Efficacy of human resource development program for young industry personnel who will be involved in future medical device development.

BACKGROUND: Training next-generation personnel from small/medium enterprises (SMEs) is an urgent issue in promoting medical device research and development (R&D). Since 2014 we have engaged in governmentally funded human resource development program for medical/non-medical SMEs, and have assessed its effectiveness by analyzing self-evaluation of achievement level (SEAL) data obtained before and after the training course. METHODS: Human resource development experts interviewed 34 key opinion leaders with deep knowledge of medical device R&D from industry, government, and academia. The skills required for R&D personnel were written down, and a set of skills was created by making a greatest common measure in the list of common elements among them. Using that skill sets, skill evaluations were conducted on trainees at "Osaka University Training Course," twice before participation and after completion of the entire program using SEAL assessment. RESULTS: There were 97 men and 25 women, with one-third in the'30 s. Among them, 61 participants (50%) were from R&D divisions, and 32 (26%) were from business/sales divisions. 94 (77%) were from medical SMEs, and 28 (23%) were from non-medical SMEs (new entry). After completing the training course, significant growth was observed in every item of both Soft and Hard skill sets. Especially in new entry SME members, a striking improvement was observed in practical medical knowledge to enhance communication with medical doctors (p < 0.0001). CONCLUSION: Our training course, though 7-day-short in total, showed that both Soft and Hard skills could be improved in young medical/non-medical SME members. Further assessment is needed to establish the necessary skill sets for our future partners from industries, to foster the creation of innovative medical devices through med-tech collaboration.

Efficacy of electrocoagulation hemostasis: a study on the optimal usage of the very-low-voltage mode.

BACKGROUND: The very-low-voltage (VLV) mode in electrosurgery can stably and deeply energize tissues even if the local electrical resistance changes with energization. Therefore, in electrosurgical hemostasis, the VLV mode is more reliable than other coagulation modes. In clinical practice, the appropriate use of combined saline drip and blood suction under the VLV mode can further enhance coagulation ability. However, the detailed mechanism is not known. The current study aimed to evaluate the association between electrosurgical activation time (ET) and hemostatic tissue effect (HTE) under the VLV mode. Further, the effect of saline drip and suction on power consumption and HTE was validated. METHODS: Twelve female pigs weighing 35 kg were included in the experiment. A liver hemorrhage model was established via an open abdominal procedure, and hemostasis in the hemorrhagic lesion was attempted using the VLV mode under different conditions (ET: 3, 6, 9, and 12 s, with/without saline drip and/or continuous suction). Electrical data (such as voltage, current, and resistance) during coagulation were extracted. Then, the vertical/horizontal extent of HTE was assessed, and the hemostasis outcome (successful or failed) was recorded. RESULTS: The vertical/horizontal HTE, power consumption, and integrated current value were positively correlated with the ET. The coagulation depth deepened with saline drip (p < 0.01). However, it was not affected by continuous suction (p = 0.20). The HTE area increased with saline drip (p < 0.01) and decreased with suction (p < 0.01). The power consumption and integrated current increased with saline drip (p < 0.01) and decreased with suction (p < 0.01). The success rate of hemostasis decreased with saline drip alone (31of 48 trials [success rate = 64.5%] in the saline drip group and 44/48 trials (success rate = 91.7%) in the control group). However, it improved with continuous suction (46/48 trials [success rate = 95.8%]). CONCLUSION: The electrosurgical activation time was positively correlated with hemostatic tissue effect. Saline drip increased heat transfer efficiency but decreased the success rate of hemostasis. Therefore, the use of continuous suction in addition to saline drip increased hemostatic efficiency.

[Dermatomyositis with squamous cell carcinoma of the lungs secondary to nivolumab treatment: a case report].

A 74-year-old man was administered nivolumab to treat recurrent squamous cell carcinoma of the lungs. He developed fatigue, redness on the front of his neck, muscle weakness, and difficulty in swallowing after receiving the third course of nivolumab. Physical and neurological examinations showed proximal limb muscle weakness, periorbital erythema, and erythema of the front of his neck as well as fingers. Laboratory investigations revealed elevated serum CK and aldolase levels, and he was diagnosed with dermatomyositis. We initiated steroid pulse therapy and intravenous immunoglobulin therapy; however, he died of advanced lung cancer. Immune checkpoint inhibitor-induced neuromuscular disease is increasingly being observed in clinical practice. We report a rare case of dermatomyositis with squamous cell carcinoma of the lungs secondary to nivolumab treatment.

