The impact of omalizumab on paid and unpaid work productivity among severe Japanese cedar pollinosis (JCP) patients.

AIMS: Japanese cedar pollinosis (JCP) is a form of seasonal allergic rhinitis that affects 38.8% of the Japanese population. Particularly severe and most severe symptoms among JCP patients can lead to impairments of paid work productivity and unpaid work activities. Indeed, the current standard of care (SoC) is not always able to relieve these symptoms. Omalizumab, a novel JCP treatment recently approved in Japan, provides an effective add-on therapy to the SoC. This study estimates the effect of omalizumab on paid and unpaid work activities (i.e. its social impact) in patients with severe and most severe JCP symptoms in Japan. METHODS: The impact of omalizumab was estimated through a one-year static cohort model using the Work Productivity and Activity Impairment Allergy Specific (WPAI-AS) questionnaire derived from a clinical trial on omalizumab enrolling patients with severe and most severe JCP symptoms, which had been conducted in Japan. This effect was quantified using Japanese official statistics on employment and time use. The human capital approach and the proxy good approach were employed to monetize paid and unpaid work activities, respectively. A sensitivity analysis was implemented to account for modeling structural uncertainties. RESULTS: Our results show that the use of omalizumab might reduce the paid and unpaid work productivity losses due to severe and most severe JCP by nearly one-third. In the severe symptom period of three weeks, 36.6 million hours of lost paid and unpaid work hours could be avoided, which sums up to a monetized productivity loss of 728.3 million USD. CONCLUSIONS: Omalizumab could provide substantial benefits in terms of paid and unpaid work activities in patients with severe and most severe JCP. Our results also highlight the importance of considering unpaid work in estimating productivity costs due to poor health.

Five-year efficacy and safety of tildrakizumab in patients with moderate-to-severe psoriasis who respond at week 28: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2).

BACKGROUND: The phase III reSURFACE 1 and reSURFACE 2 (NCT01722331/NCT01729754) trials of the anti-interleukin-23p19 monoclonal antibody tildrakizumab (TIL) for psoriasis treatment are complete. OBJECTIVES: We present 5-year pooled data from reSURFACE 1 and reSURFACE 2. METHODS: reSURFACE 1 and reSURFACE 2 were double-blind, randomized, controlled studies with optional long-term extensions. Adults with moderate-to-severe chronic plaque psoriasis were randomized 2 : 2 : 1 to TIL 100 mg (TIL 100) or 200 mg (TIL 200) or placebo at weeks 0 and 4, and every 12 weeks thereafter [reSURFACE 2 included an etanercept (ETN) arm]. Efficacy outcomes included proportions of patients achieving absolute and relative improvement from baseline Psoriasis Area and Severity Index (PASI) score through week 244 in TIL responders (≥ 75% improvement from baseline PASI; PASI 75 response) continuously receiving the same dose and ETN partial responders and nonresponders (PASI < 75 response) switched to TIL 200 at week 28. Safety was assessed from adverse events (AEs) in all patients as treated. RESULTS: Efficacy analyses included 329 and 227 week 28 responders to TIL 100 and TIL 200, respectively, and 121 ETN partial responders/nonresponders switched to TIL 200 at week 28. Of TIL 100 or TIL 200 responders and ETN partial responders/nonresponders entering the extensions, 235/302, 176/213 and 85/107, respectively, were evaluated at week 244, and 88·7%, 92·5% and 81·3%, respectively, achieved PASI 75 response. Exposure-adjusted rates of serious AEs were 6·3 and 6·0 patients with events per 100 patient-years of TIL 100 and TIL 200, respectively. CONCLUSIONS: TIL treatment provided sustained disease control over 5 years in week 28 TIL responders and ETN partial responders/nonresponders, with a reassuring safety profile.

Efficacy and safety of dupilumab in Japanese adults with moderate-to-severe atopic dermatitis: a subanalysis of three clinical trials.

