[TCL1-family negative T-cell prolymphocytic leukemia with rapid progression of extranodal disease despite a normal white blood cell count].

Here we describe the case of a 69-year-old man who was found to have moderate thrombocytopenia and severe splenomegaly during a medical checkup at the age of 67. At the first visit, his white blood cell (WBC) count was 7,400/µl with 80% lymphocytes, and bone marrow aspiration showed 24% atypical lymphocytes. Flow cytometry of atypical lymphocytes was positive for mature T-cell markers, and T-cell clonality was revealed by T-cell receptor gene rearrangement. TCL1 was negative on immunohistochemistry. We diagnosed TCL1-family negative T-cell prolymphocytic leukemia (T-PLL) and employed watchful waiting. Thirty months after diagnosis, the patient developed urinary retention and right lower-limb paresis despite a normal WBC count, and an extradural tumor around the thoracic vertebrae and spinal cord compression were detected. The tumor was diagnosed as extranodal involvement of TCL1-family negative T-PLL, but the patient's general condition deteriorated rapidly, and no treatment was possible. T-PLL is a rare disease characterized by leukocytosis, and the WBC count generally increases with disease progression. Although blood counts are recommended for observation, it is important to keep in mind that the disease may worsen even if blood counts do not change.

Compression therapy using surgical gloves is ineffective for the prevention of vincristine-induced neuropathy in patients with malignant lymphoma.

PURPOSE: Vincristine (VCR) often induces peripheral neuropathy (PN) as an adverse event. Currently, there is no consensus on the prevention of vincristine-induced PN (VIPN). In this study, we aimed to investigate the efficacy of compression therapy using surgical gloves for preventing VIPN. METHODS: Patients with malignant lymphoma (vincristine-naïve) who were receiving chemotherapy with cyclophosphamide, doxorubicin, VCR, and prednisolone, with or without rituximab, every 3 weeks for six cycles were eligible. For every VCR infusion, each patient wore two one-size-smaller gloves on one hand (study hand) for 90 min. The other hand was left bare (control hand). PN was assessed at each treatment using the Common Terminology Criteria for Adverse Events ver. 4.0. RESULTS: Fifty-one patients with malignant lymphoma were enrolled and 44 were evaluated. At 1 month after treatment, the occurrence rates of grade ≥ 2 sensory PN were 13.6 and 13.6% in the study and control hands, respectively (p = 1.0), and those of grade ≥ 2 motor PN were 15.9 and 15.9% in the study and control hands, respectively (p = 1.0). CONCLUSION: Compression therapy using surgical gloves showed no significant effect for the prevention of VIPN. TRIAL REGISTRATION: November 1, 2018, National University Hospital Council of Japan (UMIN 000034145).

Follicular lymphoma with secondary central nervous system relapse: a case report and literature review.

Secondary central nervous system (CNS) relapse by aggressive non-Hodgkin's lymphoma is a well-known complication portending a very poor prognosis. Conversely, patients with indolent lymphoma-like follicular lymphoma (FL) rarely present with CNS involvement and, thus, limited information is currently available. We herein describe a patient with FL who developed CNS involvement during chemotherapy. Treatment including high-dose methotrexate and radiation therapy was ineffective and the patient died 5 months after CNS relapse. In a literature review, there were 8 case reports of the secondary CNS relapse of FL. The findings obtained suggest that bone marrow infiltration is a risk factor for CNS relapse. Moreover, 5 out of 9 patients died within 2.5 years, indicating a poorer prognosis than that of FL. Therefore, it is important to promptly perform detailed examinations as soon as neurological findings appear.

[FIP1L1::PDGFRA-positive chronic eosinophilic leukemia showing slowly progressive cardiac impairment].

This report describes a 69-year-old man with eosinophilia that was detected during a medical check-up. A review of his medical history revealed that his absolute eosinophil count was 990/µl at the age of 55 and increased to 5,380/µl at the age of 69. Electrocardiogram revealed first-degree atrioventricular block at the age of 58, followed by ST-segment depression and a negative T wave at the age of 65. The echocardiogram was normal at the age of 65. We diagnosed him with FIP1L1::PDGFRA-positive chronic eosinophilic leukemia by detecting the FIP1L1::PDGFRA fusion gene by fluorescence in situ hybridization. He had no symptoms at the first visit; however, echocardiography and contrast-enhanced computed tomography revealed an abnormal structure, considered a thrombus, within the left ventricular apex and apex wall thickening. We initiated imatinib (100 mg/day), and the eosinophilia disappeared in a month. However, his cardiac impairment worsened, and he gradually developed symptoms of heart failure. This case is valuable because it shows the long-term course of the disease, with 15 years of laboratory findings until diagnosis. Our findings suggest that in cases of eosinophilia with an abnormal electrocardiogram, contrast-enhanced cardiac magnetic resonance imaging should be considered earlier.

