCLUSIONS: Serial screening of T. gondii-specific IgG before HSCT could contribute to the detection of Toxoplasma reactivation and allow for prompt diagnosis and treatment. The present study is the first to reveal the incidence of toxoplasmosis after auto-HSCT among seropositive patients in Japan.

Kinetics and clinical significance of human herpesvirus 6 DNA shedding in saliva after allogeneic hematopoietic stem cell transplantation.

BACKGROUND: Little is known about the kinetics and clinical significance of saliva human herpesvirus-6 (HHV-6) DNA after hematopoietic stem cell transplantation (HSCT). METHODS: In this observational study, we quantified HHV-6 DNA in serially collected plasma and saliva from allogeneic HSCT recipients. Associations between the status of salivary HHV-6 DNA and the development of HHV-6 encephalitis, depression, and oral mucosal graft-versus-host disease (GVHD) were retrospectively analyzed. RESULTS: A total of 787 plasma and 434 saliva samples were collected from 56 patients. The cumulative incidence of HHV-6 DNA in plasma and saliva at 60 days after transplantation was 51.8% and 83.9%, respectively. The peak level of salivary HHV-6 DNA was significantly higher in patients who displayed plasma HHV-6 DNA than in those who did not (median, 51,584 copies/mL vs 587 copies/mL; P < .0001). Salivary HHV-6 DNA levels increased after positive plasma HHV-6 DNA was detected and remained high during observation period. Despite the frequent occurrence of positive salivary HHV-6 DNA, no patient developed depression. Positivity of salivary HHV-6 DNA was not significantly associated with the development of HHV-6 encephalitis (P = 1.00, Fisher's exact test) or oral mucosal GVHD (P = .71, Grey's test). No significant relationship between salivary HHV-6 DNA and these diseases was found even when comparing higher HHV-6 DNA loads in saliva. CONCLUSION: Salivary HHV-6 DNA levels increased after HHV-6 DNA was detected in the blood. However, no epidemiological evidence was shown to support a role of salivary HHV-6 in the development of HHV-6 encephalitis, depression, and oral mucosal GVHD.

Salvage Therapy Using Azacitidine for Relapsed Primary Myelofibrosis after Cord Blood Transplantation.

We present the case of a 53-year-old woman with prefibrotic stage primary myelofibrosis (PMF) who underwent cord blood transplantation. Nine years after transplantation, she relapsed, which was confirmed by a bone marrow examination. We decided to treat her using azacitidine. After three courses of azacitidine, a partial cytogenetic response was confirmed. Azacitidine maintenance therapy successfully maintained a low level of recipient-origin peripheral blood cells with a stable hematological condition. Azacitidine may therefore be a promising therapeutic option for PMF patients who relapse after allogeneic stem cell transplantation.

Myocarditis with Advanced Atrioventricular Block after Allogeneic Stem Cell Transplantation: A Case Report and Literature Review.

A 51-year-old woman with Philadelphia chromosome-positive acute lymphoblastic leukemia underwent a second cord blood transplantation followed by maintenance therapy with interferon-α. After 33 months, she developed cardiogenic shock caused by advanced atrioventricular block. Laboratory tests revealed increased myocardium enzymes, and ultrasonic cardiography demonstrated mild thickening of the left ventricular wall. She was diagnosed with myocarditis and successfully treated using prednisolone. Myocarditis after allogeneic stem cell transplantation is a rare but potentially fatal complication. However, it is important for physicians to be aware of this complication because all of the symptoms may be reversed with immunosuppressive treatment.

[Successful cord blood transplantation for myelodysplastic syndrome with Behçet disease-like refractory stomatitis and multiple ileocecal ulcerations].

