Nationwide prospective registry database of patients with newly diagnosed untreated pleural mesothelioma in Japan.

Due to the scarcity of large-sized prospective databases, the Japanese Joint Committee for Lung Cancer Registry conducted a nationwide prospective registry for newly diagnosed and untreated pleural mesothelioma. All new cases diagnosed pathologically as any subtype of pleural mesothelioma in Japan during the period between April 1, 2017, to March 31, 2019, were included before treatment. Data on survival were collected in April 2021. The eligible 346 patients (285 men [82.3%]; 61 women [17.7%]; median age, 71.0 years [range, 44-88]) were included for analysis. Among these patients, 138 (39.9%) underwent surgery, 164 (47.4%) underwent non-surgical therapy, and the remaining 44 (12.7%) underwent best supportive care. The median overall survival for all 346 patients was 19.0 months. Survival rates at 1, 2, and 3 years for all patients were, 62.8%, 42.3%, and 26.5%, respectively. Median overall survival was significantly different among patients undergoing surgery, non-surgical treatment, and best supportive care (32.2 months vs. 14.0 months vs. 3.8 months, p < 0.001). The median overall survival of patients undergoing pleurectomy/decortication and extrapleural pneumonectomy was 41.8 months and 25.0 months, respectively. Macroscopic complete resection resulted in longer overall survival than R2 resection and partial pleurectomy/exploratory thoracotomy (41.8 months vs. 32.2 months vs. 16.8 months, p < 0.001). Tumor shape, maximum tumor thickness, and sum of three level thickness were significant prognostic factors. The data in the prospective database would serve as a valuable reference for clinical practice and further studies for pleural mesothelioma.

Glycosphingolipids form characteristic-sized liposomes that correlate with their antibody-inducing activities in mice.

Immunization of mice with liposomes consisting of dipalmitoylphosphatidylcholine, cholesterol, lipid A, and glycosphingolipids (GSLs) can efficiently induce the production of antibodies that recognize specific GSLs. Here, we analyzed the effect of GSL species on the particle sizes of GSL-containing liposomes. We prepared liposomes containing Gb4Cer/globoside, GM3, and several artificial GSLs, and analyzed their particle sizes in phosphate-buffered saline by dynamic light scattering. The particle sizes of liposomes were significantly altered by the addition of GSLs, and they formed 65- to 1737-nm particle sizes depending on their constituent GSL species. We compared the sizes of each GSL-containing liposome with the IgM- or IgG-inducing activity of these liposomes in mice, and found a positive correlation between increasing liposome size and IgG-inducing activity. We also determined the nucleotide sequences of the heavy and light chain variable regions of anti-Gb4Cer IgM and IgG3 obtained from the Gb4Cer-containing liposome-immunized mice, and found that they were composed of different gene segments. This result indicates that the GSL-containing liposomes induce the production of IgG3 through an immune pathway different from that of IgM, rather than efficiently inducing class switching.

A zirconia-based column chromatography system optimized for the purification of IgM from hybridoma culture supernatants.

By using EDTPA-modified zirconia particles that selectively adsorb immunoglobulins in a column, we developed a chromatography separation system for efficient concentrating and purifying of IgM from hybridoma culture supernatants. Hybridoma culture supernatants containing IgMs were diluted 3-fold with 10 mM phosphate buffer (pH 7.0) and passed through the column. During this process, zirconia particles selectively adsorbed these IgMs, and most of the contaminating proteins flowed out into the flow-through. The adsorbed IgMs were easily eluted with a small volume of 400 mM phosphate buffer (pH 8.0), and high-concentration IgM solutions were prepared. Subsequent simple processing using a Capto™ Core 400 cartridge column provided highly purified IgM. The operation is easy, and the activity of IgM is maintained because the purification process is performed using only neutral ranges of phosphate buffers. Here, we showed that anti-globoside and anti-CDw75 IgM purified by this method can be used to stain cervical cancer and Burkitt lymphoma cells that specifically express these respective tumor-associated carbohydrate antigens.

The diagnosis of early pneumoconiosis in dust-exposed workers: comparison of chest radiography and computed tomography.

