Injectable Anhydrous Poly(ethylene glycol) Polymer Liquids Form Protein Depot for Extended Controlled Release Applications Via Rapid In Situ Gelation.

Water-free preparation of protein delivery systems has the potential to overcome the limitations of hydrogel depot systems such as off-target reactions, functional group hydrolysis, and limited loading capacity. However, a major roadblock in the development and use of these systems is administration as implantation is often required. In this study, we developed a biodegradable and water-free injectable protein delivery system via inverse electron demand Diels-Alder reaction between norbornene- and tetrazine-functionalized four-armed poly(ethylene glycol) macromonomers. 1:1 mixtures of these precursors gelled rapidly in situ, taking less than 11 s to reach their gelation point. Methyl substitution of tetrazine slowed the gelation time and increased the cross-linking density, whereas oxygen incorporation into norbornene changed the mechanical properties. Introduction of hydrolytically cleavable groups enabled biodegradability. Using phenyl carbamate and phenyl carbonate ester groups, we could tune the stability. Controlled release of the protein surrogate glucose oxidase was achieved over a period of 500 days. The novel preparation method presented here is a promising step toward the development of water-free injectable protein depots for controlled drug delivery.

Targeted Delivery of Immunostimulatory CpG Oligodeoxynucleotides to Antigen-Presenting Cells in Draining Lymph Nodes by Stearic Acid Modification and Nanostructurization.

Polypod-like structured nucleic acids (polypodnas), which are nanostructured DNAs, are useful for delivering cytosine-phosphate guanine oligodeoxynucleotides (CpG ODNs) to antigen-presenting cells (APCs) expressing Toll-like receptor 9 (TLR9) for immune stimulation. Lipid modification is another approach to deliver ODNs to lymph nodes, where TLR9-positive APCs are abundant, by binding to serum albumin. The combination of these two methods can be useful for delivering CpG ODNs to lymph nodes in vivo. In the present study, CpG1668, a phosphodiester-type CpG ODN, was modified with stearic acid (SA) to obtain SA-CpG1668. Tripodna, a polypodna with three pods, was selected as the nanostructured DNA. Tripodnas loaded with CpG1668 or SA-CpG1668 were obtained in high yields. SA-CpG1668/tripodna bound more efficiently to plasma proteins than CpG1668/tripodna and was more efficiently taken up by macrophage-like RAW264.7 cells than CpG1668/tripodna, whereas the levels of tumor necrosis factor-α released from the cells were comparable between the two. After subcutaneous injection into mice, SA-CpG1668/tripodna induced significantly higher interleukin (IL)-12 p40 production in the draining lymph nodes than SA-CpG1668 or CpG1668/tripodna, with reduced IL-6 levels in plasma. These results indicate that the combination of SA modification and nanostructurization is a useful approach for the targeted delivery of CpG ODNs to lymph nodes.

In Situ Forming iEDDA Hydrogels with Tunable Gelation Time Release High-Molecular Weight Proteins in a Controlled Manner over an Extended Time.

Off-target interactions between reactive hydrogel moieties and drug cargo as well as slow reaction kinetics and the absence of controlled protein release over an extended period of time are major drawbacks of chemically cross-linked hydrogels for biomedical applications. In this study, the inverse electron demand Diels-Alder (iEDDA) reaction between norbornene- and tetrazine-functionalized eight-armed poly(ethylene glycol) (PEG) macromonomers was used to overcome these obstacles. Oscillatory shear experiments revealed that the gel point of a 15% (w/v) eight-armed PEG hydrogel with a molecular weight of 10 kDa was less than 15 s, suggesting the potential for fast in situ gelation. However, the high-speed reaction kinetics result in a risk of premature gel formation that complicates the injection process. Therefore, we investigated the effect of polymer concentration, temperature, and chemical structure on the gelation time. The cross-linking reaction was further characterized regarding bioorthogonality. Only 11% of the model protein lysozyme was found to be PEGylated by the iEDDA reaction, whereas 51% interacted with the classical Diels-Alder reaction. After determination of the mesh size, fluorescein isothiocyanate-dextran was used to examine the release behavior of the hydrogels. When glucose oxidase was embedded into 15% (w/v) hydrogels, a controlled release over more than 250 days was achieved. Overall, the PEG-based hydrogels cross-linked via the fast iEDDA reaction represent a promising material for the long-term administration of biologics.

