Real-world treatment sequencing and survival in previously treated advanced renal cell carcinoma patients receiving nivolumab monotherapy: a UK retrospective cohort study.

BACKGROUND: The CheckMate 025 trial established nivolumab monotherapy as one of the standards of care in previously treated advanced or metastatic renal cell carcinoma (aRCC). However, supporting real-world data is lacking. This study investigated characteristics, treatment sequences and clinical outcomes of patients who received nivolumab monotherapy for previously treated aRCC in the UK. METHODS: This was a retrospective cohort study of aRCC patients treated with nivolumab at second line or later (2L +) at 4 UK oncology centres. Eligible patients commenced nivolumab (index date) between 01 March 2016 and 30 June 2018 (index period). Study data were extracted from medical records using an electronic case report form. Data cut-off (end of follow-up) was 31 May 2019. RESULTS: In total, 151 patients were included with median follow-up of 15.2 months. Mean age was 66.9 years, male preponderance (72.2%), and mostly Eastern Cooperative Oncology Group performance status grade 0-1 (71.5%). Amongst 112 patients with a known International Metastatic RCC Database Consortium score, distribution between favourable, intermediate, and poor risk categories was 20.5%, 53.6%, and 25.9% respectively. The majority of patients (n = 109; 72.2%) received nivolumab at 2L, and these patients had a median overall survival (OS) of 23.0 months [95% confidence interval: 17.2, not reached]. All patients who received nivolumab at 2L had received TKIs at 1L. Amongst the 42 patients (27.8%) who received nivolumab in third line or later (3L +) the median OS was 12.4 months [95% CI: 8.8, 23.2]. The most common reasons for nivolumab discontinuation were disease progression (2L: 61.2%; 3L: 68.8%) and adverse events (2L: 34.7%; 3L: 28.1%). CONCLUSION: This study provides real-world evidence on the characteristics, treatment sequences, and outcomes of aRCC patients who received 2L + nivolumab monotherapy in the UK. Nivolumab-specific survival outcomes were similar to those achieved in the CheckMate 025 trial.

[Standardized documentation of health-related quality of life in patients with psoriatic arthritis : Validation of the German version of the psoriatic arthritis quality of life (PsAQoL) questionnaire]. / Standardisierte Erfassung der gesundheitsbezogenen Lebensqualität bei Patienten mit Psoriasisarthritis : Validierung der deutschen Version des "Fragebogen zur Lebensqualität von Patienten mit Psoriasisarthritis (PsAQoL)".

BACKGROUND: The standardized assessment of health-related quality of life is becoming increasingly more important. The English questionnaire on psoriatic arthritis quality of life (PsAQoL) is a disease-specific instrument for measuring the quality of life of patients with psoriatic arthritis (PsA). The aim of the present study was to translate the PsAQoL into German and to validate the German version in a cohort of PsA patients recruited from routine care. METHOD: The translation and validation of the PsAQoL questionnaire was carried out in a stepwise procedure involving affected patients with PsA. After translation of the original English questionnaire the German version was evaluated in a field test. The psychometric features of the questionnaire were then examined in a PsA cohort from routine care. In addition to the construct and group validity, the reliability of the questionnaire was tested using test-retest reliability and internal consistency. The physical functioning was measured with the health assessment questionnaire (HAQ) and domains of the quality of life with the Nottingham health profile (NHP). RESULTS: In a field test with 10 patients the German version of the PsAQoL questionnaire proved to be relevant, easily understandable and feasible (processing time 4.7 ± 2.1 min). A total of 126 patients (37.3% male, age 55.6 ± 11.3 years) were included in the validation cohort. The PsAQoL showed moderate correlation with the HAQ (r = 0.65) and moderate to good correlation with the NHP (subdomains r = 0.58-0.75). The internal consistency was high (Cronbach's α 0.92) and reliability in patients with stable disease course was very good (Spearman correlation coefficient 0.94). The PsAQoL can differentiate between different patient groups. CONCLUSION: The German translation of the PsAQoL provides a valid disease-specific instrument for the standardized assessment of health-related quality of life in patients with PsA. The psychometric characteristics of this questionnaire are comparable with the original English version. The German PsAQoL can therefore be recommended for clinical and scientific application.