BACKGROUND: Chest radiography (CR) is employed as the evaluation of pneumoconiosis; however, we sometimes encounter cases in which computed tomography (CT) is more effective in detecting subtle pathological changes or cases in which CR yields false-positive results. PURPOSE: To compare CR to CT in the diagnosis of early-stage pneumoconiosis. MATERIAL AND METHODS: CR and CT were performed for 132 workers with an occupational history of mining. We excluded 23 cases of arc-welder's lung. Five readers who were experienced chest radiologists or pulmonologists independently graded the pulmonary small opacities on CR of the remaining 109 cases. We then excluded 37 cases in which the CT data were not sufficient for grading. CT images of the remaining 72 cases were graded by the five readers. We also assessed the degree of pulmonary emphysema in those cases. RESULTS: The grade of profusion on CR (CR score) of all five readers was identical in only 5 of 109 cases (4.6%). The CR score coincided with that on CT in 40 of 72 cases (56%). The CT score was higher than that on CR in 13 cases (18%). On the other hand, the CT score was lower than that on CR in 19 cases (26%). The incidence of pulmonary emphysema was significantly higher in patients whose CR score was higher than their CT score. CONCLUSION: CT is more sensitive than CR in the evaluation of early-stage pneumoconiosis. In cases with emphysema, the CR score tends to be higher in comparison to that on CT.

Identification of genes for variable regions of immunoglobulins that recognize sialylated glycans.

We previously reported an antibody (clone ID: FR9, IgM-κ) that recognizes the sialyl oligosaccharide Neu5Acα2,6Galß1,4GlcNAc as an epitope on glycoproteins and glycolipids. In the present study, we developed an antibody (clone ID: AFR45, IgM-κ) that recognizes Neu5Acα2,3Galß1,4GlcNAc/Glc as an epitope on glycoproteins and glycolipids and compared the nucleotide and amino acid sequences of the immunoglobulin gene variable regions with those of FR9. The heavy chain variable (VH) regions of FR9 and AFR45 were encoded by different VH gene segments, each of which was composed of a characteristic D gene segment. The major differences between VH genes encoding various antibodies deposited in public databases and FR9 and AFR45 were identified in the D gene segment, indicating that D genes play a critical role in determining the epitope specificity of these antibodies. Surprisingly, although FR9 and AFR45 were obtained independently from different mice immunized with different immunogens, the light chain variable (VL) region nucleotide sequences were identical. The VL gene consisted of Igkv4-57 and Igkj4 gene segments (Igkv4-57j4), the sequences of which were identical to VL genes for a number of antibodies against meningococcal group C capsular polysaccharide deposited in public databases. As this polysaccharide is a sialic acid homopolymer, these results indicate that Igkv4-57j4 encodes a VL common to immunoglobulins that recognize sialylated glycans.

Interactions between Amino Acids and Zirconia Modified with Ethylenediaminetetra(methylenephosphonic acid): Mechanistic Insights into the Selective Binding of Antibodies.

Zirconia modified with ethylenediaminetetra(methylenephosphonic acid) (EDTMP) has an affinity for antibodies, including immunoglobulin G (IgG) and immunoglobulin M (IgM). However, little is known about the mechanism underlying antibody selectivity. In this study, we examined the interactions of EDTMP-modified zirconia with proteinogenic amino acids using chromatographic and batch methods to gain mechanistic insights into antibody selectivity at the amino acid level. We demonstrated that EDTMP-modified zirconia has an affinity for amino acids with a positively charged side chain, especially lysine. Similar trends were observed for oligopeptides. This affinity was reduced by the addition of sodium phosphate or sodium polyphosphates. Thus, the antibody selectivity of EDTMP-modified zirconia is primarily ascribable to electrostatic attractions between the EDTMP moieties of the zirconia surfaces and the constant region of antibodies that are rich in lysine residues. Consistent with this, the human IgG antibody has a higher adsorption ability onto EDTMP-modified zirconia than the rabbit IgG antibody, which has fewer lysine residues in the constant region. These findings are useful not only for improving antibody purification but also for developing new applications, including purification of proteins tagged with positively charged amino acid residues.

