Long-term Survival After Endoscopic Resection For Gastric Cancer: Real-world Evidence From a Multicenter Prospective Cohort.

BACKGROUND & AIMS: We aimed to clarify the long-term outcomes of endoscopic resection (ER) for early gastric cancers (EGCs) based on pathological curability in a multicenter prospective cohort study. METHODS: We analyzed the long-term outcomes of 9054 patients with 10,021 EGCs undergoing ER between July 2010 and June 2012. Primary endpoint was the 5-year overall survival (OS). The hazard ratio for all-cause mortality was calculated using the Cox proportional hazards model. We also compared the 5-year OS with the expected one calculated for the surgically resected patients with EGC. If the lower limit of the 95% confidence interval (CI) of the 5-year OS exceeded the expected 5-year OS minus a margin of 5% (threshold 5-year OS), ER was considered to be effective. Pathological curability was categorized into en bloc resection, negative margins, and negative lymphovascular invasion: differentiated-type, pT1a, ulcer negative, ≤2 cm (Category A1); differentiated-type, pT1a, ulcer negative, >2 cm or ulcer positive, ≤3 cm (Category A2); undifferentiated-type, pT1a, ulcer negative, ≤2 cm (Category A3); differentiated-type, pT1b (SM1), ≤3 cm (Category B); or noncurative resections (Category C). RESULTS: Overall, the 5-year OS was 89.0% (95% CI, 88.3%-89.6%). In a multivariate analysis, no significant differences were observed when the hazard ratio of Categories A2, A3, and B were compared with that of A1. In all the pathological curability categories, the lower limit of the 95% CI for the 5-year OS exceeded the threshold 5-year OS. CONCLUSION: ER can be recommended as a standard treatment for patients with EGCs fulfilling Category A2, A3, and B, as well as A1 (UMIN Clinical Trial Registry, UMIN000005871).

Discovery of ASP5878: Synthesis and structure-activity relationships of pyrimidine derivatives as pan-FGFRs inhibitors with improved metabolic stability and suppressed hERG channel inhibitory activity.

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer patients harboring genetic alterations in FGFR3. We identified pyrimidine derivative ASP5878 (27) with improved metabolic stability and suppressed human ether-á-go-go related gene (hERG) channel inhibitory activity by the optimization of lead compound 1. Based on prediction of the metabolites of 1, an ether linker was introduced in place of the ethylene linker to improve metabolic stability. Moreover, conversion of the phenyl moiety into the pyrazole ring resulted in the suppression of hERG channel inhibitory activity, possibly due to the weaker π-π stacking interaction with Phe656 in the hERG channel by a reduction in π-electrical density of the aromatic ring. ASP5878 showed potent in vitro FGFR3 enzyme and cell growth inhibitory activity, and in vivo FGFR3 autophosphorylation inhibitory activity. Moreover, ASP5878 did not affect the hERG current up to 10 µM by in vitro patch-clamp assay, and a single oral dose of ASP5878 at 1, 10, and 100 mg/kg did not induce serious adverse effects on the central nervous, cardiovascular, and respiratory systems in dogs. Furthermore, ASP5878 exhibited lower total clearance than hepatic blood flow and high oral bioavailability in rats and dogs, and moderate brain penetration in rats.

Synthesis and structure-activity relationships of pyrimidine derivatives as potent and orally active FGFR3 inhibitors with both increased systemic exposure and enhanced in vitro potency.

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of patients with bladder cancer harboring genetic alterations in FGFR3. We identified pyrimidine derivative 20b, which induced tumor regression following oral administration to a bladder cancer xenograft mouse model. Compound 20b was discovered by optimizing lead compound 1, which we reported previously. Specifically, reducing the molecular size of the substituent at the 4-position and replacing the linker of the 5-position in the pyrimidine scaffold resulted in an increase in systemic exposure. Furthermore, introduction of two fluorine atoms into the 3,5-dimethoxyphenyl ring enhanced FGFR3 inhibitory activity. Molecular dynamics (MD) simulation of 20b suggested that the fluorine atom interacts with the main chain NH moiety of Asp635 via a hydrogen bond.