Primary Intramuscular Classic Hodgkin Lymphoma: A Rare Case Report.

Hodgkin lymphoma (HL) is a hematologic malignancy that typically presents with lymphadenopathy. We herein report a patient with HL who presented with an intramuscular mass that required differentiation from an inflammatory lesion. A 65-year-old Japanese woman was referred to our hospital with a chief complaint of chronic and expanding tumor in her left thigh. By surgical resection, she was diagnosed with primary intramuscular, Epstein-Barr virus-positive, mixed-cellularity classic HL. She received combined modality therapy, resulting in a complete response. Primary intramuscular classic HL is extremely rare. It should be listed as a differential diagnosis of intramuscular tumors.

Correction to: Impact of oral voriconazole during chemotherapy for acute myeloid leukemia and myelodysplastic syndrome: a Japanese nationwide retrospective cohort study.

In the original publication, in Figure 1 the month range of DPC Database has been given incorrectly.

Impact of oral voriconazole during chemotherapy for acute myeloid leukemia and myelodysplastic syndrome: a Japanese nationwide retrospective cohort study.

BACKGROUND: The prevention of invasive fungal infections is important in patients with acute myeloid leukemia (AML)/myelodysplastic syndrome (MDS) receiving cytoreductive chemotherapy. However, the role of oral voriconazole (VRCZ) in such patients has not been established. This study aimed to investigate the effectiveness of oral VRCZ compared to that of first-generation azoles prescribed within 7 days after the onset of chemotherapy in adult patients with AML/MDS using the Japanese administrative database. METHODS: This nationwide retrospective cohort study was conducted using the Diagnosis Procedure Combination/Per-Diem Payment System. The primary outcome was the proportion of patients who switched to intravenous antifungal agents. Analyses using the instrumental variable method were performed to address unmeasured confounding. RESULTS: In total, data on 5517 inpatients from 142 hospitals were analyzed. An oral VRCZ prescription was significantly associated with a reduction in the proportion of patients switching to intravenous antifungal agents compared to first-generation azole prescription (21.0% (95% confidence interval [CI] - 33.4 to - 8.6)). The impact of oral VRCZ in reducing the proportion of patients switching to intravenous antifungal agents was stronger in patients aged < 65 years than in those aged ≥ 65 years (- 40.6%, 95% CI - 63.2 to - 17.9; - 21.9%, 95% CI - 35.8 to - 8.1, respectively) and in patients prescribed oral azole within 3 days from the onset of chemotherapy than in those prescribed the same later (- 32.9%, 95% CI - 46.7 to - 19.2; - 9.0%, 95% CI - 33.7 to 15.7, respectively). CONCLUSION: Oral VRCZ administration may benefit adult patients with AML/MDS undergoing chemotherapy.

[Successful Treatment of T-Cell Prolymphocytic Leukemia with Alemtuzumab].

T-cell prolymphocytic leukemia(T-PLL)is a highly aggressive hematopoietic malignancy with poor prognosis and is extremely rare in Japan. Since T-PLL cells usually express high levels of CD52, the anti-CD52 monoclonal antibody alemtuzumab is expected to exhibit an antitumor effect via its antibody-dependent cell cytotoxicity(ADCC)and complement-dependent cytotoxicity(CDC). However, the therapeutic efficiency of alemtuzumab for T-PLL has not been established in Japan. Furthermore, only a few patients have completed the treatment schedule because of adverse events. Here, we report a 64-yearold woman with multiple comorbidities who was successfully treated with alemtuzumab.

Complete Remission in Systemic Skin Interdigitating Dendritic Cell Sarcoma after ABVD Chemotherapy.

Interdigitating dendritic cell sarcoma (IDCS) is a rare and aggressive neoplasm that is thought to arise from dendritic cells. This disease usually involves the lymph nodes and, rarely, extra-nodal sites. We report a 62-year-old man presenting skin nodules in the head, body, and extremities, as well as bone marrow involvement. Morphologic analysis of a biopsied specimen from the skin lesion was consistent with IDCS. Immunohistochemical staining demonstrated that the tumor cells were positive for IDCS-associated antigens such as CD4, CD45, CD68 (KP-1), and S-100 protein. Complete remission was achieved by treatment with 6 cycles of ABVD (adriamycin, bleomycin, vinblastine, and dacarbazine) chemotherapy. Although the optimal treatment of IDSC remains unknown, the experience in the current case supports the notion that ABVD chemotherapy may be effective for IDCS, and further extends this idea to rare patients presenting multiple skin lesions.