Preparation of Protein-Peptide-Calcium Phosphate Composites for Controlled Protein Release.

Protein-peptide-calcium phosphate composites were developed for achieving sustainable and controlled protein release. Bovine serum albumin (BSA) as a model acidic protein was efficiently encapsulated with basic polypeptides such as polylysine and polyarginine during the precipitation of calcium phosphate (CaP). The prepared composites were fully characterized in terms of their morphologies, crystallinities, and the porosity of their structures, and from these analyses, it was observed that there are no significant differences between the composites. Scanning transmission electron microscopy and energy dispersive X-ray spectroscopy analysis indicated a homogeneous distribution of nitrogen and sulfur, confirming the uniform distribution of BSA and polypeptide in the CaP composite. In vitro release studies demonstrated that the composite prepared with the peptides α-polylysine and polyarginine were suitable for the gradual release of the protein BSA, while those containing ε-polylysine and no peptide were unsuitable for protein release. Additionally, these composites showed high hemocompatibility for mouse red blood cells, and the osteoblast-like cell proliferation and spread in media with the composites prepared using BSA and α-polylysine showed similar tendencies to medium with no composite. From these results, protein-peptide-CaP composites are expected to be useful as highly biocompatible protein delivery agents.

Physician requests by patients with malignant pleural mesothelioma in Japan.

BACKGROUND: Malignant pleural mesothelioma (MPM) is a fatal and rare disease that is caused by the inhalation of asbestos. Treatment and care requests made by MPM patients to their physicians were collected and analyzed. METHODS: This cross-sectional survey was part of a larger study (N = 133) regarding the quality of life of MPM patients. Specific responses to two open-ended questions related to patients' requests regarding treatment and care were quantified, analyzed and divided into categories based on content. RESULTS: Responses (N = 217) from MPM patients (N = 73) were categorized into 24 subcategories and then abstracted into 6 categories. The majority of requests were related to patient-physician communication. Patients wanted clear and understandable explanations about MPM and wanted their physician to deliver treatment based on the patient's perspective by accepting and empathizing with their anxiety and pain. Patients expected physicians to be dedicated to their care and establish an improved medical support system for MPM patients. CONCLUSION: Patients with MPM had a variety of unmet needs from their physicians. Physicians who provide care to MPM patients should receive training in both communication skills and stress management. A multidisciplinary care system that includes respiratory and palliative care for MPM patients should be established.

Hydroxyapatite Formation on Self-Assembling Peptides with Differing Secondary Structures and Their Selective Adsorption for Proteins.

Self-assembling peptides have been employed as biotemplates for biomineralization, as the morphologies and sizes of the inorganic materials can be easily controlled. We synthesized two types of highly ordered self-assembling peptides with different secondary structures and investigated the effects of secondary structures on hydroxyapatite (HAp) biomineralization of peptide templates. All as-synthesized HAp-peptides have a selective protein adsorption capacity for basic protein (e.g., cytochrome c and lysozyme). Moreover, the selectivity was improved as peptide amounts increased. In particular, peptide-HAp templated on ß-sheet peptides adsorbed more cytochrome c than peptide-HAp with α-helix structures, due to the greater than 2-times carboxyl group density at their surfaces. It can be expected that self-assembled peptide-templated HAp may be used as carriers for protein immobilization in biosensing and bioseparation applications and as enzyme-stabilizing agents.

Quality of life of survivors of malignant pleural mesothelioma in Japan: a cross sectional study.

BACKGROUND: Previous studies have indicated that people with malignant pleural mesothelioma (MPM) have a poor quality of life (QOL); however, information about the QOL of people with MPM in Japan is anecdotal. The aims of this study were to investigate the QOL of survivors of MPM in Japan and to determine the factors that correlate with their QOL. METHODS: This was a cross sectional study. The included patients were those diagnosed with MPM in Japan. We created a self-administered questionnaire consisting of 64 questions. The questionnaires were sent to hospitals and patient advocacy groups, distributed to the patients, completed, and sent back to the researchers by postal mail. QOL was assessed with the European Organization for Research and Treatment of Cancer 16 questionnaire (QLQ) and the short version of the core domains of the Comprehensive Quality of Life Outcome questionnaire (CoQoLo). RESULTS: In total, 133 questionnaires were collected. The QLQ assessments demonstrated that the survivors of MPM most frequently complained of fatigue, pain, sleep disturbances, and dyspnea. The symptom scales were acceptable, but the functional scales were significantly poorer for the patients with poor performance statuses (PSs). The short CoQoLo assessment was very unfavorable for 'Being free from physical pain.' Being a long-term survivor and a survivor with a poor PS were significantly correlated with poor global health status. CONCLUSIONS: Survivors of MPM have impaired function, a variety of symptoms, and lower QOL. Survivors of MPM, even those in good physical condition, need broad support.

