[Successful induction therapy for acute myeloid leukemia under management with extracorporeal membrane oxygenation].

A 53-year-old woman presented with shortness of breath and hyperleukocytosis and was admitted to our hospital. Shortly after, she went into cardiopulmonary arrest and was resuscitated. Her white blood cell count was 566,000/µl, with 94.5% cup-like blasts positive for MPO staining and FLT3-ITD positive, so she was diagnosed with acute myeloid leukemia (AML) M1. She also had disseminated intravascular coagulation and tumor lysis syndrome. Extracorporeal membrane oxygenation (ECMO) was started to manage bilateral pulmonary thromboembolism that had developed due to deep vein thrombosis, and induction therapy was performed under ECMO. On the third day of illness, the patient developed cerebral hemorrhage. Hematological remission was confirmed on the 39th day of illness. After consolidation therapy with chemotherapy and an FLT3 inhibitor, she underwent allogeneic hematopoietic stem cell transplantation, and remains alive. Case reports suggest strong evidence of mortality benefit from ECMO in patients with hematologic malignancies, particularly when ECMO served as a bridge through chemotherapy. Our patient suffered from cardiopulmonary arrest due to hyperleukocytosis and pulmonary thromboembolism, but was saved by induction of remission under ECMO. Improvements in supportive care should lead to reduction in early deaths during induction therapy.

Identification of putative noncanonical driver mutations in patients with essential thrombocythemia.

Essential thrombocythemia (ET) cases without canonical JAK2, CALR, or MPL mutations, that is, triple-negative (TN) ET, have been found in 10%-20% of ET cases. Owing to the limited number of TN ET cases, its clinical significance remains unclear. This study evaluated TN ET's clinical characteristics and identified novel driver mutations. Among 119 patients with ET, 20 (16.8%) had no canonical JAK2/CALR/MPL mutations. Patients with TN ET tended to be younger and had lower white blood cell counts and lactate dehydrogenase values. We identified putative driver mutations in 7 (35%): MPL S204P, MPL L265F, JAK2 R683G, and JAK2 T875N were previously reported as candidate driver mutations in ET. Moreover, we identified a THPO splicing site mutation, MPL*636Wext*12, and MPL E237K. Four of the seven identified driver mutations were germline. Functional studies on MPL*636Wext*12 and MPL E237K revealed that they are gain-of-function mutants that increase MPL signaling and confer thrombopoietin hypersensitivity with very low efficiency. Patients with TN ET tended to be younger, although this was thought to be due to the inclusion of germline mutations, hereditary thrombocytosis. Accumulating the genetic and clinical characteristics of noncanonical mutations may help future clinical interventions in TN ET and hereditary thrombocytosis.

ECPELLA as the bridge to surgery in patients with cardiogenic shock due to post-infarct papillary muscle rupture: management of mechanical circulatory support during operation.

Papillary muscle rupture is a fatal complication with a high operative mortality. Most patients experience cardiogenic shock and hypoxia due to pulmonary edema caused by severe mitral regurgitation. Although preoperative stabilization using a mechanical assist device potentially improves surgical outcomes, an appropriate strategy has not yet been established. ECPELLA, combining venoarterial extracorporeal membrane oxygenation and Impella, has the potential to stabilize preoperative status and improve outcome in patients with refractory cardiogenic shock due to papillary muscle rupture. Herein, we present 3 cases involving the efficacy of ECPELLA and our tips of surgical and ECPELLA management in patients with papillary muscle rupture.

High-dose Dexamethasone Therapy as the Initial Treatment for Idiopathic Thrombocytopenic Purpura: Protocol for a Multicenter, Open-label, Single Arm Trial.

Standard therapy for idiopathic thrombocytopenic purpura (ITP) has not been established. We are conducting a multicenter, prospective trial to determine the efficacy and safety of short-term, high-dose dexamethasone therapy in ITP patients aged 18-80 years with platelet counts of <20, 000 /µL, or with <50, 000/ µL and bleeding symptoms. The primary endpoints of this trial are the proportion of responses (complete plus partial response) on day 180 (day 46+180) after the completion of the 46-day high-dose dexamethasone therapy. The results of this investigation of the effectiveness and safety of this regimen will be essential for the establishment of standard therapy for ITP.

[Lenalidomide and low-dose dexamethasone therapy for Japanese patients with newly diagnosed multiple myeloma: updated results of the MM-025 study].

