Phase 2, randomized, double-blind, placebo-controlled, 4-week study to evaluate the safety and efficacy of OPA- 15406 (difamilast), a new topical selective phosphodiesterase type-4 inhibitor, in Japanese pediatric patients aged 2-14 years with atopic dermatitis.

The safety and efficacy of OPA-15406 (international non-proprietary name, difamilast; also referred to as MM36), a new topical, selective phosphodiesterase type-4 inhibitor, in Japanese pediatric patients with atopic dermatitis aged 2-14 years were evaluated in a phase 2, randomized, double-blind, vehicle-controlled, 4-week study. Seventy-three patients were randomized 1:1:1 to receive OPA-15406 0.3%, OPA-15406 1% or vehicle ointment twice daily for 4 weeks. The mean age of patients was similar across treatment groups. No deaths or serious treatment-emergent adverse events were reported; all treatment-emergent adverse events were mild or moderate in severity. The incidence of treatment-emergent adverse events leading to treatment discontinuation was 4.2% (1/24) in the OPA-15406 0.3% group, 4.0% (1/25) in the OPA-15406 1% group and 16.7% (4/24) in the vehicle group, all of which were worsening of atopic dermatitis. Both OPA-15406 groups demonstrated a higher incidence of success in the Investigator Global Assessment score compared with the vehicle group over the 4-week study. The OPA-15406 groups also showed greater improvements from baseline compared with the vehicle group in the Investigator Global Assessment score, Eczema Area and Severity Index overall score and subscale (erythema, induration/papulation, excoriation and lichenification) scores, Visual Analog Scale pruritus score, Patient-Oriented Eczema Measure score, and percentage of affected body surface area over the 4-week study. Topical OPA-15406 twice daily for 4 weeks was considered a safe and effective treatment option in this phase 2 study in pediatric patients with atopic dermatitis, and phase 3 development is currently ongoing.

An unconventional hydrogen effect that suppresses thermal formation of the hcp phase in fcc steels.

Iron and steels are extensively used as structural materials, and have three primary phase structures: Body-centered cubic (bcc), face-centered cubic (fcc), and hexagonal closed-packed (hcp). Controlling phase stabilities, especially by the use of interstitials, is a universal method that provides a diverse variety of functional and mechanical properties in steels. In this context, hydrogen, which can act as an interstitial species in steels, has been recognized to promote phase transformation from fcc to hcp. However, we here report a dramatic effect of interstitial hydrogen that suppresses this hcp phase transformation. More specifically, the fraction of hcp phase that forms during cooling decreases with increasing diffusible hydrogen content. This new finding opens new venues for thermodynamics-based microstructure design and for development of robust, strong, and ductile steels in hydrogen-related infrastructures.

Hepatic inflammatory pseudotumor associated with primary biliary cholangitis and elevated alpha-fetoprotein lectin 3 fraction mimicking hepatocellular carcinoma.

BACKGROUND: Hepatic inflammatory pseudotumor (IPT) is a rare benign lesion. Because there is no specific laboratory marker or radiographic appearance, the majority of reported cases of hepatic IPT have been diagnosed after surgery or at autopsy. The etiology of hepatic IPT remains unclear but several mechanisms have been postulated such as infection or immune reaction. CASE PRESENTATION: A 79-year-old woman had been seeing her family doctor for hypertension, and she had been diagnosed with liver dysfunction for about 10 years. She continued attending follow-ups because of her drinking habit. Two months before her visiting our institution, further elevation of hepatobiliary enzymes was noted, and abdominal ultrasonography showed a hepatic tumor 4 cm in diameter in the lateral segment, so she was referred to our hospital. Hepatocellular carcinoma (HCC) was suspected because alpha-fetoprotein (102 ng/ml) (AFP) and lectin 3 (L3) fraction (85.4%) were elevated and the appearance on enhanced computed tomography was not inconsistent with HCC. Thus, we performed laparoscopic hepatectomy. She recovered uneventfully and was discharged on postoperative day 7. Pathological diagnosis revealed that the tumor was hepatic IPT and that the background liver condition was primary biliary cholangitis (PBC). AFP and L3 fraction decreased to normal ranges after surgery. CONCLUSIONS: In 7 of 29 patients (24.1%) with reported cases of tumor markers in liver IPT, carbohydrate antigen 19-9 was elevated and AFP was elevated in 2 of 58 patients (3.4%). AFP is also frequently elevated in benign liver diseases such as hepatitis and liver cirrhosis, and L3 fraction has been used as a tumor marker for HCC with high specificity. To our knowledge, this is the first report of a case diagnosed with liver IPT in which AFP and L3 fraction increased before surgery and decreased to the normal range after resection. This confirms the rarity of hepatic IPT associated with PBC and elevated AFP and L3 fraction.