A 12-year-old boy was diagnosed with aplastic anemia. He was followed as an outpatient without medication, and his cytopenia improved after several years. When he was 26 years old, an annual medical checkup revealed leukocytopenia, and at the age of 31 years, he was diagnosed with myelodysplastic syndrome (MDS), refractory cytopenia with multilineage dysplasia. Chromosomal analysis of his bone marrow cells revealed trisomy 8. Ten months after being diagnosed with MDS, he developed refractory stomatitis. Two months later, he experienced abdominal pain and bloody stool, and simple punched-out ulcers similar to intestinal Behçet's disease (BD) were noted in the terminal ileum on colonoscopy. Steroids, mesalazine, and adalimumab were ineffective. Nineteen months after the MDS diagnosis, he underwent cord blood transplantation from an HLA 1-locus mismatched unrelated donor in accordance with a non-myeloablative pretransplant conditioning regimen. The patient's stomatitis and ileocecal ulcers improved following the transplantation. Currently, both MDS and BD-like symptoms are in complete remission at 36 months post transplantation, and the patient continues to take low-dose oral tacrolimus for chronic skin GVHD. Allogeneic hematopoietic stem cell transplantation could become a therapeutic choice for MDS associated with BD, even if refractory intestinal BD symptoms are present.

[Miliary tuberculosis with markedly elevated soluble interleukin-2 receptor levels mimicking intravascular large B-cell lymphoma].

An 81-year-old woman with type 2 diabetes mellitus presented to our hospital due to anorexia, leg edema, and respiratory distress. Laboratory results revealed anemia, thrombocytopenia, elevated lactate dehydrogenase, and markedly elevated soluble interleukin-2 receptor levels. Computed tomography showed ground-glass opacities and consolidation in both lung fields, but no lymphadenopathy was noted. Intravascular large B-cell lymphoma (IVLBCL) was considered as a differential diagnosis; therefore, bone marrow and random skin biopsy were performed. Her respiratory condition deteriorated, with the occurrence of acute respiratory distress syndrome, disseminated intravascular coagulation, hemophagocytic syndrome, and further alveolar hemorrhage. Methylprednisolone pulse therapy was performed, but did not improve the patient's condition. On hospital day 6, the acid-fast bacterial smear of the sputum using the Gaffky scale was 2, and on the next day, tuberculosis DNA was detected in the polymerase chain reaction. In the bone marrow biopsy, multiple epithelioid cell granulomas were found; thus, the patient was diagnosed with miliary tuberculosis. Although anti-tuberculosis therapy was started immediately, she died on hospital day 22. The soluble interleukin-2 receptor level increased up to 19,400 U/ml. The differential diagnosis should be cautiously made because miliary tuberculosis can mimic IVLBCL.

[Successful treatment with mecobalamin in a pernicious anemia patient presenting with false-normal serum vitamin B12].

An 81-year-old woman presented to our hospital with anemia. Complete blood counts revealed macrocytic anemia; however, serum vitamin B12 and folate levels were normal. Bone marrow aspiration revealed multilineage dysplasia, and the patient was initially diagnosed with refractory cytopenia and multilineage dysplasia subtype of myelodysplastic syndrome. However, blood smear revealed hypersegmented neutrophils and bone marrow aspiration showed remarkable megaloblastic changes of erythroid cells. Based on these findings, the patient was administered 1,500 µg mecobalamin per day on a trial basis. Three weeks after initiating mecobalamin, macrocytic anemia improved. Her hemoglobin levels were also normalized along with immediate resolution of peripheral blood dysplasia. The final diagnosis was pernicious anemia (PA) based on anti-intrinsic factor positivity and the efficacy of mecobalamin. Use of automated analyzers may be associated with falsely normal or falsely elevated vitamin B12 levels in the presence of anti-intrinsic factor antibodies. Our case suggests that trial administration of mecobalamin may be an important step to correctly diagnose PA associated with falsely normal or falsely elevated vitamin B12 levels, particularly when typical morphological features of PA are present.

[Clinical characteristics of vascular adverse events and significance of peripheral artery disease as a risk factor in chronic myeloid leukemia patients treated with nilotinib].

Vascular adverse events (VAEs) in chronic myeloid leukemia (CML) patients treated with nilotinib (NIL) has become a; however, studies on strategies to prevent VAEs remain limited. Therefore, the present study investigated VAEs in 19 CML patients treated with NIL at our hospital. The median age of the patients was 65 years and median follow-up period was 55 months after the initiation of NIL. VAEs occurred in 8 patients (peripheral artery disease (PAD), n=6; cerebral infarction (CI), n=3; coronary artery disease (CAD), n=4). The median elapsed time from the initiation of NIL to VAEs was 42 months. The 4-year cumulative incidence of VAEs was 23.5%. Majority of the patients with VAEs were smokers (P=0.074). All the six patients with PAD were diagnosed on the basis of the ankle-brachial index (ABI<0.9) in the asymptomatic phase; 4 of these patients had other VAEs (CI, n=1; CAD, n=2; CI and CAD, n=1). However, antecedent asymptomatic PAD was diagnosed even before CAD was diagnosed in two patients. Nevertheless, in cardiology, extensive studies have indicated that asymptomatic PAD is a risk factor for the development of cardiovascular events. In conclusion, for the effective management of CML patients treated with NIL, a routine screening with ABI to diagnose asymptomatic PAD may be beneficial in preventing severe VAEs.

