Autoimmune Hemolytic Anemia Associated with Mature Ovarian Cystic Teratoma Containing Monoclonal Immunoglobulin G: A Case Report and Review of Literature.

Background: Autoimmune hemolytic anemia (AIHA) associated with solid tumors such as mature cystic teratomas is rare and poorly understood. Here, we report a successfully treated case of secondary AIHA in a mature cystic teratoma containing antibodies against red blood cells. Case description. A 22-year-old woman was referred to our hospital with progressive anemia. Laboratory findings revealed hemolysis with a positive direct and indirect antiglobulin test. Imaging studies identified a left ovarian mass, suspected to be a mature cystic teratoma, which was later confirmed by histopathology after laparoscopic oophorocystectomy. The patient was treated with prednisolone, resulting in improved anemia. To examine the relationship between the tumor and AIHA, an indirect antiglobulin test was performed on the tumor contents. Stronger aggregations were observed at any concentration diluted by 10 times from 10 to 10,000 times of the tumor contents compared to the patient's serum. Additionally, immunofixation electrophoresis of the tumor contents revealed the presence of monoclonal immunoglobulin G-κ. Conclusion: The presence of monoclonal IgG-κ in the tumor suggests intratumoral antibody production as a possible mechanism. Further research is necessary to elucidate the pathogenic relationship between such tumors and AIHA. The report also highlights the importance of considering secondary AIHA in patients with unexplained anemia and solid tumors.

Non-nodal mantle cell lymphoma mimicking hairy cell leukemia.

This case of non-nodal mantle cell lymphoma (MCL) showcases atypical hairy cell-like features, distinguishing it via next-generation sequencing. Despite a TP53 mutation indicating poor prognosis, our case followed an indolent course, highlighting the importance of genetic testing and phenotypical examination in MCL.

[Primary myelofibrosis with double mutation in U2AF1].

A 47-year-old woman presented with subcutaneous hemorrhage. Blood tests revealed leukoerythroblastosis, anemia, and thrombocytopenia. Bone marrow biopsy led to a diagnosis of primary myelofibrosis (aaDIPSS, DIPSS-plus: intermediate-II risk). JAK2, CALR, and MPL mutations were not detected in peripheral blood, but targeted sequencing of bone marrow specimens revealed a double mutation (Q157R, S34F) in U2AF1. Allo-PBSCT was performed using an HLA-matched related donor, and post-transplantation bone marrow examination showed complete donor chimerism on day 55. Two years after allogeneic transplantation, the patient remains relapse-free. Although U2AF1 gene abnormality is known as a poor prognostic factor in primary myelofibrosis, this patient had a favorable long-term prognosis due to prompt transplantation therapy. This case highlights the importance of detailed gene mutation analysis in patients with triple-negative MF.

Clinical Utility of Flow Cytometry for Detection of Anti-Jkb IgM in Acute Haemolytic Transfusion Reaction: A Case Report.

Acute hemolytic transfusion reaction (AHTR) is a rare but life-threatening complication of transfusion. We herein report a case of anti-Jkb IgM-related AHTR. Two hours after an 80-year-old man with myelodysplastic syndrome received a packed red blood cell (RBC) A+/Rh-/Jkb+/c- transfusion, he developed acute respiratory failure and a fever. Although he had tested negative in routine screening tests, the 37 °C normal saline test was weakly positive for Jkb. We confirmed the presence of anti-Jkb IgM in the patient's serum by flow cytometry. This case demonstrates the potential utility of flow cytometry for IgM detection.

[Utility of thromboelastography in the treatment of acquired hemophilia A].

Acquired hemophilia A (AHA) is a bleeding disorder caused by the spontaneous development of inhibitory autoantibodies to factor VIII. Thromboelastography (TEG) is a clinical examination that assesses clot formation in the whole blood. However, its utility in the hemostatic management of AHA is unexplored. A 35-year-old man who developed AHA after abdominal surgery was treated for hemostasis with bypassing agents. The TEG R value, which was prolonged as bleeding worsened, was improved by switching to bypassing agents. We report this impressive case, which suggests that TEG can monitor hemostatic effects and is useful for the management of a bypassing agent regimen in addition to its previously acknowledged utility in clinical evaluation.