Structure-based drug design of 1,3,5-triazine and pyrimidine derivatives as novel FGFR3 inhibitors with high selectivity over VEGFR2.

Fibroblast growth factor receptor 3 (FGFR3) is an attractive therapeutic target for the treatment of bladder cancer. We identified 1,3,5-triazine derivative 18b and pyrimidine derivative 40a as novel structures with potent and highly selective FGFR3 inhibitory activity over vascular endothelial growth factor receptor 2 (VEGFR2) using a structure-based drug design (SBDD) approach. X-ray crystal structure analysis suggests that interactions between 18b and amino acid residues located in the solvent region (Lys476 and Met488), and between 40a and Met529 located in the back pocket of FGFR3 may underlie the potent FGFR3 inhibitory activity and high kinase selectivity over VEGFR2.

Is Additional Surgery Always Sufficient for Preventing Recurrence After Endoscopic Submucosal Dissection with Curability C-2 for Early Gastric Cancer?

BACKGROUND: When a lesion does not meet the curative criteria of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC), referred to as non-curative resection or curability C-2 in the guidelines, an additional surgery is the standard therapy because of the risk of lymph node metastasis (LNM). OBJECTIVE: This study aimed to identify high-risk patients for recurrence after additional surgery for curability C-2 ESD of EGC. METHODS: This multicenter retrospective cohort study enrolled 1064 patients who underwent additional surgery after curability C-2 ESD for EGC. We evaluated the recurrence rate and the risk factors for recurrence after additional surgery in these patients. RESULTS: The 5-year recurrence rate after additional surgery was 1.3%. Multivariate Cox analysis revealed that the independent risk factors for recurrence after additional surgery were LNM (hazard ratio [HR] 32.47; p < 0.001) and vascular invasion (HR 4.75; p = 0.014). Moreover, patients with both LNM and vascular invasion had a high rate of recurrence after additional surgery (24.6% in 5 years), with a high HR (119.32) compared with those with neither LNM nor vascular invasion. Among patients with no vascular invasion, a high rate of recurrence was observed in those with N2/N3 disease according to the American Joint Committee on Cancer TNM staging system (27.3% in 5 years), in contrast with no recurrence in those with N1 disease. CONCLUSIONS: Patients with both LNM (N1-N3) and vascular invasion, as well as those with N2/N3 disease but no vascular invasion, would be candidates for adjuvant chemotherapy after additional surgery for curability C-2 ESD of EGC.

Different risk factors between early and late cancer recurrences in patients without additional surgery after noncurative endoscopic submucosal dissection for early gastric cancer.

BACKGROUND AND AIMS: Cancer recurrence is observed in some patients without additional radical surgery after endoscopic submucosal dissection (ESD) that does not fulfill the curability criteria for early gastric cancer (EGC), categorized as "noncurative resection" or "curability C-2" in the guidelines. However, time to cancer recurrence is different in such patients. Thus, we aimed to identify the risk factors of early and late cancer recurrences in these patients. METHODS: Between 2000 and 2011, this multicenter study analyzed 905 patients who were followed up without additional radical surgery after ESD for EGC categorized as curability C-2. We evaluated the risk factors for early and late cancer recurrences, separately, after ESD. The cut-off value was defined at 2 years. RESULTS: Time to cancer recurrence in the enrolled patients showed a bimodal pattern, and the 5-year cancer recurrence rate was 3.2%. Multivariate Cox analyses revealed that lymphatic invasion (hazard ratio [HR], 8.56; P = .003) was the sole independent risk factor for early cancer recurrence. Regarding late cancer recurrence, vascular invasion (HR, 4.50; P = .039) was an independent risk factor, and lymphatic invasion tended to be a risk factor (HR, 3.63; P = .069). CONCLUSIONS: This multicenter study with a large cohort demonstrated that lymphatic invasion is mainly associated with early cancer recurrence; however, vascular invasion was a risk factor only for late recurrence in patients without additional treatment after ESD for EGC categorized as curability C-2. This finding may contribute to decision making for treatment strategies after ESD, especially for patients with a relatively short life expectancy.

