Pfizer (China)

BACKGROUND: Increases in lipid levels and cancers with tofacitinib prompted a trial of major adverse cardiovascular events (MACE) and cancers in patients with rheumatoid arthritis receiving tofacitinib as compared with a tumor necrosis factor (TNF) inhibitor. METHODS: We conducted a randomized, open-label, noninferiority, postauthorization, safety end-point trial involving patients with active rheumatoid arthritis despite methotrexate treatment who were 50 years of age or older and had at least one additional cardiovascular risk factor. Patients were randomly assigned in a 1:1:1 ratio to receive tofacitinib at a dose of 5 mg or 10 mg twice daily or a TNF inhibitor. The coprimary end points were adjudicated MACE and cancers, excluding nonmelanoma skin cancer. The noninferiority of tofacitinib would be shown if the upper boundary of the two-sided 95% confidence interval for the hazard ratio was less than 1.8 for the combined tofacitinib doses as compared with a TNF inhibitor. RESULTS: A total of 1455 patients received tofacitinib at a dose of 5 mg twice daily, 1456 received tofacitinib at a dose of 10 mg twice daily, and 1451 received a TNF inhibitor. During a median follow-up of 4.0 years, the incidences of MACE and cancer were higher with the combined tofacitinib doses (3.4% [98 patients] and 4.2% [122 patients], respectively) than with a TNF inhibitor (2.5% [37 patients] and 2.9% [42 patients]). The hazard ratios were 1.33 (95% confidence interval [CI], 0.91 to 1.94) for MACE and 1.48 (95% CI, 1.04 to 2.09) for cancers; the noninferiority of tofacitinib was not shown. The incidences of adjudicated opportunistic infections (including herpes zoster and tuberculosis), all herpes zoster (nonserious and serious), and adjudicated nonmelanoma skin cancer were higher with tofacitinib than with a TNF inhibitor. Efficacy was similar in all three groups, with improvements from month 2 that were sustained through trial completion. CONCLUSIONS: In this trial comparing the combined tofacitinib doses with a TNF inhibitor in a cardiovascular risk-enriched population, risks of MACE and cancers were higher with tofacitinib and did not meet noninferiority criteria. Several adverse events were more common with tofacitinib. (Funded by Pfizer; ORAL Surveillance ClinicalTrials.gov number, NCT02092467.).

OBJECTIVE: Tofacitinib is an oral Janus kinase (JAK) inhibitor for the treatment of rheumatoid arthritis (RA). The pathways affected by tofacitinib and the effects on gene expression in situ are unknown. Therefore, tofacitinib effects on synovial pathobiology were investigated. METHODS: A randomised, double-blind, phase II serial synovial biopsy study (A3921073; NCT00976599) in patients with RA with an inadequate methotrexate response. Patients on background methotrexate received tofacitinib 10 mg twice daily or placebo for 28 days. Synovial biopsies were performed on Days -7 and 28 and analysed by immunoassay or quantitative PCR. Clinical response was determined by disease activity score and European League Against Rheumatism (EULAR) response on Day 28 in A3921073, and at Month 3 in a long-term extension study (A3921024; NCT00413699). RESULTS: Tofacitinib exposure led to EULAR moderate to good responses (11/14 patients), while placebo was ineffective (1/14 patients) on Day 28. Tofacitinib treatment significantly reduced synovial mRNA expression of matrix metalloproteinase (MMP)-1 and MMP-3 (p<0.05) and chemokines CCL2, CXCL10 and CXCL13 (p<0.05). No overall changes were observed in synovial inflammation score or the presence of T cells, B cells or macrophages. Changes in synovial phosphorylation of signal transducer and activator of transcription 1 (STAT1) and STAT3 strongly correlated with 4-month clinical responses (p<0.002). Tofacitinib significantly decreased plasma CXCL10 (p<0.005) at Day 28 compared with placebo. CONCLUSIONS: Tofacitinib reduces metalloproteinase and interferon-regulated gene expression in rheumatoid synovium, and clinical improvement correlates with reductions in STAT1 and STAT3 phosphorylation. JAK1-mediated interferon and interleukin-6 signalling likely play a key role in the synovial response. TRIAL REGISTRATION NUMBER: NCT00976599.