In a Japanese phase II study (MM-025), the efficacy and safety of lenalidomide plus low-dose dexamethasone (Rd) were confirmed at a median follow-up of 14.2 months in patients with newly diagnosed multiple myeloma who were ineligible for hematopoietic stem cell transplantation. In the present report, we analyzed the follow-up data from the abovementioned study. Treatment was stopped for all 26 patients after a median follow-up of 31.3 months, and the median treatment duration was approximately 25 months. The overall response rate was 87.5%, and the complete response rate was 20.8%. The median duration of response and progression-free survival were 30.7 and 31.6 months, respectively. The median overall survival has not yet been reached. At least one grade 3/4 adverse event was experienced by 23 patients (88.5%), and 18 patients (69.2%) experienced serious adverse events. There were no treatment-related deaths. Therefore, the efficacy and safety of Rd were confirmed in transplant-ineligible Japanese patients with newly diagnosed multiple myeloma at the present follow-up period.

Lenalidomide and low-dose dexamethasone in Japanese patients with newly diagnosed multiple myeloma: A phase II study.

In the FIRST trial (MM-020), lenalidomide plus low-dose dexamethasone (Rd) reduced the risk of disease progression or death compared with combination melphalan-prednisone-thalidomide. As the FIRST trial did not include any Japanese patients, the efficacy and safety of continuous treatment with Rd was evaluated in 26 Japanese patients with newly diagnosed multiple myeloma (NDMM) in a single-arm, multicenter, open-label phase II trial (MM-025). Patients received lenalidomide on days 1-21 of each 28-day cycle, with a starting dose of 25 mg/day (dose adjusted for renal impairment), and 40 mg/day dexamethasone (dose adjusted for age) on days 1, 8, 15 and 22 of each 28-day cycle until disease progression or discontinuation for any reason. In the efficacy evaluable population, overall response rate was 87.5%, including 29.2% of patients who achieved a complete response/very good partial response. Median durations of response, progression-free survival and overall survival have not been reached. The most common grade 3-4 adverse events were neutropenia (23%) and anemia (19%). The efficacy and safety of Rd were consistent with data from larger studies, including the FIRST trial, thereby supporting the use of Rd continuous in Japanese patients with NDMM who are ineligible for stem cell transplantation.

Differential Hypoxia Risk in Cardiopulmonary Arrest Patients Undergoing Veno-Arterial Extracorporeal Membrane Oxygenation and IMPELLA Support.

Veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is a therapeutic strategy for managing cardiogenic shock. However, it carries the risk of cardiogenic pulmonary edema, potentially leading to differential hypoxia. Although IMPELLA can mitigate pulmonary congestion, the combination of VA-ECMO and IMPELLA has frequently resulted in differential hypoxia, requiring a transition from VA-ECMO to veno-arteriovenous extracorporeal membrane oxygenation (VAV-ECMO). Therefore, this study aimed to examine the influence of IMPELLA on the incidence of differential hypoxia, necessitating a shift to VAV-ECMO. This single-center, retrospective, observational study included patients who experienced cardiopulmonary arrest and received treatment with VA-ECMO combined with an intra-aortic balloon pump (IABP) or IMPELLA between 2017 and 2022. The primary endpoint assessed the incidence of differential hypoxia, necessitating a switch to VAV-ECMO. Patients with cardiopulmonary arrest received treatment with VA-ECMO in combination with IABP (N = 28) or IMPELLA (N = 29). There was a significant increase in differential hypoxia 96 hours post-VA-ECMO initiation in the IMPELLA group, necessitating a transition to VAV-ECMO. The combination of VA-ECMO and IMPELLA in patients experiencing cardiopulmonary arrest may significantly increase the risk of differential hypoxia. A multidisciplinary approach employing mechanical circulatory support is crucial, with ongoing consideration of the potential risks associated with differential hypoxia.

A decrease in newly diagnosed patients with adult T-cell leukemia/lymphoma in Kagoshima, a highly endemic area of HTLV-1 in southwestern Japan.