Translation and validation of the greek Psoriatic Arthritis Quality of Life Scale.

Psoriatic arthritis (PsA) is a chronic inflammatory disease that has a significant impact on patients' quality of life (QoL). The Psoriatic Arthritis Quality of Life (PsAQoL) Scale was developed in the UK to be specific to PsA patients and adopts the needs-based model of QoL. As a disease-specific measure, the PsAQoL is superior to generic measures of QoL in terms of relevance and sensitivity. The measure, which has been adapted into 50 languages, has not previously been available for use with Greek PsA patients. The aim of the study was to produce a Greek version of the PsAQoL that was suitable for native Greek speakers and that had comparable psychometric properties to the original UK version. The adaptation of the Greek PsAQoL consisted of three stages; translation, assessment of face and content validity and analysis of its psychometric properties. The translation stage adopted the dual panel methodology -a bilingual panel followed by a lay panel- to ensure conceptual equivalence of the scale to the original version. Cognitive debriefing interviews were conducted to determine the applicability and relevance of the adapted scale to patients. Finally, a postal validation survey was conducted to assess the psychometric properties of the draft measure, using the Nottingham Health Profile (NHP) as a comparator instrument. Non-parametric statistical analyses were performed to establish the reliability and construct validity of the PsAQoL. The translation panels produced a language version that sounded natural to native Greek speakers. Interviews revealed that patients found the measure comprehensible and appropriate. Only minor grammatical changes were made to the measure following these interviews. The Greek PsAQoL demonstrated good internal consistency (Cronbach's α=0.88) and excellent test-retest reliability (r=0.98). As expected, the measure correlated moderately highly with the Physical Mobility and Pain sections of the NHP and correlated moderately with other sections, indicating convergent validity. Known group validity was established by the ability of the measure to distinguish between patients who differed according to their perceived general health and disease severity. No significant differences in PsAQoL scores were observed between males and females or older and younger patients. The Greek PsAQoL was well-received by patients and demonstrated sound psychometric properties. It forms part of a growing body of disease-specific measures that are available in Greece. It is recommended for use in routine clinical practice, international clinical trials and research studies as a valid and reliable measure of QoL in PsA patients.

The "Lollypop" technique for polyethylene exchange in total ankle replacement.

UNLABELLED: We describe a simple technique for the removal of the polyethylene meniscus bearing surface in patients undergoing re-operation and meniscus bearing exchange following a previous total ankle replacement. LEVEL OF EVIDENCE: Level V.

The impact of Dupuytren disease on patient activity and quality of life.

PURPOSE: To explore the impact of Dupuytren disease (DD) from the patients' perspective. METHODS: Audio-recorded interviews were conducted for patients with Dupuytren disease (DD) attending outpatient clinics. The interviews were transcribed and subjected to content analysis. This analysis highlighted key impact areas and common themes in individuals' personal experiences. These were then allocated to categories specified by the World Health Organization International Classification of Functioning, Disability, and Health (impairments and activity limitations) and the needs-based model of quality of life (QoL). RESULTS: Qualitative unstructured interviews were conducted with 34 patients (74% men; age, 41-80 y; mean [SD], 64 [13] y). The sample had a wide range of severity and duration of DD (range, 0.5-40; mean [SD], 13 [10] y). Nine hundred fifty-three statements relating to the impact of DD were identified from the interview transcripts. These statements fell into 2 major categories of impact: activity limitations (10 themes including problems with dressing, gripping, and personal care) and QoL (6 need categories: physiological, safety and security, social, affection, esteem, and cognitive needs). CONCLUSIONS: Findings from the interviews suggest that DD affects both performance of activities and QoL. To determine accurately the effectiveness of DD interventions from the patients' perspective, it is important to determine their impacts on both activity limitations and QoL. We intend to develop valid, reproducible, and responsive DD-specific scales for this purpose. CLINICAL RELEVANCE: The study identifies key issues specific to DD that influence patients' functioning and QoL. The information reported will form the basis of DD-specific patient-reported outcomes measures for use in clinical practice and evaluations of interventions.

The BH3 mimetic HA14-1 enhances 5-fluorouracil-induced autophagy and type II cell death in oesophageal cancer cells.