The experience of flow cytometry for specific antibody against cisplatin-treated red blood cells: A case report.

BACKGROUND: Cisplatin-associated hemolysis is a rare but important adverse effect. Nonimmunological protein adsorption (NIPA) due to erythrocyte membrane modification has been reported as the leading cause of cisplatin-associated hemolysis. However, limited data exist on cisplatin-associated immunological hemolysis because of a lack of an established diagnostic method. Here, we used flow cytometry (FCM) to diagnose a patient with cisplatin-associated immunological hemolysis. STUDY DESIGN AND METHODS: A 55-year-old woman with uterocervical cancer was treated with weekly cisplatin monotherapy (40 mg/m2 ). She had no previous transfusion and medication history, nor any significant family history. On the 26th day after cisplatin administration, severe hemolysis was noted. Her red blood cells (RBCs) and sera were evaluated by direct antiglobulin test (DAT) and indirect antiglobulin test (IAT), respectively. To explore immunological reactions for cisplatin-treated RBCs, we attempted FCM using cisplatin-treated and -untreated RBCs. After incubating conditioned RBCs with the patient's serum or healthy donor serum, we evaluated their fluorescent intensity by fluorescein isothiocyanate (FITC)-conjugated anti-human immunoglobulin (Ig) G antibodies. RESULTS: The patient's DAT was positive, and an IAT using her plasma was positive for cisplatin-treated RBCs. FCM using cisplatin-treated RBCs revealed that the patient's serum had higher FITC intensity than the donor's serum, indicating the existence of cisplatin-treated RBC-specific IgGs in patient's serum. CONCLUSION: Here, we report a rare case of a patient with hemolysis diagnosed using FCM to identify specific antibodies against cisplatin-treated RBCs. NIPA and immunological mechanisms may contribute to hemolysis onset during cisplatin treatment.

Diagnostic utility of lung echography for congestive heart failure performed by junior resident doctors.

Background: Dyspnea is a high priority symptom in the emergency department, with heart failure (HF) as one of its leading causes. Recently, the "comet tail sign (CTS)," a pulmonary ultrasonographic sign, has been proposed as an efficacious tool for detecting pulmonary edema. However, to the best of our knowledge, there have been no published data regarding its utility when performed by non-experts, including junior residents. Methods: Between September 2017 and December 2018, patients with dyspnea, who were admitted to the ER, were enrolled. CTS was evaluated by junior residents at the ER. All patients were evaluated by cardiologists independently, and clinical HF was defined as requiring pharmacological intervention by a cardiologist. At the end of this study, we investigated the results of CTS, laboratory data, and available radiological images. Results: A total of 95 patients were enrolled in the current study, wherein 42 patients were treated by cardiologists as those with clinical HF. Our results showed that CTS could identify clinical HF with a sensitivity of 71.4% and a specificity of 81.1%. The sensitivity of CTS against brain natriuretic peptide (BNP) (cut-off value, 100 pg/ml) was calculated at 92.5%. Furthermore, when evaluated together with peripheral edema, CTS identified clinical HF with a sensitivity of 96%. False positives for CTS included bilateral pneumonia, hypoalbuminemia, and interstitial pneumonitis. Conclusions: Our results indicate that CTS is a simple and effective tool for the use of non-experts, including junior residents.

An experience with ibrutinib monotherapy for Richter's syndrome isolated in the central nervous system.

Richter's syndrome (RS) of the central nervous system (CNS) is known to have an extremely poor prognosis. Ibrutinib has been reported to have some activity in patients with RS, despite its poor prognosis. Although ibrutinib crosses the blood-brain barrier, its efficacy in RS patients with CNS involvement remains unknown. Here, we report a case of RS isolated in the CNS that was confirmed to be clonally related to chronic lymphocytic leukemia (CLL) by immunoglobulin heavy chain gene analysis. Although the median survival of patients with RS clonally related to CLL was significantly shorter than that of patients with RS clonally unrelated to CLL, the patient received ibrutinib monotherapy without experiencing any significant adverse events, and the disease remained stable with ibrutinib until 6 weeks later. Following whole-brain radiation therapy (40 Gy in 20 fractions) with dexamethasone, the patient has survived for five months after diagnosis. Thus, ibrutinib may be a safe and effective therapeutic option for patients with RS and CNS involvement.