Adult T-cell leukemia/lymphoma (ATL) is a peripheral T-cell malignancy caused by human T-cell leukemia virus type-I (HTLV-1). This study investigated whether the number of newly diagnosed patients with ATL is decreasing in the background of a declining number of individuals infected by HTLV-1 in Kagoshima, Japan, one of the most endemic areas of HTLV-1 in the world. We retrospectively analyzed the number of newly diagnosed patients with ATL between January 2001 and December 2021 in three major hospitals. The number of newly diagnosed patients with B-cell non-Hodgkin lymphoma (B-NHL) in the same period was examined as an internal control. One thousand eighteen and 2,029 patients with ATL and B-NHL were registered, respectively. The age-adjusted incidence of ATL steadily increased between 2001 and 2012, whereas that between 2013 and 2021 decreased. Despite the limitation of its retrospective nature, this is the first report indicating a decrease in ATL patients in Japan.

Serum hepatocyte growth factor and cancer mortality in an apparently healthy Japanese population.

BACKGROUND: In patients with cancer, hepatocyte growth factor (HGF) is elevated and is a predictor of prognosis. We investigated whether serum HGF was a predictive marker for cancer death in a population of community-dwelling Japanese. METHODS: We studied 1492 apparently healthy Japanese adults who underwent health examinations in 1999. Those who reported a history of liver disease or malignancy on a baseline questionnaire were excluded, and plasma HGF was measured in the remaining 1470 participants, who were followed periodically for 10 years. Multivariate proportional hazards regression was used to estimate cancer mortality. RESULTS: A total of 169 participants died during follow-up (61 from cancer, 32 from cerebrocardiovascular disease, and 76 from other diseases). Mean HGF at baseline was significantly higher among decedents than among survivors (0.26 ± 0.11 vs 0.23 ± 0.09 ng/ml, respectively; P < 0.01). The Cox proportional hazards model showed that age, systolic blood pressure, HGF (hazard ratio, 1.27; 95% CI, 1.06-1.52; P = 0.009), albumin level, smoking status, and creatinine were independent predictors of all-cause death. Age, HGF (hazard ratio, 1.31; 95% CI, 1.04-1.65; P = 0.02), and total cholesterol were independent predictive markers for cancer death. CONCLUSIONS: Serum HGF was a predictor of cancer death in an apparently healthy population of community-dwelling Japanese.

COVID-19 with Rapid Progression to Hypoxemia Likely due to Imbalance between Ventilation and Blood Flow: A Case Report.

BACKGROUND: In COVID-19 pneumonia, cases of severe hypoxemia in the early stage and cases of sudden deterioration in respiratory status due to silent hypoxia leading to death, have been reported. CASE SUMMARY: A 70-year-old Japanese man with essential hypertension, dyslipidemia, chronic kidney disease and emphysema was hospitalized with the novel coronavirus disease. He had hypoxemia that was disproportionate to the severity of pneumonia indicated by computed tomography (CT), along with coagulation abnormalities. We speculated that there was a high possibility that he had developed ventilation and blood flow imbalance due to pulmonary intravascular coagulopathy (PIC) or hypoxic pulmonary vasoconstriction (HPV). In this case, early, short-term combination therapy with remdesivir, nafamostat mesylate and low-dose dexamethasone (Dex) was successful. CONCLUSION: In COVID-19 patients with multiple comorbidities who have hypoxemia and coagulation abnormalities that are disproportionate to the severity of pneumonia on CT, it is important to commence antiviral and anticoagulant therapy as soon as possible, followed by use of a low dose of Dex.

Factors associated with plasma ghrelin level in Japanese general population.

OBJECTIVE: Ghrelin is a novel gastric peptide identified in 1999 as a 'hunger hormone'. Plasma ghrelin level is decreased in human obesity. Factors associated with ghrelin have been mainly investigated in western countries where the prevalence of obesity is high. The aim of this study is to examine factors associated with plasma ghrelin in a Japanese general population where obesity is not so common. METHODS: Fasting ghrelin levels were measured by ELISA in 638 subjects in 2005-2007. We measured body mass index (BMI), waist circumference and blood pressure. Blood was drawn in the morning after a 12-h fast for determinations of ghrelin, lipid, glucose (FPG), insulin, estimated glomerular filtration rate (eGFR) and uric acid levels. Univariate and multiple stepwise regression analyses were performed to find out factors associated with ghrelin. RESULTS: In our population, the mean BMI was 23·8 kg/m(2) , indicating a nonobese population. Results of univariate analysis showed that age (P<0·001), BMI (P<0·001), waist (P<0·001), triglycerides (P<0·01), FPG (P<0·01), insulin (P<0·001) and uric acid (P<0·05) were inversely associated with ghrelin. High-density lipoprotein (HDL) cholesterol (P<0·001) and eGFR (P<0·05) were positively associated with ghrelin. Men had lower ghrelin levels than women (P<0·001). Results of the multiple stepwise regression analysis revealed that age (P<0·001; inversely), female gender (P<0·001), insulin (P<0·001; inversely), HDL cholesterol (P=0·005), BMI (P=0·01; inversely) and uric acid (P=0·045; inversely) were significantly and independently associated with ghrelin. CONCLUSIONS: The present study demonstrated that age and gender affected plasma ghrelin levels more than BMI. This may well be because of the low prevalence of overweight in our population.