BACKGROUND: Resistance to chemotherapeutic agents has been associated with a failure of cancer cells to induce apoptosis. Strategies to restore apoptosis have led to the development of BH3 mimetics, which inhibit anti-apoptotic Bcl-2 family members. We examined the sensitivity of three oesophageal cancer cell lines to 5-fluorouracil (5-FU) alone and in combination with the BH3 mimetic HA14-1. METHODS: Clonogenic assays, morphology, markers of autophagy and apoptosis were used to assess the involved death mechanisms. RESULTS: In response to 5-FU treatment, OE21 cells induce apoptosis, KYSE450 and KYSE70 cells are more resistant and induce autophagy accompanied by type II cell death. Autophagy induction results in ineffective treatment as substantial numbers of cells survive and re-populate. HA14-1 did not improve 5-FU treatment or reduce colony re-growth in the apoptosis deficient KYSE70 cells. However, the sensitivity of OE21 (apoptotic) and KYSE450 cells (apoptosis deficient/type II cell death) was significantly improved. In OE21 cells, treatment with 5-FU and HA14-1 resulted in augmentation of apoptosis. In KYSE450 cells, the reduction in recovering colonies following combination treatment was due to the enhancement of type II cell death. CONCLUSION: The efficacy of HA14-1 is cell line dependent and is not reliant on apoptosis induction.

Adaptation of the Psoriatic Arthritis Quality of Life (PsAQoL) instrument for Sweden.

OBJECTIVE: The Psoriatic Arthritis Quality of Life (PsAQoL) questionnaire is the first disease-specific patient-derived instrument for assessing QoL in patients with PsA and has been extensively validated in this population. The aim of the adaptation process reported here was to develop a Swedish version of the PsAQoL that was equivalent to, and met the same psychometric and acceptability standards as, the original instrument, which was developed in the UK. METHOD: Translation of the original questionnaire into Swedish was performed by a professional and a lay panel. Field testing for face and content validity was performed by interviewing 13 patients. Finally, 123 patients with PsA were included in a test-retest postal survey designed to test reproducibility and construct validity. The PsAQoL was administered on two occasions approximately 2 weeks apart. The Nottingham Health Profile (NHP) was used as a comparator instrument. RESULTS: The Swedish version of the PsAQoL questionnaire showed good reliability at both time points and, as expected, correlated with the NHP. The scale was able to distinguish between groups based on self-reported general health and flare-up. Patients with active symptoms of both arthritis and psoriasis had worse QoL. The results also indicated that duration of disease has a progressive impact on PsAQoL scores. CONCLUSIONS: This study provides evidence that the adapted PsAQoL can be used for clinical studies in Swedish patients. The instrument provides valuable information on the long-term effects of PsA on QoL.

Curcumin induces apoptosis-independent death in oesophageal cancer cells.

BACKGROUND: Oesophageal cancer incidence is increasing and survival rates remain extremely poor. Natural agents with potential for chemoprevention include the phytochemical curcumin (diferuloylmethane). We have examined the effects of curcumin on a panel of oesophageal cancer cell lines. METHODS: MTT (3-(4,5-dimethyldiazol-2-yl)-2,5 diphenyl tetrazolium bromide) assays and propidium iodide staining were used to assess viability and DNA content, respectively. Mitotic catastrophe (MC), apoptosis and autophagy were defined by both morphological criteria and markers such as MPM-2, caspase 3 cleavage and monodansylcadaverine (MDC) staining. Cyclin B and poly-ubiquitinated proteins were assessed by western blotting. RESULTS: Curcumin treatment reduces viability of all cell lines within 24 h of treatment in a 5-50 muM range. Cytotoxicity is associated with accumulation in G2/M cell-cycle phases and distinct chromatin morphology, consistent with MC. Caspase-3 activation was detected in two out of four cell lines, but was a minor event. The addition of a caspase inhibitor zVAD had a marginal or no effect on cell viability, indicating predominance of a non-apoptotic form of cell death. In two cell lines, features of both MC and autophagy were apparent. Curcumin-responsive cells were found to accumulate poly-ubiquitinated proteins and cyclin B, consistent with a disturbance of the ubiquitin-proteasome system. This effect on a key cell-cycle checkpoint regulator may be responsible for the mitotic disturbances and consequent cytotoxicity of this drug. CONCLUSION: Curcumin can induce cell death by a mechanism that is not reliant on apoptosis induction, and thus represents a promising anticancer agent for prevention and treatment of oesophageal cancer.