OBJECTIVE: To evaluate tofacitinib's effect upon pneumococcal and influenza vaccine immunogenicity. METHODS: We conducted two studies in patients with rheumatoid arthritis using the 23-valent pneumococcal polysaccharide vaccine (PPSV-23) and the 2011-2012 trivalent influenza vaccine. In study A, tofacitinib-naive patients were randomised to tofacitinib 10 mg twice daily or placebo, stratified by background methotrexate and vaccinated 4 weeks later. In study B, patients already receiving tofacitinib 10 mg twice daily (with or without methotrexate) were randomised into two groups: those continuing ('continuous') or interrupting ('withdrawn') tofacitinib for 2 weeks, and then vaccinated 1 week after randomisation. In both studies, titres were measured 35 days after vaccination. Primary endpoints were the proportion of patients achieving a satisfactory response to pneumococcus (twofold or more titre increase against six or more of 12 pneumococcal serotypes) and influenza (fourfold or more titre increase against two or more of three influenza antigens). RESULTS: In study A (N=200), fewer tofacitinib patients (45.1%) developed satisfactory pneumococcal responses versus placebo (68.4%), and pneumococcal titres were lower with tofacitinib (particularly with methotrexate). Similar proportions of tofacitinib-treated and placebo-treated patients developed satisfactory influenza responses (56.9% and 62.2%, respectively), although fewer tofacitinib patients (76.5%) developed protective influenza titres (≥1:40 in two or more of three antigens) versus placebo (91.8%). In study B (N=183), similar proportions of continuous and withdrawn patients had satisfactory responses to PPSV-23 (75.0% and 84.6%, respectively) and influenza (66.3% and 63.7%, respectively). CONCLUSIONS: Among patients starting tofacitinib, diminished responsiveness to PPSV-23, but not influenza, was observed, particularly in those taking concomitant methotrexate. Among existing tofacitinib users, temporary drug discontinuation had limited effect upon influenza or PPSV-23 vaccine responses. TRIAL REGISTRATION NUMBERS: NCT01359150, NCT00413699.

OBJECTIVE: Tofacitinib is an oral JAK inhibitor for the treatment of rheumatoid arthritis (RA). Systemic inflammation is proposed to play a fundamental role in the altered lipid metabolism associated with RA; however, the underlying mechanisms are unknown. We undertook this study to compare cholesterol and lipoprotein kinetics in patients with active RA with those in matched healthy volunteers. METHODS: This was a phase I open-label mechanism-of-action study. Cholesterol and lipoprotein kinetics were assessed with (13) C-cholesterol and (13) C-leucine infusions. RA patients were reevaluated after receiving oral tofacitinib 10 mg twice daily for 6 weeks. RESULTS: Levels of high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, total cholesterol, and apolipoprotein A-I (Apo A-I) as well as HDL cholesterol particle number were lower in RA patients (n = 36) than in healthy volunteers (n = 33). In contrast, the cholesterol ester fractional catabolic rate was higher in RA patients, but no differences were observed in cholesterol ester transfer protein, cholesterol ester production rate, HDL-associated Apo A-I fractional catabolic rate, or LDL-associated Apo B fractional catabolic rate. Following tofacitinib treatment in RA patients, the cholesterol ester fractional catabolic rate decreased and cholesterol levels increased. The decrease in cholesterol ester fractional catabolic rate correlated significantly with the increase in HDL cholesterol. Additionally, HDL cholesterol particle number increased and markers of HDL cholesterol function improved. CONCLUSION: This is the first study to assess cholesterol and lipoprotein kinetics in patients with active RA and matched healthy volunteers. The data suggest that low cholesterol levels in patients with active RA may be driven by increases in cholesterol ester catabolism. Tofacitinib treatment reduced cholesterol ester catabolism, thereby increasing cholesterol levels toward those in healthy volunteers, and markers of antiatherogenic HDL function improved.

