Combined Immune Checkpoint Blockade Enhances Antiviral Immunity against Bovine Leukemia Virus.

Bovine leukemia virus (BLV) is a retrovirus that causes enzootic bovine leukosis (EBL) in cattle and is widespread in many countries, including Japan. Recent studies have revealed that the expression of immunoinhibitory molecules, such as programmed death-1 (PD-1) and PD-ligand 1, plays a critical role in immunosuppression and disease progression during BLV infection. In addition, a preliminary study has suggested that another immunoinhibitory molecule, T-cell immunoglobulin domain and mucin domain-3 (TIM-3), is involved in immunosuppression during BLV infection. Therefore, this study was designed to further elucidate the immunoinhibitory role of immune checkpoint molecules in BLV infection. TIM-3 expression was upregulated on peripheral CD4+ and CD8+ T cells in BLV-infected cattle. Interestingly, in EBL cattle, CD4+ and CD8+ T cells infiltrating lymphomas expressed TIM-3. TIM-3 and PD-1 were upregulated and coexpressed in peripheral CD4+ and CD8+ T cells from BLV-infected cattle. Blockade by anti-bovine TIM-3 monoclonal antibody increased CD69 expression on T cells and gamma interferon (IFN-γ) production from peripheral blood mononuclear cells from BLV-infected cattle. A syncytium formation assay also demonstrated the antiviral effects of TIM-3 blockade against BLV infection. The combined inhibition of TIM-3 and PD-1 pathways significantly enhanced IFN-γ production and antiviral efficacy compared to inhibition alone. In conclusion, the combined blockade of TIM-3 and PD-1 pathways shows strong immune activation and antiviral effects and has potential as a novel therapeutic method for BLV infection. IMPORTANCE Enzootic bovine leukosis caused by bovine leukemia virus (BLV) is an important viral disease in cattle, causing severe economic losses to the cattle industry worldwide. The molecular mechanisms of BLV-host interactions are complex. Previously, it was found that immune checkpoint molecules, such as PD-1, suppress BLV-specific Th1 responses as the disease progresses. To date, most studies have focused only on how PD-1 facilitates escape from host immunity in BLV-infected cattle and the antiviral effects of the PD-1 blockade. In contrast, how T-cell immunoglobulin domain and mucin domain-3 (TIM-3), another immune checkpoint molecule, regulates anti-BLV immune responses is rarely reported. It is also unclear why PD-1 inhibition alone was insufficient to exert anti-BLV effects in previous clinical studies. In this study, the expression profile of TIM-3 in T cells derived from BLV-infected cattle suggested that TIM-3 upregulation is a cause of immunosuppression in infected cattle. Based on these results, anti-TIM-3 antibody was used to experimentally evaluate its function in influencing immunity against BLV. Results indicated that TIM-3 upregulation induced by BLV infection suppressed T-cell activation and antiviral cytokine production. Some T cells coexpressed PD-1 and TIM-3, indicating that simultaneous inhibition of PD-1 and TIM-3 with their respective antibodies synergistically restored antiviral immunity. This study could open new avenues for treating bovine chronic infections.

Development of a high-affinity anti-bovine PD-1 rabbit-bovine chimeric antibody using an efficient selection and large production system.

Immune checkpoint molecules PD-1/PD-L1 cause T-cell exhaustion and contribute to disease progression in chronic infections of cattle. We established monoclonal antibodies (mAbs) that specifically inhibit the binding of bovine PD-1/PD-L1; however, conventional anti-PD-1 mAbs are not suitable as therapeutic agents because of their low binding affinity to antigen. In addition, their sensitivity for the detection of bovine PD-1 is low and their use for immunostaining PD-1 is limited. To address these issues, we established two anti-bovine PD-1 rabbit mAbs (1F10F1 and 4F5F2) and its chimeric form using bovine IgG1 (Boch1D10F1), which exhibit high binding affinity. One of the rabbit mAb 1D10F1 binds more strongly to bovine PD-1 compared with a conventional anti-PD-1 mAb (5D2) and exhibits marked inhibitory activity on the PD-1/PD-L1 interaction. In addition, PD-1 expression in bovine T cells could be detected with higher sensitivity by flow cytometry using 1D10F1. Furthermore, we established higher-producing cells of Boch1D10F1 and succeeded in the mass production of Boch1D10F1. Boch1D10F1 exhibited a similar binding affinity to bovine PD-1 and the inhibitory activity on PD-1/PD-L1 binding compared with 1D10F1. The immune activation by Boch1D10F1 was also confirmed by the enhancement of IFN-γ production. Finally, Boch1D10F1 was administered to bovine leukemia virus-infected cows to determine its antiviral effect. In conclusion, the high-affinity anti-PD-1 antibody developed in this study represents a powerful tool for detecting and inhibiting bovine PD-1 and is a candidate for PD-1-targeted immunotherapy in cattle.

