[Treatment of secondary engraftment failure with granulocyte colony-stimulating factor and eltrombopag after allogeneic peripheral blood stem cell transplantation in adult T-cell leukemia/lymphoma].

A 67-year-old woman diagnosed with adult T-cell leukemia/lymphoma received an induction chemotherapy and showed a partial response. She then underwent allogeneic peripheral blood stem cell transplantation from an HLA-identical sibling donor. Although cyclosporine (CS) was stopped at 120 days after transplantation, chronic graft-versus-host disease (cGVHD) of the skin developed. She was treated with a topical steroid, without exacerbation of the GVHD. She was admitted to our hospital due to the sudden development of pancytopenia at 212 days after the transplantation. She had an EB virus-associated post-transplant lymphoproliferative disorder (PTLD) in the hilum of the lung. The cGVHD of the skin resolved after the administration of prednisolone and CS. However, pancytopenia and PTLD persisted. Treatment with four cycles of rituximab (4×375 mg/m2/week) led to the complete resolution of PTLD, but transfusion-dependent cytopenia did not improve. Secondary engraftment failure was diagnosed, and granulocyte colony-stimulating factor (G-CSF) and eltrombopag (100 mg/day) were administered, leading to gradual improvement of pancytopenia. It was observed that persistent pancytopenia was caused by secondary engraftment failure due to cGVHD in this case. This case suggested that the treatment with G-CSF and eltrombopag is effective for cGVHD-associated secondary engraftment failure.

Selexipag for Chronic Thromboembolic Pulmonary Hypertension in Japanese Patients　- A Double-Blind, Randomized, Placebo-Controlled, Multicenter Phase II Study.

BACKGROUND: Selexipag is an oral prostacyclin receptor (IP receptor) agonist with a non-prostanoid structure. This study examined its efficacy and safety in Japanese patients with non-operated or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTEPH).Methods and Results:This Phase II study was a randomized, double-blind, placebo-controlled parallel-group comparison. The primary endpoint was a change in pulmonary vascular resistance (PVR) from baseline to week 17. The main analysis involved a per-protocol set group of 28 subjects. The change in PVR (mean±SD) after 17 weeks of treatment in the selexipag group was -104±191 dyn·s/cm5, whereas that in the placebo group was 26±180 dyn·s/cm5. Thus, the treatment effect after 17 weeks of selexipag treatment was calculated as -130±189 dyn·s/cm5(P=0.1553). Although the primary endpoint was not met, for the group not concomitantly using a pulmonary vasodilator the PVR in the selexipag group was significantly decreased compared with placebo group (P=0.0364). The selexipag group also showed improvement in total pulmonary resistance and cardiac index. CONCLUSIONS: Selexipag treatment improved pulmonary hemodynamics in Japanese patients with CTEPH, but PVR did not show a significant difference between the selexipag and placebo groups. (Trial registration: JAPIC Clinical Trials Information [JapicCTI-111667]).

Pretreatment evaluation of fluorescence resonance energy transfer-based drug sensitivity test for patients with chronic myelogenous leukemia treated with dasatinib.

Tyrosine kinase inhibitors (TKI) are used for primary therapy in patients with newly diagnosed CML. However, a reliable method for optimal selection of a TKI from the viewpoint of drug sensitivity of CML cells has not been established. We have developed a FRET-based drug sensitivity test in which a CrkL-derived fluorescent biosensor efficiently quantifies the kinase activity of BCR-ABL of living cells and sensitively evaluates the inhibitory activity of a TKI against BCR-ABL. Here, we validated the utility of the FRET-based drug sensitivity test carried out at diagnosis for predicting the molecular efficacy. Sixty-two patients with newly diagnosed chronic phase CML were enrolled in this study and treated with dasatinib. Bone marrow cells at diagnosis were subjected to FRET analysis. The ΔFRET value was calculated by subtraction of FRET efficiency in the presence of dasatinib from that in the absence of dasatinib. Treatment response was evaluated every 3 months by the BCR-ABL1 International Scale. Based on the ΔFRET value and molecular response, a threshold of the ΔFRET value in the top 10% of FRET efficiency was set to 0.31. Patients with ΔFRET value ≥0.31 had significantly superior molecular responses (MMR at 6 and 9 months and both MR4 and MR4.5 at 6, 9, and 12 months) compared with the responses in patients with ΔFRET value <0.31. These results suggest that the FRET-based drug sensitivity test at diagnosis can predict early and deep molecular responses. This study is registered with UMIN Clinical Trials Registry (UMIN000006358).

Association of CD8 + T cells expressing nivolumab-free PD-1 with clinical status in a patient with relapsed refractory classical Hodgkin lymphoma.

