Cancer-related thrombotic microangiopathy and disseminated intravascular coagulation in a patient with bone marrow carcinomatosis of unknown primary origin: A case report.

BACKGROUND: Cancer-related thrombotic microangiopathy (CR-TMA) is a rare type of Coombs-negative hemolytic anemia, which is caused by malignancy and has a poor prognosis. CASE: A 76-year-old female was referred to our hospital due to Coombs-negative hemolytic anemia, which was causing fatigue and dyspnea on exertion, accompanied by schistocytosis. A bone marrow examination demonstrated bone marrow carcinomatosis, and the tumor cells were morphologically suspected to be signet-ring cell carcinoma cells. As we failed to find the primary tumor site before the patient died, she was diagnosed with CR-TMA due to bone marrow carcinomatosis of unknown primary origin. Thrombotic thrombocytopenic purpura (TTP) was rapidly ruled out based on her PLASMIC score. In addition, immunohistochemical staining of a clot section of the bone marrow and tumor marker data were useful for narrowing down the likely primary tumor site. CONCLUSION: Although CR-TMA is an extremely rare phenomenon, clinicians who suspect CR-TMA should quickly rule out TTP and decide whether to provide appropriate chemotherapy or plan for palliative care.

Vulnerability to APOBEC3G linked to the pathogenicity of deltaretroviruses.

Human retroviruses are derived from simian ones through cross-species transmission. These retroviruses are associated with little pathogenicity in their natural hosts, but in humans, HIV causes AIDS, and human T-cell leukemia virus type 1 (HTLV-1) induces adult T-cell leukemia-lymphoma (ATL). We analyzed the proviral sequences of HTLV-1, HTLV-2, and simian T-cell leukemia virus type 1 (STLV-1) from Japanese macaques (Macaca fuscata) and found that APOBEC3G (A3G) frequently generates G-to-A mutations in the HTLV-1 provirus, whereas such mutations are rare in the HTLV-2 and STLV-1 proviruses. Therefore, we investigated the mechanism of how HTLV-2 is resistant to human A3G (hA3G). HTLV-1, HTLV-2, and STLV-1 encode the so-called antisense proteins, HTLV-1 bZIP factor (HBZ), Antisense protein of HTLV-2 (APH-2), and STLV-1 bZIP factor (SBZ), respectively. APH-2 efficiently inhibits the deaminase activity of both hA3G and simian A3G (sA3G). HBZ and SBZ strongly suppress sA3G activity but only weakly inhibit hA3G, suggesting that HTLV-1 is incompletely adapted to humans. Unexpectedly, hA3G augments the activation of the transforming growth factor (TGF)-ß/Smad pathway by HBZ, and this activation is associated with ATL cell proliferation by up-regulating BATF3/IRF4 and MYC. In contrast, the combination of APH-2 and hA3G, or the combination of SBZ and sA3G, does not enhance the TGF-ß/Smad pathway. Thus, HTLV-1 is vulnerable to hA3G but utilizes it to promote the proliferation of infected cells via the activation of the TGF-ß/Smad pathway. Antisense factors in each virus, differently adapted to control host cellular functions through A3G, seem to dictate the pathogenesis.

Anti-HTLV-1 immunity combined with proviral load as predictive biomarkers for adult T-cell leukemia-lymphoma.

Human T-cell leukemia virus type 1 (HTLV-1) establishes chronic infection in humans and induces a T-cell malignancy called adult T-cell leukemia-lymphoma (ATL) and several inflammatory diseases such as HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). Persistent HTLV-1 infection is established under the pressure of host immunity, and therefore the immune response against HTLV-1 is thought to reflect the status of the disease it causes. Indeed, it is known that cellular immunity against viral antigens is suppressed in ATL patients compared to HAM/TSP patients. In this study, we show that profiling the humoral immunity to several HTLV-1 antigens, such as Gag, Env, and Tax, and measuring proviral load are useful tools for classifying disease status and predicting disease development. Using targeted sequencing, we found that several carriers whom this profiling method predicted to be at high risk for developing ATL indeed harbored driver mutations of ATL. The clonality of HTLV-1-infected cells in those carriers was still polyclonal; it is consistent with an early stage of leukemogenesis. Furthermore, this study revealed significance of anti-Gag proteins to predict high risk group in HTLV-1 carriers. Consistent with this finding, anti-Gag cytotoxic T lymphocytes (CTLs) were increased in patients who received hematopoietic stem cell transplantation and achieved remission state, indicating the significance of anti-Gag CTLs for disease control. Our findings suggest that our strategy that combines anti-HTLV-1 antibodies and proviral load may be useful for prediction of the development of HTLV-1-associated diseases.

Performance evaluation of Espline HTLV-I/II, a newly developed rapid immunochromatographic antibody test for different diagnostic situations.