Volume-recorded hologram modeling, point-spread function analysis, and segmented adaptive equalization for holographic data storage.

The rapid growth in digital information throughout the world has demanded storage with a high capacity and high transfer rate. Holographic data storage (HDS) is one promising candidate for next-generation data storage because of its high potential in capacity and transfer rate. However, high-volume HDS usually suffers from inter-signal interference (ISI). Here, we first develop volume recording and reproduction models for HDS. We reveal through optical simulations based on the developed models that ISI differs not only between pages but also between areas on the same page. Then, we develop an advanced equalization technique called segmented adaptive equalization (SAE) that takes into account inter-area ISI difference. We can improve signal quality much more than conventional equalization techniques by using SAE. We are confident that SAE can enhance the realization of HDS.

Effect of professional dental prophylaxis on the surface gloss and roughness of CAD/CAM restorative materials.

BACKGROUND: This study aimed to evaluate the effect of dental prophylaxis on the surface gloss and roughness of different indirect restorative materials for computer-aided design/computer-aided manufacturing (CAD/CAM): two types of CAD/CAM composite resin blocks (Shofu Block HC and Estelite Block) and two types of CAD/CAM ceramic blocks (IPS Empress CAD and Celtra DUO). MATERIAL AND METHODS: After polishing the CAD/CAM blocks and applying prophylaxis pastes, professional dental prophylaxis was performed using four different experimental protocols (n = 5 each): mechanical cleaning with Merssage Regular for 10 s four times (Group 1); four cycles of mechanical cleaning with Merssage Regular for 10 s and Merssage Fine for 10 s (Group 2); four cycles of mechanical cleaning with Merssage Regular for 10 s and Merssage Fine for 30 s (Group 3); and mechanical cleaning with Merssage Fine for 10 s four times (Group 4). A glossmeter was used to measure surface gloss before and after mechanical cleaning, and a contact stylus profilometer was used to measure surface roughness (Ra). RESULTS: Polishing with prophylactic paste led to a significant reduction in surface gloss and increase in surface roughness among resin composite blocks, whereas the polishing-related change in surface gloss or roughness was smaller in Celtra DUO, a zirconia-reinforced lithium silicate block. CONCLUSIONS: Changes in surface gloss and roughness due to polishing with a prophylactic paste containing large particles were not improved by subsequent polishing with a prophylactic paste containing fine particles. Key words:CAD/CAM, professional dental prophylaxis, prophylactic paste, surface gloss, surface roughness.

A Novel Endoscopic Catheter for "Laparoscopy-Like" Irrigation and Suction: Its Research and Development Process and Clinical Evaluation.

BACKGROUND: Inspired by natural orifice translumenal endoscopic surgery (NOTES), the authors launched a development of novel endoscopic irrigation and suction (I/S) catheter for "laparoscopy-like" I/S in flexible gastrointestinal (GI) endoscopy. The aims were to describe its basic research and development (R&D) process and to estimate its performance in both preclinical and clinical settings. METHODS: In basic R&D phase, a layout of side hole at apex nozzle of endoscopic I/S (EIS) catheter were theoretically calculated and designed. Material of nozzle was selected based on the strength analysis. The performance of final prototype EIS catheter was then assessed preclinically in the porcine stomach, to compare with conventional endoscopic "tip irrigation" and "tip suction" as control. After regulatory clearance, safety and feasibility of I/S using EIS catheter were clinically assessed by endoscopists in small number of patients. RESULTS: Bench tests revealed 0.4 mm in diameter, 24 holes, and 6-8 holes per circumference as most suitable layout of side holes, and polyetheretherketone as an optimal nozzle material, respectively. Time to inject 500 mL saline with the EIS catheter was significantly shorter than tip irrigation (101 ± 3.1 seconds versus 154 ± 3.1 seconds; P < .05). The EIS suction was significantly weaker than conventional endoscopic tip suction, though it remained within the practical range. No mucosal injuries were noted in the EIS suction. In clinical assessments for human use, no adverse events were observed, and high degree of satisfaction for endoscopists was obtained. CONCLUSION: The newly developed EIS catheter is safely used with satisfactory performance in flexible GI endoscopy.

