Autoimmune-mediated thrombocytopenia after allogeneic hematopoietic stem cell transplantation: significance of detecting reticulated platelets and glycoprotein-specific platelet autoantibodies.

Autoimmune hematological disorders are rare complications after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Diagnosis of immune thrombocytopenia (ITP) is challenging, especially after allo-HSCT, because various complications such as graft-versus-host disease, disease relapse, viral infection, thrombotic microangiopathy, and drug side effects can also cause thrombocytopenia. Assessment of reticulated platelets (RP) and plasma thrombopoietin (TPO) levels may be useful to distinguish between ITP and hypoplastic thrombocytopenia. ITP is generally characterized by an increased percentage of RP, and a normal or slightly increased plasma TPO level. We now report three cases of thrombocytopenia after allo-HSCT. RP% was elevated in these patients, as it is in primary ITP. However, in contrast to primary ITP, plasma TPO levels were high in two of three patients. Anti-αIIbß3 and anti-GPIb/IX-specific direct IgG antibodies were detected as well, suggesting occurrence of immune-mediated platelet destruction in addition to bone marrow suppression in two patients. All three patients were successfully treated with corticosteroids and/or thrombopoietin receptor agonists (TPO-RAs). These results suggest that increased RP% and detection of glycoprotein-specific platelet autoantibodies are useful for the diagnosis of ITP after HSCT.

Different Immune Reconstitution between Cord Blood and Unrelated Bone Marrow Transplantation with Relation to Chronic Graft-versus-Host Disease.

Background: Advances of allogeneic hematopoietic cell transplantation (allo-HCT) have brought long-term survival to the patients with hematologic malignancies. Chronic graft-versus-host disease (GVHD) is one of major problems for the long- term survivors after allo-HCT. Dysregulation of immune reconstitution has been reported to be involved in the pathogenesis of chronic GVHD. Differences of immune reconstitution between cord blood transplantation (CBT) and unrelated bone marrow transplantation (UBMT) remain unclear in long-term survivors. We investigated immune reconstitution in patients surviving for more than 2 years after CBT (n=21) or UBMT (n=20) without relapse of underlying disease. Materials and Methods: Using flow cytometric analysis of peripheral blood, we investigated immune reconstitution of T cells, B cells, and NK cells between CBT and UBMT patients. We collected clinical data regarding allo-HCT and examined the relation of immune reconstitution to the development of chronic GVHD. Results: Between CBT and UBMT patients, we found significant differences in absolute cell number of CD8+ as well as CD19+ cell and CD4/CD8 ratio even more than 2 years after allo-HCT. Among UBMT patients, absolute cell number of naive CD4+ cell was significantly lower in patients with chronic GVHD. In addition, we found significant differences in absolute cell number of CD19+ cell, especially naive B cell between patients with and without chronic GVHD in both CBT and UBMT patients. Conclusion: These results suggest that differences of immune recovery between CBT and UBMT patients may exist even in patients surviving for more than 2 years and might be related to the development of chronic GVHD.

Successful treatment strategy in corporating mogamulizumab and cord blood transplantation in aggressive adult T-cell leukemia-lymphoma: a case report.

Adult T-cell leukemia-lymphoma (ATL) is a rare type of mature T cell lymphoma caused by human T-lymphotropic virus type 1 (HTLV-1) with dismal outcome with conventional chemotherapy. A humanized anti-CC chemokine receptor 4 (CCR4) monoclonal antibody, mogamulizumab (MOG), has been shown to be effective for CCR4-positive ATL. However, MOG administration before allogeneic hematopoietic stem cell transplantation (allo-HSCT) was reported to be associated with an increased risk of severe acute graft-versus-host disease (aGVHD) after allo-HSCT due to reduction of donor-derived regulatory T cells (Tregs). We herein present a patient with ATL who underwent allo-HSCT after MOG administration without developing severe GVHD while referring to serum MOG concentration. The clinical course of our case suggests that it might be possible to determine the appropriate timing of allo-HSCT with monitoring of residual MOG level while avoiding the detrimental effect of MOG on post-transplant clinical outcome without increasing the risk of relapse/progression.

