A Diagnostic Impact of Serum Autotaxin Levels in Patients with Bone Marrow Fibrosis.

BACKGROUND: Bone marrow (BM) fibrosis is a condition characterized by deposition of reticulin and collagen fibers in BM. It may confer a poor prognosis in some of hematological malignancies. However, the relationship between fibrosis and the disease pathology is not fully understood and no biomarkers for BM fibrosis are available in clinical practice. Autotaxin (ATX) is a secreted enzyme that is associated with various pathophysiological responses, including fibrosis. We conducted a pilot study to investigate the serum ATX levels in various hematological disorders in patients with or without BM fibrosis. PATIENTS AND METHODS: The serum levels of ATX in a total of 198 patients with hematological disorders and 160 healthy subjects were analyzed. Because of sexual difference in ATX level, the ATX ratio-determined by dividing the ATX level by the mean value of ATX of control subjects of the same sex-was calculated for further comparative analysis. A trephine biopsy samples from 53 patients were also evaluated to determine the Reticulin Fibrosis Index and Collagen Fibrosis Index of each sample. RESULTS: In comparison to the control group, the ATX ratio was significantly higher in patients, especially those with malignant lymphoma. The ATX ratio in lymphoma patients with BM fibrosis was significantly higher than that in patients without BM fibrosis. The Collagen Fibrosis Index showed statistically significant negative correlation with the ATX ratio. CONCLUSION: Our results suggest that the ATX ratio may be a candidate diagnostic biomarker for BM fibrosis in selected patients, including those with malignant lymphoma.

[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.

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.

[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.

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.

Early diagnosis and successful treatment of disseminated toxoplasmosis after cord blood transplantation.

A 66-year-old woman with refractory angioimmunoblastic T-cell lymphoma underwent cord blood transplantation. Prior to transplantation, a serological test for Toxoplasma gondii-specific IgG antibodies was positive. On day 96, she exhibited fever and dry cough. Chest CT showed diffuse centrilobular ground glass opacities in both lungs. The reactivation of T. gondii was identified by the presence of parasite DNA in peripheral blood and bronchoalveolar lavage fluid. Moreover, brain MRI revealed a space occupying lesion in the right occipital lobe. Therefore, disseminated toxoplasmosis was diagnosed. She received pyrimethamine and sulfadiazine from day 99. The lung and brain lesions both showed improvement but the PCR assay for T. gondii DNA in peripheral blood was positive on day 133. On day 146, she developed blurred vision and reduced visual acuity, and a tentative diagnosis of toxoplasmic retinochoroiditis was made based on ophthalmic examination results. As agranulocytosis developed on day 158, we decided to discontinue pyrimethamine and sulfadiazine and the treatment was thus switched to atovaquone. Moreover, we added spiramycin to atovaquone therapy from day 174, and her ocular condition gradually improved. In general, the prognosis of disseminated toxoplasmosis after hematopoietic stem cell transplantation (HSCT) is extremely poor. However, early diagnosis and treatment may contribute to improvement of the fundamentally dismal prognosis of disseminated toxoplasmosis after HSCT.

[Discordant lymphoma of duodenal EBV-positive peripheral T-cell lymphoma not otherwise specified and ileal diffuse large B-cell lymphoma].

A 79-year-old woman was admitted with a 5-kg weight loss and anorexia. Computed tomography showed diffuse lymphadenopathy, and thickening of the duodenal and ileal walls. The patient then underwent biopsy of these sites. Pathological examination revealed duodenal Epstein-Barr virus (EBV)-positive peripheral T cell lymphoma-not otherwise specified (PTCL-NOS) and EBV-negative ileal diffuse large B-cell lymphoma (DLBCL) to be present simultaneously. Combination chemotherapy including rituximab produced a reduction of the duodenal EBV-positive PTCL-NOS lesion, but had no effect on the EBV-negative ileal DLBCL lesion. Thereafter, new lymphadenopathy, high fever, and lactate dehydrogenase (LD) elevation developed, complicated by pneumonia. The patient died due to rapid deterioration of the lymphoma and pneumonia on day 108 after initiation of treatment. EBV-positive PTCL-NOS is reportedly rare and the prognosis is poor. Moreover, EBV-negative ileal DLBCL was diagnosed simultaneously. This case is considered to have had an extremely rare discordant lymphoma, although the exact etiology of its development remains unknown. We speculate that age-related disorders of the immune system and HCV infection may have been associated with the pathogenic mechanism of lymphomagenesis in this case.

Gastrointestinal post-transplant lymphoproliferative disorder with rapidly forming characteristic lesions after cord blood transplantation: a report of two cases.

