Diagnostic and prognostic significance of serum angiopoietin-1 and -2 concentrations in patients with pulmonary hypertension.

Several biomarkers for detecting pulmonary hypertension (PH) have been reported. However, these biomarkers are deemed insufficient to detect PH in its early stages. We evaluated the utility of serum angiopoietin (ANGP), a glycoprotein related to angiogenesis, as a diagnostic and prognostic biomarker of PH. Patients with PH who underwent right-heart catheterization, were retrospectively studied. Serum concentrations of ANGP-1 and ANGP-2 were measured using an enzyme-linked immunosorbent assay in patients with PH (n = 32), those with idiopathic pulmonary fibrosis (IPF) without PH (as a disease control, n = 75), and age-matched healthy controls (HC, n = 60). Nineteen patients (59.4%) with PH had World Health Organization group 3 PH. Serum ANGP-2 concentration, but not ANGP-1, in patients with PH was significantly higher compared with that in HC (p = 0.025) and in patients with IPF without PH (p = 0.008). Serum ANGP-2 concentration in patients with PH positively and significantly correlated with N-terminal pro-B-type natriuretic peptide (r = 0.769, p < 0.001), right ventricular diameter on echocardiography (r = 0.565, p = 0.035), and mean pulmonary arterial pressure (r = 0.449, p = 0.032) and pulmonary vascular resistance (r = 0.451, p = 0.031) on right-heart catheterization. ANGP-1 and ANGP-2 were expressed on lung vascular endothelial cells, as shown by immunohistochemistry. Patients with PH with higher ANGP-2 concentration (≥ 2.48 ng/mL) had significantly worse survival (p = 0.022). Higher ANGP-2 concentration was a significant worse prognostic factor (hazard ratio = 6.063, p = 0.037), while serum ANGP-1 concentration was not. In conclusion, serum ANGP-2 may be a useful diagnostic and prognostic biomarker in patients with PH, especially in patients with group 3 PH.

Analysis of Lutein in Mugwort (Artemisia princeps Pamp.) Paste and Evaluation of Manufacturing Processes.

Lutein, a type of xanthophyll, possesses antioxidative properties that contribute to the prevention of various diseases. Preliminary screening has shown that Japanese mugwort (Artemisia princeps Pamp.) contains high amounts of lutein. In this study, we evaluated the lutein concentration in a processed mugwort product (mugwort paste). By using high-performance liquid chromatography coupled with visible light detection or mass spectrometry, the lutein concentration in mugwort paste was determined as 38 mg/100 g dry weight, which indicates that mugwort is a potentially valuable natural food source of lutein. We also investigated the effects of the manufacturing process and found that the lutein content was significantly increased by the boiling and dehydrating processes during the production of mugwort paste. Mugwort paste that is rich in lutein may therefore serve as an effective nutraceutical.

Continuation maintenance therapy with S-1 in chemotherapy-naïve patients with advanced squamous cell lung cancer.

Objectives Maintenance therapy is a standard therapeutic strategy in non-squamous non-small-cell lung cancer. However, there is no consensus regarding the benefit of maintenance therapy for patients with squamous cell lung cancer. We assessed maintenance therapy with S-1, an oral fluoropyrimidine agent, following induction therapy with carboplatin and S-1 in patients with squamous cell lung cancer. Methods In this phase II trial, chemotherapy-naïve patients with squamous cell lung cancer were enrolled to induction therapy with four cycles of carboplatin (at an area under the curve of 5 on day 1) and S-1 (80 mg/m(2)/day on days 1-14) in a 28-day cycle. Patients who achieved disease control after induction therapy received maintenance therapy with S-1 in a 21-day cycle until disease progression or unacceptable toxicity. The primary endpoint was progression-free survival after administration of maintenance therapy. Results Fifty-one patients were enrolled in the study. The median progression-free survival from the start of maintenance therapy was 3.0 months (95 % confidence interval, 2.5-3.5). The most common toxicities associated with maintenance therapy were anemia, thrombocytopenia, and fatigue, but they were not severe. Conclusion S-1 maintenance therapy might be a feasible treatment option in patients with squamous cell lung cancer.

Sequential addition of aprepitant in patients receiving carboplatin-based chemotherapy.