Age Affects Clinical Management after Noncurative Endoscopic Submucosal Dissection for Early Gastric Cancer.

BACKGROUND: Additional surgery is recommended after noncurative endoscopic submucosal dissection (ESD) for early gastric cancer due to the risk of lymph node metastasis. However, age may affect the clinical management of these patients. OBJECTIVES: The aim of our retrospective multicenter study was to clarify whether age affects decision-making after noncurative ESD and if the decision affects long-term outcomes. METHODS: Age was classified as follows: non-elderly, <70 years (n = 811); elderly, 70-79 years (n= 760); and super-elderly, ≥80 years (n = 398). Age associations with the selection for additional surgery were evaluated using logistic regression analysis. Long-term outcomes were also evaluated in each age group. RESULTS: Age was inversely related to the rate of additional surgery, which ranged from 70.0% in the non-elderly group to 20.1% in the super-elderly group (p < 0.001). On multivariate analysis, age <70 years (versus age ≥80 years) was associated with the -selection of additional surgery (OR 18.6). Overall survival (OS) in patients who underwent additional surgery was -significantly higher in the non-elderly and elderly groups (p< 0.001), whereas the difference was not significant in the super-elderly group (p = 0.23). CONCLUSIONS: Despite the fact that almost 80% of super-elderly patients did not undergo additional surgery, the difference of OS between patients with and without additional surgery was not significant only in patients ≥80 years. Therefore, establishment of criteria for selecting treatment methods after noncurative ESD in elderly patients is required.

Long-term outcomes after non-curative endoscopic submucosal dissection for early gastric cancer according to hospital volumes in Japan: a multicenter propensity-matched analysis.

BACKGROUND: There is a lack of data regarding the long-term outcomes of endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) without curative resection, and the relationship of these outcomes with hospital volumes remains unclear. This study evaluated long-term outcomes of patients who underwent ESD for EGC without curative resection according to hospital volumes in Japan. METHODS: This multicenter retrospective study evaluated 1,969 patients who did not meet the criteria of the Japanese Gastric Cancer Association for curative resection between January 2000 and August 2011. Hospitals were classified according to the annual number of ESD procedures: low- and medium-volume group (LMVG), high-volume group (HVG), and very high-volume group (VHVG). Clinicopathological features, overall survival (OS), disease-specific survival (DSS), and recurrence-free survival (RFS) were compared across groups after a generalized propensity score matching analysis. RESULTS: In 495 pairs of generalized propensity score-matched patients, the 5-year OS, DSS, and RFS rates were 81.5%, 97.9%, and 97.6% for LMVG; 86.9%, 98.2%, and 97.0% for HVG; and 85.4%, 98.5%, and 97.6% for VHVG, respectively. The 5-year DSS and RFS rates did not significantly differ among the three groups. However, 5-year OS was significantly worse in the LMVG than in the HVG and VHVG (P < 0.001 and P = 0.008, respectively). CONCLUSIONS: DSS and RFS in patients with EGC who did not meet the criteria for curative resection did not differ across hospital volumes in Japan. Even in cases in which ESD for EGC involved non-curative resection, the procedure is feasible across Japanese hospitals with different volumes.

Synthesis and Pharmacological Evaluation of 3-[(4-Oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)(phenyl)amino]propanenitrile Derivatives as Orally Active AMPA Receptor Antagonists.