Changes of Working Responsibilities and Intentions of Industrial Physicians (Graduates of University of Occupational and Environmental Health, Japan) in a Comparison Between 2001, 2008 and 2015 Questionnaire Analyses.

For the purpose of understanding the current conditions of the duties of industrial physicians and the consciousness of graduates of the University of Occupational and Environmental Health, Japan (UOEH) engaged in industry, we performed a questionnaire survey in July, 2001 and July, 2008 and reported the results (J UOEH 2009 31: 281-91). A similar survey was carried out in July, 2015. We dispatched the questionnaire to industrial physicians and physicians in occupational health organizations who had graduated from UOEH and got the replies. The investigation asked about their career, their activities, and how they thought about their duties. We compared the three years and got the following results: 1) The ratio of respondents who were satisfied with the salary or official post was 38.3, 48.1, 65.4% in each investigation, respectively. 2) The ratio of the respondents whose official post and rank would not be promoted in the future was 25.3, 28.4, 32.3%, respectively. 3) The ratio of respondents satisfied with the relationship with the superior and the industrial health staff was 70.8, 80.3, 86.1%, respectively. The investigation performed every seven years since July, 2001 showed that the ratio of the graduates of UOEH whose official post and rank would not be promoted in the future had gradually increased, while the ratio of graduates who were satisfied with the relationship with the superior and the industrial health staff had also gradually increased.

Initial experience of laparoscopic pelvic exenteration and comparison with conventional open surgery.

BACKGROUND: Generalization of laparoscopic pelvic surgery has brought about profound knowledge of the pelvic anatomy and has encouraged expansion of indications for laparoscopic surgery to extended pelvic surgery. Pelvic exenteration (PE) is still a demanding surgical procedure and remains an essential technique for pelvic surgery although minimally invasive and function-preserving surgery is in the mainstream of surgical treatment. However, the techniques of laparoscopic PE (LPE) have been rarely explained nor has its feasibility been fully evaluated. The aim of this study was to describe important technical points and to assess the feasibility of LPE for pelvic malignancies. METHODS: Data on 67 patients with pelvic malignancies, who underwent PE between June 2006 and August 2014, were analyzed retrospectively. LPE has been indicated since 2013. Patients were divided into the LPE group (n = 9) and the conventional open PE (OPE) group (n = 58). RESULTS: Operative time in the LPE and OPE groups was similar (935 vs. 883 min, p = 0.398). Intraoperative blood loss in the LPE group was significantly less than that in the OPE group (830 vs. 2769 ml, p = 0.003). Pathological R0 resection rate was similar in both groups (77.8 vs. 75.9%). Overall incidence of any complication and major complications were much lower in the LPE group (66.7 and 0%) compared to the OPE group (89.7 and 32.8%), although not statistically significant (p = 0.094 and 0.053, respectively). Postoperative hospital stay was significantly shorter in the LPE group than in the OPE group (27 vs. 43 days, p = 0.003). CONCLUSIONS: We confirmed that LPE for pelvic malignancies resulted in less blood loss, a lower complication rate, and shorter postoperative hospital stay compared to OPE. LPE performed by an experienced pelvic surgeon was safe and efficient, and might be a promising option for carefully selected patients.

The feasibility of laparoscopic extended pelvic surgery for rectal cancer.