IMPORTANCE: The World Health Organization estimated that 5-10 million people are infected with human T-cell leukemia virus type 1 (HTLV-1). This number is likely to be underestimated because reliable endemic data are available for only approximately 1.5 billion people worldwide. The point-of-care test is a powerful tool for the easy and quick detection of infections without the requirement for expensive instruments and laboratory equipment. Espline HTLV-I/II, a newly developed rapid immunochromatographic antibody test that was evaluated in this study, might significantly advance our understanding of the global epidemiology of HTLV-1 infection.

[Onset of Testicular Plasmacytoma in a Patient with Refractory Multiple Myeloma].

A 72-year-old male patient, who had been on chemotherapy for the treatment of IgG-λ multiple myeloma, presented an enlargement of the testis 3 years and 5 months after the diagnosis. High orchiectomy was then performed, leading to the diagnosis of plasmacytoma. Due to residual disease, treatment with a combination of isatuximab and dexamethasone was initiated. The patient is currently under follow-up without recurrence. While testicular tumors are difficult to diagnose by imaging studies alone and extramedullary plasmacytomas rarely occur in the testis, pathological assessment is critical for treatment planning.

Production and nonclinical evaluation of an autologous iPSC-derived platelet product for the iPLAT1 clinical trial.

Donor-derived platelets are used to treat or prevent hemorrhage in patients with thrombocytopenia. However, ∼5% or more of these patients are complicated with alloimmune platelet transfusion refractoriness (allo-PTR) due to alloantibodies against HLA-I or human platelet antigens (HPA). In these cases, platelets from compatible donors are necessary, but it is difficult to find such donors for patients with rare HLA-I or HPA. To produce platelet products for patients with aplastic anemia with allo-PTR due to rare HPA-1 mismatch in Japan, we developed an ex vivo good manufacturing process (GMP)-based production system for an induced pluripotent stem cell-derived platelet product (iPSC-PLTs). Immortalized megakaryocyte progenitor cell lines (imMKCLs) were established from patient iPSCs, and a competent imMKCL clone was selected for the master cell bank (MCB) and confirmed for safety, including negativity of pathogens. From this MCB, iPSC-PLTs were produced using turbulent flow bioreactors and new drugs. In extensive nonclinical studies, iPSC-PLTs were confirmed for quality, safety, and efficacy, including hemostasis in a rabbit model. This report presents a complete system for the GMP-based production of iPSC-PLTs and the required nonclinical studies and thus supports the iPLAT1 study, the first-in-human clinical trial of iPSC-PLTs in a patient with allo-PTR and no compatible donor using the autologous product. It also serves as a comprehensive reference for the development of widely applicable allogeneic iPSC-PLTs and other cell products that use iPSC-derived progenitor cells as MCB.

Co-occurrence of JAK2 V617F-mutated essential thrombocythemia and chronic lymphocytic leukemia harboring der(8;17)(q10;q10).

BACKGROUND AND CASE: We herein present a case of the co-occurrence of JAK2-mutated essential thrombocythemia (ET) with chronic lymphocytic leukemia (CLL) harboring the recurrent and rare whole-arm translocation, der(8;17)(q10;q10). The co-existence of lymphoproliferative neoplasms and myeloproliferative neoplasms is suggested to be a rare event. Under this condition, the lymphoproliferative disorder presents a clinically indolent course with a low-risk biological profile. However, the present case showed aggressive disease progression, reflecting a poor prognostic factor; that is, the loss of 17p caused by the whole-arm der(8;17)(q10;q10) translocation. CONCLUSION: The present case report emphasizes the importance of considering the involvement of a genetically poor prognostic factor, regardless of the co-occurrence of CLL and ET.

[Primary Diffuse Large B-Cell Lymphoma of the Testis Developed during the Course of Mycosis Fungoides-A Case Report].

We report the case of an 84-year-old man who developed primary diffuse large B-cell lymphoma of the testes during the course of mycosis fungoides treated with topical medication. He was referred to our hospital due to bilateral testicular masses, and bilateral high orchiectomy was performed. A pathological diagnosis of diffuse large B-cell lymphoma was made after an examination of the surgical specimen. Rituximab-combined miniCHOP chemotherapy with prophylactic intrathecal injection resulted in complete remission without recurrence 1 year after diagnosis. People with mycosis fungoides are known to be at a higher risk of secondary malignancies than healthy individuals; hence, a pathological examination is important to confirm the diagnosis.

Sea-blue histiocytosis in a patient with acute myeloid leukemia with myelodysplasia-related changes harboring isolated trisomy 9: pathognomonic or a coincidence?

Although isolated trisomy 9, a form of chromosome aneuploidy, is rare in acute myeloid leukemia (AML), up to 30 cases of AML involving isolated trisomy 9 have been reported to date. We report the case of a 77-year-old female with AML, in which trisomy 9 was detected as an isolated aberration. In addition, the patient's bone marrow displayed so-called sea-blue histiocytosis. The accumulation of further cases of isolated trisomy 9-harboring AML involving sea-blue histiocytosis is necessary to determine whether the coexistence of these findings is pathognomonic or a coincidence.