Combined use of chemically modified nucleobases and nanostructured DNA for enhanced immunostimulatory activity of CpG oligodeoxynucleotide.

Oligodeoxynucleotide (ODN) containing a cytosine-phosphate-guanine (CpG) motif, or CpG ODN, is considered suitable for treating immune diseases, including allergies. Although the phosphorothioate modification is used to enhance the stability and immunostimulatory activity of CpG ODNs, it is associated with the risk of adverse effects. Construction of nanostructured DNA assemblies, such as tripod- and hexapod-like structured DNAs, tripodna and hexapodna, respectively, were also found to increase this activity. The chemical modification of nucleobases could be another approach for enhancing CpG ODN activity. Here, we examined whether chemically modified nucleobase substitutions can enhance CpG ODN activity by measuring tumor necrosis factor α (TNF-α) release after addition to murine macrophage-like RAW264.7 cells. First, the guanine at the 18th position of phosphodiester CpG 1668 was substituted with several chemically modified guanines, and then the various guanines were substituted. Among all tested substitutions, 15,18-thdG, in which two guanines outside the CpG motif were substituted with the 2-aminothieno[3,4-d]pyrimidine guanine mimic (thdG), was the most effective. Compared to 32P-CpG 1668, 32P-15,18-thdG was taken up more efficiently by the RAW264.7 cells. Then, 15,18-thdG was incorporated into tripodna and hexapodna. 15,18-thdG/tri- or hexapodna induced higher TNF-α release from the RAW264.7 cells than PO CpG 1668/tri- or hexapodna, respectively. These results indicate that the thdG substitution is a useful effective strategy for enhancing the immunostimulatory activity of CpG DNAs in both single stranded and DNA nanostructure forms.

Critical contribution of macrophage scavenger receptor 1 to the uptake of nanostructured DNA by immune cells.

Despite the efficient uptake of polypod-like nanostructured DNA, or polypodna, by macrophage-like RAW264.7 and other immune cells, the detailed mechanism has not been fully elucidated. Our previous study using HEK-Blue hTLR9 cells showed that transfection of macrophage scavenger receptor 1 (MSR1) increased the uptake of tetrapod-like structured DNA. Here, we investigated the involvement of MSR1 in the structure-dependent uptake of polypodna. Transfection of MSR1 to HEK-Blue hTLR9 cells pod number-dependently increased the uptake of polypodna, and its knockout in RAW264.7 cells reduced the uptake and subsequent cytokine release. To examine the binding of DNA with MSR1, biotinylated DNA added to RAW264.7 cells was cross-linked with cell surface proteins. Then, MSR1 cross-linked with polypodna, but not with single-stranded DNA. Similar results were obtained with murine primary immune cells. Taken together, MSR1 discriminates between simple and nanostructured DNAs and plays a dominant role in the efficient uptake of polypodna by immune cells.

Pharmacokinetics and food-effect of fosdagrocorat (PF-04171327), a dissociated agonist of the glucocorticoid receptor, in healthy adult Caucasian and Japanese subjects
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OBJECTIVE: Fosdagrocorat (PF-04171327) is a pro-drug form of PF-00251802, a dissociated agonist of the glucocorticoid receptor, under investigation for the treatment of rheumatoid arthritis. This study investigates the pharmacokinetics (PK) of single and multiple doses of fosdagrocorat in healthy Japanese and Western volunteers, the effect of food on fosdagrocorat PK, and the effect of fosdagrocorat on bone biomarkers. METHODS: This was a phase 1, randomized, placebo-controlled, dose-escalation study. For single-escalating-dose evaluation, Japanese (n = 9) and Western (n = 9) subjects were randomized (1 : 1 : 1) to treatment sequences including 3 doses of fosdagrocorat (5, 10, or 30 mg) or placebo. For multiple-dose evaluation, Japanese subjects were randomized (3 : 1) to receive fosdagrocorat 20 mg or placebo once daily (QD) for 12 days. Subjects were aged 18 - 55 years; body mass index 17.5 - 30.5 kg/m2; total body weight > 45 kg. RESULTS: Following single doses of fosdagrocorat, the PK of PF-00251802 and its metabolite PF-04015475 were similar between Japanese (PF-00251802: mean area under the curve (AUC)inf (range across doses), 791 - 3,460 ng×h/mL; individual half-life (t1/2) 14.1 - 28.9 hours; PF-04015475: mean AUCinf, 395 - 1,740 ng×h/mL; individual t1/2 21.6 - 40.3 hours) and Western (PF-00251802: mean AUCinf, 750 - 4,150 ng×h/mL; individual t1/2 17.7 - 40.4 hours; PF-04015475: mean AUCinf, 394 - 2,160 ng×h/mL; individual t1/2 24.5 - 63.7 hours) subjects. Steady-state concentrations were reached within 9 days following multiple doses of fosdagrocorat. Food did not affect total exposure of PF-00251802 and PF-04015475. Multiple-dose administration of fosdagrocorat 20 mg QD resulted in suppression of bone formation markers and cortisol and increased bone resorption markers vs. placebo. Adverse events (AEs) were mild in severity and no serious AEs, deaths, or severe AEs were reported. CONCLUSIONS: The PK profile of fosdagrocorat was similar between Japanese and Western subjects, with little effect of food on PK parameters. Fosdagrocorat was well tolerated in both Japanese and Western subjects.
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Investigation of the Impact of Hydrolytically Cleavable Groups on the Stability of Poly(ethylene glycol) Based Hydrogels Cross-Linked via the Inverse Electron Demand Diels-Alder (iEDDA) Reaction.