Evaluation of Urinary Stone Composition and Differentiation between Urinary Stones and Phleboliths Using Single-source Dual-energy Computed Tomography.

The aim of this study was to investigate the utility of single-source dual-energy computed tomography (SS-DECT) composition analysis in characterizing different types of urinary stones and differentiating them from phleboliths. This study included 29 patients with urinary stones who were scheduled for surgery. All patients were scanned, first using single-energy computed tomography acquisition and then DECT acquisition on SS-DECT. Dual-energy data were archived to a Gemstone spectral imaging (GSI) viewer (GE Healthcare, Milwaukee, WI, USA). Hounsfield units (HU) and effective atomic numbers (Zeff) were estimated using the GSI viewer. The results of dual-energy analysis were compared with the biochemical constitution of the stones. The chemical analysis determined that the stones included 32 calcium-based, 6 cystine and 1 struvite stone. Both HU and Zeff values were helpful in differentiating calcium-based stones from cystine and struvite stones and phleboliths. The Zeff values of phleboliths were significantly higher than those for struvite and cystine stones, whereas it was difficult to distinguish phleboliths from struvite and cystine stones using the HU values. Composition analysis using SS-DECT is helpful for distinguishing urinary stone types and discriminating phleboliths from urinary stones. Zeff values may be more useful than HU values for differentiating urinary stones from phleboliths.

Asbestosis and other pulmonary fibrosis in asbestos-exposed workers: high-resolution CT features with pathological correlations.

OBJECTIVE: The purpose was to identify distinguishing CT features of pathologically diagnosed asbestosis, and correlate diagnostic confidence with asbestos body burden. METHODS: Thirty-three workers (mean age at CT: 73 years) with clinical diagnoses of asbestosis, who were autopsied (n = 30) or underwent lobectomy (n = 3), were collected. Two radiologists independently scored high-resolution CT images for various CT findings and the likelihood of asbestosis was scored. Two pathologists reviewed the pathology specimens and scored the confidence of their diagnoses. Asbestos body count was correlated with CT and pathology scores. RESULTS: Pathologically, 15 cases were diagnosed as asbestosis and 18 cases with various lung fibroses other than asbestosis. On CT, only the score of the subpleural curvilinear lines was significantly higher in asbestosis (p = 0.03). Accuracy of CT diagnosis of asbestosis with a high confidence ranged from 0.73 to 0.79. Asbestos body count positively correlated with CT likelihood of asbestosis (r = 0.503, p = 0.003), and with the confidence level of pathological diagnosis (r = 0.637, p < 0.001). CONCLUSIONS: Subpleural curvilinear lines were the only clue for the diagnosis of asbestosis. However, this was complicated by other lung fibrosis, especially at low asbestos body burden. KEY POINTS: • Various patterns of pulmonary fibrosis occurred in asbestos-exposed workers. • The fibre burden in lungs paralleled confident CT diagnosis of asbestosis. • The fibre burden in lungs paralleled confident pathological diagnosis of asbestosis. • Subpleural curvilinear lines were an important CT finding favouring asbestosis.

A novel PI3K inhibitor iMDK suppresses non-small cell lung Cancer cooperatively with A MEK inhibitor.