GVHD prophylaxis by tacrolimus and mini-MTX in single-unit CBT: a single institute experience.

Tacrolimus (TAC) combined with short-term methotrexate (MTX) is widely used to prevent graft-versus-host disease (GVHD) in cord blood transplantation (CBT). As short-term MTX aggravates mucositis and delays engraftment, we reduced the dose of MTX, as previously reported in the non-CBT setting. Here, we retrospectively analyze outcomes of 20 patients who received CBT from April 2017 to December 2018. All patients received TAC with mini-MTX as GVHD prophylaxis. Mini-MTX was administered at a dose of 5 mg/m2 of MTX on days 1, 3 and 6 after CBT. Median age was 54.5 years. Median follow-up time in surviving patients was 396 days. The primary disease was acute leukemia (n = 12) or malignant lymphoma (n = 8). Three patients and 17 patients received myeloablative and reduced-intensity conditioning, respectively. Rate and median time to engraftment of neutrophils were 90.0% and 20.5 days, respectively. Cumulative incidences of grade II-IV and grade III-IV acute GVHD were 35.0% and 5.0%, respectively. At one year after CBT, the overall survival rate was 80.5%, cumulative incidence of relapse/progression was 15.0%, and non-relapse mortality rate was 5.0%. In conclusion, TAC with mini-MTX may be a promising GVHD prophylaxis regimen in single-unit CBT.

High Titer of Acquired Factor V Inhibitor Presenting with a Pseudo-deficiency of Multiple Coagulation Factors.

Acquired coagulation factor inhibitor is a rare coagulation disorder. We herein report a patient with acquired factor V inhibitor showing a decrease in multiple coagulation factor activities. A high titer of factor V inhibitor presumably led to a marked inhibition of factor V activity in the specific factor-deficient plasma used in coagulation factor activity assays based on either an activated partial thromboplastin time (APTT) or prothrombin time (PT) clotting assay, resulting in false low values of the coagulation activity. We re-examined the coagulation factor activity using several dilutions of the patient's plasma and confirmed that the high factor V inhibitor titer had caused an apparent decrease in multiple coagulation factor activities.

Acute compartment syndrome as the initial manifestation of chronic-phase chronic myeloid leukemia: a case report and review of the literature.

BACKGROUND: Acute compartment syndrome is an orthopedic emergency requiring urgent fasciotomy to prevent irreversible damage. In hematological malignancies, acute compartment syndrome caused by severe soft tissue bleeding is extremely rare. We present a patient with chronic-phase chronic myeloid leukemia who had acute compartment syndrome caused by severe soft tissue bleeding in her right forearm. CASE PRESENTATION: A 72-year-old Japanese woman was referred to our hospital with swelling and pain of her right forearm without a previous history of trauma. She was diagnosed with chronic-phase chronic myeloid leukemia. Extreme thrombocytosis was present, although no evidence of acquired von Willebrand disorder was found. Compartment syndrome caused by soft tissue bleeding was confirmed. An emergency fasciotomy for decompression was conducted. However, sustained postoperative bleeding occurred and required massive red cell concentrate transfusion. As her platelet count decreased by cytoreductive therapy, complete hemostasis was achieved. CONCLUSIONS: Patients with an extremely high platelet count might be at high risk for severe bleeding complications even without acquired von Willebrand disease. For the control of severe bleeding complications in patients with myeloproliferative disorder, the importance of thrombocyte reduction should be recognized.

Lenalidomide and Dexamethasone for a Patient of POEMS Syndrome Presenting with Massive Ascites.

POEMS syndrome is a multisystem disorder characterized by polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes. POEMS syndrome is a rare cause of refractory ascites. We report the case of a patient with POEMS syndrome presenting with massive ascites who was treated with very-low-dose lenalidomide and dexamethasone. A 57-year-old Japanese man was admitted to our hospital with pleural effusion, massive ascites, and leg edema. The diagnosis of POEMS syndrome was made based on the combination of the following findings: peripheral neuropathy, organomegaly, endocrinopathy, serum monoclonal protein elevation, skin changes, plasma VEGF elevation, and evidence of extravascular volume overload. Renal dysfunction induced by biopsy-proven renal involvement of POEMS syndrome was observed. Massive ascites of the patient dramatically diminished with long-time treatment of very-low-dose lenalidomide and dexamethasone. Lenalidomide seems to be a very promising therapy for POEMS syndrome presenting with extravascular volume overload such as edema, pleural effusion, and ascites. Very-low-dose lenalidomide might be effective especially for the patients with POEMS-related nephropathy.