[Multiple myeloma recurring as small intestinal polyposis after autologous hematopoietic stem cell transplantation].

A 52-year-old woman was diagnosed with BJP-λ multiple myeloma (MM) in November 2012. She was treated with six cycles of bortezomib and dexamethasone, resulting in a very good partial response. The patient underwent autologous peripheral blood stem cell transplantation (PBSCT) 6 months after the diagnosis, and clearly achieved a complete response thereafter. She again suffered chronic abdominal pain with spontaneous remission 9 months after the PBSCT, and, 2 months thereafter, was hospitalized due to intestinal obstruction. Two small intestinal intussusceptions and polyposis in the small intestine were found on abdominal computed tomography. As conservative treatment produced no improvement, partial resection of the small intestine was performed. The pathologic review clearly demonstrated the polyps to have atypical plasma cell infiltrates in the mucosa of the small intestine involving all layers. Immunohisto-chemistry and FISH analyses yielded positive results for CD138, CD79a, and λ light chain, consistent with extramedullary relapse of MM. It is very rare for MM to present with polyposis in the small intestine. There have been no reports describing such a case after autologous PBSCT.

Prognosis factors in Japanese elderly patients with primary central nervous system lymphoma treated with a nonradiation, intermediate-dose methotrexate-containing regimen.

BACKGROUND: Nearly half of all patients with primary central nervous system lymphoma (PCNSL) are known to be aged over 60 years. However, clinical factors affecting treatment outcomes in elderly patients are understudied. METHODS: We analyzed 38 patients with PCNSL older than 60 years. All patients were treated with a nonradiation, intermediate-dose methotrexate-containing regimen between March 2005 and May 2013 at the University of Tsukuba Hospital. RESULTS: The 3-year overall survival and progression-free survival rates were 56.2% (95% confidence interval (CI) 36.2-76.2%) and 29.8% (95% CI 9-50.6%), respectively, with a median follow-up of 36.5 months. We found that an age > 75 years, a Karnofsky performance score < 70, altered mentation, and a creatinine clearance (CrCl) > 90 ml/min were significant (p < 0.05) factors associated with a worse survival, by univariate analysis. Multivariate analysis revealed that CrCl (p < 0.05; hazard ratio (HR) = 3.39; 95% CI 1.08-10.68) and altered mentation (p < 0.05; HR = 6.27; 95%CI 1.37-28.83) were independent significant association factors. The most frequent adverse event was myelosuppression, with grade 3-4 hematologic toxicities in 28 patients. No delayed neurotoxicities were observed. CONCLUSION: More intensive therapy may be introduced in selected patients with poor prognosis factors to improve outcomes.

Prolonged Survival of a Refractory Acute Myeloid Leukemia Patient after a Third Hematopoietic Stem Cell Transplantation with Umbilical Cord Blood following a Second Relapse.

Although hematopoietic stem cell transplantation (HSCT) has been considered to be the only way for potential cure of relapsed acute myeloid leukemia (AML), there has been no report on a third HSCT in patients with multiple relapsed AML. Here, we report a case of 53-year-old female who received a successful third allogeneic HSCT after relapse of AML following a second allogeneic HSCT. She was treated with a toxicity reduced conditioning regimen and received direct intrabone cord blood transplantation (CBT) using a single unit of 5/6 HLA-matched cord blood as a graft source. Graft-versus-host disease prophylaxis was performed with a single agent of tacrolimus to increase graft-versus-leukemia effect. She is in remission for 8 months since the direct intrabone CBT. This report highlights not only the importance of individually adjusted approach but also the need for further investigation on the role of HSCT as a treatment modality in patients with refractory or multiple relapsed AML.

Glucocorticoid-induced diabetes mellitus in patients with lymphoma treated with CHOP chemotherapy.

