Epitope Mismatch at HLA-DRB1 Associates with Reduced Relapse Risk in Cord Blood Transplantation for Standard-Risk Hematologic Malignancy.

Cord blood transplantation (CBT) is an attractive therapeutic option for patients with hematologic malignancies. CBT tolerates HLA mismatches between donors and recipients, but the HLA mismatches that generate graft-versus-tumor (GVT) effects remain unknown. Given that HLA molecules contain epitopes comprising polymorphic amino acids that determine their immunogenicity, we investigated associations between epitope-level HLA mismatches and relapse following single-unit CBT. A total of 492 patients with hematologic malignancies who underwent single-unit, T cell-replete CBT were included in this multicenter retrospective study. HLA epitope mismatches (EMs) were quantified using HLA matchmaker software from donor and recipient HLA-A, -B, -C, and -DRB1 allele data. Patients were dichotomized by median EM value and divided into 2 groups: patients who underwent transplantation in complete/partial remission (standard stage: 62.4%) and others (advanced stage: 37.6%). The median number of EMs in the graft-versus-host direction (GVH-EM) was 3 (range, 0 to 16) at HLA class I and 1 (range, 0 to 7) at HLA-DRB1. Higher HLA class I GVH-EM was associated with increased nonrelapse mortality (NRM) in the advanced stage group (adjusted hazard ratio [HR], 2.12; P = .021), with no significant advantage for relapse in either stage. In contrast, higher HLA-DRB1 GVH-EM was associated with better disease-free survival in the standard stage group (adjusted HR, .63; P = .020), which was attributed to lower relapse risk (adjusted HR, .46; P = .014). These associations also were observed even within HLA-DRB1 allele-mismatched transplantations in the standard stage group, indicating that EM might have an impact on relapse risk independent of allele mismatch. High HLA-DRB1 GVH-EM did not increase NRM in either stage. High HLA-DRB1 GVH-EM may lead to potent GVT effects and a favorable prognosis following CBT, especially in patients who underwent transplantation at the standard stage. This approach may facilitate appropriate unit selection and improve the overall prognosis of patients with hematologic malignancies who undergo CBT.

NK-cell post-transplant lymphoproliferative disease successfully treated by second allogenic hematopoietic stem cell transplantation in chronic active Epstein-Barr virus infection.

Chronic active Epstein-Barr virus infection (CAEBV) is a systemic T- or NK-lymphoproliferative disorder (LPD) caused by EBV. Allogenic hematopoietic stem cell transplantation (HSCT) is the only curative therapy for CAEBV, but relapse sometimes occurs. Relapse is generally attributed to proliferation of recipient-derived CAEBV cells. We herein report a case of donor-derived CAEBV-like NK-cell post-transplant lymphoproliferative disease (PTLD) in a 41-year-old female after the first allogenic HSCT for CAEBV from an HLA-matched sibling donor. A second HSCT from an HLA-matched unrelated donor successfully controlled the disease, but EBV infection of cells derived from the second donor continued to be detected. Although the mechanisms underlying CAEBV and CAEBV-like NK-cell PTLD have not yet been elucidated in detail, the findings of the present case imply that host genetic factors, including familial factors, may be important in disease development.

Identification of an asymptomatic Shwachman-Bodian-Diamond syndrome mutation in a patient with acute myeloid leukemia.

Shwachman-Diamond syndrome (SDS) is an autosomal recessive inherited disorder characterized by bone marrow failure, exocrine pancreatic dysfunction, and skeletal abnormalities. SDS is typically caused by a pathogenic mutation in the Shwachman-Bodian-Diamond Syndrome (SBDS) gene. Patients with SDS have an increased risk of developing acute myeloid leukemia (AML) and myelodysplastic syndromes. We identified germline biallelic SBDS mutations (p.K62X and p.I167M) in a 50-year-old AML patient who had never experienced the typical symptoms of SDS. The K62X mutation is one of the most common pathogenic mutations, whereas the significance of the I167M mutation was unclear. Based on cellular experiments, we concluded that the I167M mutation contributed to the development of AML, and chemotherapy including topoisomerase inhibitors, which induce DNA double-strand breaks, may have been toxic to this patient. Our experience indicates that some asymptomatic Shwachman-Bodian-Diamond syndrome mutations contribute to the development of leukemia, and that careful treatment selection may be warranted for patients harboring these mutations.