PURPOSE: PF299804 is a potent, orally available, irreversible inhibitor of tyrosine kinase human epidermal growth factor receptors (HER) 1 (EGFR), HER2, and HER4. This first-in-human study investigated the safety, tolerability, pharmacokinetics, and pharmacodynamics of PF299804 in patients with advanced solid malignancies. EXPERIMENTAL DESIGN: PF299804 was administered once daily continuously (schedule A) and intermittently (schedule B). Dose escalation proceeded until intolerable toxicities occurred. Skin biopsies were taken predose and after 14 days of treatment to establish a pharmacokinetic/pharmacodynamic relationship. Tumor response was measured once every 2 cycles. Efficacy was correlated with tumor genotypes in non-small cell lung cancer (NSCLC) patients. RESULTS: 121 patients were included (111 in schedule A, 10 in schedule B). The maximum tolerated dose (MTD) was 45 mg/d. Dose-limiting toxicities included stomatitis and skin toxicities. Most adverse events were mild and comprised skin toxicities, fatigue, and gastrointestinal side-effects including diarrhea, nausea, and vomiting. Pharmacokinetic analyses revealed dose-dependent increases in PF299804 exposure associated with target inhibition in skin biopsy samples. Fifty-seven patients with non-small cell lung cancer (NSCLC) were treated in this study. Four patients, all previously treated with gefitinib or erlotinib (2 with exon 19 deletions, 1 with exon 20 insertion, 1 mutational status unknown), had a partial response to PF299804. CONCLUSIONS: The MTD of PF299804 is 45 mg/d. Both continuous and intermittent treatment schedules were well tolerated, and encouraging signs of antitumor activity were observed in gefitinib/erlotinib treated NSCLC patients.

Recent GWAS studies focused on uncovering novel genetic loci related to AD have revealed associations with variants near CLU, CR1, PICALM and BIN1. In this study, we conducted a genome-wide association study in an independent set of 1034 cases and 1186 controls using the Illumina genotyping platforms. By coupling our data with available GWAS datasets from the ADNI and GenADA, we replicated the original associations in both PICALM (rs3851179) and CR1 (rs3818361). The PICALM variant seems to be non-significant after we adjusted for APOE e4 status. We further tested our top markers in 751 independent cases and 751 matched controls. Besides the markers close to the APOE locus, a marker (rs12989701) upstream of BIN1 locus was replicated and the combined analysis reached genome-wide significance level (p = 5E-08). We combined our data with the published Harold et al. study and meta-analysis with all available 6521 cases and 10360 controls at the BIN1 locus revealed two significant variants (rs12989701, p = 1.32E-10 and rs744373, p = 3.16E-10) in limited linkage disequilibrium (r² = 0.05) with each other. The independent contribution of both SNPs was supported by haplotype conditional analysis. We also conducted multivariate analysis in canonical pathways and identified a consistent signal in the downstream pathways targeted by Gleevec (P = 0.004 in Pfizer; P = 0.028 in ADNI and P = 0.04 in GenADA). We further tested variants in CLU, PICALM, BIN1 and CR1 for association with disease progression in 597 AD patients where longitudinal cognitive measures are sufficient. Both the PICALM and CLU variants showed nominal significant association with cognitive decline as measured by change in Clinical Dementia Rating-sum of boxes (CDR-SB) score from the baseline but did not pass multiple-test correction. Future experiments will help us better understand potential roles of these genetic loci in AD pathology.

Recent studies conducted in the USA and the UK have shown evidence of a relationship between market orientation and company performance. The overall aim of the research reported in this paper was to build on this limited body of literature by considering the evidence from another, non‐Western, business environment, namely Hong Kong. In addition, this study sought to clarify the distinction, not often made in the literature, between a market‐ and a marketing‐orientation. Data from 73 textiles and garments manufacturers were collected using an instrument based on Narver and Slater’s (1990) scale. Consistent with previous findings in Western cultures, the results of this study are suggestive of a relationship between market orientation and company performance. However, surveyed firms exhibited a much higher marketing orientation suggesting that it is possible to be effective at implementing the marketing function without possessing a market‐oriented organisational culture.