Cognitive process modelling of controllers in en route air traffic control.

In recent years, various efforts have been made in air traffic control (ATC) to maintain traffic safety and efficiency in the face of increasing air traffic demands. ATC is a complex process that depends to a large degree on human capabilities, and so understanding how controllers carry out their tasks is an important issue in the design and development of ATC systems. In particular, the human factor is considered to be a serious problem in ATC safety and has been identified as a causal factor in both major and minor incidents. There is, therefore, a need to analyse the mechanisms by which errors occur due to complex factors and to develop systems that can deal with these errors. From the cognitive process perspective, it is essential that system developers have an understanding of the more complex working processes that involve the cooperative work of multiple controllers. Distributed cognition is a methodological framework for analysing cognitive processes that span multiple actors mediated by technology. In this research, we attempt to analyse and model interactions that take place in en route ATC systems based on distributed cognition. We examine the functional problems in an ATC system from a human factors perspective, and conclude by identifying certain measures by which to address these problems. This research focuses on the analysis of air traffic controllers' tasks for en route ATC and modelling controllers' cognitive processes. PRACTITIONER SUMMARY: This research focuses on an experimental study to gain a better understanding of controllers' cognitive processes in air traffic control. We conducted ethnographic observations and then analysed the data to develop a model of controllers' cognitive process. This analysis revealed that strategic routines are applicable to decision making.

Influence of viral load and genotype in the progression of Hepatitis B-associated liver cirrhosis to hepatocellular carcinoma.

AIM/BACKGROUND: Hepatitis B virus (HBV) is an important factor in the development of hepatocellular carcinoma (HCC). We studied the influence of HBV viral load on HCC occurrence in HBV related liver cirrhosis (LC). PATIENTS AND METHODS: Ninety-one LC patients were followed up over a period of 7 years. Twenty three patients received Interferon (IFN) therapy. RESULTS: In 7 years, 23 patients developed HCC. Of them twenty-two (95.6%) were of genotype C. HBV DNA was found to be the only significant variable associated with HCC occurrence on both univariate (P = 0.029) and multivariate analysis (odds ratio 2.33; P < 0.033). The cumulative survival at 5 years was 83% and the annual rate of hepatitis B surface antigen clearance was 0.9 %. All of 17 HCC patients observed over a period of 5 years or more belonged to the continuously high HBV DNA group (annual average >3.7 log copies/ml) and all but one belonged to the continuously high alanine aminotransferase group (annual average >40 IU/l). CONCLUSION: Patients with genotype C and a continuously high HBV DNA for 5 years or more are at a high-risk group for HCC development. Maintaining continuously low HBV DNA for 3 years or more with anti-viral therapy, may be useful in preventing or delaying HCC occurrence.

A liquid-Ga-filled carbon nanotube: a miniaturized temperature sensor and electrical switch.

Temperature control on the nanometer scale is a challenging task in many physical, chemical, and material science applications where small experimental volumes with high temperature gradients are used. The crucial difficulty is reducing the size of temperature sensors while keeping their sensitivity, working temperature range, and, most importantly, their simplicity and accuracy of temperature reading. In this work, we demonstrate the ultimate miniaturization of the classic thermometer using an expanding column of liquid gallium inside a multi-walled C nanotube for precise temperature measurements. We report that electrical conductivity through unfilled nanotube regions is diffusive with a resistance per unit length of approximately 10 kOmega microm(-1), whereas Ga-filled segments of the nanotube show metallic behavior with a low resistance of approximately 100 Omega microm(-1). No noticeable Schottky barrier exists between the nanotube carbon shell and the inner Ga filling. Based on these findings, an individual carbon nanotube partially filled with liquid Ga is used as a temperature sensor and/or switch. The nanotube's electrical resistance decreases linearly with increasing temperature as the metallic Ga column expands inside the tube channel. In addition, the tube resistance drops sharply when two encapsulated Ga columns approaching each other meet inside the nanotube, producing a switching action that can occur at any predetermined temperature, as the Ga column position inside the nanotube can be effectively pre-adjusted by nanoindentation using an atomic force microscope.