The hidden cost of skin scars: quality of life after skin scarring.

BACKGROUND: Surprisingly little is known about how skin scars affect patients' lives, though specialist clinical impressions suggest their impact is related to both their physical and psychosocial effects. Facial scars have been shown to cause high levels of anxiety and self-consciousness, but further work has been neglected. We aimed to explore the influence of skin scars on patients' quality of life (QoL) and identify potential implications for clinical practice. METHODS: We adopted a needs-based approach to QoL and conducted semi-structured interviews with scar patients at a specialist clinic. Transcribed data underwent interpretative phenomenological analysis to identify common themes in individuals' personal experiences. RESULTS: Thirty-four scar patients (24 women; aged 14-70 years, mean=35.7 years, SD=17.9 years) with a wide range of scar type, severity and onset were recruited. Five hundred and seventy-three statements were identified from interview transcripts relating to need impairment by skin scars. These were subsequently classified into 44 themes covering five main areas: physical comfort and functioning; acceptability to self and others; social functioning; confidence in the nature and management of the condition; emotional well-being. The majority of respondents were unhappy with their scar's appearance due to their perceived stigma and psychological associations, and thus adopted different coping behaviours to hide or compensate for them. Often this made them unsociable and interfered with their communication skills, personal relationships, work life and leisure activities. Concerns about the diagnosis and persistent nature of scars were common, whilst unempathic management by general physicians and frustrations of current treatment compounded distress. CONCLUSIONS: There are five main areas of impact on the needs of scar patients that should be addressed in their management, which are greater and more complex than previously considered. Support services should be made available, along with clinician and public education to improve management and help reduce patient distress. A need for a carefully designed measure of scar-related QoL is also indicated, for use in clinical settings and trials.

Plant polyphenolics as anti-invasive cancer agents.

Because invasion is, either directly or via metastasis formation, the main cause of death in cancer patients, development of efficient anti-invasive agents is an important research challenge. We have established a screening program for potentially anti-invasive compounds. The assay is based on organotypic confronting cultures between human invasive cancer cells and a fragment of normal tissue in three dimensions. Anti-invasive agents appeared to be heterogeneous with regard to their chemical nature, but plant alkaloids, polyphenolics and some of their synthetic congeners were well represented. Even within this group, active compounds were quite diverse: (+)-catechin, tangeretin, xanthohumol and other prenylated chalcones, 3,7-dimethoxyflavone, a pyrazole derivative, an isoxazolylcoumarin and a prenylated desoxybenzoin. The data gathered in this system are now applied in two projects. Firstly, structure-activity relationships are explored with computer models using an artificial neural network approach, based on quantitative structural descriptors. The aim of this study is the prediction and design of optimally efficient anti-invasive compounds. Secondly, the metabolism of orally ingested plant polyphenolics by colonic bacteria is studied in a simulator of the human intestinal microbial ecosystem (SHIME) and in human intervention trials. This method should provide information on the final bioavailability of the active compounds in the human body, with regard to microbial metabolism, and the feasibility of designing pre- or probiotics that increase the generation of active principles for absorption in the gastro-intestinal tract. The final and global aim of all these studies is to predict, synthesize and apply in vivo molecules with an optimal anti-invasive, and hence an anti-metastatic activity against cancer.

Squamous cell carcinoma arising in a dermoid cyst of the ovary: a case series.

OBJECTIVE: Malignant transformation in a dermoid cyst of the ovary is a rare complication, occurring in only 1-2% of cases, with squamous cell carcinoma being the most common type. Preoperative diagnosis is difficult because of the lack of specific symptoms and signs to suggest malignancy. Because of the small numbers of women involved, our knowledge of this rare tumour type is limited. This study aims to further characterise the population of women affected, the disease itself and the most appropriate management strategy. DESIGN: We identified 14 women with this diagnosis between 1989 and 2006. This is a descriptive study, looking at the patient characteristics, mode of presentation and the role of tumour markers and radiological imaging in diagnosis. We also examined the stage and pathological features of the tumour at presentation and the subsequent course of the disease. We have also described our experiences using surgery, chemotherapy and radiotherapy in the management of these women. RESULTS: We found that these tumours present at an age older than that of mature teratomas and that there are no reliable diagnostic tools or prognostic indicators. The behaviour of these tumours is unpredictable, and the role of chemotherapy and radiotherapy remains unclear. We suggest that repeated surgical resection of disease at the time of relapse could give a very durable response in selected women.