[Neurolymphomatosis due to enteropathy-associated T-cell lymphoma clinically diagnosed by FDG-PET/CT and subsequently confirmed by autopsy].

A 59-year-old man who complained of abdominal pain was referred to our hospital. Computed tomography (CT) revealed mesenteric lymph node swelling and intestinal perforation. Histopathological study of the resected ileum and lymph node demonstrated diffuse proliferation of medium-sized atypical lymphocytes. Immunohistochemistry results were positive for cluster of differentiation (CD) 3, CD8, and CD56 cells, negative for CD5 and CD4 cells, and negative for Epstein-Barr virus-encoded RNA-fluorescent in situ hybridization (EBER-FISH). It also revealed the expression of γδ T-cell receptors. On the basis of these findings, enteropathy-associated T-cell lymphoma (EATL) was diagnosed. Although the patient received two courses of cyclophosphamide, hydroxydaunorubicin, oncovin, and prednisone (CHOP) and dexamethasone, etoposide, ifosfamide, and carboplatin (DeVIC) therapy, facial nerve and lower limb paralysis manifested. Magnetic resonance imaging (MRI) and lumbar puncture revealed central nervous system invasion of the EATL. Despite intrathecal chemotherapy and high-dose cytarabine therapy, the patient's neurological symptoms deteriorated. Fluorodeoxyglucose positron emission tomography (FDG-PET) /CT scan showed the accumulation of FDG along both median and sciatic nerves, and he was diagnosed with neurolymphomatosis (NL). He died on day 120 after admission. Autopsy specimens exhibited infiltration of lymphoma cells in the median and sciatic nerves. Although only one case of suspected NL in a patient with type 2 EATL has been previously reported, we clinically diagnosed NL using FDG-PET/CT and confirmed the diagnosis by autopsy. This case is valuable in terms of the pathological diagnosis of NL.

Emergence of anti-mitochondrial M2 antibody in patient with angioimmunoblastic T-cell lymphoma.

A 68-year-old woman was referred to our hospital due to fever and rash on the neck and extremities. Laboratory findings revealed hepatic dysfunction and positivity for anti-mitochondrial M2 antibody (AMA-M2). Hepatosplenomegaly and systemic lymphadenopathy were detected by enhanced computed tomography. One week after her first visit, hypoxemia, ascites, and Coomb test-positive autoimmune hemolytic anemia had newly appeared in addition to worsened fever, hepatosplenomegaly, and lymphadenopathy. Results of axillary lymph node, skin, and bone-marrow biopsies led to the diagnosis of angioimmunoblastic T-cell lymphoma (AITL), for which CEPP therapy (cyclophosphamide, etoposide, procarbazine, and prednisolone) was initiated. Her serum levels of hepatobiliary enzymes normalized and AMA-M2 became negative after treatment. The unexpected positivity for AMA-M2 might have been caused by AITL cell-activated intrahepatic immune cells or the tumor cells themselves inflicting bile duct injury that mimicked primary biliary cholangitis. Alternatively, cross reactivity due to the overproduction of immunoglobulins may have caused this phenomenon. The present case may shed light on of the mechanisms of liver dysfunction accompanying AITL.

Analysis of five cases of human herpesvirus-6 myelitis among 121 cord blood transplantations.