Eight-armed poly(ethylene glycol) (PEG) hydrogels cross-linked via inverse electron demand Diels-Alder reaction between norbornene and tetrazine groups are promising materials for long-term protein delivery. While a controlled release over 265 days is achieved for 15% w/v hydrogels in the previous study, the material shows high stability over 500 days despite having cleavable ester linkages between the PEG macromonomers and their functionalities. In this study, the hydrolyzable ester linkers in the PEG-norbornene precursor structure are exchanged to reduce the degradation time. To this end, 3,6-epoxy-1,2,3,6-tetrahydrophthalimide, phenyl carbamate, carbonate ester, and phenyl carbonate ester are introduced as degradable functional groups. Oscillatory shear experiments reveal that they are not affected the in situ gelation. All hydrogel types have gel points of less than 20 s even at a low polymer concentration of 5% w/v. Hydrogels with varying polymer concentrations have similar mesh sizes, all of which fell in the range of 4-12 nm. The inclusion of phenyl carbonate ester accelerates degradation considerably, with complete dissolution of 15% w/v hydrogels after 302 days of incubation in phosphate buffer (pH 7.4). Controlled release of 150 kDa fluorescein isothiocyanate-dextran over a period of at least 150 days is achieved with 15% w/v hydrogels.

Effectiveness of Solution with 5% Detergent for Cleaning Transnasal Esophagogastroduodenoscopy Lens.

BACKGROUND/AIMS: Unsedated transnasal esophagogastroduodenoscopy (EGD) is affected by a poor scope lens-cleaning function. We have previously reported good, albeit limited, effects of an oolong tea washing solution; here, we evaluated the effectiveness of a 5% lens cleaning solution for cleaning an EGD lens. METHODS: Five percent lens cleaning solution (C), 5% dimethicone solution (D), and distilled water (W) were prepared. Study I: Lenses were soiled with pork grease, washed with each washing solution, and their image quality was judged. Study II: Patients (n=996) scheduled for transnasal EGD were randomly assigned to the C- or W-group. Lens cleanliness level, washing solution volume used, and endoscopist stress due to lens contamination were determined. RESULTS: Study I: The image quality of the lenses washed with (C) was significantly superior. (D) was clinically unsuitable because of spray nozzle clogging. Study II: Lens cleaning in the C-group was significantly superior (p<0.0001) and the solution volume required was significantly reduced (p<0.0001), while endoscopist stress was also lower (p<0.0001). CONCLUSION: For transnasal small-caliber EGD, the present 5% lens cleaning solution provided good visibility. It features a high detergency level and is simple to formulate for therapeutic endoscopy applications, such as endoscopic submucosal dissection.

The Utility of Remote Inspections During the COVID-19 Health Emergency and in the Postpandemic Setting.