BACKGROUND: Dupilumab, a human monoclonal antibody, blocks the shared receptor unit for interleukin-4 and interleukin-13. International phase II and III studies have evaluated the efficacy and safety of dupilumab in adults with moderate-to-severe atopic dermatitis (AD), but the effects of dupilumab in Japanese patients have not been reported. OBJECTIVES: To evaluate the efficacy and safety of dupilumab in Japanese patients with moderate-to-severe AD. METHODS: We analysed the efficacy and safety of dupilumab in the Japanese cohorts of a 16-week, phase IIb dose-finding trial (AD-1021; NCT01859988); a 16-week, phase III, placebo-controlled monotherapy trial (LIBERTY AD SOLO 1; NCT02277743) and a 52-week, phase III, placebo-controlled study of dupilumab with topical corticosteroids (LIBERTY AD CHRONOS; NCT02260986). RESULTS: Twenty-seven, 106 and 117 Japanese patients were enrolled in AD-1021, SOLO 1 and CHRONOS, respectively. Baseline disease severity was numerically higher in the Japanese cohort than in the overall study population. Generally, dupilumab significantly improved signs and symptoms of AD, including pruritus and patient quality of life, compared with placebo in the Japanese cohort, consistent with the overall study population. The combined safety profile of dupilumab in the Japanese cohort was similar to that in the total study populations; dupilumab was associated with an increased incidence of injection-site reactions and conjunctivitis compared with placebo. Dupilumab was associated with rapid reduction in thymus and activation-regulated chemokine and gradual IgE reductions. CONCLUSIONS: Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD, had an acceptable safety profile, and suppressed biomarkers of type 2 inflammation compared with placebo in Japanese adult patients with moderate-to-severe AD. What's already known about this topic? Differences in atopic dermatitis (AD) pathology have been reported between Asian and Western populations, in which distinct helper T-cell activation profiles have been observed. International clinical studies in adults with moderate-to-severe AD have evaluated the efficacy and safety of dupilumab, which blocks interleukin-4 and interleukin-13, key molecules in type 2 inflammation. The effects of dupilumab in Japanese patients specifically have not yet been reported. What does this study add? Dupilumab alone or with topical corticosteroids improved signs and symptoms of AD and had an acceptable safety profile compared with placebo in Japanese patients with moderate-to-severe AD. The effects were comparable with those observed in the overall study population. Reported immunological differences in AD pathology in Asian patients may be secondary to type 2 immune activation.

Long-term efficacy and safety of tildrakizumab for moderate-to-severe psoriasis: pooled analyses of two randomized phase III clinical trials (reSURFACE 1 and reSURFACE 2) through 148 weeks.

BACKGROUND: Tildrakizumab is a specific anti-interleukin-23p19 monoclonal antibody approved for the treatment of plaque psoriasis. OBJECTIVES: To evaluate the long-term efficacy and safety of tildrakizumab treatment for patients with moderate-to-severe psoriasis for up to 148 weeks. METHODS: Pooled analysis from two double-blind, randomized controlled trials: reSURFACE 1 and reSURFACE 2. Efficacy was assessed for responders (≥ 75% improvement in Psoriasis Area and Severity Index; PASI 75) and partial responders (PASI 50-75) to tildrakizumab 100 mg and 200 mg at week 28 who were maintained on the same dose (administered every 12 weeks), and for partial responders or nonresponders (PASI < 50) to etanercept 50 mg at week 28 who, after a 4-week washout, were switched to tildrakizumab 200 mg (administered at weeks 32 and 36, and every 12 weeks thereafter). Safety was assessed in the all-patients-as-treated population. Three different methods of imputing missing data were used: nonresponder imputation (NRI), multiple imputation and observed cases. The Clinicaltrials.gov numbers are NCT01722331 (reSURFACE 1) and NCT01729754 (reSURFACE 2). RESULTS: At week 148 (NRI), 72·6%, 53·8% and 28·9% of tildrakizumab 100-mg responders and 80·2%, 59·9% and 32·6% of tildrakizumab 200-mg responders had PASI 75, 90 and 100 responses, respectively. For partial responders to tildrakizumab 100 mg and 200 mg, the proportions of patients achieving PASI 75, 90 and 100 responses were 32·5%, 25·0% and 10·0%; and 47·1%, 27·5% and 12·8%, respectively. For patients who were partial responders or nonresponders to etanercept, the proportions of patients achieving PASI 75, 90 and 100 responses were 66·9%, 43·8% and 14·9% at week 148. Rates of discontinuations due to adverse events [tildrakizumab 100 mg: 1·7 per 100 patient-years (PYs); tildrakizumab 200 mg: 1·2 per 100 PYs] and exposure-adjusted rates of serious adverse events (5·9 per 100 PYs; 5·5 per 100 PYs), severe infections (1·1 per 100 PYs; 1·1 per 100 PYs), malignancies (0·6 per 100 PYs; 0·4 per 100 PYs) and major adverse cardiovascular events (0·4 per 100 PYs; 0·5 per 100 PYs) were low. CONCLUSIONS: Tildrakizumab was well tolerated and efficacy was well maintained in week 28 responders who continued tildrakizumab treatment through 3 years, or improved among etanercept partial responders or nonresponders who switched to tildrakizumab. What's already known about this topic? Tildrakizumab 100 mg and 200 mg are efficacious and well tolerated with short-term use in the treatment of patients with moderate-to-severe plaque psoriasis. What does this study add? High levels of efficacy are maintained for up to 3 years of psoriasis treatment with tildrakizumab. There is a favourable long-term safety profile with both tildrakizumab 100 mg and 200 mg, with a low incidence of adverse events of special interest through 3 years.