A 37-year-old man with refractory classical Hodgkin lymphoma (cHL) underwent PD-1 blockade therapy with nivolumab, which resulted in a partial response. However, treatment was discontinued due to immune-related adverse events (irAEs), including myasthenia gravis and myositis. Retreatment with nivolumab resulted in a complete metabolic response and hepatic irAE. Subsequently, nivolumab was administered at extended dosing intervals. Intermittent infusion of ten doses of nivolumab for a total dose of 2400 mg/body helped control the relapsed/refractory cHL over three years. During nivolumab treatment, disease progression and emergence of irAEs were associated with the proportion of CD8 + T cells expressing nivolumab-free PD-1 relative to the total number of CD8 + T cells. The findings in this nivolumab-sensitive patient highlight the clinical utility of monitoring immune cells expressing nivolumab-free PD-1 in patients with cHL who have been treated with nivolumab and have experienced irAEs.

Multidetector-row computed tomography-based clinical assessment of fondaparinux for treatment of acute pulmonary embolism and acute deep vein thrombosis in Japanese patients.

BACKGROUND: Unfractionated heparin (UFH) is the standard drug for the initial treatment of pulmonary embolism (PE) and deep vein thrombosis (DVT) in Japan, whereas fondaparinux is the standard drug in Europe and the United States. Here, we examine the efficacy and safety of fondaparinux in Japanese patients. METHODS AND RESULTS: In 2 randomized, open-label, multicenter studies, 80 Japanese patients with acute PE or DVT received either subcutaneous fondaparinux or intravenous UFH as a non-comparative reference, in a 3:1 ratio, for 5-10 days. Concomitant warfarin therapy was continued until Day 90. Multidetector-row computed tomography-based assessment showed that 57.9% and 45.9% of the patients with acute PE and acute proximal DVT had proximal DVT and PE as a complication, respectively. There was no recurrence of symptomatic venous thromboembolism. In the fondaparinux group, the respective improvement rates at the end of the initial treatment and follow-up periods were 71.4% and 86.8% for 42 patients with PE, and 57.8% and 83.3% for 46 patients with DVT; similar results were noted in the UFH group. One patient in the fondaparinux group experienced major bleeding during the initial treatment, but no such episode in the UFH group. CONCLUSIONS: Once-daily, subcutaneous fondaparinux is as effective and safe without monitoring as adjusted-dose intravenous UFH for the initial treatment of acute PE and DVT in Japanese patients.

A case of pulmonary arterial hypertension complicated by anti-neutrophil cytoplasmic antibody-associated vasculitis and systemic sclerosis.

Pulmonary arterial hypertension (PAH) is a rare complication of ANCA-associated vasculitis (AAV). We report a 37-year-old man with PAH complicated by both AAV and SSc who presented with dyspnea, cardiac enlargement, positive myeloperoxidase (MPO)-ANCA, anti-centromere antibodies, proteinuria, and urinary casts. Elevated pulmonary arterial pressure (58/22/34 mmHg) and low PAWP (2 mmHg) were confirmed by right heart catheterization. Treatment with glucocorticoids (GC) decreased urinary protein and serum MPO-ANCA; however, PAH did not respond to GC. Therefore, a combination of beraprost, bosentan, and tadalafil was needed. The differences in responses to GC suggest that the pathophysiology of nephropathy is different from that of PAH. We considered that nephropathy was associated with AAV but that PAH was associated with SSc in the present case. We discuss the pathophysiology and treatment response of PAH complicated by AAV, referring to nine past cases.

Long-term treatment of pulmonary arterial hypertension with macitentan in Japanese patients.

Objective: Macitentan, a novel dual endothelin receptor antagonist, was approved for the treatment of pulmonary arterial hypertension (PAH) in Japan. However, long-term effects in Japanese patients of macitentan are currently unavailable. This study sought to assess the long-term efficacy and safety of macitentan in Japanese patients with PAH.Methods: In this multicenter, open-label, clinical extension study (JapicCTI-121986), efficacy was evaluated based on the change from baseline at 24, 48, 72, 96 and 120-week in the 6-minute walk distance (6MWD), World Health Organization (WHO) functional class, and serum N-terminal pro-brain natriuretic peptide (NT-pro-BNP) levels. In addition, the time to a hospitalization related to PAH and a morbidity/mortality event was determined. As for safety, the incidence of adverse events and changes in laboratory data and vital signs were assessed.Results: Macitentan was administered at a once-daily dose of 10 mg in 30 PAH patients with a median treatment period of 2.4 years (range, 229-1037 days). The improvements in 6MWD, WHO functional class and NT-pro-BNP at week 24 were maintained throughout the long-term follow-up. Hospitalization related to PAH occurred in 2 patients. Levels of liver enzyme and hemoglobin remained unchanged throughout the study period.Conclusions: This study suggests that the long-term use of macitentan is well tolerated and effective in Japanese patients with PAH. We concluded that macitentan can be a possible approach to reduce morbidity/mortality in Japanese PAH patients.