PURPOSE: The COVID-19 pandemic has affected the management and operation of regulatory agencies and the pharmaceutical industry around the world. It has prompted regulatory authorities to consider new ways of working and introduced, among others, remote inspections to validate the integrity of the regulatory data submitted by companies, to evaluate the quality of production and manufacturing sites, and to ensure the conformity with Good Regulatory Practices with the overall goal of guaranteeing patient safety during the crisis. METHOD: This article summarizes and discusses remote inspection guidelines and other related information made available by the Therapeutic Goods Administration (Australia), the European Medicines Agency (EMA), the Pharmaceutical and Medical Devices Agency (Japan), the Medicines and Healthcare Products Regulatory Agency (United Kingdom), and the US Food and Drug Administration (FDA). We also analyze the effect of the pandemic on inspections conducted by the inspectorates of the EMA and the FDA. FINDINGS: The regulatory authorities that we studied all recognized the importance of implementing regulatory policies on remote inspections in response to the COVID-19 pandemic. The remote inspection guidelines from the 5 selected regulatory authorities aimed at mitigating the impact of the pandemic but, while providing valuable advice to the pharmaceutical companies and being similar in intent, were not always aligned in terms of approach and solutions. IMPLICATIONS: On-site inspections are likely to continue to be the norm and the preferred standard for the foreseeable future. However, health authorities will need to further adopt a risk-based inspection approach and stimulate the increased uptake of inspection reliance as proposed by the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Co-operation Scheme not to overwhelm the pharmaceutical companies with repeat and redundant inspections. Remote inspections have proven to be a new inspection tool, but health authorities should align on their approach to remote inspections in terms of methods applied and documentation requested.

Regulatory Agilities in the Time of COVID-19: Overview, Trends, and Opportunities.

PURPOSE: Crucial steps have been adopted by health and regulatory authorities around the world to respond to the COVID-19 pandemic. This review aims to highlight these steps by providing an overview of the regulatory approaches adopted during the onset of the pandemic, provide an assessment of observed trends, and offer some reflections and proposals to leverage learnings and opportunities from this current pandemic. METHODS: Documents and informational materials on regulating the development and management of medical products during the COVID-19 pandemic were collected and classified. These materials were sourced from official websites and press releases from health authorities and international bodies from selected markets across the globe, and covered the period between January and July 2020. Additional information to support this study was gathered through a literature review and analysis of related data available from the public domain, and was complemented with the authors' personal experience. FINDINGS: Communication has been vital in addressing the impact of COVID-19. A total of 1705 documents and informational materials related to health or regulatory response to the COVID-19 pandemic were gathered. Of these, 343 (around 20%) were identified as regulatory agilities. These agile approaches were classified into 3 categories, namely, where health and regulatory authorities had: (1) facilitated product management across the entire lifecycle, notably in expediting medical product use for COVID-19, ensuring the continuity of clinical trials, and addressing supply chain issues; (2) strengthened international cooperation; and (3) addressed regulatory burden with the adoption of electronic and digital tools. IMPLICATIONS: While many regulatory measures have been introduced temporarily as a response to the COVID-19 crisis, there are opportunities for leveraging an understanding from these approaches in order to collectively achieve more efficient regulatory systems and to mitigate and address the impact of COVID-19 and further future-proof the regulatory environment.

[A new anti-mycobacterial agent, rifabutin].

This is a review of non-clinical and clinical study results of rifabutin (Mycobutin, RBT) which was approved as a new anti-mycobacterial agent 38 years after rifampicin (RFP) was approved in Japan. The anti-bacterial actions of RBT were similar to those of RFP, but its potency was stronger (4 to 32 times in MIC90). RBT showed excellent penetration in cells (9 times in neutrophil, 15 times in monocyte, against plasma concentration) and in tissues (5 to 10 times in pulmonary tissue). Clinical efficacy of RBT (150 mg, as well as 300 mg daily) was comparable to that of RFP 600 mg daily, in the treatment of newly diagnosed tuberculosis, drug-resistant tuberculosis, and the NTM diseases. In addition, RBT 300 mg showed significant prophylactic effect on the development of disseminated MAC infection in HIV positive subjects. Most of the adverse events of RBT were the same as those of RFP, including drug-drug interactions related to the induction of CYP3A4. The concomitant use of RBT (over 450 mg) with clarithromycin induces uveitis, which warrants special attention. It is expected that the efficacy and safety of RBT in Japanese subjects will be evaluated in Japan through the accumulation of clinical experience.

Real-world Evidence of Diffusion-weighted Imaging Combined With Magnetic Resonance Cholangiopancreatography for Pancreatic Tumor Screening: A Cross-Sectional Diagnostic Accuracy Study.