In our search for novel orally active α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor antagonists, we found that conversion of an allyl group in the lead compound 2-[allyl(4-methylphenyl)amino]-4H-pyrido[3,2-e][1,3]thiazin-4-one (4) to a 2-cyanoethyl group significantly increased inhibitory activity against AMPA receptor-mediated kainate-induced toxicity in rat hippocampal cultures. Here, we synthesized 10 analogs bearing a 2-cyanoethyl group and administered them to mice to evaluate their anticonvulsant activity in maximal electroshock (MES)- and pentylenetetrazol (PTZ)-induced seizure tests, and their effects on motor coordination in a rotarod test. 3-{(4-Oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)[4-(trifluoromethoxy)phenyl]amino}propanenitrile (25) and 3-[(2,2-difluoro-2H-1,3-benzodioxol-5-yl)(4-oxo-4H-pyrido[3,2-e][1,3]thiazin-2-yl)amino]propanenitrile (27) exhibited potent anticonvulsant activity in both seizure tests and induced minor motor disturbances as indicated in the rotarod test. The protective index values of 25 and 27 for MES-induced seizures (10.7 and 12.0, respectively) and PTZ-induced seizures (6.0 and 5.6, respectively) were considerably higher compared with those of YM928 (5) and talampanel (1).

Short-term outcomes of multicenter prospective cohort study of gastric endoscopic resection: 'Real-world evidence' in Japan.

OBJECTIVES: A Japanese multicenter prospective cohort study examining endoscopic resection (ER) for early gastric cancer (EGC) has been conducted using a Web registry developed to determine the short-term and long-term outcomes based on absolute and expanded indications. We hereby present the short-term outcomes of this study. METHODS: All consecutive patients with EGC or suspected EGC undergoing ER at 41 participating institutions between July 2010 and June 2012 were enrolled and prospectively registered into the Web registry. The baseline characteristics were entered before ER, and the short-term outcomes were collected at 6 months following ER. RESULTS: Nine thousand six hundred and sixteen patients with 10 821 lesions underwent ER (endoscopic submucosal dissection [ESD]: 99.4%). The median procedure time was 76 min, and R0 resections were achieved for 91.6% of the lesions. Postoperative bleeding and intraoperative perforation occurred in 4.4% and 2.3% of the patients, respectively. Significant independent factors correlated with a longer procedure time (120 min or longer) were as follows: tumor size >20 mm, upper-third location, middle-third location, local recurrent lesion, ulcer findings, gastric tube, male gender, and submucosa. Histopathologically, 10 031 lesions were identified as common-type gastric cancers. The median tumor size was 15 mm. Noncurative resections were diagnosed for 18.3% of the lesions. Additional surgery was performed for 48.6% (824 lesions) of the 1695 noncurative ER lesions with a possible risk of lymph node (LN) metastasis. Among them, 64 (7.8%) exhibited LN metastasis. CONCLUSIONS: This multicenter prospective study showed favorable short-term outcomes for gastric ESD.

Is the eCura system useful for selecting patients who require radical surgery after noncurative endoscopic submucosal dissection for early gastric cancer? A comparative study.

BACKGROUND: We have established a risk-scoring system, termed the "eCura system," for the risk stratification of lymph node metastasis in patients who have received noncurative endoscopic submucosal dissection (ESD) for early gastric cancer (EGC). We aimed to clarify whether this system contributes to the selection of patients requiring radical surgery after ESD. METHODS: Between 2000 and 2011, 1,969 patients with noncurative ESD for EGC were included in this multicenter study. Depending on the treatment strategy after ESD, we had patients with no additional treatment (n = 905) and those with radical surgery after ESD (n = 1,064). After the application of the eCura system to these patients, cancer recurrence and cancer-specific mortality in each risk category of the system were compared between the two patient groups. RESULTS: Multivariate Cox analysis revealed that in the high-risk category, cancer recurrence was significantly higher (hazard ratio = 3.13, p = 0.024) and cancer-specific mortality tended to be higher (hazard ratio = 2.66, p = 0.063) in patients with no additional treatment than in those with radical surgery after ESD, whereas no significant differences were observed in the intermediate-risk and low-risk categories. In addition, cancer-specific survival in the low-risk category was high in both patient groups (99.6 and 99.7%). A limitation of this study is that it included a small number of cases with undifferentiated-type EGC (292 cases). CONCLUSIONS: The eCura system is a useful aid for selecting the appropriate treatment strategy after noncurative ESD for EGC. However, caution is needed when applying this system to patients with undifferentiated-type EGC.