Establishment of a novel diagnostic test algorithm for human T-cell leukemia virus type 1 infection with line immunoassay replacement of western blotting: a collaborative study for performance evaluation of diagnostic assays in Japan.

BACKGROUND: The reliable diagnosis of human T-cell leukemia virus type 1 (HTLV-1) infection is important, particularly as it can be vertically transmitted by breast feeding mothers to their infants. However, current diagnosis in Japan requires a confirmatory western blot (WB) test after screening/primary testing for HTLV-1 antibodies, but this test often gives indeterminate results. Thus, this collaborative study evaluated the reliability of diagnostic assays for HTLV-1 infection, including a WB-based one, along with line immunoassay (LIA) as an alternative to WB for confirmatory testing. RESULTS: Using peripheral blood samples from blood donors and pregnant women previously serologically screened and subjected to WB analysis, we analyzed the performances of 10 HTLV-1 antibody assay kits commercially available in Japan. No marked differences in the performances of eight of the screening kits were apparent. However, LIA determined most of the WB-indeterminate samples to be conclusively positive or negative (an 88.0% detection rate). When we also compared the sensitivity to HTLV-1 envelope gp21 with that of other antigens by LIA, the sensitivity to gp21 was the strongest. When we also compared the sensitivity to envelope gp46 by LIA with that of WB, LIA showed stronger sensitivity to gp46 than WB did. These findings indicate that LIA is an alternative confirmatory test to WB analysis without gp21. Therefore, we established a novel diagnostic test algorithm for HTLV-1 infection in Japan, including both the performance of a confirmatory test where LIA replaced WB on primary test-reactive samples and an additional decision based on a standardized nucleic acid detection step (polymerase chain reaction, PCR) on the confirmatory test-indeterminate samples. The final assessment of the clinical usefulness of this algorithm involved performing WB analysis, LIA, and/or PCR in parallel for confirmatory testing of known reactive samples serologically screened at clinical laboratories. Consequently, LIA followed by PCR (LIA/PCR), but neither WB/PCR nor PCR/LIA, was found to be the most reliable diagnostic algorithm. CONCLUSIONS: Because the above results show that our novel algorithm is clinically useful, we propose that it is recommended for solving the aforementioned WB-associated reliability issues and for providing a more rapid and precise diagnosis of HTLV-1 infection.

[Bacteremia Due to Edwardsiella tarda Emerging after Chemotherapy for Recurrent Ph-Positive Acute Lymphoblastic Leukemia].

We report the case ofa 76-year-old man who had bacteremia due to Edwardsiella tarda during the course ofchemotherapy, including ponatinib, for the treatment of recurrent Philadelphia-positive acute lymphoblastic leukemia. Treatment with cefepime improved his general condition. The number ofreported cases ofbacteremia due to Edwardsiella tarda is limited. Further accumulation ofcases is necessary to obtain accurate data such as the risk factors of Edwardsiella tarda bacteremia.

Hodgkin-like adult T-cell leukemia/lymphoma that developed during the follow-up of HTLV-1 associated myelopathy/tropical spastic paraparesis.

Hodgkin-like adult T-cell leukemia/lymphoma (ATLL) is a rare variant of ATLL, which represents the early neoplastic phase of ATLL that follows an indolent clinical course compared with typical ATLL. Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disorder characterized by the paralysis of lower limbs and urinary disturbance. Although these diseases are caused by HTLV-1 infection, there are no reports describing the coexistence of Hodgkin-like ATLL and HAM/TSP. Here, we report the first case of Hodgkin-like ATLL complicated by HAM/TSP. The patient was a 56-year-old man with right inguinal lymphadenopathy who had been using the neurology outpatient service for 13 years after being diagnosed with HAM/TSP. He was unable to receive intensive chemotherapy or allogeneic stem cell transplantation due to a poor performance status, but his condition was stable for approximately two years.

An isolated der(1;21)(q10;q10) translocation in a patient with myelodysplastic syndrome: a case report.

Whole-arm translocations are relatively rare among hematological malignancies. There are a few reports on myeloid malignancies harboring der(1;21)(q10;q10). A 65-year-old male was referred to our hospital due to squamous cell carcinoma of the lung. Pembrolizumab monotherapy resulted in progression, and so chemotherapy involving nab-paclitaxel and carboplatin was administered thereafter. The patient developed cytopenia, and his bone marrow exhibited dysplasia. Chromosomal analysis revealed a whole-arm translocation, der(1;21)(q10;q10). Thus, the patient was diagnosed with myelodysplastic syndrome. The der(1;21)(q10;q10) translocation is a rare variant of the der(1;7)(q10;p10) translocation, which is an adverse prognostic factor for myeloid neoplasms. Clarifying the clinical features of myeloid neoplasms in patients with der(1;21)(q10;q10) would facilitate the elucidation of their tumorigenic mechanisms.