Epstein-Barr virus (EBV)-related post-transplant lymphoproliferative disorder (PTLD) frequently involves the gastrointestinal tract, but the endoscopic characteristics of this condition have not been discussed in detail. We report two cases of EBV-related PTLD involving rapidly forming characteristic lesions. Case 1 was a 60-year-old man with acute myeloid leukemia who underwent cord blood transplantation (CBT) after which he initially achieved complete remission (CR). He developed nausea and vomiting on day 99. Gastrointestinal endoscopy showed no tumor-like lesions in his stomach. However, a second endoscopic evaluation, which was performed 7 days after the first, revealed multiple raised lesions in his stomach, and a histopathological examination of the biopsy specimen resulted in a diagnosis of EBV-related PTLD. Case 2 was a 36-year-old man with acute myeloid leukemia who underwent CBT after achieving his second CR. He suffered nausea and pharyngalgia on day 309. Although the initial gastrointestinal endoscopic examination showed only multiple erosive or small ulcerative lesions, a second endoscopic evaluation, which was performed 10 days after the first, revealed a raised lesion with a central ulcer in the duodenum. Histopathological examination of the biopsy specimen yielded a diagnosis of EBV-related PTLD. Both patients were successfully treated by reducing the dose of immunosuppressive agents and administering rituximab.

[Primary graft failure in a patient with refractory acute myeloid leukemia successfully treated with modified 'one-day'-based preparative regimen followed by cord blood transplantation].

A 32-year-old woman with acute myeloid leukemia failed to achieve remission with two courses of induction chemotherapy, and she received cord blood transplantation (CBT) in a non-remission state, using an HLA-matched cord blood (CB) graft after a conditioning regimen of fludarabine (Flu) at 125 mg/m² + melphalan at 140 mg/m² + total body irradiation (TBI) at 4 Gy. Chimerism analysis of the bone marrow (BM) cells performed on day 21 after CBT revealed 99% of these cells to be the recipient type. We diagnosed the patient as having graft failure (GF), and then carried out a second CBT using an HLA-matched male CB graft on day 29 after the first CBT. The conditioning regimen (modified 'one-day'-based regimen) consisted of Flu at 30 mg/m² (3 days) + cyclophosphamide (CY) at 2 g/m² (1 day) + TBI 2 Gy. She achieved neutrophil engraftment on day 18. FISH analysis of BM cells on day 13 showed 96% to be of male origin. She has remained in complete remission for 18 months, to date, since the salvage CBT. This case suggests that salvage CBT following a modified 'one-day'-based regimen may preserve a strong graft versus leukemia effect.

[Chromosomally integrated human herpesvirus-6 requiring differential diagnosis of reactivation after allogeneic hematopoietic stem cell transplantation].

Human herpesvirus-6 (HHV-6) is known to cause critical encephalitis, as a central nervous system infection, in some hematopoietic stem cell transplantation (HSCT) recipients. Chromosomally integrated human herpesvirus-6 (CIHHV-6) persistently shows HHV-6 DNA in blood, but this does not necessarily suggest active infection. The true clinical significance in HSCT is not clear. The prevalence of CIHHV-6 in Japan is reportedly 0.21%. We herein report two HSCTs: from a CIHHV-6-positive donor to a negative recipient and from a negative donor to a positive recipient. In the CIHHV-6-positive donor case, the recipient's plasma, which had been negative for HHV-6 before HSCT, became positive after transplantation and the level then remained high, although the subject was asymptomatic. In the CIHHV-6-positive recipient case, the patient's plasma viral load was high just after transplantation, although the subject was asymptomatic, and the load gradually decreased after engraftment. Antivirals had no effect on the viral load in either case. We should consider CIHHV-6 when the HHV-6 DNA load in blood persists asymptomatically after HSCT, to avoid misdiagnosis of reactivated HHV-6 infection and overuse of antivirals. It is also useful to monitor HHV-6 DNA in blood before HSCT, to distinguish HHV-6 reactivation from CIHHV-6.

[Successful long-term control of recurrent primary central nervous system anaplastic large cell lymphoma after autologous hematopoietic stem cell transplantation with concurrent whole brain and spinal cord radiotherapy].

A 24-year-old woman was hospitalized with seizures in 2002. Magnetic resonance imaging demonstrated an intraspinal mass and inhomogeneous gadolinium enhancement along the cerebrospinal meninges. Cerebrospinal fluid (CSF) cytology showed large atypical cells expressing CD2, cytoplasmic CD3, CD7, CD13 and CD30. The patient was finally diagnosed with primary central nervous system anaplastic large cell lymphoma (ALCL). She completed 5 courses of methotrexate (MTX)/ procarbazine (PCZ)/ vincristine (VCR) (MPV) chemotherapy, followed by 2 courses of high dose cytarabine (AraC) and achieved a complete remission. In 2003, she suffered from headache. CSF analysis showed atypical lymphoid cells expressing CD 30. First CNS relapse was diagnosed. She then underwent autologous peripheral blood stem cell transplantation (auto-PBSCT) after administration of thiotepa, buslfan, and cyclophosphamide. However, second CNS relapse occurred in 2004. She received 5 courses of MPV chemotherapy followed by 36 Gy of craniospinal irradiation. Although there was no recurrence of the CNS disease, a third relapse was detected in the right breast in 2009. Pathological and immunohistochemistry analysis revealed ALK-1 positive ALCL. She was treated with 6 courses of cyclophosphamide/adriamycin/vincristine/predonine (CHOP) chemotherapy and 30.6 Gy of local radiation therapy. She has remained in remission for 6 years, to date, since the last therapy and has an excellent quality of life.