Efficacy of vinorelbine and zoledronate combination therapy against postoperative recurrence of lung cancer.

UNLABELLED: We report a case of a response to long-term treatment with vinorelbine and zoledronate in a patient with lymph node and multiple bone metastases after lung cancer surgery. CASE: The patient was a 70-year-old male initially examined by a local physician for an abnormal shadow that had been detected on a chest X-ray during a screening examination. CT revealed a mass shadow measuring 28 mm in diameter in the left S10, and because lung cancer was suspected, the patient was admitted to our hospital for the first time and examined. Lung cancer was diagnosed intraoperatively, and left lower lobectomy was performed. The pathological stage was III a, and postoperative adjuvant chemotherapy was performed, but recurrences in the form of lymph node and multiple bone metastases were detected. After diagnosis of the recurrence, the patient was treated with long-term vinorelbine (VNR)biweekly and zoledronate (ZOL) monthly, and a response was obtained. CONCLUSIONS: A patient with postoperative recurrence of lung cancer associated with multiple bone metastases responded to combination chemotherapy with VNR and ZOL. VNR was effective against postoperative recurrence in an elderly lung cancer patient with complications, and could be administered safely long-term. ZOL also had a favorable protective effect against skeletal-related events (SREs) in lung cancer, and the results suggested that it also had an antitumor effect in this patient.

Dental-care utilization patterns and factors associated with regular dental check-ups in elderly.

The purpose of this study was to investigate dental care utilization patterns in the elderly and to evaluate factors associated with regular dental check-ups in this age group. A total of 211 elderly people (50 men, 161 women) aged between 60 and 98 years were investigated. A cross-sectional survey by questionnaire was carried out on visitors to the Mihama Ikiiki Plaza (an institution for the elderly) in the city of Chiba, Japan between July and September, 2008. Items on the questionnaire included self-reported oral status, use of dentures, use of regular medication, oral problems, cleaning of teeth/dentures and dental care utilization patterns. The results showed that 135 (64.0%) of the responders had visited a dentist in the past year, 185 (87.7%) had visited the same dentist and 85 (40.3%) had had regular dental check-ups. A stepwise multiple logistic regression analysis adjusting for age and sex revealed that the factors associated with regular dental check-ups were significantly higher ADLs (odds ratio (OR)=0.439 in the partially insured and 0.192 in the fully insured in comparison with healthy subjects, p=0.0012), visiting the same dentist (OR=11.978 in comparison with not visiting the same dentist, p=0.0183) and cleaning teeth/dentures three or more times per day (OR=1.962 in comparison with cleaning them two or fewer times per day, p=0.0368). In this study, a higher ADL, visiting the same dentist and cleaning teeth/dentures three or more times per day were associated with having regular dental check-ups in the elderly. The best predictive factor for regular dental check-ups was a high ADL in the elderly.

Factors associated with root surface caries in elderly.

The purpose of this study was to determine the risk factors for root surface caries in the elderly and to evaluate the factors associated with gingival recession, one of the main risk factors for root surface caries. A total of 153 elderly people (35 men, 118 women) aged between 60 and 94 years (73.5+/-7.5 years) were surveyed. All participants were relatively healthy elderly who did not need special care in their daily lives. The survey was conducted in Chiba prefecture, Japan, and oral examinations and a questionnaire with face-to-face interviews were also carried out. Correlation analysis revealed that number of present teeth (p<0.001), gingival recession (p<0.001), bleeding on probing (p<0.001) and presence or absence of dentures (p<0.05) were significantly correlated with number of root surface caries. Stepwise multiple linear regression analysis for root surface caries revealed that the risk factors for increasing numbers of teeth with root surface caries were number of teeth with gingival recession (p<0.0001), bleeding on probing (p=0.0017) and self-reported dry mouth (p=0.0454). Sex (p<0.05), number of present teeth (p<0.001), bleeding on probing (p<0.01), the presence or absence of systemic disease (p<0.01), dentures (p<0.01), drinking alcohol (p<0.01) and smoking (p<0.01) were significantly correlated with amount of gingival recession by correlation analysis. Moreover, the risk factors for increasing number of teeth with gingival recession were living in an institution (p=0.0244), number of present teeth (p<0.0001) and smoking (p=0.0037), as determined by stepwise multiple linear regression analysis for gingival recession.