Long-Term Outcomes After Pancreatectomy for Pancreatic Ductal Adenocarcinoma in Elderly Patients: Special Reference to Postoperative Adjuvant Chemotherapy.

BACKGROUND: The benefit of pancreatectomy for elderly patients with pancreatic ductal adenocarcinoma (PDAC) remains controversial. Moreover, adjuvant chemotherapy (AC) for elderly patients has not been fully evaluated. We investigated the long-term outcomes after pancreatectomy for PDAC in elderly patients with special reference to AC. METHODS: The medical records of 123 patients who underwent pancreatectomy for PDAC from 2007 to 2016 were retrospectively reviewed. The patients were divided into two groups: young (<75 years) and elderly patients (≥75 years). RESULTS: The study population comprised 91 young and 32 elderly patients. The postoperative clinical courses were not different between the two groups. AC was more frequently administered to young (85%) than elderly patients (66%; P = 0.04). The weekly dose of tegafur/gimeracil/oteracil potassium (S1) for AC was significantly lower in elderly (median 423 mg/m2) than young patients (median 491 mg/m2; P = 0.02). The prevalence of adverse events and the completion rate of AC were not significantly different between the two groups. There were no significant differences in recurrence-free survival (P = 0.73) or overall survival (P = 0.68) between the two groups in univariate analysis. Receipt of AC was not a significant independent factor for survival, and completion of planned AC was a significant independent factor for recurrence-free survival and overall survival in multivariate analysis. CONCLUSIONS: The benefit of pancreatectomy for PDAC was the same between young and elderly patients. Completion of planned AC was important, and lowered-dose AC using S1 for elderly patients might be safe and therapeutically useful.

Phase III trial comparing the efficacy and safety of recombinant- or urine-derived human chorionic gonadotropin for ovulation triggering in Japanese women diagnosed with anovulation or oligo-ovulation and undergoing ovulation induction with follitropin-alfa.

Aim: Outside of Japan, recombinant-human chorionic gonadotropin (r-hCG) is widely used for the induction of final follicular maturation and early luteinization in women undergoing ovulation induction; whereas in Japan, urine-derived hCG (u-hCG) is predominantly used. The primary objective of this study was to demonstrate the non-inferiority of r-hCG to u-hCG for ovulation induction, as assessed by the ovulation rate. Methods: This was an open-label, parallel-group, randomized, multicenter, phase III trial in Japanese women with anovulation or oligo-ovulation secondary to hypothalamic-pituitary dysfunction or polycystic ovary syndrome, undergoing ovulation induction with recombinant-human follicle-stimulating hormone. The women were randomized (2:1) to receive either a single 250 µg s.c. dose of r-hCG or a single 5000 IU i.m. dose of u-hCG for ovulation triggering. Results: Eighty-one women were randomized to either r-hCG (n=54) or u-hCG (n=27). Ovulation occurred in 100% of the participants and treatment with r-hCG was observed to be non-inferior to u-hCG for ovulation induction. Overall, the type and severity of adverse events were as expected for women receiving fertility treatment. Conclusion: This study demonstrated that r-hCG was non-inferior to u-hCG for inducing ovulation. Furthermore, r-hCG demonstrated an expected safety profile, with no new safety concerns identified.

Astragaloside-IV prevents acute kidney injury and inflammation by normalizing muscular mitochondrial function associated with a nitric oxide protective mechanism in crush syndrome rats.