OBJECTIVES: The aim was to clarify the sensitivity and specificity of diffusion-weighted imaging, as well as of that in combination with magnetic resonance cholangiopancreatography for pancreatic tumor diagnosis in real-world clinical setting. METHODS: Subjects were 217 consecutive patients who underwent both magnetic resonance imaging and contrast-enhanced ultrasound sonography. Cases positive for a pancreatic tumor were confirmed based on pathological diagnosis, whereas negative cases were defined when no solid pancreatic tumor was detected by contrast-enhanced ultrasound sonography or a solid mass was detected but the diagnosis was ultimately denied based on pathological results. Diffusion-weighted imaging-positive was defined as a case with high signals and magnetic resonance cholangiopancreatography-positive when localized main pancreatic duct stenosis with caudal dilation was detected.We calculated sensitivity and specificity of each modality and those in combination based on sequential use for pancreatic tumor diagnosis. RESULTS: Diffusion-weighted imaging showed a sensitivity of 94.4% and specificity of 94.5%, whereas those values for magnetic resonance cholangiopancreatography alone were 83.3% and 99.0%, respectively, and for the modalities in combination were 100% and 94.5%, respectively. CONCLUSIONS: Diffusion-weighted imaging was more sensitive than magnetic resonance cholangiopancreatography, whereas those used in combination resulted in increased sensitivity.

A Drug-Drug Interaction Study to Evaluate the Effect of TAS-303 on CYP3A Activity in the Small Intestine and Liver.

TAS-303 (4-piperidinyl 2,2-diphenyl-2-[propoxy-1,1,2,2,3,3,3-d7 ] acetate hydrochloride) is a novel selective noradrenaline reuptake inhibitor being developed for the treatment of stress urinary incontinence. An in vitro study and a physiologically based pharmacokinetic model simulation showed that TAS-303 had inhibitory potential against cytochrome P450 (CYP) 3A. This open-label, single-group study investigated the effect of TAS-303 on CYP3A activity by evaluating the pharmacokinetics (PK) of single-dose oral simvastatin 5 mg or intravenous midazolam 1 mg after repeated oral administration of TAS-303 3 mg in 12 healthy participants. TAS-303 plus simvastatin resulted in a 1.326-fold and a 1.420-fold increase of simvastatin in peak plasma concentration and area under the plasma concentration-time curve from time zero to time t, where t is the final time of detection (AUC0-t ), respectively. The addition of midazolam resulted in a 1.090-fold increase in the midazolam AUC0-t . TAS-303 had a weak PK interaction with simvastatin but no apparent interaction with midazolam. TAS-303 at 3 mg/day is a weak inhibitor of intestinal but not hepatic CYP3A activity. No clinically important safety concerns related to TAS-303 were raised.

The Relationship Between Polypharmacy and Hospital-stay Duration: A Retrospective Study.

Background There have been very few studies on the association of polypharmacy with clinical course. In this paper, we seek to evaluate the relationship between polypharmacy and hospitalization period. Methods We retrospectively analyzed 322 patients hospitalized from February to September 2017, after excluding short-term and orthopedic cases. Patients with polypharmacy were defined as those who were prescribed more than five drugs at the time of admission. The primary endpoint for all subjects regardless of polypharmacy was the hospitalization period. Using Mann-Whitney U test results, we compared the average number of hospital days between patients with and without polypharmacy. Secondary endpoints were hospitalization period with and without polypharmacy for each disease type. Results The hospitalization period was significantly extended for patients with polypharmacy as compared to those without (31.6 vs. 23.2 days, p: 0.002). Those with an infection had significantly longer hospitalization than those without polypharmacy (27.6 vs. 18.1 days, p: 0.007). Malignancy, heart disease, and cerebrovascular disease did not have a significant effect on hospitalization regardless of polypharmacy. Conclusion Polypharmacy is related to an extended hospitalization period and is found to occur more frequently in patients hospitalized for an infection.

Anti-MAdCAM-1 antibody (PF-00547659) for active refractory Crohn's disease in Japanese and Korean patients: the OPERA study.