Influence of finishing/polishing procedures on the surface texture of two resin composites.

This study compared surface roughness and gloss produced by different finishing/polishing procedures for two resin composites, Clearfil AP-X (AP-X) and Estelite Sigma (ES). A total of 70 composite discs (n=35 for each resin composite) were prepared and divided at random into seven finishing/polishing groups (n=5): glass-pressed control; using a super-fine-grit diamond bur (SF); using CompoMaster (CM) after SF-finishing (SF+CM); using White Point (WP) after SF-finishing (SF+WP); using CM after SF+WP-finishing (SF+WP+CM); using Stainbuster (SB) after SF-finishing (SF+SB); and using CM after SF+SB-finishing (SF+SB+CM). After the finishing/polishing procedures, average surface roughness (R(a)) and surface gloss (Gs(60( degrees ))) of all specimens were assessed with a surface profilometer and specimen gloss meter, respectively. Glass-pressed controls for both AP-X and ES composites showed the best surface finish in terms of both R(a) and Gs(60( degrees )). SF-finishing produced the roughest surface and led to almost complete loss of gloss. While additional polishing with CM reduced R(a) and increased Gs(60( degrees )), the additional finishing effect of WP or SB between SF-finishing and CM-polishing was not found for either AP-X or ES.

Malignant pleural mesothelioma in a 14-year-old boy with right aortic arch.

We report successful surgery for malignant pleural mesothelioma (MPM) in a 14-year-old boy with right aortic arch. Pleural biopsy by video-assisted thoracic surgery yielded a diagnosis of MPM, epithelial type. As the disease was not changed after combination chemotherapy with three cycles of cisplatin and gemcitabine, we performed left extrapleural pneumonectomy, including resection of the pericardium and diaphragm for MPM, and aortopexy for right aortic arch. The postoperative course was uneventful, and the patient has remained alive without disease for 10 months postoperatively.

[A possibility of overcoming local tumor immune tolerance by radiofrequency ablation in combination with intratumoral injection of naïve dendritic cell].

Recently we reported the systemic antitumor efficacy of intratumoral naive dendritic cell injection (IT-DC) in combination with local photodynamic therapy in Clinical Cancer Research 2006. In general, tumor cells secrete several immune suppression cytokines which could induce immune tolerance in a tumor microenvironment. The rationale and advantages of IT DC in combination with conventional antitumor therapy are as follows: (1) dying tumor cells release some tumor antigens, (2) sufficient number of DC recruiting occurs at tumor site, (3) there is naive DC capturing some tumor antigens in vivo, (4) DC activation by inflammatory cytokines are released from dying tumor cells, and (5) DC migration happens in regional lymph nodes and induces adoptive tumor immunity. Conventional antitumor therapy before IT DC could destroy the immune tolerance at a tumor site and induce durable DC vaccination. In this report, we demonstrated the mechanism of (4) and (5) by radiofrequency ablation plus IT DC using mouse tumor model.

Peripheral leukocytes with HLA-DR+/CD8- phenotype are associated with prognosis in patients with lung cancer.

BACKGROUND: We have previously reported that the most significant immunological prognostic factors in patients with lung cancer are the percentages of peripheral HLA-DR+ lymphocytes. PATIENTS AND METHODS: We performed two-color flow cytometric analyses using two combinations of double-staining to identify lymphocyte phenotypes HLA-DR/CD4 and HLA-DR/CD8, and examined the correlation between the expression of these subsets and survival in 51 patients with non-small cell lung cancer. RESULTS: The percentages of HLA-DR+, HLA-DR+/CD4+ (activated helper/inducer T cells) and HLA-DR+/CD8+ (activated cytotoxic/suppressor T cells) did not correlate with survival. However, survival was better when the percentage of HLA-DR+/CD8- was below normal (p = 0.0267). The 4-year survival rate in patients with high and low percentages of peripheral HLA-DR+/CD8- lymphocytes was 26.0% and 53.2%, respectively. CONCLUSION: The subset of HLA-DR+/CD8- lymphocytes powerfully predicts the survival of patients with non-small cell lung cancer.

Significance of expression of TGF-beta in pulmonary metastasis in non-small cell lung cancer tissues.