BACKGROUND: Crush syndrome (CS) is a serious medical condition characterized by muscle cell damage resulting from decompression after compression (i.e., ischemia/reperfusion injury). A large number of CS patients develop cardiac failure, kidney dysfunction, and systemic inflammation, even when fluid therapy is administered. We evaluated whether the administration of astragaloside-IV (AS)-containing fluid improved survival by preventing kidney and muscular mitochondrial dysfunction in a rat model of CS. RESULTS: The CS model was generated by subjecting anesthetized rats to bilateral hind limb compression with a rubber tourniquet for 5 h. Rats were then randomly divided into four groups: (1) sham; (2) CS with no treatment; (3) CS with normal saline treatment; and (4) CS with normal saline + 10 mg/kg AS. AS-containing fluid improved kidney function by improving shock and metabolic acidosis in CS rats. In addition, there was a reduction in oxidative damage. The attenuation of hyperkalemia was significantly related to improving muscle injury via preventing mitochondrial dysfunction. Moreover, this mitochondria protection mechanism was related to the nitric oxide (NO) generated by activation of endothelial nitric oxide synthase, which provided an anti-oxidative and anti-inflammatory effect. CONCLUSIONS: Treatment with AS-containing fluid led to a dramatic improvement in survival following CS because of direct and indirect anti-oxidative effects in the kidney, and improvements in mitochondrial dysfunction and inflammation owing to AS acting as an NO donor in injured muscle.

Effect of postoperative major complications on prognosis after pancreatectomy for pancreatic cancer: a retrospective review.

PURPOSE: To investigate the impact of postoperative complications on survival after curative resection for pancreatic cancer. METHODS: We reviewed retrospectively the medical records of 122 patients who underwent curative R0 resection for pancreatic cancer. Major complications included pancreatic fistula and hemorrhage of grade B or C according to the International Study Group of Pancreatic Fistula or Surgery criteria, and other complications of grade ≥III according to the Clavien-Dindo classification. RESULTS: Thirty-eight patients (31 %) suffered major postoperative complications and 40 patients (33 %) suffered minor complications only. Univariate survival analysis showed that patients with major complications had a significantly worse prognosis than those without major complications, with regard to recurrence-free survival (RFS) (P < 0.01) and overall survival (OS) (P < 0.01), whereas minor complications did not affect survival. Major complications significantly inhibited or delayed adjuvant chemotherapy. Multivariate survival analysis showed that the absence of postoperative major complications was an independent favorable factor for RFS (hazard ratio 0.48; 95 % confidence interval: 0.28-0.85) and OS (hazard ratio 0.47; 95 % confidence interval 0.27-0.81). CONCLUSIONS: Postoperative major complications after pancreatectomy for pancreatic cancer affect the prognosis.

Validity of the management strategy for intraductal papillary mucinous neoplasm advocated by the international consensus guidelines 2012: a retrospective review.

PURPOSE: The aim of this study was to investigate the validity of the management strategy for intraductal papillary mucinous neoplasms (IPMNs) advocated by the international consensus guidelines 2012 (ICG2012). METHODS: The medical records of 49 patients who underwent pancreatectomy for IPMN were retrospectively reviewed. RESULTS: According to preoperative imaging, 10 patients (20 %) had main-duct IPMNs, 20 (41 %) had mixed IPMNs, and 19 (39 %) had branch-duct IPMNs, with malignancy frequencies of 80, 15, and 37 %, respectively. Twenty-seven patients had high-risk stigmata and 21 had worrisome features, with malignancy frequencies of 59 and 10 %, respectively. The sensitivity, specificity, and positive and negative predictive values of high-risk stigmata for malignancy were 88, 65, 59, and 91 %, respectively. Lesions were malignant in 88 % of patients with an enhanced solid component, which was significantly correlated with the prevalence of malignancy (P < 0.01). However, of the 10 patients who underwent pancreatectomy solely due to a main pancreatic dilation of ≥10 mm, 9 (90 %) had benign IPMNs. CONCLUSIONS: Many mixed IPMNs defined according to ICG2012 are benign. Although the management strategy advocated by ICG2012 has been improved relative to the Sendai criteria, the different high-risk stigmata carry unequal weights. Consequently, ICG2012 remains suboptimal for predicting malignant IPMN.

Crossover from capacitive to inductive electromagnetic responses in near self-complementary metallic checkerboard patterns.