Diffuse Pulmonary Meningotheliomatosis with Sarcomatous Transformation in a Shiba Dog.

A 2-year-old neutered female Shiba dog exhibited laboured breathing for 1 month. Computed tomography of the thoracic cavity revealed multiple nodules (2-5 mm diameter) in the lungs. Grossly, the lungs were firm and normal in shape. The nodules were grey-white in colour. Microscopically, the nodules were non-encapsulated and exhibited an irregular shape. They were composed of polygonal or spindle cells with indistinct cell borders arranged in sheets. The cells had large, round, hyperchromatic nuclei and abundant pale eosinophilic cytoplasm with no atypia. Intrapulmonary arterial emboli and infiltration into the bronchioles were observed. Immunohistochemically, the cells were positive for vimentin and negative for cytokeratin, glial fibrillary acidic protein and α-smooth muscle actin. Ultrastructurally, the cells displayed cytoplasmic processes, desmosomes and intermediate filaments. These findings led to a diagnosis of diffuse pulmonary meningotheliomatosis with sarcomatous transformation. To the best of our knowledge, this is the first report of diffuse pulmonary meningotheliomatosis in a dog.

Efficacy and safety of mirikizumab (LY3074828) in the treatment of moderate-to-severe plaque psoriasis: results from a randomized phase II study.

BACKGROUND: Inhibiting interleukin (IL)-23 in patients with psoriasis has demonstrated high levels of skin clearance. OBJECTIVES: To investigate, in a phase II (AMAF; NCT02899988), multicentre, double-blind trial, the efficacy and safety of three doses of mirikizumab (LY3074828), a p19-directed IL-23 antibody, vs. placebo in patients with moderate-to-severe plaque psoriasis. METHODS: Adult patients were randomized 1 : 1 : 1 : 1 to receive placebo (n = 52), mirikizumab 30 mg (n = 51), mirikizumab 100 mg (n = 51) or mirikizumab 300 mg (n = 51) subcutaneously at weeks 0 and 8. The primary objective was to evaluate the superiority of mirikizumab over placebo in achieving a 90% improvement in the Psoriasis Area and Severity Index (PASI 90) response at week 16. Comparisons were done using logistic regression analysis with treatment, geographical region and previous biological therapy in the model. Missing data were imputed as nonresponses. RESULTS: Ninety-seven per cent of patients completed the first 16 weeks of the study. The primary end point was met for all mirikizumab dose groups vs. placebo, with PASI 90 response rates at week 16 of 0%, 29% (P = 0·009), 59% (P < 0·001) and 67% (P < 0·001) for patients receiving placebo, and mirikizumab 30 mg, 100 mg and 300 mg, respectively. There were two (1%) serious adverse events in mirikizumab-treated patients vs. one (2%) in a placebo-group patient. CONCLUSIONS: At week 16, 67% of patients treated with mirikizumab 300 mg at 8-week intervals achieved PASI 90. The percentage of patients reporting at least one treatment-emergent adverse event was similar among patients treated with placebo or mirikizumab.

Prognostic significance of hypermethylation of death-associated protein kinase (DAPK) gene CpG island in dogs with high-grade B-cell lymphoma.

Death-associated protein kinase (DAPK) is a serine/threonine kinase and a tumour suppressor gene. Diffuse large B-cell lymphomas with inactivated DAPK through hypermethylation of a CpG island is known to result in a biologically aggressive phenotype in humans. This retrospective study was carried out to analyse the prognostic significance of DAPK CpG island hypermethylation in canine lymphoma. We hypothesized that DAPK CpG island hypermethylation can be a negative prognostic indicator in dogs with nodal high-grade B-cell lymphoma. Forty-seven dogs with high-grade B-cell lymphoma, according to the updated Kiel classification, were evaluated after being treated with a CHOP (vincristine, cyclophosphamide, doxorubicin and prednisolone)-based chemotherapy protocol. The methylation status of the DAPK CpG island was examined by methylation-specific PCR. Progression-free survival (PFS) and overall survival (OS) were compared using the Kaplan-Meier analysis and log-rank test. The cox proportional hazard regression model was used to evaluate the effect of multiple variables. Hypermethylation of the DAPK CpG island was detected in 21 of the 47 dogs. The PFS and OS in dogs with the hypermethylation (median: 220 and 266 days, respectively) were significantly shorter than those of dogs without hypermethylation (median: 301 and 412 days, respectively) (PFS, P = .036; OS, P = .007). In the multivariate analysis, hypermethylation of the DAPK CpG island remained an independent prognostic factor in predicting shortened PFS (P = .047) and OS (P = .021) as well as clinical substage b. Overall, hypermethylation of the DAPK CpG island was a negative prognostic factor in canine high-grade B-cell lymphoma.