Recent studies have evaluated the cytokine network involved in the local immune response to tumors. In addition to infiltrating inflammatory cells, tumors also produce cytokines and growth factors that may alter tumor growth and tumor immunogenicity. Ninety-one samples of NSCLC were used in this study. We measured the expression of VEGF, TNF-alpha, TGF-beta, IL-6, IL-8, IL-12, INF-gamma, and MCP-1 in NSCLC tissues, by ELISA. The expression of IL-6 and IL-8 were significantly higher in squamous cell carcinoma than in adenocarcinoma (p=0.016 and p<0.001, respectively). The expression of TGF-beta, MCP-1 and IL-8 were significantly higher in pulmonary metastasis positive than negative cases (p=0.002, p=0.001, and p=0.008, respectively). In multivariate logistic regression analysis, the expression of TGF-beta was an independent risk factor for the occurrence of pulmonary metastasis (p=0.008, 95% CI=1.002-1.011). We confirmed that tumor infiltrating stromal cells were major sources of TGF-beta by immunohistochemical analysis. The expression of VEGF and IL-8 were significantly higher in cases with central necrosis (p=0.006 and p=0.011, respectively). We speculated that TGF-beta expression in tumor infiltrating stromal cells may regulate the occurrence of spontaneous pulmonary metastasis in NSCLC. (Ann Thorac Cardiovasc Surg 2003; 9: 295-300)

Comparison of immunohistochemistry and real-time reverse transcription-polymerase chain reaction to detect expression of carcinoembryonic antigen in lung cancer.

Real-time reverse transcription-polymerase chain reaction (RT-PCR) can detect mRNA of carcinoembryonic antigen (CEA) quantitatively. We compared the serum concentration, localization, and mRNA expression of CEA to determine the relationship between these three factors in patients with lung cancer. Tumors from ten patients who underwent surgery were analyzed. The serum concentration of CEA was measured before initiating therapy using a quantitative latex agglutination reaction. Immunohistochemical staining of pathologic specimens of resected tumors was performed to localize CEA. Real-time RT-PCR to detect mRNA of CEA was performed for isolating RNA from a piece of fresh-frozen tumor. Positivity for CEA production was 20% for serum, 60% for immunohistochemistry, and 80% for real-time RT-PCR. Thus, the percentage of mRNA and protein positivity of CEA in lung cancer was much higher than for the serum CEA concentration. No statistically significant correlation between the serum CEA concentration and the amount of mRNA expression was found (p=0.0932). Real-time RT-PCR is useful to quantify specific mRNA expression from a small piece of tissue.

Chromosomal instability detected by fluorescence in situ hybridization in surgical specimens of non-small cell lung cancer is associated with poor survival.

PURPOSE: Chromosomal instability (CIN) in non-small cell lung cancer (NSCLC) has yet to be well studied. We examined the relationship between CIN detected by fluorescence in situ hybridization and survival in patients with NSCLC. EXPERIMENTAL DESIGN: Touch preparations from 50 surgical specimens of NSCLC were studied. Tumors included 34 adenocarcinomas, 15 squamous cell carcinomas, and 1 large cell carcinoma. The pathologic stage was IA in 14, IB in 17, IIB in 8, IIIA in 9, and IIIB in 2 cases. Enumeration of chromosomes 3, 10, 11, and 17 was used to determine which tumors carried CIN. The association between CIN and survival was also analyzed. RESULTS: Disomy was most common, but tetrasomy and trisomy of the examined chromosomes were seen frequently. Fourteen tumors (28%) showed heterogeneity of all four chromosomes examined and were judged to be carrying CIN. Both univariate and multivariate analyses revealed that two factors, lymph node metastasis and CIN, were significant poor prognostic factors. CONCLUSIONS: CIN in NSCLC detected by fluorescence in situ hybridization is an independent factor predicting a poor prognosis.

cDNA microarray analysis of gene expression in pathologic Stage IA nonsmall cell lung carcinomas.