A bifurcation concept for B-lymphoid/plasmacytoid dendritic cells with largely fluctuating transcriptome dynamics.

Hematopoiesis was considered a hierarchical stepwise process but was revised to a continuous process following single-cell RNA sequencing. However, the uncertainty or fluctuation of single-cell transcriptome dynamics during differentiation was not considered, and the dendritic cell (DC) pathway in the lymphoid context remains unclear. Here, we identify human B-plasmacytoid DC (pDC) bifurcation as large fluctuating transcriptome dynamics in the putative B/NK progenitor region by dry and wet methods. By converting splicing kinetics into diffusion dynamics in a deep generative model, our original computational methodology reveals strong fluctuation at B/pDC bifurcation in IL-7Rα+ regions, and LFA-1 fluctuates positively in the pDC direction at the bifurcation. These expectancies are validated by the presence of B/pDC progenitors in the IL-7Rα+ fraction and preferential expression of LFA-1 in pDC-biased progenitors with a niche-like culture system. We provide a model of fluctuation-based differentiation, which reconciles continuous and discrete models and is applicable to other developmental systems.

[A hemolytic episode following COVID-19 in a case with atypical hemolytic uremic syndrome].

Atypical hemolytic uremic syndrome (aHUS) is a lethal disease resulting in systemic thrombotic microangiopathies due to complement dysregulation. Immune activation by viral infections, such as SARS-CoV-2, may trigger hemolytic attack. A 38-year-old man, who had been previously diagnosed with aHUS due to complement component 3 mutation, was proven to be positive for SARS-CoV-2 without respiratory symptoms. No specific intervention was given to the patient, and he developed hematuria and oliguria three days after diagnosis. The patient was subsequently referred to our hospital and treated with eculizumab (900 mg). Afterward, the hemolytic symptoms improved rapidly. To the best of our knowledge, there have been reports of at least ten cases of hemolysis triggered by COVID-19 in patients with aHUS, and a potential clinical benefit of eculizumab for hemolytic attack, as well as for COVID-19, has been suggested. Here, we report the findings of a case, which indicate the efficacy of eculizumab introduction at an early stage.

Irbesartan, an angiotensin II type 1 receptor blocker, inhibits colitis-associated tumourigenesis by blocking the MCP-1/CCR2 pathway.

The introduction of anti-inflammatory therapies has enabled substantial improvement of disease activity in patients with inflammatory bowel diseases (IBD). However, IBD can lead to serious complications such as intestinal fibrosis and colorectal cancer. Therefore, novel therapies reducing the development of these complications are needed. Angiotensin II (Ang II) promotes tissue inflammation by stimulating the production of monocyte chemoattractant protein-1 (MCP-1) or proinflammatory cytokines. It plays a pivotal role in IBD progression. Although blockade of Ang II has been reported to ameliorate experimental colitis and reduce colorectal cancer risk, the cellular and molecular mechanisms remain poorly understood. Our previous work showed that irbesartan, an Ang II type 1 receptor blocker, reduced the number of C-C chemokine receptor 2-positive (CCR2+) monocytic cells in the inflamed pancreas. This study aimed to investigate the possible antifibrotic and antitumour effects of irbesartan using the azoxymethane/dextran sodium sulphate mouse model. Irbesartan suppressed MCP-1 production and the accumulation of Ly6C+CCR2+ monocytes and fibrocytes in the inflamed colon, downregulated the expression of type 1 collagen and matrix metalloproteinase 9 and inhibited the development of intestinal fibrosis and tumours. Our observations suggest that blocking the MCP-1/CCR2 pathway using irbesartan might be beneficial in preventing colitis-associated colon tumours.