Efficacy and safety of topical JTE-052, a Janus kinase inhibitor, in Japanese adult patients with moderate-to-severe atopic dermatitis: a phase II, multicentre, randomized, vehicle-controlled clinical study.

BACKGROUND: JTE-052 is a novel Janus kinase inhibitor presently under clinical development for the topical treatment of atopic dermatitis (AD). OBJECTIVES: To evaluate the efficacy and safety of JTE-052 ointment in Japanese adult patients with AD. METHODS: Patients with moderate-to-severe AD were randomized (2: 2: 2: 2: 1: 1) to receive JTE-052 ointment at 0·25%, 0·5%, 1% or 3%, the vehicle ointment or tacrolimus 0·1% ointment (reference) twice daily for 4 weeks. The primary efficacy end point was the percentage change in modified Eczema Area Severity Index (mEASI) score from baseline at the end of treatment (EOT). Secondary efficacy end points included change from baseline in the pruritus numerical rating scale (NRS) score. RESULTS: In total, 327 patients were enrolled. At EOT, the least-squares mean percentage changes from baseline in mEASI score for JTE-052 at 0·25%, 0·5%, 1% and 3% and the vehicle ointment were -41·7%, -57·1%, -54·9%, -72·9% and -12·2%, respectively. All JTE-052 groups showed significant reductions of mEASI score vs. the vehicle group (P < 0·001 for all). In the tacrolimus group, the mean percentage change in mEASI score was -62·0%. The JTE-052 groups also showed significant improvement in other parameters; notably, the pruritus NRS score was reduced as early as day 1 night-time. JTE-052 ointment at doses up to 3% was safe and well tolerated. CONCLUSIONS: Topical JTE-052 markedly and rapidly improved clinical signs and symptoms in Japanese adult patients with moderate-to-severe AD, with a favourable safety profile. The study results indicate that topical JTE-052 is a promising therapeutic option for AD. The trial registration number is JapicCTI-152887.

Cancer screening for older people: to screen or not to screen.

In this scoping review, the evidence of the benefits of screening older people for the five most common types of cancer in Hong Kong, namely colorectal, lung, breast, liver, and prostate cancers, is discussed. Although cancer treatments can be extensive and a good prognosis is less likely if cancer is diagnosed at a late stage, screening programmes for older people in primary care remain a matter of contention. The general recommendation for the screening of older people is to adopt an individualised approach that takes account of not only age but also co-morbidity, life expectancy, harms and benefits, and patient's preference.

Characterization of PTEN mutations in brain cancer reveals that pten mono-ubiquitination promotes protein stability and nuclear localization.

PTEN is a PIP3 phosphatase that antagonizes oncogenic PI3-kinase signalling. Due to its critical role in suppressing the potent signalling pathway, it is one of the most mutated tumour suppressors, especially in brain tumours. It is generally thought that PTEN deficiencies predominantly result from either loss of expression or enzymatic activity. By analysing PTEN in malignant glioblastoma primary cells derived from 16 of our patients, we report mutations that block localization of PTEN at the plasma membrane and nucleus without affecting lipid phosphatase activity. Cellular and biochemical analyses as well as structural modelling revealed that two mutations disrupt intramolecular interaction of PTEN and open its conformation, enhancing polyubiquitination of PTEN and decreasing protein stability. Moreover, promoting mono-ubiquitination increases protein stability and nuclear localization of mutant PTEN. Thus, our findings provide a molecular mechanism for cancer-associated PTEN defects and may lead to a brain cancer treatment that targets PTEN mono-ubiquitination.

Genetic and epigenetic aberrations of p16 in feline primary neoplastic diseases and tumor cell lines of lymphoid and non-lymphoid origins.