The PI3K-AKT pathway is expected to be a therapeutic target for non-small cell lung cancer (NSCLC) treatment. We previously reported that a novel PI3K inhibitor iMDK suppressed NSCLC cells in vitro and in vivo without harming normal cells and mice. Unexpectedly, iMDK activated the MAPK pathway, including ERK, in the NSCLC cells. Since iMDK did not eradicate such NSCLC cells completely, it is possible that the activated MAPK pathway confers resistance to the NSCLC cells against cell death induced by iMDK. In the present study, we assessed whether suppressing of iMDK-mediated activation of the MAPK pathway would enhance anti-tumorigenic activity of iMDK. PD0325901, a MAPK inhibitor, suppressed the MAPK pathway induced by iMDK and cooperatively inhibited cell viability and colony formation of NSCLC cells by inducing apoptosis in vitro. HUVEC tube formation, representing angiogenic processes in vitro, was also cooperatively inhibited by the combinatorial treatment of iMDK and PD0325901. The combinatorial treatment of iMDK with PD0325901 cooperatively suppressed tumor growth and tumor-associated angiogenesis in a lung cancer xenograft model in vivo. Here, we demonstrate a novel treatment strategy using iMDK and PD0325901 to eradicate NSCLC.

Immobilization of an Enzyme Into Nano-Space of Nanostructured Carbon and Evaluation as Electrochemical Sensors.

The aims of this study are immobilization of formaldehyde dehydrogenase (FDH) into nano-space of nanostructured carbon and evaluation as a possible sensor detecting low concentration formaldehyde. In order to understand the effect of carbon pore size on activity and stability of FDH, mesoporous carbon (MC), originally made in our lab, and commercially available ketjen black (KB) were used in this study. Enzyme activity and electrochemical sensing ability of FDH encapsulated into such two carbon materials were compared. Our original MC resulted in favourable in some evaluated conditions but not in other conditions. MC adsorbed FDH less than KB, but enzyme activity was higher on MC per FDH. Stability against methanol increased on MC, but stability against water was rather lower on MC. Electrochemical sensing ability toward formaldehyde resulted in much better on KB, which was able to detect the sub-ppb level of formaldehyde. Consequently, such dependence is resulted by available nano-space of carbon, and so tuning the pore size of carbon is an important factor in order to develop enzyme based electrochemical sensors with high sensitivity and stability.

Pilot Analysis of Asbestos-induced Diffuse Pleural Thickening with Respiratory Compromise.

We investigated the clinical features of asbestos-induced diffuse pleural thickening (DPT) with severe respiratory compromise. We conducted a retrospective study of consecutive subjects with asbestos-induced DPT. Medical data such as initial symptoms, radiological findings, respiratory function test results, and clinical course were collected and analyzed. There were 24 patients between 2003 and 2012. All were men, and the median age at the development of DPT was 74 years. The top occupational category associated with asbestos exposure was dockyard workers. The median duration of asbestos exposure was 35.0 years, and the median latency from first exposure to the onset of DPT was 49.0 years. There were no significant differences in respiratory function test results between the higher and lower Brinkman index groups or between unilateral and bilateral DPT. Thirteen patients had a history of benign asbestos pleural effusion (BAPE), and the median duration from pleural fluid accumulation to DPT with severe respiratory compromise was 28.4 months. DPT with severe respiratory compromise can develop after a long latency following occupational asbestos exposure and a history of BAPE.

Asbestos-related diffuse pleural thickening.

BACKGROUND: The clinical features of asbestos-related diffuse pleural thickening (DPT) remain unclear. OBJECTIVES: To clarify the association between radiological findings of DPT and respiratory function. METHODS: Medical data from patients with asbestos-related DPT were collected, including their history of occupational or neighborhood asbestos exposure, initial symptoms, modified Medical Research Council dyspnea grade, smoking history, radiological findings, and respiratory function test results. RESULTS: There were 106 DPT patients between 2005 and 2010 [i.e. 103 men (97.2%) and 3 women (2.8%)]. The median age at diagnosis was 69 years (range 46-88). Patient occupations related to asbestos exposure included: asbestos product manufacturing (n = 17); the shipbuilding industry (n = 14); the construction industry (n = 13); heat insulation work (n = 12); plumbing, asbestos spraying, and electrical work (n = 7 each), and transportation and demolition work (n = 4 each). The median duration of asbestos exposure was 25 years (range 2-54), and the median latency period before the onset of DPT was 46 years (range 25-66). Involvement of the costophrenic angle (CPA) was also negatively correlated with the percent vital capacity (%VC; r = -0.448, p < 0.01). Pleural thickness and the craniocaudal and horizontal extension of pleural thickening, as determined by chest computed tomography (CT), were also negatively correlated with %VC (r = -0.226, p < 0.05; r = -0.409, p < 0.01, and r = -0.408, p < 0.01, respectively). CONCLUSIONS: DPT develops after a long latency period following occupational asbestos exposure and causes marked respiratory dysfunction. The extension of DPT should be evaluated by chest CT, and chest X-ray would be important for the evaluation of the involvement of the CPA.