Voriconazole as a secondary prophylaxis for cryptococcal meningitis during hematopoietic stem cell transplantation.

Antifungal prophylaxis is crucial for successful hematopoietic stem cell transplantation (HSCT). Maintenance therapy with fluconazole (FLCZ) is generally prescribed as secondary prophylaxis in patients with human immunodeficiency virus infection and non-immunocompromised hosts. However, previous reports have revealed that FLCZ is insufficient as a secondary prophylaxis for cryptococcal infection in HSCT cases. There is no well-established evidence of effective secondary prophylaxis against cryptococcal infection in conditions of severe immunosuppression, such as in HSCT. Herein, we report a case of atypical chronic myeloid leukemia (aCML) presenting with cryptococcal meningitis. A 58-year-old man with progressive leukocytosis and headache was referred to our hospital. Bone marrow biopsy revealed aCML. Because the estimated overall survival was limited, HSCT was indicated. Furthermore, enhanced magnetic resonance imaging and lumbar puncture aided in diagnosing cryptococcal meningitis, which was treated with a combination therapy comprising liposomal amphotericin B and 5-fluorocystine for 28 days. Given the high recurrence rate of cryptococcal meningitis, voriconazole (VRCZ) dose was calculated using the trough concentration of VRCZ in the cerebrospinal fluid. Eventually, HSCT was successfully performed at an appropriate therapeutic range of VRCZ. To the best of our knowledge, there is no case report on HSCT with secondary prophylaxis against cryptococcal meningitis. Our report thus emphasizes the efficacy of VRCZ maintenance therapy as secondary prophylaxis for cryptococcal infection.

Sézary Syndrome with CD4/CD8 Double-Negative Neoplastic T Cells in Peripheral Blood.

Sézary syndrome is a rare leukemic type of cutaneous T-cell lymphoma characterized by the presence of neoplastic T cells with cerebriform nuclei (Sézary cells) in the skin, lymph nodes, and peripheral blood. Typical Sézary cells have a CD3+CD4+CD8- phenotype; however, in cases of the aberrant loss of antigens on Sézary cells, especially the loss of critically important T-cell antigens such as CD4, there is a possibility of misdiagnosing the disease or underestimating the tumor burden of the disease. Here, we report a rare case of Sézary syndrome with CD4/CD8 double-negative Sézary cells in the peripheral blood. Most of the Sézary cells in the peripheral blood had lost CD4 expression, and we diagnosed the disease and evaluated the tumor burden by multicolor flow cytometry. Intriguingly, the Sézary cells showed a typical CD4+CD8-CD7- phenotype in the skin even though the cells in the peripheral blood lacked CD4. The patient responded well to treatment with bexarotene and narrow-band ultraviolet B therapy. Analysis by multicolor flow cytometry is essential to diagnose this rare type of Sézary syndrome and evaluate the tumor burden.

A Rare Case of Immunotactoid Glomerulopathy Associated with Hodgkin Lymphoma.

Immunotactoid glomerulopathy (ITG) is characterized by Congo red-negative microtubular deposits, and it has been reported as a rare paraneoplastic syndrome due to hematologic malignancies, viral infections, or autoimmune diseases. In hematologic malignancies, multiple myeloma and other mature B-cell malignancies are the most common hematologic malignancies, and Hodgkin lymphoma (HL) is extremely rare. A 59-year-old woman was admitted to our hospital because of a pulmonary mass and proteinuria. Computed tomography-guided lung biopsy confirmed the presence of HL stage IIA. Immunofixation of peripheral blood was positive for immunoglobulin G (IgG) kappa. Renal biopsy showed mesangial proliferation with deposits in the subendothelial lesion and no invasion of the HL. These deposits were positive for IgG3, C3, and kappa light chain but negative for C1q and lambda light chain. Electron microscopy showed randomly aligned tubular structures with a diameter of approximately 50 nm. We diagnosed the patient with immunotactoid nephropathy and HL. After systemic chemotherapy, the patient achieved a complete response and loss of proteinuria. On the contrary, her serum monoclonal gammopathy was observed after chemotherapy. The existence of a monoclonal antibody itself might not be a sufficient factor for ITG in some cases, and an additive trigger is necessary for development.