PURPOSE: The present study aimed to assess the safety and feasibility of laparoscopic extended pelvic surgery for primary or recurrent rectal cancer. METHODS: The data on 77 patients, who underwent extended pelvic surgery between February 2008 and June 2014, were retrospectively analyzed. The patients were divided, based on their treatment history, into an open surgery (OS) group (n = 41) and a laparoscopic surgery (LS) group (n = 36). RESULTS: The operative time in the LS group was significantly longer than that in the OS group (766 vs. 561 min; p < 0.001). In contrast, the LS group was associated with a significantly lower volume of intraoperative blood loss (195 vs. 923 ml; p < 0.001), fluid balance (5.38 vs. 8.23 ml/kg/h; p < 0.001) and rate of complications (40.0 vs. 68.3 %; p = 0.035), and a significantly shorter postoperative hospital stay. The postoperative levels of colloid osmotic pressure and albumin were significantly higher in the LS group. CONCLUSION: The operative time of the LS group was longer than that of the OS group; however, the LS group experienced less blood loss and fewer complications. Moreover, LS was associated with a reduction in intraoperative infusions and a reduced fluid balance, which maintained homeostasis.

The effects of bevacizumab on intestinal anastomotic healing in rabbits.

PURPOSES: The aim of this study was to investigate the effects of the preoperative administration of BV on the healing process of intestinal anastomosis in a rabbit model. METHODS: Twenty male white rabbits were randomly divided into two groups. The control group received saline 1 week before surgery, and the BV group received intravenous BV 1 week before surgery. Each rabbit underwent an enteroenterostomy and a colocolostomy. On postoperative day 7, the bursting pressures of the anastomoses, CD31 and α-smooth muscle actin (α-SMA) staining by immunohistochemistry, the gene expression of α-SMA, and collagen deposition using Picrosirius Red at the site of anastomosis were evaluated. RESULTS: The bursting pressure of small bowel anastomoses was significantly lower in the BV group than in the control group (control 184 ± 10 mmHg vs. BV 140 ± 9 mmHg; p = 0.004). The microvessel counts in the anastomotic tissue were significantly lower in the BV group than in the control group in both the small bowel (p = 0.023) and colon (p = 0.008). The expression of α-SMA, and the degree of collagen deposition decreased in the anastomotic tissue in the BV group compared with the control group. CONCLUSION: The preoperative use of BV may therefore negatively affect the rigidity of intestinal anastomosis.

Clinical Significance of Para-Aortic Lymph Node Dissection for Advanced or Metastatic Colorectal Cancer in the Current Era of Modern Chemotherapy.

BACKGROUND/AIMS: Surgical resection is not generally indicated for para-aortic lymph node (PALN) metastasis from colorectal cancer. However, the clinical significance of PALN dissection (PALND) in the current era of modern chemotherapy has not been fully discussed. METHODS: Between November 2006 and February 2013, 14 patients underwent PALND for colorectal cancer and were proven as having pathological PALN metastasis. The median follow-up was 33.2 months. RESULTS: Primary location was the right-colon in 2 patients, and the left-colon or rectum in 12 patients. The timing of metastasis was metachronous in 5 patients and synchronous in 9 patients. Eleven patients (79%) received perioperative aggressive modern chemotherapy. Neoadjuvant chemotherapy with targeted drugs was introduced in 9 patients (64%) and 6 patients received adjuvant chemotherapy. Recurrence after PALND occurred in 12 patients (86%). The most common site was the lung in 6 patients (43%). The 1- and 3-year disease-free survivals were 39.3 and 7.9%, respectively. The 3-year overall survival were 41.2%. CONCLUSION: The recurrence rate after PALND for strictly selected patients was quite high even in the current era of modern chemotherapy. However, some patients achieved long-term survival or could be cured. Therefore, we should re-evaluate the efficacy of PALND in a larger prospective study.

[University of Occupational and Environmental Health, Japan: 2013 alumni physician statistics].

The University of Occupational and Environmental Health, Japan (UOEH) is a publically funded medical school for occupational health physician and researchers. All students are funded through six years of medical school and commit to a nine-year health services of occupational medicine after graduation. Between 1984 and 2013, the number of physicians graduating from UOEH was 2,875. Of these, 473 were medical residents in our postgraduate residency programs and 526 were occupational health physicians affiliated with different companies. A total of 252 graduates became UOEH research/teaching staff, 219 obtained employment as physicians at Rousai hospital (hospital operated by Japan Labour Health and Welfare Organization), and 84 entered industrial hygiene and health check organizations. UOEH alumni are distributed throughout Japan in large workplaces/ business establishments. Many physicians continued in their job after the nine-year obligation, thus contributing to the increasing number of occupational health physicians during recent decades. We suggest that funding and postgraduate residency programs contribute to the increasing numbers of physicians, but further analysis needs to be done.