Chemotherapy-induced nausea and vomiting is a challenging issue. Although aprepitant is sometimes used as a therapeutic option in patients receiving moderately emetogenic chemotherapy, the potential benefit of sequential addition of aprepitant to dexamethasone and a 5-hydroxytryptamine-3 (5-HT3) receptor antagonist during the second cycle of carboplatin-based chemotherapy remains unclear. Chemo-naïve patients with advanced non-small cell lung cancer (NSCLC) who received carboplatin-based chemotherapy were treated with doublet antiemetic therapy with dexamethasone and a 5-HT3 receptor antagonist during the first cycle of chemotherapy. Aprepitant was then added during the second cycle of chemotherapy. The primary endpoint was overall complete response rate, defined as no vomiting and no rescue therapy during the 120 h after administration of chemotherapy. Sixty-seven patients were enrolled, 63 of whom were eligible after two cycles of chemotherapy. The overall complete response rate was significantly improved in the second cycle [87.3 %, 95 % confidence interval (CI) 76.5-94.4 %] compared with the first cycle (65.1 %, 95 % CI 52.0-76.7 %; p < 0.001). Improvement was observed in the delayed phase, but not in the acute phase. Subsequent addition of aprepitant significantly improved the overall complete response rate in NSCLC patients receiving a second cycle of carboplatin-based chemotherapy.

Changes in cross-sectional area of pulmonary vessels on chest computed tomography after chemotherapy in patients with advanced non-squamous non-small-cell lung cancer.

PURPOSE: Chemotherapy is associated with a risk of vascular damage. Novel anti-angiogenic agents, which can directly affect tumor angiogenesis, are increasingly being used. However, the effects of these agents on normal vasculature are not well understood. Here, we evaluated the effects of chemotherapy in general, and the anti-angiogenic agent bevacizumab, more specifically, on the pulmonary vasculature in patients with advanced non-squamous non-small-cell lung cancer (NSCLC). For this, we used the cross-sectional area of pulmonary vessels (CSA), which is an easily measurable indicator of small pulmonary vasculature on non-contrast chest computed tomography (CT). METHODS: We retrospectively reviewed CT scans of the lungs of 75 chemo-naïve patients with advanced non-squamous NSCLC, for measurement of CSA, before and after first-line platinum-based chemotherapy, using a semi-automatic image-processing program. Measured vessels were classified in two groups: small vessels with CSA <5 mm(2) and large vessels with CSA between 5 and 10 mm(2). The CSAs for each group of vessels were calculated and summed separately, and expressed as a percentage of the total lung area (%CSA<5 and %CSA5-10). RESULTS: Chemotherapy was associated with a selective decrease in small-diameter vessels, with a significant decrease in %CSA<5, but not %CSA5-10. When comparing chemotherapy with bevacizumab (n = 38) and without bevacizumab (n = 37), there was no significant difference in the reduction of %CSA<5. CONCLUSIONS: Platinum-based chemotherapy might induce small pulmonary vascular damage. Use of bevacizumab does not enhance the reduction in area of pulmonary vessels.

Atypical interfollicular hyperplasia of tonsils resembling mucosa-associated lymphoid tissue lymphoma: a clinicopathological, immunohistochemical study and epstein-barr virus findings in 12 cases.

This study attempted to clarify the clinicopathological and immunohistochemical findings and presence or absence of Epstein-Barr virus (EBV) in tonsillar atypical interfollicular hyperplasia (AIFH). A total of 597 consecutive specimens from tonsillectomies performed in Dokkyo University School of Medicine between 1999 and July 2013 were reexamined. Using formalin-fixed, paraffin-embedded sections, histological and immunohistochemical analyses, and in situ hybridization (ISH) were performed. AIFH was identified in the tonsils in 12 (2.0%) cases. These included 7 males and 5 females, aged 3 to 19 years (mean, 7). Histologically, there was expansion of the interfollicular areas by polymorphous infiltration resulting in distortion, but not obliteration of the normal tonsillar architecture. In some areas, the lymphoid follicles had hyperplastic germinal centers with ill-defined borders surrounded by sheet-like proliferation of polymorphous infiltrate showing a marginal zone distribution pattern. The infiltrate was composed of small to medium-sized (transformed) lymphocytes and immunoblasts accompanied by numerous plasma cells and plasmacytoid cells, and resembling monocytoid B cells. The numerous immunoblasts were MUM1(+), CD10(-), BCL-6(-). An ISH study demonstrated EBV-encoded small RNA-1 (EBER-1)(+) cells in 9 lesions. Moreover, in 3 lesions, numerous EBER-1(+) cells were present in germinal centers as well as in interfollicular areas. The present study indicated that EBV may cause at least a portion of tonsillar AIFH in children and adolescents. In conclusion, an atypical lymphoid infiltration resulting in distortion of tonsillar architecture with numerous MUM1(+), CD10(-), BCL-6(-) immunoblasts should raise the suspicion of a reactive process.