Transmission spectra of near-self-complementary metallic checkerboard patterns (MCPs) exhibit a drastic change when the metal squares are brought into contact with each other from a noncontact state. Transmission spectra of near-self-complementary samples, which are fabricated by printing technology, show rather gradual systematic change with changing the nominal metal square size while keeping the period because of randomness naturally introduced by the limited accuracy of the printer. The spectra have transmission-invariant frequencies, which means that the spectra are a superposition of two types of spectra, the ratio of which depends on the nominal square size. The correlation seen in the real and imaginary parts of the complex amplitude spectra can be interpreted based on the Kramers-Kronig relation. As an application of the sensitiveness of the transmission spectrum of the MCPs to connectivity of the metal squares, the revealing of an optically hidden pattern by a terahertz beam is demonstrated.

Question answering system using Q & A site corpus Query expansion and answer candidate evaluation.

Question Answering (QA) is a task of answering natural language questions with adequate sentences. This paper proposes two methods to improve the performance of the QA system using a Q&A site corpus. The first method is for the relevant document retrieval module. We proposed modification of measure of mutual information for the query expansion; we calculate it between two words in each question and a word in its answer in the Q&A site corpus not to choose the words that are not suitable. The second method is for the candidate answer evaluation module. We proposed to evaluate candidate answers using the two measures together, i.e., the Web relevance score and the translation probability. The experiments were carried out using a Japanese Q&A site corpus. They revealed that the first proposed method was significantly better than the original method when their accuracies and MRR (Mean Reciprocal Rank) were compared and the second method was significantly better than the original methods when their MRR were compared.

A novel, potent, and long-lasting dipeptidyl peptidase-4 inhibitor, teneligliptin, improves postprandial hyperglycemia and dyslipidemia after single and repeated administrations.

Dipeptidyl peptidase-4 (DPP-4) inhibitors have been demonstrated to improve glycemic control, in particular postprandial hyperglycemic control, in patients with type 2 diabetes. Teneligliptin is a novel chemotype prolylthiazolidine-based DPP-4 inhibitor. The present study aimed to characterize the pharmacological profiles of teneligliptin in vitro and in vivo. Teneligliptin competitively inhibited human plasma, rat plasma, and human recombinant DPP-4 in vitro, with IC(50) values of approximately 1 nmol/l. Oral administration of teneligliptin in Wistar rats resulted in the inhibition of plasma DPP-4 with an ED(50) of 0.41 mg/kg. Plasma DPP-4 inhibition was sustained even at 24h after administration of teneligliptin. An oral carbohydrate-loading test in Zucker fatty rats showed that teneligliptin at ≥ 0.1mg/kg increased the maximum increase in plasma glucagon-like peptide-1 and insulin levels, and reduced glucose excursions. This effect was observed over 12h after a dose of 1mg/kg. An oral fat-loading test in Zucker fatty rats also showed that teneligliptin at 1mg/kg reduced triglyceride and free fatty acid excursions. In Zucker fatty rats, repeated administration of teneligliptin for two weeks reduced glucose excursions in the oral carbohydrate-loading test and decreased the plasma levels of triglycerides and free fatty acids under non-fasting conditions. The present studies indicate that teneligliptin is a potent, competitive, and long-lasting DPP-4 inhibitor that improves postprandial hyperglycemia and dyslipidemia by both single and repeated administrations.

Discovery and preclinical profile of teneligliptin (3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine): a highly potent, selective, long-lasting and orally active dipeptidyl peptidase IV inhibitor for the treatment of type 2 diabetes.

Dipeptidyl peptidase IV (DPP-4) inhibition is suitable mechanism for once daily oral dosing regimen because of its low risk of hypoglycemia. We explored linked bicyclic heteroarylpiperazines substituted at the γ-position of the proline structure in the course of the investigation of l-prolylthiazolidines. The efforts led to the discovery of a highly potent, selective, long-lasting and orally active DPP-4 inhibitor, 3-[(2S,4S)-4-[4-(3-methyl-1-phenyl-1H-pyrazol-5-yl)piperazin-1-yl]pyrrolidin-2-ylcarbonyl]thiazolidine (8 g), which has a unique structure characterized by five consecutive rings. An X-ray co-crystal structure of 8 g in DPP-4 demonstrated that the key interaction between the phenyl ring on the pyrazole and the S(2) extensive subsite of DPP-4 not only boosted potency, but also increased selectivity. Compound 8 g, at 0.03 mg/kg or higher doses, significantly inhibited the increase of plasma glucose levels after an oral glucose load in Zucker fatty rats. Compound 8 g (teneligliptin) has been approved for the treatment of type 2 diabetes in Japan.