Reports of myelitis associated with human herpesvirus-6 (HHV-6) following allogeneic transplantation are rare. Of 121 cases of cord blood transplantation (CBT) performed at Nagano Red Cross Hospital, five cases (4.1%) of HHV-6 myelitis developed at around the time of engraftment. The major symptom identified in all five patients was superficial pain or pruritus linked to segmental levels of the spinal cord. Other identified symptoms were fever or low-grade fever in all five patients, autonomic nerve disorder in four patients, bladder and rectal disturbance in two patients, and extrapyramidal disorder in two patients. These symptoms were experienced primarily 16-39 days after CBT. HHV-6 PCR tests were all positive for cerebrospinal fluid and for plasma. Of the four cases tested by magnetic resonance imaging (MRI), three showed spinal cord abnormality. Antiviral therapy using foscarnet or ganciclovir was effective in every case. Although one case treated from 12 days after onset experienced long-term pain resembling postherpetic neuralgia, symptoms in the four cases were completely relieved after antiviral therapy. In summary, the major symptoms of HHV-6 myelitis were superficial pain linked to segmental levels of the spinal cord. Prognosis may be improved by early initiation of antiviral therapy.

Multicentric Castleman's disease with multiple hepatic mass lesions mimicking malignant liver tumors.

Multicentric Castleman's disease (MCD) is a rare, non-malignant lymphoproliferative disorder. We report a case of MCD with multiple liver masses. A 26-year-old woman presented with asymptomatic anemia and hypoalbuminemia. Laboratory tests detected high CRP levels and findings indicative of polyclonal gammopathy. Abdominal CT revealed multiple hepatic large masses (≤10 cm) and partial calcification in the right lobe. Multiple enlarged lymph nodes were also identified in the cardiophrenic angle and porta hepatis. We suspected hepatic malignancy, but pathological examinations of the liver and lymph nodes demonstrated polyclonal plasma cell infiltration and fibrosis. IL-6 staining was positive for plasma cell infiltration of lymph nodes. A few plasma cells were positive for IgG4, and tests for HIV and HHV-8 were negative. Serum IL-6 and plasma VEGF levels were both elevated (45 and 536 pg/ml, respectively). The patient was diagnosed with plasma cell type MCD. We started treatment with PSL 1 mg/kg/day, which led to improvement of anemia, hypoalbuminemia, and high CRP levels. Marginal regression of liver masses was also observed. At the last follow-up, the patient had been progression-free for 18 months. To our knowledge, this is the first report of a plasma cell type MCD with liver masses.

Cyclic thrombocytopenia synchronizing with the menstrual cycle showing periodic phases of thrombocytopenia and rebound thrombocytosis.

A 37-year-old woman was admitted to our hospital for purpura involving the extremities and thrombocytopenia. Prednisolone (PSL) was administered based on a diagnosis of idiopathic thrombocytopenic purpura (ITP), but was not effective for maintaining her platelet count within the normal range, which showed cyclic fluctuation corresponding to the menstrual cycle. Therefore, we discontinued PSL, and cyclic thrombocytopenia (CTP) was diagnosed. CTP is a rare disease which is usually treated as ITP but with no response. Although the exact cause of CTP is uncertain, in our case, a hormonal mechanism may be responsible for fluctuating platelet count.

Clinical characteristics and computed tomography findings of pulmonary toxoplasmosis after hematopoietic stem cell transplantation.

The prognosis of pulmonary toxoplasmosis, including disseminated toxoplasmosis involving the lungs, following hematopoietic stem cell transplantation (HSCT) is extremely poor due to the difficulties associated with early diagnosis and the rapidly progressive deterioration of multiorgan function. In our institution, we identified nine cases of toxoplasmosis, representing incidences of 2.2 and 19.6 % among all HSCT recipients and seropositive HSCT recipients, respectively. Of the patients with toxoplasmosis, six had pulmonary toxoplasmosis. Chest computed tomography (CT) findings revealed centrilobular, patchy ground-glass opacities (n = 3), diffuse ground-glass opacities (n = 2), ground-glass opacities with septal thickening (n = 1), and marked pleural effusion (n = 1). All cases died, except for one with suspected pulmonary toxoplasmosis who was diagnosed by a polymerase chain reaction assay 2 days after the onset of symptoms. In pulmonary toxoplasmosis, CT findings are non-specific and may mimic pulmonary congestion, atypical pneumonia, viral pneumonitis, and bronchopneumonia. Early diagnosis and treatment is crucial for overcoming this serious infectious complication. Pulmonary toxoplasmosis should be considered during differential diagnosis in a recipient with otherwise unexplained signs of infection and CT findings with ground-glass opacities, regardless of the distribution.