A synthetic porphyrin as an effective dual antidote against carbon monoxide and cyanide poisoning.

Simultaneous poisoning by carbon monoxide (CO) and hydrogen cyanide is the major cause of mortality in fire gas accidents. Here, we report on the invention of an injectable antidote against CO and cyanide (CN-) mixed poisoning. The solution contains four compounds: iron(III)porphyrin (FeIIITPPS, F), two methyl-ß-cyclodextrin (CD) dimers linked by pyridine (Py3CD, P) and imidazole (Im3CD, I), and a reducing agent (Na2S2O4, S). When these compounds are dissolved in saline, the solution contains two synthetic heme models including a complex of F with P (hemoCD-P) and another one of F with I (hemoCD-I), both in their iron(II) state. hemoCD-P is stable in its iron(II) state and captures CO more strongly than native hemoproteins, while hemoCD-I is readily autoxidized to its iron(III) state to scavenge CN- once injected into blood circulation. The mixed solution (hemoCD-Twins) exhibited remarkable protective effects against acute CO and CN- mixed poisoning in mice (~85% survival vs. 0% controls). In a model using rats, exposure to CO and CN- resulted in a significant decrease in heart rate and blood pressure, which were restored by hemoCD-Twins in association with decreased CO and CN- levels in blood. Pharmacokinetic data revealed a fast urinary excretion of hemoCD-Twins with an elimination half-life of 47 min. Finally, to simulate a fire accident and translate our findings to a real-life scenario, we confirmed that combustion gas from acrylic cloth caused severe toxicity to mice and that injection of hemoCD-Twins significantly improved the survival rate, leading to a rapid recovery from the physical incapacitation.

[Systemic chemotherapy combined with thrombopoietin receptor agonist for the treatment of diffuse large B-cell lymphoma complicated with aplastic anemia].

Immunosuppressive therapies, including antithymocyte globulin and cyclosporine (CsA), are used for the treatment of aplastic anemia, but they reportedly cause lymphoproliferative diseases. Here, we report two cases of aplastic anemia in which diffuse large B-cell lymphoma developed during treatment with CsA. In both the cases, CsA was discontinued and combination therapy with R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisolone) plus the thrombopoietin receptor agonist eltrombopag was initiated. Furthermore, supportive care, including blood transfusion and granulocyte colony-stimulating factor, was provided. After six or eight courses of R-CHOP therapy, a complete metabolic response was achieved without serious adverse events. These cases illustrate the safety of combining R-CHOP with eltrombopag therapy in patients at a high risk of severe pancytopenia.

A Case of Primary Myelofibrosis in Which Ruxolitinib Therapy Ameliorated the Fibrosis, but Resulted in Fatty Marrow.

A 63-year-old woman was referred to our department in 2015 because of anemia and thrombocytosis. MPL W515/K was positive, JAK-2V617F and CALR exon 9 were negative. Bone marrow(BM)biopsy led to a diagnosis of primary myelofibrosis (PMF)in the prefibrotic/early stage(Grade 1). BMbiopsy performed in 2016 showed overt fibrotic stage(Grade 2). She was classified according to the Dynamic International Prognostic Scoring System(DIPSS)as intermediate(Int)-Ⅱrisk. Ruxolitinib 10 mg daily was initiated. Ruxolitinib was suspended for hepatic dysfunction after the dose was increased to 15 mg. Subsequently, ruxolitinib was resumed at 10 mg. BM biopsy performed in 2017 showed progression of myelofibrosis(MF)to Grade 3. BM biopsy performed in 2018 showed improved to Grade 0-1, however, BM was fatty. Currently in 2019, she continues to be on ruxolitinib. Results of immunohistochemical staining of BM biopsy specimens for cytokines and CD34 suggested the role of cytokines in the pathogenesis of the PMF. It was speculated that ruxolitinib blocked the production of cytokines to ameliorate the MF and restore the hematopoietic function of the BM. Although the pathogenesis of the fatty marrow remained unclear, the possibility of involvement of ruxolitinib cannot be denied.

