Osimertinib plus platinum-pemetrexed in newly diagnosed epidermal growth factor receptor mutation-positive advanced/metastatic non-small-cell lung cancer: safety run-in results from the FLAURA2 study.

BACKGROUND: The phase III FLAURA2 (NCT04035486) study will evaluate efficacy and safety of first-line osimertinib with platinum-pemetrexed chemotherapy versus osimertinib monotherapy in epidermal growth factor receptor mutation-positive (EGFRm) advanced/metastatic non-small-cell lung cancer (NSCLC). The safety run-in, reported here, assessed the safety and tolerability of osimertinib with chemotherapy prior to the randomized phase III evaluation. PATIENTS AND METHODS: Patients (≥18 years; Japan: ≥20 years) with EGFRm locally advanced/metastatic NSCLC received oral osimertinib 80 mg once daily (QD), with either intravenous (IV) cisplatin 75 mg/m2 or IV carboplatin target area under the curve 5, plus pemetrexed 500 mg/m2 every 3 weeks (Q3W) for four cycles. Maintenance was osimertinib 80 mg QD with pemetrexed 500 mg/m2 Q3W until progression/discontinuation. The primary objective was to evaluate safety and tolerability of the osimertinib-chemotherapy combination. RESULTS: Thirty patients (15 per group) received treatment [Asian, 73%; female, 63%; median age (range) 61 (45-84) years]. Adverse events (AEs) were reported by 27 patients (90%): osimertinib-carboplatin-pemetrexed, 100%; osimertinib-cisplatin-pemetrexed, 80%. Most common AEs were constipation (60%) with osimertinib-carboplatin-pemetrexed and nausea (60%) with osimertinib-cisplatin-pemetrexed. In both groups, 20% of patients reported serious AEs. No specific pattern of AEs leading to dose modifications/discontinuations was observed; one patient discontinued all study treatments including osimertinib due to pneumonitis (study-specific discontinuation criterion). Hematologic toxicities were as expected and manageable. CONCLUSIONS: Osimertinib-chemotherapy combination had a manageable safety and tolerability profile in EGFRm advanced/metastatic NSCLC, supporting further assessment in the FLAURA2 randomized phase.

Anti-leukemic activity and tolerability of anti-human CD47 monoclonal antibodies.

CD47, a broadly expressed cell surface protein, inhibits cell phagocytosis via interaction with phagocyte-expressed SIRPα. A variety of hematological malignancies demonstrate elevated CD47 expression, suggesting that CD47 may mediate immune escape. We discovered three unique CD47-SIRPα blocking anti-CD47 monoclonal antibodies (mAbs) with low nano-molar affinity to human and cynomolgus monkey CD47, and no hemagglutination and platelet aggregation activity. To characterize the anti-cancer activity elicited by blocking CD47, the mAbs were cloned into effector function silent and competent Fc backbones. Effector function competent mAbs demonstrated potent activity in vitro and in vivo, while effector function silent mAbs demonstrated minimal activity, indicating that blocking CD47 only leads to a therapeutic effect in the presence of Fc effector function. A non-human primate study revealed that the effector function competent mAb IgG1 C47B222-(CHO) decreased red blood cells (RBC), hematocrit and hemoglobin by >40% at 1 mg/kg, whereas the effector function silent mAb IgG2σ C47B222-(CHO) had minimal impact on RBC indices at 1 and 10 mg/kg. Taken together, our findings suggest that targeting CD47 is an attractive therapeutic anti-cancer approach. However, the anti-cancer activity observed with anti-CD47 mAbs is Fc effector dependent as are the side effects observed on RBC indices.

Risk factors and possible mechanisms of intravenous port catheter migration.