BACKGROUND/AIMS: PF-00547659 is a monoclonal antibody against human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) that prevents the binding of α4ß7+ lymphocytes to MAdCAM-expressing sites in the gastrointestinal tract with high affinity and selectivity, and is being developed for the treatment of Crohn's disease (CD). METHODS: OPERA is a randomized, multicenter, double-blind, placebo-controlled study to investigate the efficacy, safety, and pharmacokinetics of PF-00547659 following subcutaneous administration in subjects with active CD, a history of failure or intolerance to anti-tumor necrosis factor and/or immunosuppressants, high-sensitivity C-reactive protein > 3.0 mg/L, and ulcers on colonoscopy. The primary endpoint was Crohn's Disease Activity Index-70 response at week 8 or 12. Subpopulation analyses for Asian subjects were performed as some differences are observed in genetics and clinical phenotypes in Asian CD patients compared with Western patients. RESULTS: In this study, 265 CD subjects were randomized, with a subpopulation of 21 subjects (8 Japanese and 13 Korean) defined as the Asian population. In the overall and Asian populations; PF-00547659 was pharmacologically active as evidenced by soluble MAdCAM and circulating ß7+ central memory CD4+ T-lymphocytes, although no clear evidence of efficacy was observed in any clinical endpoints; pharmacokinetics of PF-00547659 in the Asian subpopulation was generally comparable to the overall population; and the safety profile of PF-00547659 appeared acceptable up to 12 weeks of treatment. CONCLUSIONS: In the overall and Asian populations, efficacy of PF-00547659 could not be demonstrated using any clinical endpoints compared with placebo. Pharmacokinetics and safety of PF-00547659 were generally comparable. Further studies with larger numbers of patients are required to confirm our results. (Trial Registration Number: NCT01276509).

Effect of Age on Effectiveness of Vonoprazan in Triple Therapy for Helicobacter pylori Eradication.

Objective We evaluated the efficacy of vonoprazan-based eradication therapy for Helicobacter pylori (H. pylori), including the effects of age, gender, and grade of atrophy in comparison to proton pump inhibitor-based therapy. Method We retrospectively reviewed the records of 1,172 patients who received first-line triple therapy with amoxicillin, clarithromycin, and vonoprazan or a proton pump inhibitor (PPI) for H. pylori eradication, as well as 157 patients treated with second-line therapy consisting of amoxicillin, metronidazole, and vonoprazan or a PPI. Results The eradication rate of all cases treated with first-line triple therapy was 86.9% (1,019/1,172), while that in those treated with vonoprazan-based therapy was 92.5% (384/415). Our analysis showed that the use of vonoprazan resulted in a significantly improved success rate of first-line eradication therapy in comparison to proton pump inhibitor-based therapy [odds ratio (OR), 2.36; 95% confidence interval (CI) 1.55 to 3.56]. The superiority of vonoprazan was remarkable in non-elderly patients, while its effect was unclear in elderly patients. When used as second-line eradication therapy, the advantage of vonoprazan over PPI administration was not clear. Conclusion The inclusion of vonoprazan increased the success rate of first-line eradication therapy; however, the advantage was reduced with aging and remained unclear in elderly patients.

Use of anticoagulant or antiplatelet agents is not related to epistaxis in patients undergoing transnasal endoscopy.

BACKGROUND AND STUDY AIMS: Unsedated transnasal endoscopy (uTNE) has become accepted as a safe and tolerable method for upper gastrointestinal tact examinations. Epistaxis is 1 of the major complications of TNE, though its risk factors have not been elucidated. Generally, patients administered an anticoagulant or antiplatelet drug are considered to have an increased risk of epistaxis during TNE. Here, we investigated risk factors of epistaxis in patients undergoing uTNE, with focus on those who received antithrombotic agents. PATIENTS AND METHODS: We enrolled 6860 patients (average age 55.6 ±â€Š12.97 years; 3405 males, 3455 females) who underwent uTNE and received the same preparations for the procedure. Epistaxis was evaluated using endoscopic images obtained while withdrawing the scope through the nostril. We also noted current use of medications including anticoagulant or antiplatelet agents prior to the endoscopic examination. RESULTS: Epistaxis occurred in 3.6 % of the enrolled patients (245/6860), and that rate was significantly higher in younger patients (average age 49.31 ±â€Š11.8 years for epistaxis group vs. 55.83 ±â€Š13.0 years for no epistaxis group, P  < 0.01) as well as females (4.78 % vs. 2.35 %, P  < 0.01). The odds ratio for occurrence of epistaxis was 2.31 (95 %CI: 1.746 - 3.167) in the younger patients and 2.02 (95 % CI: 1.542 - 2.659) in females. In contrast, there was no significant difference for rate of epistaxis between patients with and without treatment with an antithrombotic agent (3.0 % vs. 3.6 %). CONCLUSIONS: The rate of epistaxis was higher in younger and female patients. Importantly, that rate was not significantly increased in patients who were administered an antithrombotic agent.