Acquired hypofibrinogenemia in a patient with multiple myeloma.

We report a case of acquired hypofibrinogenemia with multiple myeloma presenting λ-type IgG monoclonal protein. The patient had anemia and renal deficiency, and also developed bleeding tendency due to severe coagulopathy. Her fibrinogen level was under the detectable limits in a functional assay. Enzyme-linked immunosorbent assay (ELISA) and immunoblotting analysis results were consistent with functional assay results, and deficiency patterns observed in cross-mixing tests for PT and aPTT confirmed the diagnosis of hypofibrinogenemia. To determine the cause of hypofibrinogenemia, we purified the patient's immunoglobulin via protein A agarose, and confirmed that fibrinogen was included in the bound fraction, strongly indicating paraprotein interference with fibrinogen. As accelerated removal of fibrinogen was indicated, we incubated the patient's plasma up to 48 h, but did not observe significant loss of fibrinogen. In sharp contrast, fibrinogen returned to below the detection level 12 h after infusion of fresh frozen plasma. These findings support leukocyte-mediated fibrinogen removal, rather than paraprotein-triggered fibrinogen instability. Surprisingly, the patient's paraprotein was IgG2, but we speculate the amount of paraprotein (IgG 5346 mg/dL) compensated for lower affinity to Fcγ receptors.

Borderline Case of TAFRO Syndrome and POEMS Syndrome.

TAFRO syndrome and POEMS syndrome are lymphoproliferative disorders with elevated interleukin-6 and vascular endothelial growth factor (VEGF) levels; however, their underlying pathogenic mechanisms remain unclear. Similarities have been reported in the pathological findings of the lymph nodes of TAFRO syndrome, Multicentric Castleman disease (MCD), and some cases of POEMS syndrome. However, there is no consensus on the relationship among them. We encountered a case of lymphoproliferative disorder that presented with manifestations of both TAFRO syndrome and POEMS syndrome. This case may be a subtype of idiopathic MCD and will be very important for establishing the disease concept of TAFRO syndrome and POEMS syndrome.

Efficacy of salvage therapy with MTX-HOPE for elderly patients with heavily pretreated non-Hodgkin's lymphoma.

Methotrexate, hydrocortisone, vincristine, sobuzoxane, and etoposide (MTX-HOPE) chemotherapy was originally reported in 2007 as a salvage regimen for relapsed or refractory non-Hodgkin's lymphoma. To clarify the safety and efficacy of this regimen, we retrospectively analyzed patients at our institute. We analyzed 18 patients, including 16 with diffuse large B-cell lymphoma (DLBCL), one with follicular lymphoma (FL), and one with T-cell lymphoma. The median age at MTX-HOPE therapy was 79 (range: 68-87). Ten patients received more than 3 previous chemotherapy regimens. The median period from the initial treatment to the first MTX-HOPE administration was 53 months. No patient had severe renal dysfunction. The overall response rate was 78%, with 39% achieving CR and 39% achieving PR. The median OS and PFS after the initiation of MTX-HOPE were 10 months (range: 0.5-86 months) and 7 months (range: 0.2-86 months), respectively. The one-year OS rate was 44% and the two-year OS rate was 22%. The median number of treatment cycles was 7 (range: 1-46), and 6 patients received more than 10 cycles. Among eight patients who were over 80 years of age, 7 responded to the therapy, and the median OS and PFS of this subgroup were 19 months and 11 months, respectively. All patients tolerated the treatment well, mostly on an outpatient basis, except for one who died from infection and one who developed intracranial hemorrhage. MTX-HOPE may be a promising treatment option for elderly patients with refractory or relapsed malignant lymphoma.

[MYC gene amplification attributed to double minutes in a patient with atypical chronic myeloid leukemia].