BACKGROUND: The relationship between altered gene expression and tumor progression in lung carcinoma has yet to be characterized. Gene expression in pathologic Stage IA nonsmall cell lung carcinoma specimens was analyzed using a cDNA microarray. METHODS: Surgical specimens were used for the current study. The pathologic stage was IA (AJCC) in five tumors, IB in two, IIA in one, IIIA in one, and IIIB in one. Seven tumor specimens were adenocarcinomas and three were squamous cell carcinomas. Paired mRNAs from carcinoma cells and normal lung tissue specimens from the same lobe were labeled with different fluorochromes during cDNA probe synthesis in a reverse-transcription reaction. Both synthesized, labeled cDNA probes were mixed and hybridized to the microarray. The signal intensity of each spot was measured by laser scanner and gene expression was quantified as the tumor-to-normal fluorescence ratio (T:N ratio). The gene was overexpressed when the T:N ratio was greater than 2.0 and underexpressed when the ratio was less than 0.5. RESULTS: Overall, 40 (9.4%) of the 425 genes evaluated were overexpressed, and 74 genes (17.4%) were underexpressed. In the 5 Stage IA tumor specimens, 31 (7.3%) genes were overexpressed and 76 (17.9%) were underexpressed. For 30 genes (7.1%), expression was different in Stage IA tumor specimens compared with more advanced tumor specimens. CONCLUSIONS: The cDNA microarray system showed that numerous alterations of gene expression were present in early-stage nonsmall cell lung carcinoma specimens.

Correlation between encoded protein overexpression and copy number of the HER2 gene with survival in non-small cell lung cancer.

The HER2 oncogene, which encodes the tyrosine kinase receptor, is commonly overexpressed in several types of cancer. Treatment using a humanized monoclonal antibody bound to HER2 product is becoming standard therapy for advanced breast cancer. Overexpression occurs in approximately 30% of non-small cell lung cancers (NSCLCs) and has been associated with poor prognosis. However, the frequency of a genetic aberration in the HER2 gene in lung cancer and the association between gene amplification and prognosis are poorly defined. To clarify these relationships, we simultaneously analyzed protein overexpression by immunohistochemistry (IHC) and determined the gene copy number by FISH in 50 surgical specimens of NSCLC. A low-grade increase in the copy number (3 to 8 copies) of the HER2 gene was detected in 44% of tumors. Most represented polysomy of chromosome 17. Protein overexpression was observed in 26%. Overexpression was detected in adenocarcinoma more frequently than in squamous cell carcinoma. No significant correlation was observed between copy number increase and overexpression. Neither gene copy number increase nor overexpression correlated with survival. We conclude that the significance of HER2 status in NSCLC is different from that in breast cancer because high-grade amplification occurs rarely.

Immunologic parameters as significant prognostic factors in lung cancer.

Immunologic prognostic factors in lung cancer have not been fully clarified. We report the results of a prospective study undertaken to clarify the correlation between various cellular immunologic parameters and the survival of lung cancer patients. A total of 287 lung cancer patients were enrolled in this study. Representative in vitro cellular immune activities including lymphoblastogenesis and natural killer cell activities, in addition to the percentage of main lymphocyte subsets (CD3, CD4, CD8, HLA-DR, and Fc gamma R III on T cells) in the peripheral blood were evaluated before the initiation of therapy. The immune factors that influence the prognosis were analyzed by the log rank test and a multivariate analysis using the Cox proportional hazards model. Univariate analysis of the survival curves revealed a significant difference with regard to disease stage (P<0.0001), age (P=0.007), gender (P=0.0037), and HLA-DR (%) (P=0.048), when all the non-small cell lung cancer (NSCLC) patients (n=257) were analyzed together. This analysis, based on the histologic type, revealed that HLA-DR (%) was a significant predictor of survival in squamous cell carcinoma (P=0.0013) and small cell carcinoma (P=0.0025). A decreased CD4/CD8 ratio in small cell carcinoma (P=0.0062) and male gender in adenocarcinoma (P=0.0086) were factors associated with a worse prognosis. Multivariate analysis identified a significant correlation between survival and disease stage (P<0.0001) and gender (P=0.0243) in adenocarcinoma, disease stage (P<0.0001), age (P=0.0436) and HLA-DR (%) (P=0.0142) in squamous cell carcinoma, and HLA-DR (%) (P=0.0212) and CD4/CD8 (P=0.0112) in small cell carcinoma, suggesting independent prognostic significance. A variety of immunologic indices have prognostic significance for the different types of lung cancer. Among these, the HLA-DR (%) in the peripheral blood is the most reliable factor for squamous cell carcinoma and small cell carcinoma.