Effects of Lacticaseibacillus paracasei Strain Shirota on Daytime Performance in Healthy Office Workers: A Double-Blind, Randomized, Crossover, Placebo-Controlled Trial.

Lacticaseibacillus paracasei strain Shirota (LcS) modulates psychological homeostasis via the gut-brain axis. To explore the possible efficacy of LcS for improving daytime performance, we conducted a double-blind, randomized, crossover, placebo-controlled study of 12 healthy office workers with sleep complaints. The participants received fermented milk containing viable LcS (daily intake of 1 × 1011 colony-forming units) and non-fermented placebo milk, each for a 4-week period. In the last week of each period, the participants underwent assessments of their subjective mood and measurements of physiological state indicators via an electroencephalogram (EEG) and heart rate variability in the morning and afternoon. The attention score in the afternoon as assessed by the visual analog scale was higher in the LcS intake period than in the placebo intake period (p = 0.041). Theta power on EEG measured at rest or during an auditory oddball task in the afternoon was significantly lower in the LcS period than in the placebo period (p = 0.025 and 0.009, respectively). The change rate of theta power was associated with the change in attention score. Treatment-associated changes were also observed in heart rate and the sympathetic nerve activity index. These results indicate that LcS has possible efficacy for improving daytime performance, supported by observations of the related physiological state indicators.

Enhancement of Vaccine-Induced T-Cell Responses by PD-L1 Blockade in Calves.

Interactions between programmed death 1 (PD-1) and PD-ligand 1 (PD-L1) cause functional exhaustion of T cells by inducing inhibitory signals, thereby attenuating effector functions of T cells. We have developed an anti-bovine PD-L1 blocking antibody (Ab) and have demonstrated that blockade of the interaction between PD-1 and PD-L1 reactivates T-cell responses in cattle. In the present study, we examined the potential utility of PD-1/PD-L1-targeted immunotherapy in enhancing T-cell responses to vaccination. Calves were inoculated with a hexavalent live-attenuated viral vaccine against bovine respiratory infections in combination with treatment with an anti-PD-L1 Ab. The expression kinetics of PD-1 in T cells and T-cell responses to viral antigens were measured before and after vaccination to evaluate the adjuvant effect of anti-PD-L1 Ab. PD-1 expression was upregulated in vaccinated calves after the administration of a booster vaccination. The activation status of CD4+, CD8+, and γδTCR+ T cells was enhanced by the combination of vaccination and PD-L1 blockade. In addition, IFN-γ responses to viral antigens were increased following combinatorial vaccination with PD-L1 blockade. In conclusion, the blockade of the PD-1/PD-L1 interaction enhances T-cell responses induced by vaccination in cattle, indicating the potential utility of anti-PD-L1 Ab in improving the efficacy of current vaccination programs.

Elevated Lipoprotein(a) as a potential residual risk factor associated with lipid-rich coronary atheroma in patients with type 2 diabetes and coronary artery disease on statin treatment: Insights from the REASSURE-NIRS registry.

BACKGROUND AND AIMS: The residual risk of atherosclerotic cardiovascular disease (ASCVD) in patients with diabetes on statin therapy warrants identification of other pro-atherogenic drivers. Lipoprotein(a) [Lp(a)] promotes the formation of necrotic cores within vessel walls. Given that patients with diabetes have an Lp(a)-associated ASCVD risk, Lp(a) might lead to plaque vulnerability in patients with diabetes on statin therapy. METHODS: We analyzed target lesions that underwent PCI in 312 patients with coronary artery disease (CAD) on statin treatment from the REASSURE-NIRS registry (NCT04864171). Maximum 4-mm lipid-core-burden index (maxLCBI4mm) in target lesions was measured with near-infrared spectroscopy (NIRS) imaging. The relationship between Lp(a) levels and maxLCBI4mm was investigated in patients with and without diabetes. RESULTS: High-intensity statin use (p = 0.49) and on-treatment low-density lipoprotein cholesterol (LDL-C) (p = 0.32) and Lp(a) levels (p = 0.09) were comparable between patients with and without diabetes. Lp(a) levels were significantly associated with maxLCBI4mm in patients with diabetes (p = 0.01) but not in patients without diabetes (p = 0.96). Multivariate analysis showed that LDL-C levels (p = 0.03) predict maxLCBI4mm in patients without diabetes, but not Lp(a) levels (p = 0.91). Both LDL-C (p = 0.01) and Lp(a) (p = 0.04) levels were independent predictors of maxLCBI4mm in patients with diabetes. Even in patients with diabetes achieving LDL-C <1.8 mmol/L (70 mg/dL), Lp(a) levels remained associated with maxLCBI4mm (p = 0.04). CONCLUSIONS: A significant relationship between Lp(a) and maxLCBI4mm exists in patients with diabetes and CAD on statin treatment, even with LDL-C <1.8 mmol/L (70 mg/dL). Lp(a) might be associated with more vulnerable coronary atheroma in patients with diabetes despite receiving statin therapy.