OBJECTIVE: To identify the risk factors for catheter migration and demonstrate possible mechanisms of this migration. DESIGN: Retrospective study. SETTING: Chang Gung Memorial Hospital, a tertiary medical centre in Taiwan. PATIENTS: Patients who underwent implantation of intravenous ports via the superior vena cava (SVC). INTERVENTIONS: Procedures involving catheter placement and re-intervention for catheter migration. MAIN OUTCOME MEASURES: The anatomic location of the catheter tip was confirmed by plain chest X-rays (postero-anterior view). From these plain radiographs, the distance (in cm) between the carina and catheter tip and the angle (in degrees) between the locking nut and catheter were measured. METHODS: A total of 1542 procedures related to intravenous port implantation were retrospectively reviewed but only procedures involving implantation via the SVC were included in the analysis. The study group was composed of 31 interventions because of catheter migration, while the control group consisted of 1475 implantation and re-intervention procedures except those involving catheter migrations. RESULTS: Shallow catheter-tip location (p < 0.0001) and the presence of lung cancer (p = 0.006) were risk factors for catheter migration. CONCLUSIONS: Shallow catheter-tip location and the presence of lung cancer are risk factors for catheter migration. Strategies that ensure low catheter-tip location and avoid increased thoracic pressure may be useful preventive measures.

Atherogenic serum lipid profile is an independent predictor for gouty flares in patients with gouty arthropathy.

OBJECTIVE: Atherogenic serum lipid profile possesses pro-inflammatory properties and is associated with more active RA. While prevalent in patients with gout, whether atherogenic lipid profile is associated with gouty flares is unknown. This study aims to investigate whether atherogenic serum lipid predicts gouty flares in patients with gout. METHODS: Adult patients (age > or =21 yrs) who suffered from gout were prospectively followed between September 2006 and November 2007 and their demographic, clinical and laboratory data were collected. Episodes of gouty flares over this observation period were recorded and factors predictive of gouty flares were studied by regression models. RESULTS: Of the 100 patients, 80 were men, 65 were ethnic Chinese, 31 were Malay and the rest were Indian and Caucasian. The mean age and duration of gout (+/-S.D.) were 61.9 +/- 14.0 and 6.6 +/- 7.8 yrs, respectively. The mean serum uric acid and creatinine levels were 537.6 +/- 142.8 and 173.6 +/- 119.9 micromol/l, respectively. In univariate analysis, longer duration of gout, higher adjusted mean serum creatinine, lower adjusted mean fasting serum, total cholesterol and high-density lipoprotein cholesterol (HDL-C) levels were associated with gouty flares. After adjustment for potential confounders in multivariate regression models, longer duration of gout and lower adjusted mean fasting serum HDL-C level remained independently predictive of gouty flares. CONCLUSIONS: Low serum high-density lipoprotein cholesterol level was an independent predictor for gouty flares. Whether optimizing serum HDL-C level can benefit patients with gout in terms of reducing gouty flares needs to be addressed by controlled trials.

Neuropsychiatric lupus and reversible posterior leucoencephalopathy syndrome: a challenging clinical dilemma.

Reversible posterior leucoencephalopathy syndrome (RPLS) has been increasingly recognized and reported in the literature. While the condition has been well described in patients with acute hypertension, pre-eclampsia, eclampsia, post-transplantation and chemotherapy, RPLS has been increasingly identified in patients with autoimmune diseases such as systemic lupus erythematosus (SLE). Though experience in the diagnosis and management of RPLS in patients with SLE is likely accumulating, few have systematically worked out the strategy to distinguish RPLS from neuropsychiatric SLE (NPSLE) and lupus-related complications of the central nervous system (CNS). Prompt recognition of, and differentiation between, these conditions is essential since their clinical presentations substantially overlap and yet their management strategy and subsequent outcomes can be entirely different. Indeed, inappropriate treatment such as augmentation of immunosuppression may be detrimental to patients with RPLS. A high index of suspicion of RPLS, prompt magnetic resonance imaging of the brain, including diffusion imaging, exclusion of CNS infection and metabolic derangement, a comprehensive medication review accompanied by timely and aggressive control of blood pressure and seizure are keys to successful management of RPLS. Such treatment strategy ensures a very high chance of total neurological recovery in lupus patients with RPLS.

Modelling variability of quality of life scores: a study of questionnaire version and bilingualism.