[Combination therapy].

The goal of combination therapy in patients with pulmonary arterial hypertension (PAH) is aimed at maximizing therapeutic efficacy while limiting toxicity and drug interactions. Because PAH is a rare disease, it is difficult to adequately power therapeutic trials to evaluate significant morbidity or mortality differences between various drug therapies. At this point, it is premature to either dismiss or strongly favor any one combination of therapies over another. There is debate among PAH specialists as to whether combination therapy should be reserved for patients whose condition deteriorates (add on therapy) or should be started up front and followed by maintenance therapy with one or more agents once patients have improved. Careful design of future trials testing these comparisons is very important.

Descriptive patterns of severe chronic pulmonary hypertension by chest radiography.

BACKGROUND: To find chest roentgenographic (CXR) features to help differentiate two representative diseases with severe chronic pulmonary hypertension (PH). STUDY SUBJECTS: Thirty-six consecutive patients with chronic thromboembolic PH (CTEPH), 38 with primary PH (PPH), and 37 with left heart disease and PH. METHODS: CXRs were reviewed about 6 features (left 2nd arc protrusion, right descending pulmonary artery diameter (rPAD), cardiothoracic ratio (CTR), right 2nd arc width, avascular area and pleural abnormality). Hemodynamic data and the degree of tricuspid regurgitation (TR) on echocardiography were compared with CXR findings. RESULTS: The diagnostic pattern of CTEPH was the presence of one of two findings, an avascular area or marked rPAD (>20mm) together with pleuritic change. The diagnostic pattern of PPH was one of the two features; without pleuritic abnormality, marked left 2nd arc protrusion (>10mm) or moderate left 2nd arc protrusion (5-10mm) with marked rPAD (<20mm). The sensitivity for the diagnosis of CTEPH among the three diseases was 78% and specificity was 92%. The sensitivity for the diagnosis of PPH was 45% and specificity was 88%. CTR and right 2nd arc width were related to the degree of TR in CTEPH and PPH. CONCLUSIONS: Characteristic roentgenographic findings can help differentiate two frequent diseases associated with chronic pulmonary hypertension and reflect the severity of disease.

Pulmonary pressure-flow relation as a determinant factor of exercise capacity and symptoms in patients with regurgitant valvular heart disease.

BACKGROUND: Exertional dyspnea is a frequent limiting symptom in patients with chronic heart failure. Furthermore, dyspnea and a plateau in VO(2) (oxygen consumption) at peak exercise often co-exist in chronic heart failure, especially in patients with severe regurgitant valvular heart disease (RVHD), their relevance to hemodynamics and subjective symptoms during exercise have not been fully understood. OBJECTIVES: The purpose of this study was to examine the determinant factor of exercise capacity in patients with RVHD. METHODS: We performed a symptom-limited cardiopulmonary exercise test using a sitting cycle ergometer with right heart catheterization in 20 patients with severe RVHD. VO(2) and hemodynamics were measured at rest and during exercise, and symptomatic end-point at peak exercise was evaluated by using Borg's score. RESULTS: Of the 20 patients, 11 attained a plateau in VO(2) at peak exercise (Group 1). At peak exercise, pulmonary arterial pressure (PAP) was higher, and cardiac output (CO) and VO(2) were lower in Group 1 than in patients without a plateau in VO(2) (Group 2) (mean PAP: 60+/-10 vs. 48+/-9 mm Hg, P=0.05; CO: 8.3+/-2.6 vs. 11.2+/-2.6 l/min, P=0.01; VO(2): 1059+/-259 vs. 1359+/-328 ml/min, P=0.01). In Group 1, 6 patients complaining of dyspnea rather than leg fatigue at peak exercise had lower CO (7.1+/-1.8 vs. 9.7+/-3.0 l/min, P=0.05) and higher slope of mean PAP-CO relation (P-Q slope) (10.6+/-3.6 vs. 5.4+/-1.7, P=0.01), compared with the other 5 patients with leg fatigue. CONCLUSIONS: Development of pulmonary hypertension during exercise is the important limiting factor for exercise capacity in patients with RVHD. The limitation of increase in CO concomitant with pulmonary hypertension could be an important factor in the appearance of dyspnea.

Exercise training without ventricular remodeling in patients with moderate to severe left ventricular dysfunction early after acute myocardial infarction.