The p16 gene acts as a tumor suppressor by regulating the cell cycle and is frequently inactivated in human and canine cancers. The aim of this study was to characterize genetic and epigenetic alterations of the p16 in feline lymphoid and non-lymphoid malignancies, using 74 primary tumors and 11 tumor cell lines. Cloning of feline p16 and subsequent sequence analysis revealed 11 germline sequence polymorphisms in control cats. Bisulfite sequencing analysis of the p16 promoter region in a feline lymphoma cell line revealed that promoter methylation was associated with decreased mRNA expression. Treatment with a demethylating agent restored mRNA expression of the silenced p16. PCR amplification and sequencing analysis detected homozygous loss (five tumors, 6.7%) and a missense mutation (one tumor, 1.4%) in the 74 primary tumors analyzed. Methylation-specific PCR analysis revealed promoter methylation in 10 primary tumors (14%). Promoter methylation was frequent in B cell lymphoid tumors (7/21 tumors, 33%). These genetic and epigenetic alterations were also observed in lymphoma and mammary gland carcinoma cell lines, but not detected in non-neoplastic control specimens. These data indicate that molecular alterations of the p16 locus may be involved in the development of specific types of feline cancer, and warrant further studies to evaluate the clinical value of this evolutionarily-conserved molecular alteration in feline cancers.

Changes in Foxp3-Positive Regulatory T Cell Number in the Intestine of Dogs With Idiopathic Inflammatory Bowel Disease and Intestinal Lymphoma.

Although regulatory T cells (Tregs) play an integral role in immunologic tolerance and the maintenance of intestinal homeostasis, their involvement in canine gastrointestinal diseases, including idiopathic inflammatory bowel disease (IBD) and intestinal lymphoma, remains unclear. Here we show altered numbers of forkhead box P3 (Foxp3)-positive Tregs in the intestine of dogs with IBD and intestinal lymphoma. IBD was diagnosed in 48 dogs; small cell intestinal lymphoma was diagnosed in 46 dogs; large cell intestinal lymphoma was diagnosed in 30 dogs; and 25 healthy beagles were used as normal controls. Foxp3-positive Tregs in the duodenal mucosa were examined by immunohistochemistry and immunofluorescence. Duodenal expression of interleukin-10 mRNA was quantified by real-time reverse transcription polymerase chain reaction. The number of Foxp3-positive lamina propria cells and the expression of interleukin-10 mRNA were significantly lower in dogs with IBD than in healthy dogs and dogs with intestinal lymphoma. The number of Foxp3-positive intraepithelial cells was higher in dogs with small cell intestinal lymphoma. Some large cell intestinal lymphoma cases had high numbers of Foxp3-positive cells, but the increase was not statistically significant. Double-labeling immunofluorescence showed that CD3-positive granzyme B-negative helper T cells expressed Foxp3. In small cell intestinal lymphoma cases, the overall survival of dogs with a high Treg density was significantly worse than that of dogs with a normal Treg density. These results suggest that a change in the number of Foxp3-positive Tregs contributes to the pathogenesis of canine IBD and intestinal lymphoma by disrupting mucosal tolerance and suppressing antitumor immunity, respectively.

Clinical evaluation of the additive effect of diquafosol tetrasodium on sodium hyaluronate monotherapy in patients with dry eye syndrome: a prospective, randomized, multicenter study.

PURPOSE: To assess the additive effect of diquafosol tetrasodium on sodium hyaluronate monotherapy in patients with dry eye syndrome. METHODS: This study evaluated 64 eyes of 32 patients (age: 62.6±12.8 years (mean±SD)) in whom treatment with 0.1% sodium hyaluronate was insufficiently responsive. The eyes were randomly assigned to one of the two regimens in each patient: topical administration of sodium hyaluronate and diquafosol tetrasodium in one eye, and that of sodium hyaluronate in the other. Before treatment, and 2 and 4 weeks after treatment, we determined tear volume, tear film break-up time (BUT), fluorescein and rose bengal vital staining scores, subjective symptoms, and adverse events. RESULTS: We found a significant improvement in BUT (P=0.049, Dunnett test), fluorescein and rose bengal staining scores (P=0.02), and in subjective symptoms (P=0.004 for dry eye sensation, P=0.02 for pain, and P=0.02 for foreign body sensation) 4 weeks after treatment in the diquafosol eyes. On the other hand, we found no significant change in these parameters after treatment in the control eyes. CONCLUSIONS: In dry eyes, where sodium hyaluronate monotherapy was insufficient, diquafosol tetrasodium was effective in improving objective and subjective symptoms, suggesting its viability as an option for the additive treatment of such eyes.