A 61-year-old man was admitted to our hospital with fever and massive leukocytosis. A bone marrow smear revealed an increased density of myeloid cells in various stages of maturation as well as dysplasia in the neutrophils. There was no proliferation of blasts, eosinophils, or basophils. Genomic analysis of the bone marrow cells revealed no detectable abnormalities associated with myeloproliferative neoplasms, including BCR-ABL1. Therefore, the patient was diagnosed with atypical chronic myeloid leukemia (aCML). Chromosomal analysis revealed the presence of 1-17 double minute chromosomes (dmin) in 20 of 20 tumor cells examined. Multiple MYC signals were detected via interphase fluorescence in situ hybridization, indicating MYC gene amplification in the dmins. Three months after the oral administration of hydroxyurea, leukocytosis reoccurred. Therefore, induction therapy followed with umbilical cord blood transplantation was performed. However, MYC signals remained detectable in the bone marrow sample obtained immediately after neutrophil engraftment, indicating the presence of residual tumor cells. To the best of our knowledge, this is the first case report of aCML with dmin gene amplification, suggesting that the dmin MYC amplification exacerbated the patient's disease.

[Essential thrombocythemia correctly diagnosed through the guidance of comprehensive genomic profiling].

In 2003, a 60-year-old man presenting with thrombocytosis was referred to our hospital. Laboratory tests revealed normal white blood cell count and hemoglobin level. Bone marrow examination showed an increased number of megakaryocytes with dysplasia. G-banded karyotype analysis revealed del (5q). Initially, the patient was diagnosed with myelodysplastic/myeloproliferative neoplasm (MDS/MPN), and it was treated with aspirin and hydroxyurea. During the treatment course, fluorescence in situ hybridization for CSF1R and EGR1 was performed to detect del (5q), which showed negative results. In 2017, the patient had increased platelet count despite receiving treatment. A comprehensive genomic profiling revealed that the deleted region in this case was present in 5q14-5q23, which was different from the common deleted region of 5q- syndrome (5q32-5q33, where CSF1R was present) and that of high-risk MDS or acute myeloid leukemia (5q31, where EGR1 was present). Moreover, a CALR mutation was also detected. This case met the diagnostic criteria of essential thrombocythemia. The platelet count decreased with the administration of anagrelide. In conclusion, comprehensive genetic profiling is very important, and it leads to accurate diagnosis and therapy.

Enantiomeric differentiation by synthetic helical polymers.

Recent advances in the synthesis of helical polymers and their applications as chiral materials, in particular chiral stationary phases (CSPs), for high-performance liquid chromatography (HPLC) are reviewed with an emphasis on the key role of the helical conformations with one-handedness for the prominent chiral recognition of enantiomers. The historical background of artificial optically active helical polymers is also briefly described.

Streamer discharge reduces pollen-induced inflammatory responses and injury in human airway epithelial cells.

Although epidemiological studies have demonstrated that cedar pollen influences respiratory health, effective method for inactivating cedar pollen has not been established. Streamer discharge is a type of plasma discharge in which high-speed electrons collide with oxygen and nitrogen molecules. It reportedly has the ability to eliminate bacteria, mould, chemical substances and allergens. The present study investigated the influence of pollen on BEAS-2B cell line, derived from human airway epithelial cells, as well as the efficiency of streamer discharge on pollen-induced health effects. Airway epithelial cells were exposed to non-treated pollen and streamer-discharged pollen at doses of 100 and 1000 µg/mL for 6 or 24 h. Non-treated pollen at a dose of 1000 µg/mL significantly decreased cell viability and induced both mRNA and protein expression of interleukin-6, whereas streamer-discharged pollen showed the attenuated changes as compared with non-treated pollen. Further, scanning electron micrographs showed that streamer discharge caused the fine structural changes of pollen. These results provide the first experimental evidence that pollen at a high dose affects cell viability and inflammatory responses, and streamer discharge technology attenuates their influences by decomposing pollen.

Usefulness of balloon angioplasty for the right ventricle-pulmonary artery shunt with the modified Norwood procedure.