[A case of pancreatic metastasis from breast cancer during multimodality therapy].

We report a case of pancreatic metastasis from breast cancer during multimodality therapy. A 53-year-old woman received right breast-conserving surgery for invasive ductal carcinoma and then chemo-radiotherapy for liver, brain, bone, neck and axillary lymphnodes, mediastinum, pleural, and spinal cord metastasis. Although she then survived in a tumor-free condition, a blood examination performed 4 years after the surgery showed an elevated serum amylase level. Abdominal CT and US revealed swelling of the pancreas head and body with main pancreatic duct dilatation of the pancreatic tail. ERCP showed diffuse stenosis of the extrahepatic bile duct and the main pancreatic duct of the pancreatic head and body. Immunohistochemical staining of the biopsy specimen from the pancreatic head confirmed pancreatic metastasis from breast cancer. Despite the intensive chemotherapy including trastuzumab, she died 2 years after the onset of pancreatic metastasis. Metastatic breast cancer to the pancreas is very rare. However, considering the recent advances of multimodality therapy for breast cancer, this clinical state may become more common.

A TLR7 agonist activates bovine Th1 response and exerts antiviral activity against bovine leukemia virus.

Bovine leukemia virus (BLV) infection is a bovine chronic infection caused by BLV, a member of the genus Deltaretrovirus. In this study, we examined the immunomodulatory effects of GS-9620, a toll-like receptor (TLR) 7 agonist, in cattle (Bos taurus) and its therapeutic potential for treating BLV infection. GS-9620 induced cytokine production in peripheral blood mononuclear cells (PBMCs) as well as CD80 expression in CD11c+ cells and increased CD69 and interferon (IFN)-γ expressions in T cells. Removing CD11c+ cells from PBMCs decreased CD69 expression in T cells in the presence of GS-9620. These results suggest that TLR7 agonism promotes T-cell activation via CD11c+ cells. Analyses using PBMCs from BLV-infected cattle revealed that TLR7 expression in CD11c+ cells was upregulated during late-stage BLV infection. Furthermore, GS-9620 increased IFN-γ and TNF-α production and inhibited syncytium formation in vitro, suggesting that GS-9620 may be used to treat BLV infection.

The enhancement of Th1 immune response by anti-PD-L1 antibody in cattle infected with Mycobacterium avium subsp. paratuberculosis.

Johne's disease, caused by Mycobacterium avium subsp. paratuberculosis (MAP), is a chronic enteritis of ruminants. Previous studies have shown that programmed death-ligand 1 (PD-L1) is associated with the disease progression, and PD-L1 blockade activates MAP-specific Th1 responses in vitro. Here, we performed anti-PD-L1 antibody administration using 2 MAP-infected cattle at the late subclinical stage of infection. After administration, bacterial shedding was reduced or maintained at a low level. Additionally, MAP-specific Th1 cytokine production was upregulated, and CD69 expression was increased in T cells. Collectively, the treatment has a potential as a novel control method against Johne's disease.

Direct evidence of the preventive effect of milk replacer-based probiotic feeding in calves against severe diarrhea.