Screening for Gaucher Disease Using Dried Blood Spot Tests: A Japanese Multicenter, Cross-sectional Survey.

Objective For patients with Gaucher disease (GD), a rare, inherited lysosomal storage disease, obtaining a definitive diagnosis is currently time-consuming and costly. A simplified screening method to measure the glucocerebrosidase (GBA) activity using dried blood spots (DBS) on filter paper has recently been developed. Using this newly developed screening method, we evaluated real-world GD screening in patients suspected of having GD. Methods This multicenter, cross-sectional, observational study with a diagnostic intervention component evaluated real-world screening in patients suspected of having GD based on their clinical symptoms and a platelet count <120,000/µL. The endpoint was the number of patients with low GBA activity determined using DBS. Results In 994 patients who underwent initial DBS screening, 77 had low GBA activity. The assay was not repeated in 1 patient who was diagnosed as having a high possibility of GD due to clinical symptoms, and a further 21 patients completed the study without undergoing the second assay. Of the remaining 55 patients who had 2 DBS assays performed, 11 had a low GBA activity in both assays. Overall, DBS screening identified 12 (1.2%) patients with a low GBA activity, a proportion consistent with prior screening studies. Conclusion These results suggest that the simplified DBS method was less burdensome to patients, was easily utilized by many physicians, and could be a useful first-tier screening assay for GD prior to initiating burdensome genetic testing.

Comparison of prognostic scores in transplant-ineligible patients with peripheral T-cell lymphoma not otherwise specified and angioimmunoblastic T-cell lymphoma: a retrospective study from the national hospital organization in Japan.

We retrospectively analyzed the risk factors for outcomes among patients with peripheral T-cell lymphoma not otherwise specified (PTCL-NOS, n = 100) and angioimmunoblastic T-cell lymphoma (AITL, n = 128) who did not receive hematopoietic stem cell transplantation between 2008 and 2018. We designed a comparison of prognostic scores specifically for PTCL-NOS and AITL. The international prognostic index (IPI) was useful for investigating the risk factors associated with outcomes among transplant-ineligible patients with PTCL-NOS (Harrell's c-statistic 0.715) and AITL (c-statistic 0.615). The prognostic index for T-cell lymphoma (PIT), modified PIT, and the International Peripheral T Cell Lymphoma Project for overall survival (OS) seemed to identify separate prognostic groups, based on visual assessment of Kaplan-Meier curves. However, better c-statistics (>0.7) were only found for the IPI score for OS in PTCL-NOS. Strategies that carefully select PTCL patients with higher IPI scores may help to identify individuals suitable for novel therapies.

Evaluation of prognosis following early disease progression in peripheral T-cell lymphoma.

Recently, progression of disease within 24 months (POD24) has been demonstrated as a strong prognostic indicator in various types of malignant lymphoma. Peripheral T-cell lymphoma (PTCL) has an aggressive course and poor clinical outcomes. In this multicenter retrospective study, 111 consecutively registered patients with newly diagnosed PTCL were analyzed. Of these patients, 72 (64.9%) experienced POD24 (POD24 group), and the other 39 patients (35.1%) were analyzed as the no POD24 group. In the POD24 group, overall survival (OS) was significantly inferior to all patients, and in the no POD24 group, subsequent OS was significantly superior to the POD24 group, although the clinical characteristics between the POD24 group and no POD24 group were not significantly different. Twenty-three patients (20.7%) showed primary refractory disease to first-line therapy, and the prognosis was poor. The International Prognostic Index score and POD24 were identified as independent predictors in multivariate analysis for OS in all patients, and only performance status was an independent prognostic factor for OS in the POD24 group in multivariate analysis. In conclusion, the clinical significance of assessing POD24 in PTCL and the poor prognosis in patients with early disease progression were demonstrated.

High-dose dexamethasone therapy as the initial treatment for idiopathic thrombocytopenic purpura.