Immunohistochemical evaluation of oxidative stress markers in chronic hepatitis C.

Oxidative stress (OS) plays a major role in chronic hepatitis C. Various OS markers have been found to be elevated in hepatitis C virus (HCV)-related liver disease. This study detected the presence of OS in serum and liver biopsy specimens of HCV patients. Reactive oxygen molecules (ROM) in sera of 54 HCV patients were compared with 23 controls. OS markers 8-hydroxydeoxyguanosine (8-OHdG), 4-hydroxy-2-nonenal, malondialdehyde, and thioredoxin were measured in liver biopsy specimens of 18 HCV patients with fibrosis staging F1 (six); F2 (two), F3 (four), and F4 (six). The interferon (IFN) response and hepatocellular carcinoma (HCC) occurrence in the presence of OS markers were also evaluated. The level of ROM in HCV patients was 318 +/- 56.7 Carr compared with 248 +/- 40.8 Carr in controls (p=0.032). Multivariate analysis found age (p=0.0236) to be the only independent variable associated with increase in ROM in sera. In liver biopsy specimens, OS markers were found mainly around the area of piecemeal necrosis or the periportal area. The presence of OS markers seemed to increase with fibrosis staging, although not significantly. The OS DNA damage marker 8-OHdG was detected in the nucleus of hepatocytes. Thirteen patients received IFN therapy. During the 4-year follow-up period, HCC developed in four nonresponders to IFN and in one untreated patient. OS markers were stained in both HCC cells and non-HCC cells in HCC patients. OS markers were found in serum and liver specimens of HCV-associated liver disease and in HCC tissue. Detection of OS markers may be important for monitoring disease progression in HCV patients. Antioxidant therapy in combination with antiviral therapy may minimize liver damage and aid in the prevention and subsequent development of HCC.

Long term follow-up of a group of chronic hepatitis C patients treated with anti-inflammatory drugs following initial interferon therapy.

BACKGROUND: A relationship between hepatocellular carcinoma (HCC) recurrence and serum alanine aminotransferase (ALT) in a group of hepatectomized patients has been reported. Another study suggested the development of HCC is more rapid in a high ALT group of hepatitis C virus (HCV)-associated cirrhotic patients. To find a relationship between ALT and HCC occurrence, we observed changes in ALT over a period of 6 years, in a group of non-cirrhotic, chronic hepatitis C (CHC) patients treated with anti-inflammatory drugs post interferon (IFN) therapy. METHOD: Eighty three CHC patients, with fibrosis stage 1, 2, 3 (F1, F2, F3) who had a partial (PR) or non-response (NR) to initial IFN therapy, were treated with anti-inflammatory drugs for 6 years. Over a period of 6 years HCC developed in nine patients. Of them, one belonged to F2 and eight to F3. Within the first 2 years HCC developed among two patients in F3. Multivariate analysis revealed that in F3, the 6 year average ALT activity (odds ratio 5.59; P<0.05) was the only significant variable associated with HCC occurrence. All other variables remained insignificant. Among the six F3 patients in whom HCC developed, the likelihood of HCC occurrence was found to be significantly higher (odds ratio 1.89; P<0.001) in patients who showed elevated ALT activity (>80 IU) two or more times during the 6 year period, compared to those with ALT (>80 IU) for less than 2 years. CONCLUSION: These findings suggest that continuous elevation of ALT seems to be important for HCC diagnosis. Patients with ALT >==80 IU for 2 years or more are at a greater risk of HCC development. It is necessary to continue treatment with anti-inflammatory drugs, following initial IFN therapy to suppress ALT below 80 IU, to prevent HCC occurrence or delay the time of HCC occurrence in order to prolong life.