BACKGROUND: The purpose of this study was to determine whether or not patients with moderate to severe left ventricular (LV) dysfunction benefit from exercise training starting early after acute myocardial infarction (AMI) without deteriorating LV remodeling. METHODS: We investigated changes in exercise capacity and LV end-diastolic dimension (LVDd by two-dimensional echocardiography) before and after exercise training in 126 patients after AMI. Patients were divided into three groups according to LV ejection fraction (EF) at the beginning of exercise training: 74 patients with LVEF>/=45% (Group H), 35 patients with 35%

BMPR2 gene mutation in pulmonary arteriovenous malformation and pulmonary hypertension: a case report.

The transforming growth factor-ß superfamily signaling pathway is thought to be involved in the pathogenesis of pulmonary arteriovenous malformation (PAVM). However, the association between bone morphogenetic protein receptor type 2 (BMPR2) gene mutations and PAVM remains unclear. We present a case of concurrent PAVM and pulmonary arterial hypertension (PAH), with a deletion mutation in exon 6 and exon 7 of the BMPR2 gene. Drug treatment for PAH improved the patient's hemodynamics and exercise capacity, but worsened oxygenation. This case suggests that BMPR2 gene mutation may be associated with the complex presentation of PAVM combined with PAH.

Effects of long-acting beraprost sodium (TRK-100STP) in Japanese patients with pulmonary arterial hypertension.

The long-acting beraprost preparation TRK-100STP is formulated to provide sustained release of an orally active prostacyclin derivative to maintain the optimal plasma concentration for a longer period of time compared with the currently used conventional beraprost sodium. In the present study, we evaluated the efficacy of this newly developed formulation for pulmonary arterial hypertension (PAH).An open-label, 12-week multicenter clinical trial was performed in 46 patients with PAH. They were initially treated with 120 microg of TRK-100STP divided into 60 microg twice daily, followed by a stepwise increase to 360 microg given as 180 microg twice daily. The 6-minute walking distance showed a significant increase by 33.4+/-66.0 m (95% confidence interval [CI], 13.4 to 53.5) from the baseline measurement. Mean pulmonary artery pressure, total pulmonary vascular resistance, and pulmonary vascular resistance decreased by -2.8+/-5.5 mmHg (95% CI, -4.6 to -1.0), by -0.92+/-2.63 mmHg*L(-1)*min (95% CI, -1.78 to -0.05), and by -0.89+/-2.81 mmHg*L(-1)*min (95% CI, -1.84 to 0.06), respectively, from the baseline measurements. A higher efficacy was observed in patients with a maximum tolerated dose of 360 microg daily than those of 240 microg daily or less.Treatment with TRK-100STP for a 12-week period improved the exercise capacity, mean pulmonary artery pressure, and total pulmonary vascular resistance. TRK-100STP was effective for Japanese patients with PAH.

Cough reflex by ventricular premature contractions.

A 72-year-old man was referred for further assessment of a chronic cough. He noticed an association between the episodes of coughing and palpitations. Electrocardiography (ECG) revealed normal sinus rhythm and sporadic unifocal ventricular premature contractions (VPCs). Each cough was preceded by a premature beat. Continuous wave Doppler echocardiography revealed a VPC-induced transient increase in the pulmonary artery blood flow. He was successfully treated for VPCs with oral disopyramide, resulting in subsidence of both the coughing and palpitations. We suspect that the VPC-induced hemodynamic changes in the pulmonary circulation might be responsible for coughing in our patient. Premature contractions should be considered as a possible cause of chronic dry cough in the clinical setting.

A case of congenital pulmonary vein stenosis in an adult.

A 35-year-old Japanese woman, complaining of dyspnea after her first delivery, was diagnosed as having primary pulmonary hypertension. Continuous intravenous prostacyclin resulted in an improvement in her cardiac function, 6-min walk and New York Heart Association class, before she died of pulmonary hypertension crisis during further evaluation for pulmonary transplantation. Since the autopsy findings revealed that all 4 pulmonary veins were extremely stenotic due to hypoplasia, she was diagnosed as having had congenital pulmonary vein hypoplasia with stenosis.

O2 extraction during exercise determines training effect after cardiac rehabilitation in myocardial infarction.

Correlations between baseline hemodynamic and oximetric variables during an invasive exercise test and an improvement in peak oxygen uptake (peak VO2) after exercise training (ET) were examined in 20 patients who participated in a cardiac rehabilitation program after acute myocardial infarction (AMI). Peak VO2 significantly increased by 23 +/- 21% (p < 0.01) after ET and the improvement best correlated with the change in O2 extraction fraction ([arterial O2 content-venous O2 content]/arterial O2 content) during an exercise testbefore ET (r = -0.61, p<0.01). Exercise capacity was improved to a greater extent by ET in patients with a smaller increase in O2 extraction fraction during an exercise test before ET. Thus, O2 extraction fraction during an exercise test before ET may be a useful predictor of the improvement in exercise capacity after ET in post-AMI patients.