Cyclooxygenase-2 inhibitors demonstrate anti-proliferative effects in oesophageal cancer cells by prostaglandin E(2)-independent mechanisms.

The incidence of oesophageal cancer (OC) has risen in recent decades, with survival rates remaining poor despite surgical treatment and adjuvant chemotherapy. Studies have reported cyclooxygenase-2 (COX-2) overexpression in OC and current evidence suggests NSAIDs have major potential for chemoprevention through COX-2 inhibition. However, several reports have questioned the specificity of these inhibitors, suggesting they may act through mechanisms other than COX-2. We evaluated the effects of specific COX-2 inhibitors, NS-398 and nimesulide, on cell lines of both histological types of OC. COX-2 protein expression varied in the cell lines and corresponded with levels of prostaglandin E(2) (PGE(2)) production. Following treatment with low concentrations of NS-398 (0.1 microM), PGE(2) production was reduced dramatically, indicating inhibition of COX-2 activity. Examination of cellular morphology, caspase-3 activity and mitochondrial membrane integrity found no major induction of apoptotic cell death at concentrations below 100 microM. Tumour cell proliferation was significantly reduced at high concentrations (50-100 microM) of both inhibitors over 6 days. Cellular responses were more evident in NS-398-treated adenocarcinoma cells. However, concentrations required to inhibit proliferation were up to 1000-fold higher than those needed to inhibit enzyme activity. Addition of exogenous PGE(2) to NS-398-treated adenocarcinoma cells failed to reverse the inhibitory effects, indicating PG and COX-2 independence. It remains possible that in vivo COX-2 is the primary target, as enzyme inhibition can be achieved at low concentrations, however, inhibition of proliferation is not the primary mechanism of their anti-tumour activity.

Beta-catenin transcriptional activity is inhibited downstream of nuclear localisation and is not influenced by IGF signalling in oesophageal cancer cells.

Aberrant expression/localisation of beta-catenin has been implicated in the progression of oesophageal cancer. As a member of the Wnt-signalling pathway, activated beta-catenin translocates into the nucleus and drives gene transcription. Insulin-like growth factors (IGFs) have been implicated in modulation of beta-catenin localisation and transcriptional activity. We have demonstrated that beta-catenin is abundantly expressed by oesophageal cancer cells, and is both cytoplasmic and nuclear in location. beta-catenin was transcriptionally inactive in 4 of 5 cell lines. All cells expressed the IGF-1 receptor. Addition of exogenous IGFs activated the PI-3 kinase pathway but did not enhance beta-catenin/T-cell factor- (TCF) mediated transcription. Activation of Wnt signalling by lithium induced beta-catenin stabilisation in 2 cell lines but this did not increase transcriptional activity. In contrast 2 cell lines without lithium-enhanced stabilisation or re-distribution of beta-catenin did exhibit beta-catenin/TCF-mediated transcriptional activity. This study shows that beta-catenin accumulation and nuclear localisation is not indicative of transcriptional activity, and therefore is not supportive of a major role in these oesophageal cancer cells. It also questions the value of immunohistochemical studies that examine only expression. Co-operative signalling from other growth factors or adhesive molecules is likely to be required to relieve nuclear inhibition of transcriptional activity, and the nature of this is currently unknown.

Evaluation of cellular uptake and gene transfer efficiency of pegylated poly-L-lysine compacted DNA: implications for cancer gene therapy.