BACKGROUND AND OBJECTIVES: Modelling variability of quality of life scores can not only improve our understanding of the characteristics of the measurement tools, but also shed light on sample size requirements. Although the English and Chinese versions of the Short Form 36 Health Survey (SF-36) are commonly considered equivalent, they have not been compared in terms of variability. Furthermore, bilingual and monolingual persons may differ in cognition and responses to questionnaires. METHODS: In a community-based survey of quality of life in Singapore, a society where both English and Chinese are widely used and bilingualism is prevalent, 2590 respondents answered either version of the SF-36. We studied the impact of questionnaire version and bilingualism on the variability of SF-36 scores by regression modelling, with adjustment for covariates. RESULTS: The Chinese version had smaller variances in the physical functioning (PF) and the physical component summary scores than the English version. The variance ratios (VRs) were respectively 0.32 and 0.60 (each p < 0.01), controlling for covariates. Bilingualism was not associated with variability in SF-36 scores except PF (VR = 0.78; p < 0.05). CONCLUSIONS: As a result of a smaller variance, using the Chinese version of SF-36 among bilingual Chinese people may require a smaller sample size than using the English version.

Measuring health-related quality of life in Singapore: normal values for the English and Chinese SF-36 Health Survey.

OBJECTIVE: To determine norms for assessing Health-related Quality of Life (HRQOL) in Singapore using the Short Form 36 Health Survey (SF-36). MATERIALS AND METHODS: Mean SF-36 scores were calculated for 24 population subgroups (categorised by age, gender, ethnicity and questionnaire language) and for subjects with self-reported co-morbid conditions using data from a community-based survey in Singapore. RESULTS: The English and Chinese SF-36 was completed by 4122 and 1381 subjects, respectively, 58% (n = 3188) of whom had self-reported co-morbid conditions. SF-36 scores varied in subgroups differing in age, gender and ethnicity. In general, subjects with self-reported co-morbid conditions had lower SF-36 scores than those without these conditions, the magnitude of which exceeded 20 points in several instances. A method for calculation of SF-36 scores adjusted for age, gender, ethnicity and questionnaire language is described. CONCLUSION: We present norms for English and Chinese SF-36 versions in Singapore and describe potential uses for these data in assessing HRQOL in Singapore.

Abdominal crisis in a young man with systemic lupus erythematosus.

Medium-sized artery aneurysms are rare in patients with systemic lupus erythematosus (SLE). We report on a 21-year-old Chinese man with SLE and secondary antiphospholipid syndrome (APS) who presented with acute abdominal pain due to a ruptured right hepatic artery aneurysm. He was also found to have aneurysms of the left hepatic artery and splenic artery on autopsy. There have been only eight cases of hepatic artery aneurysm and one case of splenic artery aneurysm associated with SLE in the English literature. Abdominal aneurysm must be suspected in SLE patients presenting with acute abdominal pain, haemoperitoneum or occult bleeding.

A Chinese version of the Rheumatology Attitudes Index is a valid and reliable measure of learned helplessness in patients with SLE.

Despite the prognostic importance of learned helplessness (LH) in rheumatic diseases, there are no validated measures of LH in Chinese or other Asian languages. We therefore assessed the validity of a Chinese translation of the Rheumatology Attitudes Index (CRAI; a widely used measure of LH) and its Helplessness (CHS) and Internality (CIS) subscales in patients with SLE. Chinese-speaking SLE patients (n = 69) completed identical, self-administered questionnaires containing the CRAI and assessing demographic/socio-economic variables twice within 2 weeks. SLE activity, damage and quality of life were assessed using the BILAG, SLICC/ACR Damage Index and SF-36 respectively. Scale psychometric properties were assessed through Cronbach's alpha, intra-class correlations, quantifying test-retest differences, factor analysis and known-groups construct validity. Internal consistency and reliability were acceptable, with Cronbach's alpha for the CHS, CIS and CRAI being 0.70, 0.69 and 0.74, respectively. Mean differences in test-retest scores spanned 1.6-2.4% of possible scale ranges and intra class correlations ranged from 0.72 to 0.88. Factor analysis identified two major factors corresponding to the CHS and CIS subscales of the CRAI. Eight of 10 a priori hypotheses relating the CRAI and CHS to demographic, disease and quality of life variables were confirmed, supporting the construct validity of these scales. The CRAI and its helplessness subscale are valid and reliable measures of learned helplessness in Chinese-speaking SLE patients.

A community-based study of scaling assumptions and construct validity of the English (UK) and Chinese (HK) SF-36 in Singapore.