OBJECTIVE: Interleukin 13 (IL-13) is thought to play a key role as an effector cytokine in UC. Anrukinzumab, a humanised antibody that inhibits human IL-13, was evaluated for the treatment of UC. DESIGN: In a multicentre, randomised, double-blind, placebo-controlled study, patients with active UC (Mayo score ≥4 and <10) were randomised to anrukinzumab 200, 400 or 600 mg or placebo. Patients received five intravenous administrations over 14 weeks. The primary endpoint was fold change from baseline in faecal calprotectin (FC) at Week 14. Secondary endpoints included safety, pharmacokinetics and IL-13 levels. RESULTS: The modified intention-to-treat population included 84 patients (21 patients/arm). Fold change of FC from baseline at Week 14 was not significantly different for any treatment groups compared with the placebo. The study had a high dropout rate, in part, related to lack of efficacy. The exploratory comparisons of each dose were not significantly different from placebo in terms of change from baseline in total Mayo score, clinical response, clinical remission and proportion of subjects with mucosal healing. An increase in serum total IL-13 (free and bound to anrukinzumab) was observed for all anrukinzumab groups but not with placebo. This suggests significant binding of anrukinzumab to IL-13. The safety profile was not different between the anrukinzumab and placebo groups. CONCLUSIONS: A statistically significant therapeutic effect of anrukinzumab could not be demonstrated in patients with active UC in spite of binding of anrukinzumab to IL-13. TRIAL REGISTRATION NUMBER: ClinicalTrials.gov number NCT01284062.

Cyclin-dependent kinase 4/6 (CDK4/6) inhibitors, which block the transition from the G1 to S phase of the cell cycle by interfering with Rb phosphorylation and E2F release, have shown potent antitumor activity and manageable toxicity in HR+/HER2- breast cancer patients. Some clinical trials involving CDK4/6 inhibitors in other tumors have achieved preliminary impressive efficacy. Whether CDK4/6 inhibitors possess great potential as broad-spectrum antitumor drugs and how to maximize their clinical benefits remain uncertain. TCGA database analysis showed that CDK4/6 genes and related genes are widely expressed among various tumors, and high or moderate expression of CDK4/6 genes commonly indicates poor survival. CDK4/6 gene expression is significantly higher in COAD, ESCA, STAD, LIHC, and HNSC, suggesting that CDK4/6 inhibitors could be more efficacious in those tumors. Moreover, network analysis with the STRING database demonstrated that CDK4/6-related proteins were co-expressed or co-occurred with the classical tumor signaling pathways, such as the cell cycle pathway, RAS pathway, PI3K pathway, Myc pathway, and p53 pathway. The extensive antitumor effects of CDK4/6 inhibitors may be achieved by synergizing or antagonizing with other signaling molecule inhibitors, and combination therapy might be the most effective treatment strategy. This article analyzed the feasibility of expanding the application of CDK4/6 inhibitors at the genetic level and further summarized the associated clinical/preclinical studies to collect supportive evidence. This is the first study that presents a theoretical foundation for CDK4/6 inhibitor precision therapy via combined analysis of comprehensive gene information and clinical research results.

BACKGROUND: Numerous epidemiology studies on dyslipidemia have been conducted in China. However, a nationally representative estimate for dyslipidemia prevalence is lacking. The aim of this study is to appraise the nationwide prevalence, awareness, treatment, and control rates of dyslipidemia in adults in China. METHODS: We performed a systematic review of the related observational studies published since 2003 by searching English and Chinese literature databases. Meta-analyses were conducted in eligible studies using a random effect model to summarize the dyslipidemia prevalence, awareness, treatment, and control rates. Heterogeneity and publication bias were analyzed. Sensitivity analyses were performed to explain heterogeneity and examine the impact of study quality on the results of meta-analyses. RESULTS: Thirty-eight papers were included for meta-analyses, with a total sample size of 387,825. The prevalence, awareness, treatment, and control rates of dyslipidemia were 41.9% (95% CI: 37.7% - 46.2%), 24.4% (95% CI: 14.4% - 38.4%), 8.8% (95% CI: 7.7% - 10.0%), and 4.3% (95% CI: 4.1% - 4.5%), respectively. The prevalence of hypercholesterolemia, hypertriglyceridemia, mixed hyperlipidemia, low levels of high-density lipoprotein cholesterol, and high levels of low-density lipoprotein cholesterol were 10.1% (95% CI: 5.8% - 16.9%), 17.7% (95% CI: 14.0% - 22.1%), 5.1% (95% CI: 3.1% - 8.2%), 11.0% (95% CI: 8.0% - 15.0%), and 8.8% (95% CI: 4.1% - 17.8%), respectively. Sensitivity analyses revealed that males had a higher prevalence of dyslipidemia (43.2%) than females (35.6%). Study samples of age 30 and above in the eastern region tended to have higher prevalence of dyslipidemia. The quality of the studies has a slight impact on the pooled estimates. CONCLUSIONS: The overall pooled prevalence of dyslipidemia in Chinese adults was estimated to be 41.9%, with males having a higher rate than females.