OBJECTIVE: We sought to evaluate the efficacy of balloon angioplasty (BA) for severely desaturated patients due to a stenotic right ventricle (RV) to pulmonary artery (PA) shunt following modified Norwood procedure. METHODS: Of 87 patients who underwent a Norwood procedure with the RV-PA shunt between February 1998 through March 2010, 22 (25%) patients underwent BA. The efficacy of BA was assessed by angiographic measurement of the changes in the internal diameters of the stenotic portions of the shunt, changes in arterial saturation and clinical outcomes. RESULTS: BA was performed for stenotic RV-PA shunts following stage I palliation (n = 17, 77%), or those placed as an additional blood source (n = 5, 23%, 3 patients awaiting biventricular repair, 2 patients following stage II palliation). The location of the BA was at the distal anastomosis in 12 (54.5%), proximal anastomosis in 21 (95.4%) and in the mid-portion of the shunt in 11 (50%) cases. The diameters of these three shunt portions were measured from the anterior-posterior and lateral angiographic images, increasing significantly after BA (p < 0.0001) in all. Arterial saturation significantly improved after BA in all cases (66.5 ± 4.3% to 79.4 ± 3.4%, p < 0.0001). Freedom from reintervention was 100%. All patients underwent subsequent elective planned surgery at an appropriate age with no mortality. CONCLUSIONS: A BA-alone strategy for a stenotic RV-PA shunt was effective for all three shunt portions, minimizing shunt-related premature surgical intervention.

[Successful testicular sperm extraction in a non-obstructive azoospermic man with severe testicular microlithiasis : a case report].

A 45-year-old man was referred to our hospital for treatment of azoospermia. On physical examination, right testicular volume was 2 ml, left testicular volume was 3 ml, and pubic Tanner stage was 5. Scrotal ultrasonography revealed a high echoic lesion with acoustic shadowing at surfaces of bilateral testes. Semen analysis showed azoospermia and serum follicle stimulating hormone value was high (28.42 mIU/ml). He was diagnosed with non-obstructive azoospermia, and underwent microdissection testicular sperm extraction. Both testes were filled with shiny granular materials. In excised tissue of the testes, seminiferous tubules containing spermatozoa were found and motile spermatozoa were successfully retrieved. The histological examination revealed many small calcifications which had laminated structure. Spermatogenesis was slightly impaired, and Johnsen's score count was 9. Testicular microlithiasis has been reported to be an infrequent condition associated with conditions such as testicular tumors and testicular dysgenesis syndrome. Such a severe testicular microlithiasis has not been reported previously.

Application of real-time three-dimensional transesophageal echocardiography using a matrix array probe for transcatheter closure of atrial septal defect.

BACKGROUND: The aim of this study was to demonstrate the utility of real-time three-dimensional (3D) transesophageal echocardiography (RT3D-TEE) using a matrix array 3D transesophageal echocardiographic probe for morphologic evaluation and guidance of transcatheter closure of atrial septal defects (ASDs). METHODS: Forty-eight consecutive patients scheduled for the intervention were included. Two-dimensional (2D) transesophageal echocardiography (2D-TEE) and RT3D-TEE were performed before and during the procedures. Measurements of maximal ASD diameter and surrounding rims obtained on RT3D-TEE were compared with those obtained on 2D-TEE. RESULTS: In 46 patients (96%), optimal 3D images for the morphologic evaluation of ASDs were obtained. RT3D-TEE facilitated the evaluation of ASD morphology and surrounding rims and was able to provide intraprocedural information clearly. A Bland-Altman plot showed a mean maximal diameter difference of -0.12 mm between the means (95% limits of agreement, -2.2 to 2.5 mm). CONCLUSION: RT3D-TEE is a clinically useful, complementary option to 2D-TEE for evaluation of ASD morphology and for interventional guidance.

Preoperative management for tricuspid regurgitation in hypoplastic left heart syndrome.

BACKGROUND: Tricuspid regurgitation (TR) is an important finding in hypoplastic left heart syndrome (HLHS). The aim of the present study was to investigate changes in the degree of TR after the preoperative management of HLHS with mechanical ventilation, and whether the improvement of TR under preoperative management would affect the short-term prognosis of Norwood operation. METHODS: Clinical and echocardiographic data of 55 patients with HLHS who underwent preoperative echocardiography and management at Department of Pediatrics, Okayama University Graduate School of Medicine and Dentistry, were retrospectively reviewed. Preoperative management with mechanical ventilation was performed in 31 of these patients. Based on echocardiography the 55 patients were divided into a trivial-mild TR group (group A) and a moderate-severe TR group (group B). RESULTS: After preoperative management, TR improved in six of the 31 patients and was unchanged in 25; in five of the nine group B patients, TR before management improved to the level of group A after management. In-hospital deaths after surgery included 17 of the 48 patients in group A and five of the six in group B, but there was only one death in the five patients for whom TR improved from group B to group A level. CONCLUSION: Preoperative management of HLHS resulted in an improvement in the degree of TR. The short-term prognosis was better for the patients in group A than those in group B, and so preoperative management is useful for HLHS patients, especially those with moderate or severe TR at admission, with the exception of severe dysplasia of tricuspid valve.