The Role of an Undifferentiated Component in Submucosal Invasion and Submucosal Invasion Depth After Endoscopic Submucosal Dissection for Early Gastric Cancer.

BACKGROUND/AIMS: The role of an undifferentiated component in submucosal invasion and submucosal invasion depth (SID) for lymph node metastasis (LNM) of early gastric cancer (EGC) with deep submucosal invasion (SID ≥500 µm from the muscularis mucosa) after endoscopic submucosal dissection (ESD) has not been fully understood. This study aimed to clarify the risk factors (RFs), including these factors, for LNM in such patients. METHODS: We enrolled 513 patients who underwent radical surgery after ESD for EGC with deep submucosal invasion. We evaluated RFs for LNM, including an undifferentiated component in submucosal invasion and the SID, which was subdivided into 500-999, 1,000-1,499, 1,500-1,999, and ≥2,000 µm. RESULTS: LNM was detected in 7.6% of patients. Multivariate analysis revealed that an undifferentiated component in submucosal invasion (OR 2.22), in addition to tumor size >30 mm (OR 2.51) and lymphatic invasion (OR 3.07), were the independent RFs for LNM. However, the SID was not significantly associated with LNM. CONCLUSION: An undifferentiated component in submucosal invasion was one of the RFs for LNM, in contrast to SID, in patients who underwent ESD for EGC with deep submucosal invasion. This insight would be helpful in managing such patients.

Long-term oncological outcomes of submucosal manipulation during non-curative endoscopic submucosal dissection for submucosal invasive gastric cancer: a multicenter retrospective study in Japan.

BACKGROUND: Sufficient information is not available on the extent to which lymph node metastasis (LNM) and prognosis are affected by submucosal manipulation during endoscopic submucosal dissection (ESD) for submucosal invasive gastric cancer (SMGC). We aimed to identify the effects of submucosal manipulation during ESD on LNM and prognosis in patients with SMGC. METHODS: From 19 institutions in Japan, 2526 patients who failed to meet the current curative criteria for ESD between 2000 and 2011 were recruited. After exclusion, 1969 patients were remained. Based on the treatment strategy after ESD, 1064 patients underwent additional radical surgery. A total of 890 of 1064 patients with SMGC, LNM and cancer recurrence, and prognosis were retrospectively reviewed. RESULTS: The median follow-up duration was 67 months. A total of 214 patients had SM1 (depth of tumor invasion from the muscularis mucosae <500 µm) invasive cancer and 676 patients had SM2 (depth of tumor invasion from the muscularis mucosae ≥500 µm) invasive cancer. LNM was found in 84 patients (9.4%), and 14 patients (1.6%) developed cancer recurrence. The 3-year and 5-year overall survival rates were 96.1 and 91.7%, respectively. The 3-year and 5-year disease-specific survival rates were 99.3 and 98.5%, respectively. CONCLUSIONS: The rates of LNM and cancer recurrence, and prognosis of patients who underwent additional radical surgery after non-curative ESD for SMGC were excellent. Submucosal manipulation during ESD for SMGC does not seem to enhance the risk for LNM or worsen the prognosis compared to surgical series.

ASP5878, a selective FGFR inhibitor, to treat FGFR3-dependent urothelial cancer with or without chemoresistance.

FGF/FGFR gene aberrations such as amplification, mutation and fusion are associated with many types of human cancers including urothelial cancer. FGFR kinase inhibitors are expected to be a targeted therapy for urothelial cancer harboring FGFR3 gene alternations. ASP5878, a selective inhibitor of FGFR1, 2, 3 and 4 under clinical investigation, selectively inhibited cell proliferation of urothelial cancer cell lines harboring FGFR3 point mutation or fusion (UM-UC-14, RT-112, RT4 and SW 780) among 23 urothelial cancer cell lines. Furthermore, ASP5878 inhibited cell proliferation of adriamycin-resistant UM-UC-14 cell line harboring MDR1 overexpression and gemcitabine-resistant RT-112 cell line. The protein expression of c-MYC, an oncoprotein, in gemcitabine-resistant RT-112 cell line was higher than that in RT-112 parental cell line and ASP5878 decreased the c-MYC expression in both RT-112 parental and gemcitabine-resistant RT-112 cell lines. Once-daily oral administration of ASP5878 exerted potent antitumor activities in UM-UC-14, RT-112 and gemcitabine-resistant RT-112 xenograft models without affecting body weight. These findings suggest that ASP5878 has the potential to be an oral targeted therapy against urothelial cancer harboring FGFR3 fusion or FGFR3 point mutation after the acquisition of gemcitabine- or adriamycin-resistance.