[Examination of Optimal Frequency Processing in X-ray Images for Occult Femoral Neck Fractures].

PURPOSE: Osteosclerotic images are known as an image appearance of occult femoral neck fractures in X-ray images. The aim of this study is to investigate frequency enhancement processing that improves the visibility of the osteosclerotic image. METHODS: We acquired three sclerotic bone images with different thicknesses, and self-made bone equivalent phantoms were set up on a pelvic phantom. The frequency processing type and high-density enhancement coefficients were applied to the X-ray images taken at RF-A(1.0, 2.0), C(2.0, 4.0), D(1.0), and H(2.0, 4.0). For the physical index, we compared the difference in signal values between the sclerotic and background normal bone. We evaluated the preference using Scheffé's paired comparison methods for the visual index. RESULTS: For the physical index, RF-C(4.0) had the most significant signal value difference for all 3 bone stiffness images. For the visual index, RF-C(4.0) showed the highest preference. CONCLUSION: Using frequency-enhanced processing, RF-C(4.0) was suggested to improve the visibility of the osteosclerosis image.

A case of hemorrhagic Meckel's diverticulum diagnosed by transabdominal ultrasound.

A 23-year-old man with a history of anemia of unknown cause was referred to our hospital. He had experienced melena three times: at 6 months, 10 years, and 20 years of age. He underwent upper and lower gastrointestinal endoscopy at 10 and 20 years of age, and small intestinal capsule endoscopy twice at 20 years of age, but the site of bleeding could not be identified. At first, a transabdominal ultrasound was performed for suspected Meckel's diverticulum. A cystic diverticulum was found in the ileum, with an apertural diameter of 5 mm and a total size of 4 cm. The cyst showed an area of loss of wall stratification, which appeared to be an ulcer scar. Based on these observations, we diagnosed anemia resulting from a hemorrhagic Meckel's diverticulum and performed laparoscopic resection. Postoperative histopathology revealed ectopic gastric mucosa and ulcer formation within the Meckel's diverticulum, which was thought to be the cause of the bleeding. Meckel's diverticulum should be considered in cases of hemorrhage in young patients. A transabdominal ultrasound as a screening test detected a diverticulum with an ulcer scar in the ileum, which led to the identification of the underlying disease.

A case of strangulated bowel obstruction in which transabdominal ultrasound was useful for preoperative diagnosis.

A 74-year-old man presented to the emergency department with the chief complaint of abdominal pain. A computed tomography scan showed paralytic ileus. An ileostomy tube was placed, but the symptoms of bowel obstruction did not improve. Two days after admission, the patient's renal function deteriorated. Transabdominal ultrasound (TUS) showed linear high-intensity echoes consistent with a fibrotic band and microbubbles suggestive of circulatory disturbance in the dilated intestinal tract. Subsequent contrast-enhanced ultrasound revealed circulatory disturbance of the small bowel wall. Emergency surgery was performed under the diagnosis of strangulated ileus. Intraoperative examination revealed that the terminal ileum was strangulated by a fibrotic band from the retroperitoneum, which was confirmed by TUS. The fibrotic band was resected, the strangulation was released, and ileocecal resection was performed. Postoperatively, intestinal peristalsis was rapidly restored. TUS was able to depict the fibrotic band, which could not be detected by a computed tomography scan, allowing the patient to undergo immediate surgical treatment. We herein report this case of strangulated bowel obstruction in which TUS and contrast-enhanced ultrasound were useful in preoperative assessment of the patient's condition.