Clinical and molecular features of patients with prefibrotic primary myelofibrosis previously diagnosed as having essential thrombocythemia in Japan.

OBJECTIVE: Prefibrotic/early primary myelofibrosis (pre-PMF) and essential thrombocythemia (ET) exhibited different features of bone marrow; however, this is not always easy to judge objectively, making pathologists' distinction often suboptimal. In the WHO 2008 criteria, pre-PMF was not defined as a subgroup of PMF; therefore, affected patients were at a higher risk of misdiagnosis with ET. In this study, we examined the prevalence of pre-PMF patients among those previously diagnosed with ET in Japan. METHOD: We reviewed bone marrow specimens and clinical and molecular parameters of patients who were previously diagnosed with ET by the WHO 2008 criteria. RESULTS: Among 107 ET patients, 13 patients were redefined as having pre-PMF. Pre-PMF patients exhibited a higher frequency of MPL mutation and increased platelet counts compared to true ET patients. Molecular analysis revealed the frequencies of high-risk molecular mutations, such as ASXL1, EZH2, and SRSF2, were significantly increased in pre-PMF patients than those in true ET patients. CONCLUSION: These results demonstrated the value of reexamining clinical records for patients diagnosed with ET by the WHO 2008 criteria and emphasized that adequate examinations of patients' bone marrow are crucial for an accurate diagnosis of pre-PMF and ET.

[Rapidly fatal streptococcal toxic shock syndrome due to Streptococcus agalactiae in a patient with chronic myeloid leukemia and cirrhosis].

A 72-year-old woman with chronic myeloid leukemia (CML) and cirrhosis complicated with blood blisters on her right upper arm and ascites was admitted. She presented with shock vital on admission. Initial gram staining of blood cultures showed gram-positive cocci in chains, suggesting streptococcal toxic shock syndrome (STSS). Amputation of the right upper arm was performed owing to necrotizing fasciitis. Despite continued antibiotic therapy and systemic management, the blood blisters rapidly spread to the skin of the whole body, and she died 41 h after admission. Blood and fluid cultures from the blisters showed group B streptococci. Reports of patients with leukemia complicated with STSS are rare, and all cases have followed fatal courses. Particularly in this case, various risk factors, such as neutropenia due to tyrosine kinase inhibitor, neutrophil dysfunction due to cirrhosis, and elderly CML, overlapped. In the future, we believe that the lives of patients with leukemia complicated with STSS may be saved by establishing treatment methods and determining the detailed pathogenesis of STSS.

Clinical Evaluation of the Efficacy and Safety of Anagrelide Used with or without Hydroxycarbamide in Japanese Patients with Essential Thrombocythemia-A Retrospective Single-Center Study of 35 Cases.

OBJECTIVE: The clinical features(CF), laboratory data, disease transformation pattern and drug metabolism in essential thrombocythemia(ET)differ between Japan and Western countries. The CF of ET in clinical practice(CP)are more diverse than in prospective clinical studies. We should conduct retrospective analyses in CP. The present study was aimed at evaluating the efficacy, safety and tolerability of anagrelide(ANA)monotherapy and combined ANA plus hydroxycarbamide(HC)in Japanese ET. PATIENTS AND METHODS: We have a total of 35 cases. Sixteen patients received ANA monotherapy, 10 received ANA plus HC, and 9 received ANA plus other drugs. RESULTS: Comparison among three groups revealed the absence of differences in response rate(platelet count C60×10 / / 4/mL, platelet count C40×104/mL)(43.8%, 6.3% vs. 50.0%, 10.0% vs. 44.4%, 11.1%), treatment continuation rate(81.3% vs. 40.0% vs. 55.6%), median daily dose of ANA(1.00 mg in all three groups)or median treatment period(days)(259 vs. 198.5 vs. 161.0), the treatment continuation rate tended to be lower in the combined ANA plus HC. The incidence of all adverse events(AEs)was higher in the ANA monotherapy(45.7%)than ANA plus HC(28.6%)or ANA plus other drugs(25.7%), the AEs were mild in all groups. CONCLUSION: The tolerability of ANA monotherapy, ANA plus HC, and ANA plus other drugs were good.