Optical transmission anomalies in a double-layered metallic slit array.

We theoretically predicted the existence of an anomalous optical transmittance dip, which must be observed for a metamaterial structure with two metallic slabs with cut-through slit arrays of a constant period d under a normal incident condition. By changing the relative lateral displacement l between the two slabs, the dip frequency varies across that of a so-called Rayleigh-Wood's (RW) anomaly frequency. The mechanism of this anomaly is quite different from that of the RW anomaly and interpreted in terms of the interference between the propagating and evanescent waves. For the present double-layered system, furthermore, it is suggested that the RW anomaly vanishes for l = 0 and d/2. In experiments in the terahertz region, we observe that the fundamental features agree with these theoretical predictions.

Disparities in the survival improvement of recurrent breast cancer.

BACKGROUND: The therapeutic advances in breast cancer have improved the survival of patients with early disease; however, survival improvement of patients with recurrent disease remains ambiguous. In this retrospective study, we examined whether disparities in survival improvement exist in patients with recurrent breast cancer with distant metastasis. METHODS: The survival time of 126 patients who experienced recurrence at distant sites from 1990 through 1996 was compared to that of 195 patients who did from 1997 through 2003. RESULTS: A significant survival improvement was observed in the patients who experienced recurrence in the period of 1997-2003 in comparison to the other period in the subsets with estrogen receptor (ER)-positive disease, those who received adjuvant hormonal therapy, and those with a disease-free interval (DFI) of 24 months or more. However, no significant survival improvement was observed in each counterpart. The median survival time (MST) from the first relapse of patients with ER-positive disease in the recurrence period of 1997-2003 was 18.8 months longer than that in the recurrence period of 1990-1996 (46.6 months vs. 27.8 months). The MST of patients with a DFI of 24 months or more in 1997-2003 was 20.3 months longer than that in the other time period (47.2 months vs. 26.9 months). CONCLUSION: The survival of recurrent breast cancer has improved with disparities. The ER status and the DFI are associated with a survival improvement of women with recurrent breast cancer with distant metastases.

[A case of long survival with unresectable duodenal papilla cancer treated with oral chemotherapy using combination UFT and cyclophosphamide].

A 69-year-old female patient underwent a choledochojejunostomy for unresectable duodenal papilla cancer with para-aortic lymph node metastases. Both tegafur-uracil(UFT) and cyclophosphamide were given orally every day after surgery. Twenty-eight months from the initiation of the chemotherapy the tumor had remarkably reduced and the objective response was evaluated as a PR. The patient is now doing well. Lymph node metastasis is considered an important prognostic factor of papilla Vater carcinoma, and especially with para-aortic lymph node metastases the long-term prognosis is poor. Combination chemotherapy using UFT and cyclophosphamide would be a therapeutic option for elderly or high-risk patients.

[A case of peritoneal disseminated sigmoid colon cancer with liver metastasis responding to S-1].

In October 2004, a 73-year-old man underwent loop ileostomy because of unresectable peritoneal disseminated sigmoid colon cancer with liver metastasis. The oral chemotherapy by S-1 was administered(80 mg/day for 4 weeks followed by a 2-week rest period). A half year later, the primary lesion was remarkably diminished on barium enema, and peritoneal dissemination and liver metastasis disappeared on CT. Because he was unwilling to have an ileostomy, we decided to resect the primary lesion and close the ileal stoma in May 2005. There was no obvious peritoneal dissemination, and operation was successful. He died without intestinal stoma one year after second operation. This therapy can be orally administered at home, and is considered to be useful from the viewpoint of QOL as well. S-1 is expected to be an effective agent for the treatment of colon cancer.