[Successful treatment with cyclosporine in a patient with rituximab-refractory thrombocytopenic purpura].

Acquired thrombotic thrombocytopenic purpura (aTTP) is a life-threatening systemic thrombotic microangiopathy characterized by the presence of anti-ADAMTS13 antibodies (inhibitor). Here we report the case of a patient with refractory aTTP successfully treated with cyclosporine. A 69-year-old man presenting with hematuria and petechiae was referred to our hospital; he was disoriented and febrile. Laboratory results revealed Coombs-negative hemolytic anemia, thrombocytopenia, and renal failure. Undetectable ADAMTS13 activity and presence of anti-ADAMTS13 antibodies (inhibitor) confirmed the diagnosis of aTTP. Despite performing plasma exchange and administering prednisolone and rituximab (375 mg/m2), we were unable to restore his platelet counts to the normal level. Therefore, he was treated with cyclophosphamide (500 mg/bodyweight), vincristine (1.4 mg/m2), bortezomib (1.3 mg/m2), and cyclosporine (2.5 mg/kg). After the cyclosporine therapy, his platelet counts gradually normalized. Continuous cyclosporine maintenance therapy led to complete disappearance of the inhibitor. Therapeutic strategies for refractory aTTP have not yet been established. Further investigations are warranted to establish a therapeutic strategy for refractory aTTP.

MPL exon 10 mutations other than canonical MPL W515L/K mutations identified by in-house MPL exon 10 direct sequencing in essential thrombocythemia.

MPL exon 10 mutations are one of the driver mutations in essential thrombocythemia (ET) or myelofibrosis (MF). We have established an in-house MPL mutation analysis system, covering the entire region of MPL exon 10 by direct sequencing. Since 2009, MPL exon 10 mutation analysis has been performed for diagnosis of myeloproliferative neoplasms (MPN) without JAK2 V617F or CALR exon 9 mutations. So far, 11 cases of MPL exon 10 mutation have been found in 51 patients with suspected MPN. In patients with ET, we detected five non-canonical MPL mutations including one novel mutation, MPL R514_P518delinsK, and one canonical MPL W515L mutation. Notably, three ET patients without canonical MPL mutations had thrombotic events. Meanwhile, in primary or secondary MF, only canonical MPL W515L/K mutations were found. Further cases need to be examined to elucidate the full MPL mutation profile in MPN. However, our data indicate that analysis of the whole of MPL exon 10 is warranted for the diagnosis of MPL mutations, especially in ET, and that the use of Japanese commercial laboratory tests that only detect canonical MPL W515L/K mutations may miss a significant percentage of MPL exon 10 mutations, which could delay the administration of anti-thrombotic therapy.

Successful Management of Immune Thrombocytopenia Presenting with Lethal Alveolar Hemorrhage.

Immune thrombocytopenic purpura (ITP) typically presents with bleeding due to immunologic thrombocytopenia. Severe hemorrhage due to ITP is sometimes lethal, and the urgent recovery of platelets is necessary. In addition to conventional therapeutic strategies, romiplostim shows promising efficacy for chronic ITP. However, there is little evidence for the utilization of this treatment for acute ITP or acute exacerbation of chronic ITP. We report the case details of three elderly ITP patients presenting with lethal diffuse alveolar hemorrhage. These patients had the following underlying pulmonary diseases: case 1, nontuberculous mycobacterial infection and sarcoidosis; case 2, cryptogenic organizing pneumonia; case 3, pulmonary emphysema. These patients recovered following treatment with romiplostim at a higher dose (10 µg/kg), in addition to conventional therapies including corticosteroids and high-dose intravenous immunoglobulin. In summary, the addition of romiplostim resulted in earlier recovery of thrombocytopenia than has been previously reported. Our three cases suggest that early romiplostim at a higher dose could be an efficacious therapeutic option for acute ITP patients with severe lethal bleeding.