Scaling assumptions and validity of the English (UK) and Chinese (HK) short form 36 health survey (SF-36) were assessed in a community-based survey of 5,503 Chinese, Malays and Indians in Singapore using the international quality of life assessment project approach of item and scale level validation. Missing data for SF-36 items and scales occurred in less than 1.0% of subjects. Item level validation of both versions generally supported assumptions underlying Likert scoring and hypothesised item-order clustering. Item level factor analysis supported the eight-scale structure of the SF-36. In scale level validation, SF-36 scale scores showed wide variability and acceptable internal-consistency reliability (Cronbach's alpha > 0.70 for six English and seven Chinese scales), conformed to hypothesised patterns and generally varied according to hypotheses in subjects known to differ in quality of life. Scale level factor analysis of both versions yielded very similar patterns of factor correlation, comparable to that found in Japan, but differing from that seen in Western populations. Taken together, these results support the validity of the English (UK) and Chinese (HK) SF-36 versions in the multi-ethnic Asian socio-cultural context of Singapore.

Life-threatening angioedema in systemic lupus erythematosus.

Life-threatening angioedema involving the upper respiratory tract is an uncommon manifestation in systemic lupus erythematosus (SLE). We report three patients in their late adolescence who had laryngeal oedema causing airway obstruction and requiring mechanical ventilation during active disease following symptoms of a respiratory tract infection. All of them had major organ involvement from lupus and none had a family history of hereditary angioedema (HAE). The mechanisms of angioedema in SLE are heterogeneous. There has been little evidence so far of anti-Cl inhibitor (Cl INH) autoantibody in SLE patients with angioedema. These are the first three cases reported in the literature of life-threatening angioedema following respiratory tract infection in SLE.

A comparative study of the clinical manifestations of systemic lupus erythematosus in Caucasians in Rochester, Minnesota, and Chinese in Singapore, from 1980 to 1992.

OBJECTIVE: To examine the relationship between ethnicity and major organ involvement at and after diagnosis in community-based cohorts of Caucasian and Chinese systemic lupus erythematosus (SLE) patients resident in Rochester, Minnesota, and Singapore, respectively. METHODS: Clinical manifestations at and after diagnosis were compared in Caucasian and Chinese SLE patients. The association between ethnicity and disease manifestations at and after diagnosis was determined using logistic regression and Cox proportional hazards models, respectively, adjusting for the influence of demographic, socioeconomic, disease-related, and therapy-related factors. RESULTS: At diagnosis, Caucasian SLE patients were 3 times more likely than Chinese SLE patients to have serositis (odds ratio [OR] 3.11, 95% confidence interval [CI] 1.01-9.71), nearly 7 times more likely to have a hematologic disorder (OR 6.95, 95% CI 2.20-21.97), and far less likely to have a malar rash (OR 0.19, 95% CI 0.07-0.54) or positive antinuclear antibodies (OR 0.11, 95% CI 0.03-0.52). Ethnicity was not associated with the prevalence of proteinuria or central nervous system (CSN) and other major organ involvement at diagnosis. After diagnosis, there was a trend toward less development of proteinuria and other major organ involvement in Caucasians (relative risk [RR] 0.47, 95% CI 0.19-1.15, and RR 0.22, 95% CI 0.05-1.04, respectively). CONCLUSION: Chinese SLE patients are far less likely to have serositis or a hematologic disorder at diagnosis and may be more likely to develop proteinuria or CNS or other major organ involvement over the course of the disease, compared with Caucasian SLE patients. This may contribute to the increased mortality seen in Chinese SLE patients.

Accuracy of medical record scoring of the SLICC/ACR damage index for systemic lupus erythematosus.

OBJECTIVE: To study the accuracy of medical record scoring of the SLICC/ACR Damage Index (DI) for SLE. METHODS: Medical record DI (MDI) scoring of 60 SLE patients by one physician was compared with prospective direct DI (DDI) scoring a median of 2 y earlier. Agreement between DDI and MDI total and organ system scores was compared using Cohen's kappa, the degree of misclassification by MDI and the significance of differences between DDI and MDI scores. RESULTS: The mean duration of SLE at DDI scoring was 5.2 y. The median/mean (SD) DDI and MDI total scores were 0/0.78 (1.38) and 0/0. 85 (1.44). Damage was present on DDI and MDI scoring in 36.7% (22/60) and 38.3% (23/60) of patients. Qualitative MDI and DDI total scores (damage present/absent) showed good agreement (kappa=0.61, 95% CI=0.40-0.82, 18.3% misclassification). Quantitative MDI and DDI total scores (degree of damage) showed moderate agreement (kappa=0. 47, 95% CI=0.28-0.66, 36.7% misclassification). 9 of 12 MDI organ system scores misclassified <10% of subjects. There was no statistically significant difference between DDI and MDI total or organ system scores. CONCLUSION: MDI total scoring is a good qualitative and moderate quantitative reflection of SLE related damage. MDI organ system scores are more accurate than MDI total scores.