Intrahepatic Cholangiolocellular and Cholangiocellular Carcinoma - Differences in the 18F-FDG PET/CT Findings.

Cholangiolocellular carcinoma is a minor primary cancerous tumor of the liver and its coexistence with intrahepatic cholangiocarcinoma in the liver is rare. We herein report a case of concurrent cholangiolocellular carcinoma and intrahepatic cholangiocarcinoma in the liver, in addition to a rectal G1 neuroendocrine tumor, a so-called carcinoid. The intrahepatic tumors showed a different uptake in the 18F-fluoro-2-deoxyglucose (FDG) positron-emission tomography (PET)/computed tomography (CT) findings. In addition to conventional dynamic contrast-enhanced CT, we concluded that FDG PET/CT could therefore be a helpful modality to identify the properties of both cholangiolocellular carcinoma and intrahepatic cholangiocarcinoma.

Tofacitinib for the treatment of moderate to severe chronic plaque psoriasis in Japanese patients: Subgroup analyses from a randomized, placebo-controlled phase 3 trial.

Tofacitinib is an oral Janus kinase inhibitor. These post-hoc analyses assessed tofacitinib efficacy and safety in Japanese patients with psoriasis enrolled in a 52-week global phase 3 study. Patients received tofacitinib 5 mg, tofacitinib 10 mg or placebo twice daily (b.i.d.); placebo-treated patients advanced to tofacitinib at week 16. Primary efficacy end-points were the proportions of patients with 75% or more reduction from baseline Psoriasis Area and Severity Index (PASI-75) and Physician's Global Assessment (PGA) of "clear" or "almost clear" (PGA response) at week 16. Other end-points included: Itch Severity Item (ISI), Dermatology Life Quality Index (DLQI) score and Nail Psoriasis Severity Index (NAPSI). Adverse events (AEs) were recorded throughout the study. Overall, 58 Japanese patients were included in this analysis (tofacitinib 5 mg b.i.d., n = 22; 10 mg b.i.d., n = 24; placebo, n = 12); 29 completed the study. At week 16, significantly more patients receiving tofacitinib 5 and 10 mg b.i.d. versus placebo achieved PASI-75 (50% and 75% vs 0%, P < 0.01) and PGA response (59% and 75% vs 0%, P < 0.001). Substantial improvements in ISI, DLQI and NAPSI score were observed with both tofacitinib doses. Over 52 weeks, similar rates of AEs were reported across treatment groups; one serious AE occurred with tofacitinib 10 mg b.i.d. Herpes zoster occurred in three patients receiving tofacitinib 10 mg b.i.d. No deaths, serious infections, malignancies or gastrointestinal perforations were reported. Results were generally consistent with global analysis, suggesting sustained efficacy and a manageable safety profile, with increased herpes zoster incidence, of tofacitinib in Japanese patients with psoriasis.

Helicobacter pylori-negative intestinal-type gastric adenoma successfully treated by endoscopic submucosal dissection: a case report.

BACKGROUND AND STUDY AIMS: A 49-year-old woman underwent an esophagogastroduodenoscopy as part of a health check at our hospital. Endoscopic observation revealed a flat elevated lesion 6 mm in diameter in the gastric antrum (Paris Classification type IIa). Magnifying endoscopy using narrow-band imaging showed a slightly irregular micro-surface pattern with round and oval pits, as well as a regular micro-vascular pattern without a demarcation line. Atrophy and intestinal metaplasia were not recognized in the background gastric mucosa. Furthermore, Helicobacter pylori infection was not detected by histologic, serologic, and urea breath test results. Endoscopic resection was performed for histologic evaluation, and a pathologic diagnosis of intestinal-type gastric adenoma occurring in pyloric mucosa without atrophy or metaplasia was established. Immunohistochemistry findings of the lesion showed the intestinal epithelium phenotype with positive staining for MUC2, CD10, and CDX2. Furthermore, irregular distribution with a higher positive proportion of Ki-67 was found in the lesion, indicating its malignant potential. We report here a rare case of gastric adenoma without surrounding intestinal metaplasia occurring in a Helicobacter pylori-negative patient.