Pancreatic metastasis from renal cell carcinoma 13 years after a nephrectomy: report of a case.

The pancreas is an uncommon site of metastasis from renal cell carcinoma. We herein present the case of a 59-year-old woman in whom pancreatic metastasis from renal cell carcinoma, found 13 years after undergoing a nephrectomy, was successfully resected and who has since showed no evidence of recurrence or metastasis. The efficacy of performing a pancreatectomy for metastatic renal cell carcinoma is also presented. We recommend careful long-term follow-up in patients with a history of renal cell carcinoma. Imaging modalities should be used during the routine follow-up to detect any asymptomatic metastases at an early stage.

Neutrophil-mediated liver injury during hepatic ischemia-reperfusion in rats.

BACKGROUND: Neutrophil plays an important role in hepatic ischemia-reperfusion injury. We investigated neutrophil infiltration in liver tissue, Kupffer cells' role in neutrophil accumulation, and apoptosis and regeneration of hepatocytes in liver ischemia-reperfusion injury. METHODS: Vascular microclamps were placed across the pedicles of the median and left lateral lobes for 90 minutes after 30% hepatectomy with the resection of caudate, right lateral and quadrate lobes and papillary process. Gadolinium chloride (GdCl(3)) was used to destroy Kupffer cells. Neutrophil activity was inhibited with Urge-8, a monoclonal antibody against neutrophil produced in our laboratory. GdCl(3) (10 mg/kg) and Urge-8 (50 mg/kg) were given intravenously in respective groups. Ischemia control, GdCl(3) and Urge-8 groups were compared. RESULTS: Following hepatic reperfusion, serum interleukin-8 (IL-8) levels and hepatic neutrophil counts peaked at 3 hours, and peak concentrations of alanine aminotransferase (ALT) occurred at 6 hours. Animals of the control group showed increases in neutrophil infiltration in liver tissue, liver enzyme levels, and apoptosis index of hepatocytes and decreases in overall survival rate and proliferating cell nuclear antigen (PCNA) expression of hepatocytes. The survival rates and PCNA proportion of hepatocytes were higher and the levels of hepatic neutrophil infiltration, liver enzymes, and hepatocyte apoptosis after reperfusion were lower in the GdCl(3) and Urge-8 groups than those in the ischemia control group. CONCLUSIONS: Blockades of Kupffer cells' activity and neutrophil infiltration by GdCl(3) and Urge-8 eliminate neutrophil-mediated hepatic injury and enhance subsequent hepatic regeneration during liver ischemia-reperfusion.

Double mapping with subareolar blue dye and peritumoral green dye injections decreases the false-negative rate of dye-only sentinel node biopsy for early breast cancer: 2-site injection is more accurate than 1-site injection.

BACKGROUND: The optimum sentinel node biopsy (SNB) mapping method for breast cancer remains to be determined. No matter which mapping agents are used, 2-site injection may be superior to 1-site injection in limiting the false-negative rate. METHODS: We examined whether a double-mapping method with subareolar injection of blue dye and peritumoral injection of green dye would decrease the false-negative rate of dye-only SNB in 145 patients with early breast cancer. RESULTS: The identification rate for blue-dyed and/or green-dyed (including mixed color-dyed) lymph nodes was 96.6% (140/145). Sensitivity and specificity were 95.1% (39/41) and 100% (99 of 99), respectively. Accuracy was 98.6% (138/140) with a false-negative rate of 4.9% (2/41). There were 4 patients in whom nodes of each color were found, but nodes of only 1 color were shown to be positive. The primary tumors of these 4 patients and of the 2 patients with false-negative results were located in the upper-outer quadrant of the breast. When only blue-dyed or green-dyed nodes (including mixed color-dyed nodes) were counted, the false-negative rates were 10.3% (4/39) for the subareolar mapping technique and 10.0% (4/40) for the peritumoral mapping technique. CONCLUSIONS: The double-mapping method based on subareolar and peritumoral injections decreases the false-negative rate of dye-only SNB for early breast cancer. Variations in lymphatic channels may exist in the lateral half of the breast and thus may influence identification of positive sentinel nodes. This finding should be taken into account in cases of multicentric breast cancer.