Cardiovascular (CV) morbidity and mortality are increased in patients with active, untreated rheumatoid arthritis (RA), despite lower levels of total and low-density lipoprotein cholesterol reported in individuals with active RA compared with those without RA. Alterations in non-traditional lipid assessments, such as high-density lipoprotein (HDL) function and HDL-associated proteins, have been described in patients with active RA, including elevated HDL-associated serum amyloid A and decreased paraoxonase-1 activity. We review changes in both traditional lipoprotein concentrations and non-traditional lipoprotein assessments in multiple studies of treatment with disease-modifying antirheumatic drugs (DMARDs), including non-biologic and biologic DMARDs and tofacitinib. In addition, data from a recently published clinical trial with tofacitinib that describe a potential mechanism for suppression of cholesterol levels in active RA patients are reviewed. Finally, CV event data from various studies of DMARDs are presented, and the current management of RA patients with regard to the CV risk is reviewed.

INTRODUCTION: Few studies have examined the epidemiology of herpes zoster (HZ) and postherpetic neuralgia (PHN) in China. The aim of this study was to estimate the prevalence of HZ and PHN in China, and to examine the clinical characteristics of patients identified with PHN. METHODS: This was a cross-sectional study conducted in 24 hospitals in seven cities in China. Prevalence of HZ and PHN was determined by physician (n = 100) chart review of patients (n = 36,170) aged ≥ 40 years seeking medical care over a 30- to 60-day period. The health history of patients identified with PHN was obtained and included time since diagnosis of HZ or PHN, time since onset of PHN-related pain, and the methods used for diagnosing HZ and PHN. RESULTS: The prevalence rates of HZ and PHN were 7.7% [95% confidence interval (CI) 7.5-8.0] and 2.3% (95% CI 2.2-2.5), respectively. Of patients with HZ, 29.8% developed PHN. Rates of HZ and PHN increased with age and were highest in patients aged ≥ 70 years (10.6% and 4.1%, respectively). The majority of patients with PHN were diagnosed with HZ (80.9%) and PHN (83.8%) for < 1 year, and had experienced PHN-related pain for < 1 year (80.5%). Patient description and clinical examination were most commonly used to diagnose HZ and PHN. CONCLUSION: These results provide current estimates of the prevalence of HZ and PHN in the general adult population in urban China. These rates are similar to previously reported rates in China and worldwide, and highlight the global nature of HZ and PHN. FUNDING: Pfizer Inc.

INTRODUCTION: Streptococcus pneumoniae causes mucosal and invasive diseases with high morbidity and mortality. Introduction of the 7-valent pneumococcal conjugate vaccine (PCV7) into routine infant immunization programs worldwide resulted in serotype 19A becoming a leading cause of the remaining pneumococcal disease burden in vaccinated and nonvaccinated individuals. This article reviews the impact of the latest generation PCVs (10-valent PCV, PCV10, and 13-valent PCV, PCV13) on serotype 19A. Areas covered: This article covers immune responses elicited by PCV7, PCV10 and PCV13 against serotype 19A and their impact on nasopharyngeal (NP) carriage and disease in vaccinated and unvaccinated populations using data from surveillance systems, randomized controlled trials, and observational studies. Expert commentary: As expected from a PCV containing serotype 19A, PCV13 elicits significantly higher functional immune responses against serotype 19A than PCV7 and PCV10. Higher responses are likely to be linked to both direct impact in vaccinated populations and reductions in 19A NP carriage in children, thus inducing herd protection and reducing 19A invasive pneumococcal disease (IPD) in nonvaccinated children and adults. In contrast, PCV7 and PCV10 have shown mixed evidence of direct short-lived cross-protection and little to no impact on 19A carriage, resulting in continued transmission and disease.