A Case of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with Aspergillus Brain Abscess and Invasive Pulmonary Aspergillosis Successfully Treated with Voriconazole Followed by Cord Blood Transplantation.

A 59-year-old female was diagnosed as pulmonary aspergillosis(IPA)while remission induction therapy for Philadelphia chromosome-positive acute lymphoblastic leukemia. Liposomal amphotericin B improved the fungal serodiagnostic markers, however,the IPA worsened. She also developed an Aspergillus brain abscess,which, while being undetectable on CT,was detected as multiple nodular lesions by MRI. A definitive diagnosis was made by polymerase chain reaction(PCR)of brain biopsy specimens. Voriconazole(VRCZ)was effective,and cord blood transplantation was performed. She has received VRCZ for a long time. There are no relapse of either the IPA or the Aspergillus brain abscess.

Retrospective Analysis of 20 Patients with DLBCL Who Received MCVAC Followed by Autologous Peripheral Blood Stem Cell Transplantation.

Autologous peripheral blood stem cell transplantation(auto-PBSCT)combined with high-dose chemotherapy has been considered as the standard therapy for relapsed or induction therapy-refractory aggressive lymphomas sensitive to chemotherapy. While various regimens have been applied as the conditioning,none has yet been established as the standard. We have begun to employ high-dose ranimustine,cytarabine,etoposide and cyclophosphamide(MCVAC)regimen. The present study was undertaken to review the efficacy and safety of MCVAC. Regimen: We carried out a retrospective analysis of 20 patients diagnosed as diffuse large B-cell lymphoma. The median follow-up duration of 20 patients was 13.05 months(range, 0.57-49.5 months). The 4-year OS and PFS were 57.8% and 30.2%,respectively. Relapse was the most frequent cause of treatment failure(n=7). The major toxicities were anorexia/nausea(95%),diarrhea (75%),hypokalemia (70%). One patient died of hepatic veno-occlusive disease(VOD). The serious adverse events included hypokalemia,arrhythmia,cerebral hemorrhage,and heart failure(1 case[5%]each). There was 1 case of a late-onset adverse event: therapy-related myelo- dysplastic syndrome/acute myeloblastic leukemia(MDS/AML). MCVAC regimen was concluded as effective and well-toler- ated. However,we should carefully monitored for the possible development of VOD and MDS/AML. Further follow-up is needed to evaluate the long-term efficacy and safety.

Chromosomal Abnormalities as a Predisposition to Secondary Neurolymphomatosis in Patients with Diffuse Large B-Cell Lymphoma: A Report of Two Cases and a Literature Review.

Introduction: Neurolymphomatosis (NL) is a rare condition characterized by the infiltration of malignant lymphoma cells into the peripheral nervous system. The optimal treatment for NL remains unclear, and patients with secondary NL have a poor prognosis. Although early recognition of NL may contribute to successful treatment, the predictive factors for secondary NL are yet to be established. Case Presentation: Here, we present our investigation on the predictive factors for secondary NL, and report two cases of secondary NL with a literature review. We analyzed chromosomal abnormalities in patients with secondary NL and found a common deletion of chromosome 10 and add(11)(p11). The chromosomal abnormalities might be a predictive factor for secondary NL; therefore, confirmation of chromosomal abnormalities can possibly give a hint for early detect of secondary NL. Prompt histopathological examination or imaging techniques can lead to early diagnosis of secondary NL in patients with diffuse large B-cell lymphoma (DLBCL). Conclusion: When neurological symptoms manifest in patients with DLBCL and there are chromosomal abnormalities, the possible development of secondary NL should be considered.