PURPOSE: Glucocorticoid-induced diabetes mellitus (GDM) is a major complication arising from corticosteroid administration, but there is lack of studies on GDM attributing to CHOP chemotherapy. We studied the incidence and risk factors for GDM development in patients with lymphoma during CHOP chemotherapy. METHODS: We analyzed 80 patients with lymphoma treated with a CHOP regimen with or without rituximab between 2004 and 2012 at the University of Tsukuba hospital. Patients with a known history of DM were excluded. Diagnosis of DM was performed according to the American Diabetes Association's criteria. RESULTS: Among the 80 patients, 26 (32.5 %) developed GDM. We found that age ≥ 60 years, glycated hemoglobin (HbA1c) levels >6.1 %, body mass index (BMI) >30 kg/m(2), prednisolone administration prior to chemotherapy, history of hypertension or hypertension at admission, and the presence of metabolic syndrome were significant (p ≤ 0.05) factors associated with GDM development by univariate analysis. Multivariate analysis revealed that age ≥ 60 years [p<0.05; hazard ratio (HR)=3.59; 95 % confidence interval (CI), 1.22-10.51], HbA1c levels >6.1 % (p<0.05; HR=9.35; 95%CI, 1.45-60.34), and BMI >30 kg/m(2) (p=0.052; HR=6.27; 95%CI, 0.98-40.00) were independently significant association factors. CONCLUSION: The results suggest a guideline for plasma glucose monitoring during CHOP chemotherapy in patients with no history of DM.

[A case of intravascular large B-cell lymphoma associated with transverse myelopathy].

We present a 68-year-old man suffering from transverse myelopathy since May 2010. The spinal cord MRI showed a T2- hyperintense lesion invading the Th5 level spinal cord. Although the patient transiently responded to steroid-pulse therapy, his neurological symptoms degenerated three months after wards. On admission, he had an apparent hepatosplenomegaly, but no lymphadenopathy. A laboratory examination revealed bicytopenia and increased levels ofLDH and soluble IL-2 receptors. Histological analysis ofa skin biopsy specimen demonstrated proliferation of large atypical lymphoid cells positive for CD20 and CD79a in the small capillaries, leading to our diagnosis of intravascular large B-cell lymphoma(IVLBCL). Thus, the patient's progressive myelopathy was probably caused by IVLBCL invasion. The patient responded well to Rituximab-combined CHOP therapy(R-CHOP), and his neurological symptoms improved immediately. A spinal cord MRI showed the disappearance of the abnormal signal after two courses of R -CHOP. IVLBCL often presents with neurological manifestations, including transverse myelopathy.

Comparison of response to 17 beta-estradiol and 17 beta-trenbolone among three small fish species.

Three small fish species, medaka (Oryzias latipes), fathead minnow (Pimephales promelas), and zebrafish (Danio rerio), were exposed to an estrogen, 17 beta-estradiol (E2), and an androgen, 17 beta-trenbolone (TB), for 21 d under flow-through conditions to compare the susceptibility among these three small fish species to the substances. Effects on gross morphology, including secondary sex characteristics and gonadosomatic index, as well as on blood or liver vitellogenin (VTG) levels were assessed. In E2 exposures, significant increases in estrogenic activity were observed in both sexes of all three fish species. The lowest-observed-effect concentrations (LOECs) of E2 for VTG induction in males of medaka, fathead minnow, and zebrafish were less than or equal to 8.94, 28.6, and 85.9 ng/L, respectively. In TB exposures, we observed masculinization of secondary sex characteristics in females as a result of the androgenic activity of TB in medaka with a LOEC of 365 ng/L and in fathead minnow with a LOEC of 401 ng/ L. We also found VTG reduction in females of all three fish species. These results suggest that the susceptibility of medaka to estrogenic chemicals may be higher than those of fathead minnow and zebrafish and that the susceptibility of medaka to androgenic chemicals may be almost equal to that of fathead minnow in the 21-d fish assay.

Tubulointerstitial nephritis and uveitis syndrome associated with hyperthyroidism.

We report a 17-year-old male patient with tubulointerstitial nephritis and uveitis (TINU) associated with hyperthyroidism. He presented with a 2-month history of fatigue, loss of appetite, low-grade fever, and a 12-kg weight loss when he was admitted to our hospital. He had iritis, which was complicated by fibrin in the anterior chamber, diagnosed by slit-lamp examination. On laboratory examinations, deteriorated renal function (blood urea nitrogen level was 25.9 mg/dl and creatinine level was 2.82 mg/dl) and elevated urinary levels of N-acetyl-beta-D-glucosaminidase (33.1 U/l) and beta2-microglobulin (78,600 microg/l) were observed. Serum thyroid-stimulating hormone (TSH) was undetectable, at less than 0.01 microIU/ml, and free triiodothyronine and free thyroxine were elevated, up to 5.23 pg/ml and 2.85 ng/dl, respectively. The titers of antithyroglobulin and antithyroid microsomal and TSH-receptor antibodies were not elevated. Abdominal and thyroidal ultrasonography showed evident bilateral enlargement of the kidneys and diffuse enlargement of the thyroid gland. Iodine-123 scintigraphy showed low uptake in the thyroid gland. The biopsied renal specimen showed mild edema and severe diffuse infiltration of mononuclear cells and few eosinophils in the interstitium, without any glomerular or vascular abnormalities. Based on the clinical features and pathological findings, a diagnosis of TINU syndrome with associated hyperthyroidism was made. Treatment was started with 30 mg/day of prednisolone. The iritis disappeared, and the patient's clinical status improved remarkably. This case suggests the possibility of thyroid dysfunction in some patients with TINU syndrome, and we believe thyroid function should be measured in all TINU patients. Moreover, histopathological diagnosis of the thyroid glands before treatment is necessary for TINU patients with thyroid dysfunction.