A Scoring System to Stratify Curability after Endoscopic Submucosal Dissection for Early Gastric Cancer: "eCura system".

OBJECTIVES: Although radical surgery is recommended for patients not meeting the curative criteria for endoscopic submucosal dissection (ESD) of early gastric cancer (EGC) because of the potential risk of lymph node metastasis (LNM), this recommendation may be overestimated and excessive. We aimed to establish a simple scoring system for decision making after ESD. METHODS: This multicenter retrospective study consisted of two stages. First, the risk-scoring system for LNM was developed using multivariate logistic regression analysis in 1,101 patients who underwent radical surgery after having failed to meet the curative criteria for ESD of EGC. Next, the system was internally validated by survival analysis in another 905 patients who also did not meet the criteria and did not receive additional treatment after ESD. RESULTS: In the development stage, based on accordant regression coefficients, five risk factors for LNM were weighted with point values: three points for lymphatic invasion and 1 point each for tumor size >30 mm, positive vertical margin, venous invasion, and submucosal invasion ≥500 µm. Then, the patients were categorized into three LNM risk groups: low (0-1 point: 2.5% risk), intermediate (2-4 points: 6.7%), and high (5-7 points: 22.7%). In the validation stage, cancer-specific survival differed significantly among these groups (99.6, 96.0, and 90.1%, respectively, at 5 years; P<0.001). The C statistic of the system for cancer-specific mortality was 0.78. CONCLUSIONS: This scoring system predicted cancer-specific survival in patients who did not meet the curative criteria after ESD for EGC. ESD without additional treatment may be an acceptable option for patients at low risk.

Survival Benefit of Additional Surgery After Non-curative Endoscopic Submucosal Dissection for Early Gastric Cancer: A Propensity Score Matching Analysis.

BACKGROUND AND PURPOSE: Previous studies comparing survival outcomes between patients who did and did not undergo additional surgery after non-curative endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) were limited in that the baseline characteristics differed significantly between the groups. We aimed to address this limitation and compared survival outcomes between these two groups using propensity score matching analysis. METHODS: The study enrolled 1969 consecutive patients who underwent non-curative ESD for EGC between 2000 and 2011 at any of 19 institutions across Japan. Using propensity score matching analysis, patients who underwent additional surgery (n = 1064) were compared with patients who did not (n = 905). Overall survival (OS) and disease-specific survival (DSS) after ESD were compared between both groups. RESULTS: Propensity score matching analysis yielded 553 matched pairs and well-balanced baseline characteristics between the two groups. The 5-year OS rates were 91.0% in the additional surgery group and 75.5% in the no additional surgery group, and the 5-year DSS rates were 99.0 and 96.8%, respectively. OS and DSS in the additional surgery group were significantly higher than in the no additional surgery group (OS, p < 0.001; DSS, p = 0.013). In Cox proportional hazard analysis, additional surgery significantly reduced gastric cancer-related death after non-curative ESD for EGC (hazard ratio 0.33, 95% confidence interval 0.12-0.79, p = 0.012). CONCLUSIONS: Our findings suggest that additional surgery reduces mortality after non-curative ESD for EGC. We recommend additional surgery for patients after non-curative ESD for EGC.

Optimal fiber design for large capacity long haul coherent transmission [Invited].

Fiber figure of merit (FOM), derived from the GN-model theory and validated by several experiments, can predict improvement in OSNR or transmission distance using advanced fibers. We review the FOM theory and present design results of optimal fiber for large capacity long haul transmission, showing variation in design results according to system configuration.