Diarrhea is a major cause of death in calves and this is linked directly to economic loss in the cattle industry. Fermented milk replacer (FMR) has been used widely in clinical settings for calf feeding to improve its health and growth. However, the protective efficacy of FMR on calf diarrhea remains unclear. In this study, we verified the preventive effects of FMR feeding on calf diarrhea using an experimental infection model of bovine rotavirus (BRV) in newborn calves and a field study in dairy farms with calf diarrhea. In addition, we evaluated the protective efficacy of lactic acid bacteria-supplemented milk replacer (LAB-MR) in an experimental infection model. In the experimental infection, calves fed FMR or high-concentrated LAB-MR had diarrhea, but the water content of feces was lower and more stable than that of calves fed normal milk replacer. The amount of milk intake also decreased temporarily, but recovered immediately in the FMR- and LAB-MR-fed calves. As compared with the control calves, FMR- or LAB-MR-fed calves showed less severe or reduced histopathological lesions of enteritis in the intestinal mucosa. In a field study using dairy calves, FMR feeding significantly reduced the incidence of enteritis, mortality from enteritis, duration of a series of treatment for enteritis, number of consultations, and cost of medical care for the disease. These results suggest that feeding milk replacer-based probiotics to calves reduces the severity of diarrhea and tissue damage to the intestinal tract caused by BRV infection and provides significant clinical benefits to the prevention and treatment of calf diarrhea.

The association between the extent of lipidic burden and delta-fractional flow reserve: analysis from coronary physiological and near-infrared spectroscopic measures.

BACKGROUND: Vulnerable plaque features including lipidic plaque have been shown to affect fractional flow reserve (FFR). Given that formation and propagation of lipid plaque is accompanied by endothelial dysfunction which impairs vascular tone, the degree of lipidic burden may affect vasoreactivity during hyperemia, potentially leading to reduced FFR. Our aim is to elucidate the relationship of the extent of lipidic plaque burden with coronary physiological vasoreactivity measure. METHODS: We analyzed 89 subjects requeuing PCI due to angiographically intermediate coronary stenosis with FFR ≤0.80. Near-infrared spectroscopy (NIRS) and intravascular ultrasound were used to evaluate lipid-core burden index (LCBI) and atheroma volume at both target lesion (maxLCBI4mm; maximum value of LCBI within any 4 mm segments) and entire target vessel (LCBIvessel: LCBI within entire vessel). In addition to FFR, delta-FFR was measured by difference of distal coronary artery pressure/aortic pressure (Pd/Pa) between baseline and hyperemic state. RESULTS: The averaged FFR and delta-FFR was 0.74 (0.69-0.77), and 0.17±0.05, respectively. On target lesion-based analysis, maxLCBI4mm was negatively correlated to FFR (ρ=-0.213, P=0.040), and it was positively correlated to delta-FFR (ρ=0.313, P=0.002). Furthermore, target vessel-based analysis demonstrated similar relationship of LCBIvessel with FFR (ρ=-0.302, P=0.003) and delta-FFR (ρ=0.369, P<0.001). Even after adjusting clinical characteristics and lesion/vessel features, delta-FFR (by 0.10 increase) was independently associated with maxLCBI4mm (ß=57.2, P=0.027) and LCBIvessel (ß=24.8, P=0.007) by mixed linear model analyses. CONCLUSIONS: A greater amount of lipidic plaque burden at not only "target lesion" alone but "entire target vessel" was associated with a greater delta-FFR. The accumulation of lipidic plaque materials at both local site and entire vessel may impair hyperemia-induced vasoreactivity, which causes a reduced FFR.

The feasibility and limitation of coronary computed tomographic angiography imaging to identify coronary lipid-rich atheroma in vivo: Findings from near-infrared spectroscopy analysis.

BACKGROUND: Coronary computed tomography angiography (CCTA) non-invasively visualizes lipid-rich plaque. However, this ability is not fully validated in vivo. The current study aimed to elucidate the association of CCTA features with near-infrared spectroscopy-derived lipidic plaque measure in patients with coronary artery disease. METHODS: 95 coronary lesions (culprit/non-culprit = 51/44) in 35 CAD subjects were evaluated by CCTA and NIRS imaging. CT density, positive remodeling, spotty calcification, napkin-ring sign and NIRS-derived maximum 4-mm lipid-core burden index (maxLCBI4mm) were analyzed by two independent physicians. The association of CCTA-derived plaque features with maxLCBI4mm ≥ 400 was evaluated. RESULTS: The median CT density and maxLCBI4mm were 57.7 Hounsfield units (HU) and 304, respectively. CT density (r = -0.75, p < 0.001) and remodeling index (RI) (r = 0.58, p < 0.001) were significantly associated with maxLCBI4mm, respectively. Although napkin-ring sign (p < 0.001) showed higher prevalence of maxLCBI4mm ≥ 400 than those without it, spotty calcification did not (p = 0.13). On multivariable analysis, CT density [odds ratio (OR) = 0.95, 95% confidence interval (CI) = 0.93-0.97; p < 0.001] and positive remodeling [OR = 7.71, 95%CI = 1.37-43.41, p = 0.02] independently predicted maxLCBI4mm ≥ 400. Receiver operating characteristic curve analysis demonstrated CT density <32.9 HU (AUC = 0.92, sensitivity = 85.7%, specificity = 91.7%) and RI ≥ 1.08 (AUC = 0.83, sensitivity = 74.3%, specificity = 85.0%) as optimal cut-off values of maxLCBI4mm ≥ 400. Of note, only 52.6% at lesions with one of these plaque features exhibited maxLCBI4mm ≥ 400, whereas the frequency of maxLCBI4mm ≥ 400 was highest at those with both features (88.5%, p < 0.001 for trend). CONCLUSIONS: CT density <32.9 HU and RI ≥ 1.08 were associated with lipid-rich plaque on NIRS imaging. Our findings underscore the synergistic value of CT density and positive remodeling to detect lipid-rich plaque by CCTA.