Relationship between substances in seminal plasma and Acrobeads Test results.

OBJECTIVE: To asses the effects of seminal plasma on sperm function. DESIGN: Retrospective case-control study. SETTING: University hospital. PATIENT(S): One hundred fourteen infertile men. INTERVENTION(S): Acrobeads Test scores (0-4) and measurement of interleukin (IL)-6, soluble IL-6 receptor, epidermal growth factor, insulin-like growth factor-I (IGF-I), transforming growth factor-beta I, superoxide dismutase, calcitonin, and macrophage migration inhibitory factor (MIF) levels in seminal plasma. MAIN OUTCOME MEASURE(S): Kruskal-Wallis test to compare the concentrations of substances as a nonparametric test for differences among Acrobeads Test scores and a multivariable logistic regression model to find independent risk factors associated with abnormal Acrobeads Test results. RESULT(S): The Acrobeads Test score was 0 for 7 samples, 1 for 20 samples, 2 for 18 samples, 3 for 28 samples, and 4 for 41 samples. Age, abstinence period, and semen parameters, except for sperm motility and percentage of sperm with abnormal morphology, had no effect on the Acrobeads Test results. Concentrations of IGF-I and MIF were significantly higher in patients with abnormal Acrobeads Test results. Multivariate analysis indicated that MIF and IGF-I were significantly associated with abnormal Acrobeads Test results (scores 0 to 1). CONCLUSION(S): Although further studies are needed, IGF-I and MIF in seminal plasma may have negative effects on sperm function.

Androgen decline in patients with nonobstructive azoospemia after microdissection testicular sperm extraction.

OBJECTIVES: Microdissection testicular sperm extraction (TESE) is the ideal procedure for obtaining a high sperm retrieval rate. However, few studies of the postoperative endocrinologic course have been reported. We evaluated the endocrinologic course for 1 year after microdissection TESE and compared the results with the testicular histologic findings. METHODS: A total of 69 patients with nonobstructive azoospermia who had undergone microdissection TESE were included. The overall sperm retrieval rate was 50.7%. The endocrinologic data were evaluated before and 3, 6, and 12 months after surgery. RESULTS: The mean serum total testosterone level in patients with hypospermatogenesis decreased postoperatively and had recovered by 12 months (102%). The mean serum total testosterone level in patients with Klinefelter syndrome also decreased postoperatively but had recovered to only 50% of the baseline value at 12 months after microdissection TESE. At 12 months, the mean serum total testosterone level in patients with maturation arrest was 93.1% of the preoperative level and that in patients with Sertoli cell-only syndrome was 80.6% of the preoperative level. The preoperative serum luteinizing hormone and follicle-stimulating hormone in patients with Klinefelter syndrome was high and remained high after microdissection TESE. The mean serum luteinizing hormone and follicle-stimulating hormone levels in patients with hypospermatogenesis did not change, and those in patients with maturation arrest increased continuously after microdissection TESE. Finally, those in patients with Sertoli cell-only syndrome increased up to 6 months after surgery and decreased after that. CONCLUSIONS: The results of our study indicate that long-term endocrinologic follow-up is necessary after microdissection TESE, particularly for patients with Klinefelter syndrome to detect hypogonadism.

Coil embolization of a patent ductus venosus in a 52-day-old girl with congenital heart disease.

We present the case of 52-day-old girl with a common atrioventricular canal. Severe liver dysfunction persisted following complete repair of the cardiac defect. A patent ductus venosus appeared to be the source of the hemodynamic disturbance responsible for hepatic dysfunction. Given her critical condition, coil embolization of the ductus venosus was performed, after which the patient improved rapidly. The ductus venosus should be tested for patency when liver dysfunction persists after the corrective cardiac surgery, and coil embolization is the treatment of choice in gravely ill children.