Recent success in phase I/II clinical trials (Konstan, M. W.; Davis, P. B.; Wagener, J. S.; Hilliard, K. A.; Stern, R. C.; Milgram, L. J.; Kowalczyk, T. H.; Hyatt, S. L.; Fink, T. L.; Gedeon, C. R.; Oette, S. M.; Payne, J. M.; Muhammad, O.; Ziady, A. G.; Moen, R. C.; Cooper, M. J. Hum. Gene Ther. 2004, 15 (12), 1255-69) has highlighted pegylated poly-L-lysine (C1K30-PEG) as a nonviral gene delivery agent capable of achieving clinically significant gene transfer levels in vivo. This study investigates the potential of a C1K30-PEG gene delivery system for cancer gene therapy and evaluates its mode of cellular entry with the purpose of developing an optimally formulated prototype for tumor cell transfection. C1K30-PEG complexes have a neutral charge and form rod-like and toroid-like nanoparticles. Comparison of the transfection efficiency achieved by C1K30-PEG with other cationic lipid and polymeric vectors demonstrates that C1K30-PEG transfects cells more efficiently than unpegylated poly-L-lysine and compares well to commercially available vectors. In vivo gene delivery by C1K30-PEG nanoparticles to a growing subcutaneous murine tumor was also demonstrated. To determine potential barriers to C1K30-PEG gene delivery, the entry mechanism and intracellular fate of rhodamine labeled complexes were investigated. Using cellular markers to delineate the pathway taken by the complexes upon cellular entry, only minor colocalization was observed with EEA-1, a marker of early endosomes. No colocalization was observed between the complexes and the transferrin receptor, which is a marker for clathrin-coated pits. In addition, complexes were not observed to enter late endosomes/lysosomes. Cellular entry of the complexes was completely inhibited by the macropinocytosis inhibitor, amiloride, indicating that the complexes enter cells via macropinosomes. Such mechanistic studies are an essential step to support future rational design of pegylated poly-L-lysine vectors to improve the efficiency of gene delivery.

Local gene therapy of solid tumors with GM-CSF and B7-1 eradicates both treated and distal tumors.

Gene therapy-induced expression of immunostimulatory molecules at tumor cell level may evoke antitumor immune mechanisms by recruiting and enhancing viability of antigen-processing cells and specific tumoricidal lymphocytes. The antitumor efficacy of a plasmid, coding for granulocyte-macrophage colony-stimulating factor (GM-CSF) and the B7-1 costimulatory immune molecule, delivered into growing solid tumors by electroporation was investigated. Murine fibrosarcomas (JBS) growing in Balb/C mice (

Double-blind placebo-controlled study of testosterone patch therapy on bone turnover in men with borderline hypogonadism.

Clinical studies suggest there may be a threshold concentration of serum testosterone below which replacement will result in skeletal and psychological benefit. We evaluated the response to testosterone in men with borderline hypogonadism. A randomized double-blind placebo-controlled trial in 39 men over age 40 years presenting with sexual dysfunction and a borderline low testosterone level (total testosterone <10 nmol/L or free androgen index <30%). Patients were randomized to Testoderm TTS body patch (5 mg/day, n = 20) or a placebo patch (n = 19) for 6 months, followed by open-label testosterone replacement for a further 6 months in all patients. During the placebo-controlled phase of the study serum testosterone increased significantly on testosterone vs. placebo treatment (p = 0.004); this was associated with a decrease in total body fat mass (p = 0.019) and increase in haemoglobin level (p = 0.036). There were no significant changes in lean body mass, markers of bone turnover, and measures of bone mineral density (BMD). There was evidence of difference in quality of life according to the Male Erectile Dysfunction Quality of Life questionnaire (MEDQoL score, p = 0.017), mainly accounted for by deterioration in the placebo arm. When the active treatment period was combined for placebo and testosterone groups, the within-patient analysis showed a significant effect of testosterone to decrease markers of bone resorption (uNTX/Cr, p = 0.007; iFDPD/Cr, p = 0.0006) and to increase lean body mass (p = 0.001). There was little convincing evidence from this study that testosterone replacement is likely to have major benefit in men over age 40 years with borderline hypogonadism and sexual dysfunction. However, there was evidence of suppression in bone resorption and hence longer and larger studies are needed to examine its effect on BMD.

Observational study of the natural history of eosinophilic bronchitis.