Real-world status of treatment for lymphoid neoplasms developed during the course of myeloproliferative neoplasms in Japan.

OBJECTIVES: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study. METHODS: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma. RESULTS: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n = 8; essential thrombocythemia, n = 14; and primary myelofibrosis, n = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed (n = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy. CONCLUSION: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.

Two autopsy cases of pulmonary leukemic infiltration mimicking severe pneumonia in patients with acute myeloid leukemia.

Although a previous autopsy series demonstrated that pulmonary leukemic infiltration (PLI) is a major pulmonary complication in patients with acute myeloid leukemia (AML), an antemortem diagnosis of PLI is rare. Diverse pulmonary complications cause acute respiratory failure (ARF) in patients with AML undergoing chemotherapy. This article reports two elderly patients with AML who presented with ARF due to PLI mimicking severe pneumonia during induction chemotherapy. Accurate antemortem diagnosis of PLI was almost impossible without pathological examination since the clinical course was not typical of PLI. We recommend considering PLI in patients with AML who have an unknown etiology of ARF.

Intravascular large B-cell lymphoma as a recurrence of primary central nervous system lymphoma after chemotherapy: A case report.

We report about a 48-year-old woman diagnosed with primary central nervous system lymphoma (PCNSL). After chemotherapy and autologous stem cell transplantation, she presented with a continuous high-grade fever. Positron emission tomography-computed tomography revealed prominent hepatosplenomegaly and high diffuse uptake of 18F-fluorodeoxyglucose in the liver, spleen, and lungs. Intravascular large B-cell lymphoma (IVLBCL) was diagnosed using random skin biopsy. There were no symptoms of IVLBCL at the time of diagnosis of PCNSL. The histopathological features of PCNSL and IVLBCL were nearly similar. These findings suggest that IVLBCL was the recurrence of PCNSL rather than a separate entity.

Clinical impacts of the mutational spectrum in Japanese patients with primary myelofibrosis.

Patients with primary myelofibrosis (PMF) have a poorer prognosis than those with other subtypes of myeloproliferative neoplasms (MPNs). To investigate the relationship between gene mutations and the prognosis of Japanese PMF patients, we analyzed mutations in 72 regions located in 14 MPN-relevant genes (CSF3R, MPL, JAK2, CALR, DNMT3A, TET2, EZH2, ASXL1, IDH1/2, SRSF2, SF3B1, U2AF1, and TP53) utilizing a target resequencing platform. In our cohort, ASXL1 mutations were more frequently detected in both overt and prefibrotic PMF patients than other mutations. The frequency of ASXL1 mutations was slightly higher among overt PMF patients than among prefibrotic PMF patients (44.6% vs 25.0%, FDR = 0.472). Decision tree classification algorithms revealed that ASXL1, EZH2, and SRSF2 mutations were associated with a poor prognosis for overt PMF. Overall survival was significantly shorter in patients harboring ASXL1, EZH2, or SRSF2 mutations than in those without these mutations (p = 0.03). These results suggest that, as reported in Western countries, MIPSS70 is applicable to Japanese PMF patients and ASXL1, EZH2, and SRSF2 mutations may be utilized as surrogate markers of a poor prognosis.

Cell-autonomous megakaryopoiesis associated with polyclonal hematopoiesis in triple-negative essential thrombocythemia.