[Case of organizing pneumonia associated with sweet's syndrome].

A 76-year-old male was admitted to our hospital because of fever and erythema on the face and extremity. Skin biopsy of the erythematous lesions showed dense neutrophilic infiltrations and diagnosis of Sweet's syndrome was made. Chest computed tomography on admission revealed ground glass opacities in the right upper and lower lung fields. Bronchoalveolar lavage (BAL) showed increased lymphocytes and neutrophils. A search for bacteria, mycobacteia and fungi in BAL fluid was negative. Trans-bronchial lung biopsy revealed intraluminal organization and fibrinous exudates. Neutrophilic infiltrations were scant. These pathological findings were compatible with organizing pneumonia. Bone marrow aspiration was performed because of slight anemia and thrombocytopenia, and a diagnosis of myelodysplastic syndrome was made. Oral prednisone (PSL) of 30 mg/day induced rapid resolution of radiologic and cutaneous lesions and was tapered to 10 mg/day, then radiologic lesions worsened. Steroid pulse therapy followed by PSL 45 mg and immunosuppressive agent resulted in a resolution of his conditions. This case was rare in that organizing pneumonia was associated with Sweet's syndrome.

An autopsy case of malignant pleural mesothelioma associated with nephrotic syndrome.

A 64-year-old man who had been exposed to asbestos was referred to our hospital for a detailed examination of left pleural effusion. A laboratory examination of the urine and blood revealed nephrotic syndrome. A thoracoscopic examination did not yield a definitive diagnosis. Twenty months later, a left pleural tumor became apparent, and the patient died of respiratory failure and cachexia. An autopsy revealed epithelioid malignant pleural mesothelioma. The glomeruli appeared normal under light microscopy. A review of the English literature revealed only three reports of malignant mesothelioma associated with minimal-change nephrotic syndrome. The natural course of malignant mesothelioma with nephrotic syndrome has not been previously reported.

Incipient chordoma: a report of two cases of early-stage chordoma arising from benign notochordal cell tumors.

Chordomas are rare malignant bone tumors primarily involving both ends of the axial skeleton that present as destructive bone lesions with a large soft tissue mass. Chordomas were previously believed to arise from notochordal remnants. However, recent studies suggest the possibility that chordomas arise from benign notochordal cell tumors. We present two cases of coccygeal incipient chordoma that strengthen the new hypothesis. The first case was an 83-year-old man who died of prostatic adenocarcinoma. The second case was a 79-year-old man who died of hepatocellular carcinoma. The coccygeal tumors were composed of intraosseous and extraosseous infiltrative lesions. The intraosseous lesions consisted of both benign notochordal cell tumor and incipient chordoma. The extraosseous lesions were consistent with incipient chordoma. In addition, two other small benign notochordal cell tumors were found at a different level in case 1. It is conceivable that pre-existing intraosseous benign notochordal cell tumors transform into incipient chordoma and then extend through the cortex into the surrounding soft tissue. The incidence of incipient chordoma appears much higher than expected because chordomas are rare tumors with an incidence of one case per 1 000 000 persons per year. We suspect that unknown factors transform incipient chordoma into classic chordoma.

Benign notochordal cell tumors: A comparative histological study of benign notochordal cell tumors, classic chordomas, and notochordal vestiges of fetal intervertebral discs.

Intraosseous benign notochordal cell tumors are recently recognized conditions that may undergo malignant transformation to classic chordomas. This study attempts to define the morphologic and immunohistochemical characteristics of 34 benign notochordal cell tumors by contrasting them with classic chordomas and the notochordal vestiges in fetal intervertebral discs. Benign notochordal cell tumors were characterized by well-demarcated though unencapsulated sheets of adipocyte-like vacuolated and less vacuolated eosinophilic cells within axial bones. The round nuclei were mildly polymorphic but bland. The tumor cells often contained cytoplasmic eosinophilic hyaline globules and lack any intercellular myxoid matrix or necrosis. The involved bone trabeculae were often sclerotic without evidence of bone destruction. The histologic features were different from those of both notochordal vestiges in fetal intervertebral discs and classic chordomas. There was overlap in immunohistochemical reactivity of benign notochordal cell tumors and chordomas, but notochordal vestiges failed to demonstrate cytokeratin 18 positivity. A more appropriate term for the lesions is "benign notochordal cell tumor" rather than "notochordal rest" or "notochordal hamartoma" as they are not rests and do not fulfill the definition of hamartoma. Benign notochordal cell tumors do not need any surgical procedure and must be adequately recognized to prevent unnecessary operations.