BACKGROUND: Eosinophilic bronchitis is an important cause of chronic cough. Treatment with inhaled corticosteroids is associated with a short-term improvement in cough and reduced sputum eosinophil count but the long-term outcome is uncertain. OBJECTIVE: To determine the long-term outcome in patients diagnosed with and treated for eosinophilic bronchitis. METHODS: We have performed a longitudinal study of symptoms, eosinophilic airway inflammation, spirometry and airway hyper-responsiveness in all patients diagnosed with eosinophilic bronchitis over 7 years. RESULTS: We identified 52 patients with eosinophilic bronchitis and longitudinal data of greater than 1 year (mean 3.1 years) was available in 32 patients, all of whom were treated with inhaled steroids. Three (9%) patients developed symptoms consistent with asthma and a methacholine PC20<8 mg/mL on one or more occasion. Five (16%) patients developed fixed airflow obstruction defined by a persistent post-bronchodilator forced expiratory volume in 1 s (FEV1)/forced vital capacity<70%. One (3%) patient had complete resolution of symptoms and eosinophilic airway inflammation off treatment. The remaining patients had ongoing eosinophilic airway inflammation and/or continuing symptoms. Multiple linear regression identified smoking, female gender and area under the curve of sputum eosinophil count over time as the most important predictors of decline in FEV1. CONCLUSIONS: The most common outcome in eosinophilic bronchitis is continuing disease and complete resolution is rare. Asthma and fixed airflow obstruction developed in relatively few patients. The most important factors associated with a more rapid decline in FEV1 were female gender, smoking and prolonged eosinophilic airway inflammation.

Airway function and markers of airway inflammation in patients with treated hypothyroidism.

BACKGROUND: There is increasing evidence of an association between organ specific autoimmune diseases, particularly autoimmune thyroid disease and respiratory morbidity. A study was undertaken to determine whether patients with autoimmune thyroid disease have objective evidence of airway inflammation and dysfunction. METHODS: Twenty six non-smoking women with treated hypothyroidism and 19 non-smoking controls completed a symptom questionnaire and underwent full lung function tests, capsaicin cough reflex sensitivity measurement, methacholine challenge test, and sputum induction over two visits. RESULTS: Symptoms of cough (p = 0.01), dyspnoea (p = 0.01), sputum production (p = 0.004), and wheeze (p = 0.04) were reported more commonly in patients than controls. Patients with hypothyroidism had heightened cough reflex sensitivity compared with controls (geometric mean concentration of capsaicin causing five coughs: 40 v 108 mmol/l; mean difference 1.4 doubling doses; 95% confidence interval of difference 0.4 to 2.5; p = 0.008) and a significantly higher proportion of patients had airway hyperresponsiveness (methacholine provocative concentration (PC(20)) <8 mg/ml: 38% v 0%; p = 0.016). Patients with hypothyroidism also had a significantly higher induced sputum total neutrophil cell count (p = 0.01), total lymphocyte count (p = 0.02), and sputum supernatant interleukin-8 concentrations (p = 0.048). CONCLUSION: Patients with treated hypothyroidism report more respiratory symptoms and have objective evidence of airway dysfunction and inflammation.

Development of the PsAQoL: a quality of life instrument specific to psoriatic arthritis.

BACKGROUND: Patient reported outcome measures used in studies of psoriatic arthritis (PsA) have been found to be inadequate for determining the impact of the disease from the patient's perspective. OBJECTIVE: To produce the PsAQoL, a PsA-specific quality of life (QoL) instrument, employing the needs based model of QoL that would be relevant and acceptable to respondents, valid, and reliable. METHODS: Content was derived from qualitative interviews conducted with patients with PsA. Face and content validity were assessed by field test interviews with a new sample of patients with PsA. A postal survey was conducted to improve the scaling properties of the new measure. Finally, a test-retest postal survey was used to identify the final measure and to test its scaling properties, reliability, internal consistency, and validity. RESULTS: Analysis of the qualitative interview transcripts identified a 51 item questionnaire. Field test interviews confirmed the acceptability and relevance of the measure. Analysis of data from the first postal survey (n = 94) reduced the questionnaire to 35 items. Rasch analysis of data from the test-retest survey (n = 286) identified a 20 item version of the PsAQoL with good item fit. This version had excellent internal consistency (alpha = 0.91), test-retest reliability (0.89), and validity. CONCLUSIONS: The PsAQoL is a valuable tool for assessing the impact of interventions for PsA in clinical studies and trials. It is well accepted by patients, taking about three minutes to complete, is easy to administer, and has excellent scaling and psychometric properties.