A prospective study of factors affecting quality of life in systemic lupus erythematosus.

OBJECTIVE: To prospectively identify factors influencing quality of life (QOL) over 6 months in patients with systemic lupus erythematosus (SLE). METHODS: Ninety ethnically diverse patients with SLE completed questionnaires administered 6 months apart assessing QOL (using the Medical Outcomes Study Short Form-36) and demographic, socioeconomic, psychosocial, and behavioral factors. Disease activity, damage, and treatment were recorded at both evaluations. Multiple linear regression (adjusting for baseline health status) was used to identify factors influencing mental and physical health. RESULTS: Improved physical health after 6 months was associated with reductions in learned helplessness (p = 0.034), improved mental health (p<0.001), longer disease duration (p = 0.009), and better physical health at baseline (p = 0.027). Improved mental health after 6 months was associated with better family support (p = 0.002), improvements in physical health (p<0.001), disease activity, and prednisolone dose (interaction term p = 0.019), less disease related damage (p<0.001), non-use of cytotoxic drugs (p = 0.02), and older age at diagnosis (p = 0.007). CONCLUSION: Potentially modifiable psychosocial, disease, and therapy related factors influence QOL in patients with SLE.

Validation of a Chinese version of the Medical Outcomes Study Family and Marital Functioning Measures in patients with SLE.

The objective was to validate a Chinese translation of the Medical Outcomes Study Family and Marital Functioning Measures (FFM and MFM) in patients with systemic lupus erythematosus (SLE). Chinese-speaking SLE patients (n = 69) completed a self-administered questionnaire containing the FFM and MFM and assessing demographic and socio-economic status twice within a 2 week period. SLE activity, disease-related damage and quality of life were assessed using the BILAG, SLICC/ACR Damage Index and SF-36 Health Survey, respectively. Scale psychometric properties were assessed through factor analysis, Cronbach's alpha, quantifying test-retest differences and known-groups construct validity. Factor analysis identified 1 factor corresponding to the FFM and 2 factors corresponding to the MFM. Internal consistency for the FFM was excellent (alpha = 0.92) while that for the MFM was acceptable (alpha = 0.62). Mean (s.d.) test-retest differences were 0.06 (1.54) points for the FFM and 0.03 (2.08) points for the MFM. 11 and 10 of 13 a priori hypotheses relating the FFM and MFM, respectively, to demographic, disease and quality of life variables were confirmed, supporting the construct validity of these scales. The Chinese FFM and MFM are valid and reliable measures of family and marital functioning in Chinese-speaking SLE patients, with psychometric properties very similar to the source English version.

Validation of the Chinese SF-36 for quality of life assessment in patients with systemic lupus erythematosus.

We studied the reliability and validity of the Chinese Short-Form 36 Health Survey (SF-36) in a cross sectional study of patients with systemic lupus erythematosus (SLE). Sixty-nine consecutive subjects completed a questionnaire containing the Chinese SF-36 twice within 14 d. Disease activity and damage were assessed using the British Isles Lupus Activity Group (BILAG) and SLICC/ACR Damage Index (DI) scales, respectively. Internal consistency was assessed using Cronbach's alpha, reliability using Spearman's correlation and repeatability coefficients, and relationships between SF-36, BILAG and DI scores using Spearman's correlation. The Chinese SF-36 showed high internal consistency (alpha = 0.72-0.91) and good reliability, with correlations exceeding 0.70 for 7 scales and mean scale score differences of < 2 points for 6 scales. SF-36 scores correlated weakly with BILAG scores (-0.27 to -0.41) and DI scores (-0.24 to -0.35), and subjects' mean SF-36 scores were 6-24 points lower than the general population, supporting construct validity of the SP-36. These data suggest that the Chinese SF-36 is a reliable and valid measure of quality of life in patients with SLE.