There is a controversy which short term high dose dexamethasone therapy (HDD) or standard dose prednisolone therapy as the initial treatment leads to long term efficacy in idiopathic thrombocytopenic purpura (ITP) patients. We conducted a multicenter, prospective trial to determine the efficacy and safety of short-term HDD in ITP patients aged 18-80 years with platelet counts of < 20 × 109/l, or < 50 × 109/l and bleeding symptoms. The primary endpoints are the proportion of complete response (CR) plus partial response (R) on day 180 after the completion of the 46-day HDD. Twenty-three patients were enrolled. Test for Helicobacter pylori (H. pylori) was positive for 6 patients and negative for 17 patients. In positive patients, 5 were received successful H. pylori eradication therapy. The proportion of CR + R was 60.9% (14/23) with 90% confidence interval of 41.7-77.8%. For patients with positive H. pylori and successful eradication, the proportion of CR + R was 80.0% (4/5). There was one grade 4 adverse event. Although we have enrolled relatively old, severe ITP patients with a median age of 63 years in this study, the efficacy was comparable to the reported clinical trials with HDD therapy.

Plasma level of asymmetric dimethylarginine (ADMA) as a predictor of carotid intima-media thickness progression: six-year prospective study using carotid ultrasonography.

This study was designed to determine the relationship between plasma asymmetric dimethylarginine (ADMA) and the development of carotid atherosclerosis. Cross-sectional studies have revealed that plasma ADMA concentration is correlated with the intima-media thickness (IMT) of the carotid artery, but no prospective studies have appeared. Therefore we prospectively investigated whether or not plasma ADMA level can predict IMT progression. In a community-based cohort, we enrolled 712 subjects who were over 40 years old and who had no apparent cardiovascular diseases according to high-resolution carotid ultrasonography. Blood chemistries including ADMA were measured at baseline. In 575 subjects, IMT was re-measured 6 years later. The value of baseline ADMA for predicting IMT changes was investigated by multivariable analysis. At baseline, there was a significant (beta=0.321; p<0.001) relationship between IMT and ADMA levels. Multiple linear regression analysis revealed that baseline ADMA (beta=0.241; p<0.01) was the only predictor of IMT progression after adjustments for age, sex, baseline IMT, and four major risk factors (hypertension, hypercholesterolemia, diabetes mellitus, and smoking) plus hyperuricacidemia. Plasma ADMA was a predictor of carotid IMT progression.

Clinical characteristics and outcomes of diffuse large B-cell lymphoma in adolescents and young adults.

Clinical information regarding non-Hodgkin lymphoma (NHL) in adolescents and young adults (AYA) is lacking. We retrospectively analyzed 1426 consecutively registered patients with newly diagnosed NHL. Of 798 DLBCL patients, 42 (5.3%) were identified as AYA (16-39 years). The characteristics of AYA DLBCL patients showed no significant differences compared to older adult DLBCL patients (age ≥ 40 years). Progression-free survival (PFS) and overall survival (OS) in AYA were similar to those in patients aged 40-60 years. However, in older adult groups, PFS and OS were significantly different according to the age group (40-60, 61-79, and ≥ 80 years). In univariate analysis in AYA, performance status, clinical stage, International Prognostic Index (IPI), and age-adjusted IPI significantly affected both PFS and OS. In multivariate analysis, only clinical stage was identified as an independent predictor among AYA. In conclusion, disease characteristics and outcomes of DLBCL in AYA were nearly the same as those in older adults.

Two cases of secondary acute myeloid leukemia accompanying adult T-cell leukemia/lymphoma.

We identified 2 cases of secondary acute myeloid leukemia (AML) following adult T-cell leukemia/lymphoma (ATL) in patients who had previously received chemotherapy. Both cases were thought to represent therapy-related AML because the patients had previously received combination chemotherapy including epipodophyllotoxin, anthracycline, and alkylating agents for the ATL. The cases were diagnosed as AML M4 with eosinophilia and AML M2, with the chromosomal abnormalities inv(16)(p13q22) and t(8;21)(q22;q22), respectively. In our hospital, only these 2 cases of secondary AML accompanying ATL were identified among 90 cases of acute- or lymphoma-type ATL diagnosed from October 1999 to July 2006. The frequency of coexisting AML and ATL is lower than that reported for acute leukemia coexisting with other lymphoid malignancies. The low frequency of secondary leukemia with ATL may be associated with the short survival times of ATL patients.