OBJECTIVE: To examine the relationship between hypertension and health-related quality of life in patients attending hospital clinics in China. DESIGN AND METHODS: A cross-sectional survey. Patients over the age of 35 years attending outpatient clinics in 18 hospitals of eight major cities of northern and southern China were interviewed between June and July, 1999. Trained fieldworkers completed questionnaires regarding demographics, hypertension knowledge and awareness, treatment history and quality of life issues. Qualified physicians performed blood pressure assessments. RESULTS: A total of 9703 volunteers were enrolled; 4510 (46.5%) had hypertension. The results showed that hypertensive subjects scored lower in the multiple linear regression analyses in most questions on the quality of life questionnaire than those without hypertension after controlling for age, sex, sociodemographic factors, and co-morbidity. There was a strikingly high prevalence of physical complaints or symptoms. Among the variables considered, age, sex, hypertension, body mass index, educational level, smoking, history of cholesterol, family history of cardiovascular diseases and history of diabetes were statistically significantly correlated with health-related quality of life. Subjects aware of having high blood pressure had a lower health-related quality of life score than subjects with high blood pressure but unaware of the diagnosis. Among treated subjects, those with controlled hypertension had higher health-related quality of life scores than those with poorly controlled hypertension. CONCLUSIONS: Hypertensive individuals represent a vulnerable population that merits special attention from healthcare providers and systems. This is especially important given that low health-related quality of life can be a risk factor for subsequent cardiovascular events or complications.

Nonsteroidal anti-inflammatory drugs (NSAIDs) are often coadministered with proton-pump inhibitors (PPIs) to reduce NSAID-induced gastrointestinal (GI) adverse events. This coadministration is generally regarded as safe, and is included in many of the guidelines on NSAID prescription. However, recent evidence indicates that the GI risks associated with NSAIDs can be potentiated when they are combined with PPIs. This review discusses the GI effects and complications of NSAIDs and how PPIs may potentiate these effects, options for prevention of GI side effects, and appropriate use of PPIs in combination with NSAIDs.

INTRODUCTION: Ulcerative colitis (UC) is an idiopathic, chronic inflammatory disease of the colon, characterized by relapsing and remitting symptoms. Although traditionally viewed as a Western disease, the incidence and prevalence of UC is increasing in developing regions, including Asian countries. AREAS COVERED: A PubMed search identified articles describing epidemiology, disease burden, patient demographics, clinical characteristics, risk factors, and treatment of UC across Asia. We review the epidemiology and disease course of UC across Asia, including region-specific factors that may aid development of more cost-effective treatment approaches tailored to the needs of Asian populations. EXPERT OPINION: The opinion of non-Pfizer-affiliated practicing gastroenterologists is that epidemiological data from the last four decades have shown 1.5-fold to almost 20-fold increases in the incidence and prevalence of UC in some Asian countries, although prevalence remains generally lower than in the West. As the prevalence of UC rises, so will overall healthcare costs. Disparities in healthcare systems and funding mean that different Asian countries face unique challenges in how best to use available resources, including selection from a growing number of emerging treatment options. More clinical trial and real-world data are required to help define treatment approaches that will most benefit Asian populations.

The Regional Resistance Surveillance program monitored susceptibility rates and developing resistance by geographic region, including 12 Asia-Pacific (APAC) countries. Reference broth microdilution methods for susceptibility/interpretations were applied, processing 5,053 strains. Among Staphylococcus aureus isolates (37% methicillin-resistant S. aureus [MRSA], highest in South Korea [73%]), linezolid (LZD), tigecycline (TIG), and vancomycin were 100% active, but 33 and 34% of strains were levofloxacin (LEV) or macrolide resistant, respectively. Streptococcus pneumoniae was most resistant to β-lactams and macrolides (45%) but was LZD, LEV, and TIG susceptible (>98%). Extended-spectrum β-lactamase (ESBL) phenotype rates in Escherichia coli and Klebsiella spp. were 48 and 47%, respectively, and were highest in Taiwan, at 75 to 91%. The best anti-ESBL-phenotype agents were amikacin (81 to 96% susceptible), colistin (COL; >98%), TIG (>98%), and carbapenems (81 to 97%). Pseudomonas aeruginosa showed ≥20% resistance to all drugs except COL (99% susceptible). In conclusion, endemic evolving antimicrobial resistances in APAC nations show compromised roles for many commonly used antimicrobials.