Identification of tenascin-C as a key molecule determining stromal cell-dependent erythropoiesis.

OBJECTIVE: We previously established 33 bone marrow stromal cell lines from SV40 T-antigen transgenic mice. Of these, 27 clones supported erythroid colony formation, while 6 did not. The objective of this study is to identify the molecules that determine these erythroid colony-forming activities. MATERIALS AND METHODS: We compared gene expression profiling by DNA microarray between cell lines that support erythropoiesis (E(+); TBR9, 184, 31-2) and cell lines that do not (E(-); TBR17, 33, 511). Among the differentially expressed genes, we selected candidate genes with results of quantitative reverse transcriptase polymerase chain reaction, and examined the effect of small interfering RNA (siRNA) and the addition of exogenous proteins on the erythroid colony formation. RESULTS: Out of 7226 genes examined, 138 and 282 genes were upregulated and downregulated in E(+) by threefold or more, respectively. We have selected one of the upregulated genes, tenascin-C (TN-C), as a candidate. Expressions of TN-C in E(+) were all higher than the three E-cell lines, with a mean of 3.6-fold. The number of erythroid colonies in the presence of TN-C siRNA was significantly lower than that of control siRNA in TBR9 (20.7 +/- 6.3 vs 4.7 +/- 4.8 colonies; p = 0.01) and in TBR184 (13.3 +/- 5.3 vs 0.3 +/- 0.5; p = 0.02). Moreover, addition of exogenous TN-C enhanced the number of erythroid colonies in TBR184 (13.3 +/- 3.5 vs 20.0 +/- 2.0; p = 0.04) and in TBR31-2 (7.5 +/- 3.1 vs 13.5 +/- 2.6; p = 0.03). CONCLUSION: These results suggest that TN-C is responsible for determining the stromal cell-dependent erythropoiesis.

Fish full life-cycle testing for 17beta-estradiol on medaka (Oryzias latipes).

We studied the chronic effects of 17beta-estradiol (E2) on the reproductive status of medaka (Oryzias latipes) over two generations under continuous exposure to assess its hazard on this species. The exposure of parental (F0) medaka to E2 was begun on embryos within 12 h postfertilization and continued for up to 101 d; the assessment endpoints included embryological development, hatching, posthatch survival, growth, sexual differentiation, reproduction, and hepatic vitellogenin (VTG) levels under flow-through exposure to E2 at each mean measured concentration of 0.939, 2.86, 8.66, 27.9, and 92.4 ng/L. Eggs (F1) spawned from the F0 fish at 98, 99, and 100 d posthatch were also examined for hatchability, survival after hatching, growth, sexual differentiation, and hepatic VTG level until 59 d posthatch. In the F0 medaka, no concentration-related effect of E2 was observed on hatching, posthatch mortality, and growth. However, we observed abnormal sex differentiation, induction of VTG, and reproductive impairment in a dose-dependent manner. The lowest-observed-effect concentration and no-observed-effect concentration of E2 for these effects were 8.66 and 2.86 ng/L, respectively. In the F1 medaka treated with E2 at < or = 8.66 ng/L, however, dose-dependent effects were not observed in any parameter. The results indicate that E2 can have significant effects on reproductive potential of medaka at concentrations as low as 8.66 ng/L, suggesting that the ecological risk of E2 is higher than that of weak estrogens, such as nonylphenol and octylphenol.

Erythropoietin-resistant anaemia in a predialysis patient with Klinefelter syndrome.

A diabetic predialysis patient who had significantly reduced sensitivity to erythropoietin therapy was admitted to Tsukuba University Hospital. Many factors that might have been the cause of the erythropoietin resistance were examined, and a diagnosis of refractory anaemia was made based on a bone marrow aspiration biopsy. A cytogenetic abnormality (47, XXY) was also detected in the bone marrow biopsy specimen, and hence the patient was also diagnosed with Klinefelter syndrome. It was suspected that the sex chromosome abnormality influenced glucose intolerance, renal insufficiency, and erythropoietin resistance due to myelodysplastic changes in the bone marrow.