[Necessary number of dedicated industrial physicians in Japan: evaluated from the establishment and enterprise census].

The required number of dedicated industrial physicians has been enacted by the Ministry of Health, Labour and Welfare in Japan. However, the number of workplaces requiring an appointment of industrial physicians is unknown, because of the lack of official publication from the Ministry of Health, Labor and Welfare. The Bureau of Statistics in the Ministry of Internal Affairs and Communications has published the Establishment and Enterprise Census. Based on this statistical data, we estimated the minimal necessary number of dedicated industrial physicians in Japan. There are 1,228 workplaces where 1,000 workers or more are regularly employed. Considering that the number of hazardous workplaces where 500-999 workers are regularly employed is around 1,500, it is estimated that at least 2,000-2,500 dedicated industrial physicians are required in Japan.

[Optic lesions in patients with epiphora during S-1 therapy].

PURPOSE: To elucidate the features of optic lesions in patients with epiphora during S-1 therapy. PATIENTS: Twelve patients with epiphora in 123 patients during S-1 therapy. RESULTS: Age range was 38-84 years (mean 68.4 years). There were 4 cases in 81 men (5%) and 8 in 42 women (19%). Epiphora occurred significantly more often in women (p=0.02). The administration period was from 10 days to 36 months. Lesions were superficial punctate keratopathy in 10 cases with cornea and obstruction of inferior punctum in 2, stenosis of nasolacrimal duct in 1 and suspected occlusion of the nasolacrimal duct in 1 with lacrimal duct. Local therapy was eye drops in all cases. Of the whole 12 patients, S-1 was continued or discontinued in 6 each of all 12 cases, in 5 each of 10 cases with superficial punctate keratopathy, and in 2 each of 4 cases with lacrimal duct lesions. Epiphora/optic lesions improved with a range from 10 days to 1.5 months in cases of discontinuation and with that from 2 weeks to 1 month in cases of continuation. DISCUSSION: Our results revealed superficial punctate keratopathy in many cases, lacrimal duct lesions in a few cases, and discontinuation of medication provided improvement of optic events. CONCLUSIONS: When epiphora is observed in patients on S-1 therapy, it is necessary to assess optic disorders by an opthalmologist immediately because of suspicion of injury to the cornea and lacrimal duct.

[A case of recurrent colon cancer with angina pectoris and interstitial pneumonia during cetuximab therapy with death by carcinomatous lymphangiosis].

The case was a man in his 60s with no past history of heart and lung. Chest tightness was felt during the first course of cetuximab therapy for recurrent colon cancer. He was diagnosed as having vasospastic angina, and administration of vasodilatation agents was done. After the therapy, no chest pain attack was seen. Chemotherapy was continued. After 3 courses, fever elevation, chest tightness and dyspnea were seen. Chest X-ray and CT revealed diffuse interstitial pneumonia in bilateral lung. Although steroid pulse therapy and intensive therapy with mandatory ventilation were performed, he died of respiratory failure. Pathological findings of autopsy revealed remarkable metastasis of cancer cells to the bilateral lungs accompanied chiefly with carcinomatous lymphangiosis. Furthermore, acute and subacute interstitial pneumonia with diffuse alveolar damage were seen in the background of the lungs. Cardiopulmonary disorder as well as skin disorder should be considered as possible adverse events of cetuximab therapy.