Direct generation of 12.5-GHz-spaced optical frequency comb with ultrabroad coverage in near-infrared region by cascaded fiber configuration.

We generated a 12.5-GHz-spacing optical frequency comb that can be resolved over 100 THz, from 1040 to 1750 nm, without spectral mode filtering. To cover such a broad spectrum, we used electro-optic modulation of single frequency light and line-by-line pulse synthesis to produce a clear pulse train and subsequent spectral broadening in highly nonlinear fibers (HNLFs). We numerically and experimentally investigated a configuration of the HNLFs and find that a two-stage broadening through different HNLFs is required when using limited pulse energy at a high repetition rate. We designed and fabricated solid silica-based HNLFs with small zero-dispersion wavelengths to obtain strong spectral broadening, especially at the shorter wavelengths. The individual lines of the proposed frequency comb are resolvable with high contrast over the entire spectral range. The results described in this paper should lead to the development of multicarrier sources for wavelength-division-multiplexing communication and super-multi-point frequency calibration for spectrometers, especially in astrophysics.

Thienopyridine derivatives as risk factors for bleeding following high risk endoscopic treatments: Safe Treatment on Antiplatelets (STRAP) study.

BACKGROUND AND STUDY AIMS: The optimal method of perioperative management of antiplatelet agents during endoscopic procedures that carry a high risk of bleeding is still controversial. The aim of this study was to evaluate the safety of continuing aspirin treatment during these procedures in an Asian population. PATIENTS AND METHODS: A multicenter, prospective, observational cohort study was conducted at six high volume endoscopy centers in Japan. The study included patients at high risk of thromboembolism who were regularly taking antiplatelet agents (e. g. thienopyridine derivatives and aspirin). Enrolled patients continued their aspirin therapy, and underwent endoscopic procedures that had a high risk of bleeding for treatment of lesions in the upper and lower gastrointestinal tracts. The primary end point was the rate of major bleeding complications after endoscopic procedures. RESULTS: The study was terminated in accordance with predetermined safety criteria because 7 of 28 consecutive patients experienced major bleeding complications (25.0 %; 95 % confidence interval 10.7 % - 44.9 %). All major bleeding complications occurred following endoscopic submucosal dissection (ESD; 6 stomach, 1 colon). Univariate analysis showed that postoperative administration of thienopyridine derivatives was the only significant factor associated with postoperative bleeding (P = 0.01). Subanalysis of gastric ESD (23 lesions in 19 patients) confirmed that the administration of thienopyridine derivatives (P = 0.01) and that of multiple agents (P = 0.02) were the significant factors. All bleeding complications (postoperative day 11.2 ±â€Š3.5) occurred after resuming thienopyridine derivative therapy postoperatively (postoperative day 2.3 ±â€Š2.4). CONCLUSION: In Asian patients taking thienopyridine derivatives with aspirin, cautious postoperative care is necessary for those undergoing endoscopic procedures that are associated with a high risk of bleeding, especially gastric ESD. Continuation of aspirin alone during these endoscopic procedures may be acceptable. STUDY REGISTRATION: UMIN000009176.

[Use of dexmedetomidine hydrochloride as a sedative during local therapy for hepatocellular carcinoma].

Sedation using dexmedetomidine hydrochloride (DEX) was administered to patients with hepatocellular carcinoma (HCC) prior to local therapy. Case 1 was a 58-year-old man undergoing radiofrequency ablation in combination with transcatheter arterial chemoembolization for HCC in S3. In accordance with the package insert, the initial loading dose was set at 6 µg/kg/hour. Although a favorable sedative effect was achieved, his blood pressure and pulse rate decreased. Case 2 was a 79-year-old woman undergoing percutaneous ethanol injection therapy for HCC in S6. Half the initial loading dose indicated in the package insert (3 µg/kg/hour) was administered, but the sedative effect was appreciable. No marked blood pressure or pulse rate decreases were observed. We believe that the use of DEX as a sedative agent in local therapy for HCC can be expected to increase. However, the optimal dose setting for DEX requires further examination.