Tick-borne encephalitis virus (TBEV) causes mild or moderate febrile illness in humans that may progress to encephalitis, leading to severe long-term complications and sometimes death. TBEV is prevalent in the Eurasian continent and has been isolated in China, Japan and Republic of Korea (ROK). The TBEV isolates from Japan are of the Far-Eastern subtype; in ROK, the isolates are of the Western subtype; and all TBEV isolates in China are of the Far-Eastern subtype, except one strain that was identified most recently as the Siberian subtype. TBE is endemic to the northeast, northwest and southeast of China; only two confirmed TBE cases have been reported in Japan to date; and no TBE case has been confirmed in ROK. For TBE patients in China, the onset of disease is acute with no biphasic course for disease presentation. The clinical spectrum of disease phenotypes may be wider than currently understood, since serological evidence suggests the presence of TBEV infections in healthy people, indicating that asymptomatic or unspecific manifestations of TBEV infection may exist. The current treatment for TBE is supportive care. In China, vaccines against TBEV have been developed and are available with demonstrated immunogenicity and safety, although efficacy data are lacking. No vaccines are available in ROK or Japan.

OBJECTIVE: To establish the reliability, validity, and sensitivity to change of the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) among Chinese subjects with osteoarthritis (OA) of the knee, living in mainland China. METHODS: A multicenter, randomized, double-blind, placebo-controlled, parallel-group study was conducted for validation of the electronic personal digital assistant version of the WOMAC Numerical Rating Scale (NRS) 3.1 Index in China. A total of 287 subjects with OA of the knee were randomized to receive either meloxicam (15 mg) or placebo. Psychometric properties of the WOMAC were evaluated by estimating the reliability, validity, and sensitivity to change. Equivalence of the electronic version was also compared with the paper version. RESULTS: Intraclass correlation coefficients for the WOMAC pain, stiffness, and physical function subscales were 0.81, 0.76, and 0.85, respectively, indicating good test-retest reliability. Similarly, internal consistency was strong (Cronbach's alpha for the 3 WOMAC subscales was 0.84, 0.86, and 0.96, respectively). Pearson's correlation coefficients for WOMAC pain and Short Form 36 health survey (SF-36) bodily pain, as well as WOMAC physical function and SF-36 physical functioning domains were >0.4, indicating convergent validity, whereas the coefficients for all 3 WOMAC domains with SF-36 mental health and mental health component scores were <0.4, indicating divergent validity. There was strong discriminant validity between healthy volunteers and OA patients. The effect sizes of change from baseline to week 12 in WOMAC subscale scores were large, demonstrating sensitivity to change. Equivalence between paper and electronic versions was very high. CONCLUSION: The culturally and linguistically validated Chinese version of the WOMAC NRS 3.1 for mainland China is psychometrically robust in its validity, reliability, and sensitivity to change for patients with OA of the knee.

Attaining complete remission of acute lymphoblastic leukemia (ALL) before hematopoietic stem cell transplantation (HSCT) correlates with better post-transplant outcomes. Inotuzumab ozogamicin (InO), an anti-CD22 antibody conjugated to calicheamicin, has shown significantly higher rates of remission, minimal residual disease negativity, and HSCT versus standard chemotherapy in treating relapsed/refractory (R/R) ALL. We investigated the role of previous transplant and proceeding directly to HSCT after remission as factors in determining post-transplant survival in the setting of InO treatment for R/R ALL. The analyzed population comprised InO-treated patients who proceeded to allogeneic HSCT in 2 clinical trials (phase 1/2: NCT01363297 and phase 3: NCT01564784). Overall survival (OS) was defined as time from HSCT to death (any cause). Of 236 InO-treated patients, 101 (43%) proceeded to allogeneic HSCT and were included in this analysis. Most received InO as first salvage (62%); 85% had no previous HSCT. Median (95% confidence interval [CI]) post-transplant OS was 9.2 months (5.1, not evaluable) with 2-year survival probability (95% CI) of 41% (32% to 51%). In first-HSCT patients (n = 86), median (95% CI) post-transplant OS was 11.8 months (5.9, not evaluable) with 2-year survival probability (95% CI) of 46% (35% to 56%); some patients relapsed and needed additional treatment before HSCT (n = 28). Those who went directly to first HSCT upon remission with no additional salvage/induction treatment (n = 73) fared best: median post-transplant OS was not reached with a 2-year survival probability (95% CI) of 51% (39% to 62%). In patients with R/R ALL, InO followed by allogeneic HSCT provided an optimal long-term survival benefit among those with no previous HSCT who went directly to transplant after remission.