A subset of essential thrombocythemia (ET) cases are negative for disease-defining mutations on JAK2, MPL, and CALR and defined as triple negative (TN). The lack of recurrent mutations in TN-ET patients makes its pathogenesis ambiguous. Here, we screened 483 patients with suspected ET in a single institution, centrally reviewed bone marrow specimens, and identified 23 TN-ET patients. Analysis of clinical records revealed that TN-ET patients were mostly young female, without a history of thrombosis or progression to secondary myelofibrosis and leukemia. Sequencing analysis and human androgen receptor assays revealed that the majority of TN-ET patients exhibited polyclonal hematopoiesis, suggesting a possibility of reactive thrombocytosis in TN-ET. However, the serum levels of thrombopoietin (TPO) and interleukin-6 in TN-ET patients were not significantly different from those in ET patients with canonical mutations and healthy individuals. Rather, CD34-positive cells from TN-ET patients showed a capacity to form megakaryocytic colonies, even in the absence of TPO. No signs of thrombocytosis were observed before TN-ET development, denying the possibility of hereditary thrombocytosis in TN-ET. Overall, these findings indicate that TN-ET is a distinctive disease entity associated with polyclonal hematopoiesis and is paradoxically caused by hematopoietic stem cells harboring a capacity for cell-autonomous megakaryopoiesis.

Methotrexate-associated Hodgkin Lymphoma in a Patient with Rheumatoid Arthritis Successfully Treated with Brentuximab Vedotin in Combination with Doxorubicin, Vinblastine, and Dacarbazine (BV+AVD).

A 53-year-old woman had been diagnosed with rheumatoid arthritis (RA) in X-6. She was started on methotrexate (MTX) in X-1. She developed a cough, and chest computed tomography showed abnormalities. In X, MTX was discontinued, but the cough persisted. A lung biopsy revealed a diagnosis of nodular sclerosis classic Hodgkin lymphoma (CHL-NS). She was considered to have "other iatrogenic immunodeficiency-associated lymphoproliferative disorders" (OIIA-LPD), MTX-associated Hodgkin lymphoma (MTX-HL). She received six courses of brentuximab vedotin (BV) in addition to AVD (BV+AVD). A complete metabolic response was obtained, and the RA went into remission. This is the fourth reported case of BV+AVD for MTX-HL.

Significant role of magnetic resonance imaging for the diagnosis and evaluation of cardiac amyloidosis in primary light chain amyloidosis.

A 47-year-old male with macroglossia presented with dyspnea on effort and chest pain at rest. Cardiac MRI revealed diffuse global subendocardial late gadolinium enhancement below the left ventricular endocardium and a dark blood pool of intracardiac contrast medium. Tongue biopsy revealed amyloid deposition, which was limited in the myocardium. He was diagnosed with primary light chain amyloidosis. His condition was stage I according to the Mayo Clinic staging system. He underwent autologous peripheral blood stem cell transplantation. On Day 10, he developed chest pain and died suddenly on Day 11. Postmortem examination revealed amyloid deposition throughout the heart.

Three cases of relapsed/refractory multiple myeloma under hemodialysis treated with panobinostat/bortezomib/dexamethasone (FVD).

Three patients under hemodialysis (HD) with relapsed/refractory multiple myeloma (MM) were administered panobinostat/bortezomib/dexamethasone (FVD). Case 1: The patient was a 66-year-old male with BJP-κ. FVD was effective, but HD could not be discontinued. He developed Grade 3 adverse events (AEs), including nausea, dehydration, and fatigue, following the common terminology criteria for adverse events v4.0. FVD was discontinued after the third course, while HD was continued. Case 2: The patient was a 65-year-old female with IgG-λ + BJP-λ. Amyloidosis was complicated. The first course of FVD was effective, but HD could not be discontinued. She developed G2 AEs, including nausea and fatigue. The cardiac amyloidosis worsened, and she died of heart and renal failure. Case 3: The patient was a 79-year-old male with BJP-κ. FVD was effective, and the HD could be discontinued on day 12 of treatment. No AEs were noted. However, he declined continuation of the FVD and died of MM relapse and renal failure. We analyzed the pharmacokinetics of panobinostat. There were no correlations between dose level and blood level of panobinostat or between blood level, efficacy, and incidence of AEs. We additionally measured the rate of elimination of the drug by HD.