Surgical Outcome Measures in a Cohort of Patients at High Risk of Breast Cancer Treated by Bilateral Risk-Reducing Mastectomy and Breast Reconstruction.

BACKGROUND: Women with breast cancer-related genetic pathogenic variants (e.g., BRCA1 , BRCA2 ) or with a strong family history carry lifetime risks of developing breast cancer of up to 80 to 90 percent. A significant proportion of these women proceed to bilateral risk-reducing mastectomy. The authors aimed to document the surgical morbidity of risk-reducing mastectomy and establish whether a diagnosis of breast cancer at the time of surgery impacted outcomes. METHODS: Clinical details of 445 women identified as having a greater than 25 percent lifetime risk of developing breast cancer who underwent risk-reducing mastectomy and breast reconstruction were interrogated for surgical outcomes such as planned, unplanned, and emergency procedures; complication rates; length of stay; and longevity of breast reconstruction. These outcome measures were recorded in women diagnosed with breast cancer perioperatively (cancer group) and those without malignancy (benign group). RESULTS: Median follow-up was similar in both groups (benign group, 70 months; cancer group, 73 months). Patients were older in the cancer group than in the benign group (43 years versus 39 years; p < 0.001). Women in the cancer group required more planned procedures to complete reconstruction than those in the benign group (four versus two; p = 0.002). Emergency procedures, unplanned surgical interventions (e.g., capsulectomy), and postreconstruction complication rates were similar between groups. One in five women overall required revision surgery. Patients with autologous reconstructions had a revision rate of 1.24 per 1000 person-years compared with 2.52 per 1000 person-years in the implant reconstruction group. CONCLUSIONS: Women contemplating risk-reducing mastectomy can be reassured that this is a safe and effective procedure but will likely take multiple interventions. This knowledge should be integral to obtaining informed consent. CLINICAL QUESTION/LEVEL OF EVIDENCE: Risk, II.

Psychosexual Morbidity in Women With Ovarian Cancer: Evaluation by Germline BRCA Gene Mutational Status.

INTRODUCTION: Up to 75% of women with ovarian cancer experience psychosexual morbidity and approximately 15-20% of women with ovarian cancer have a germline BRCA1/2 mutation (gBRCAm). However, psychosexual morbidity remains unexplored in women with gBRCAm ovarian cancer. AIM: Given their younger age, genetic diagnosis, breast cancer risk, and increased prevalence of surgically-induced menopause, we aim to assess whether women with gBRCAm ovarian cancer experience distinct psychosexual morbidity. METHODS: Psychosexual morbidity was investigated in 2 cohorts of women with ovarian cancer: women with gBRCAm ovarian cancer vs women with gBRCA wildtype (gBRCAwt) ovarian cancer. Between August 2019 and March 2020, women with high-grade serous carcinoma of the ovary, Fallopian tube or primary peritoneum were approached in clinic or telephoned and invited to take part. Exclusion criteria included: women with alternative histology; women admitted from clinic; and women who lacked capacity to independently complete the questionnaire. The Female Sexual Function Index (FSFI) and background information were collected at a single time-point per patient. Scores below 26.55 were interpreted to suggest psychosexual dysfunction. MAIN OUTCOME MEASURE: Responses including total and domain FSFI scores, self-reported psychosexual problems and interest in psychosexual support were compared. RESULTS: Of 103 women approached, 53% returned questionnaires. In this exploratory analysis, women with gBRCAm ovarian cancer were significantly younger (51-60 years vs 61-70 years, gBRCAwt, P = .010). There was a trend towards increased prevalence of surgical menopause (57% vs 27%, P = .097) and breast surgery (53% vs 22%, P = .132, gBRCAm vs gBRCAwt, respectively). Women with gBRCAm ovarian cancer scored higher in the FSFI questionnaire, particularly women under 60 years (15.1 vs 2.7, P = .070), approaching significance. Women with gBRCAm ovarian cancer expressed more interest for face-to-face services (P = .018), especially psychosexual therapy (65% vs 30%) and more often felt the service was insufficient, approaching significance (71% vs 44%, gBRCAm vs gBRCAwt, respectively, P = .076). CONCLUSION: Women with gBRCAm ovarian cancer are younger, express more interest for specialist psychosexual support and potentially different psychosexual problems, warranting further exploration. Logue C, Pugh J, Foden P, et al., Psychosexual Morbidity in Women With Ovarian Cancer: Evaluation by Germline BRCA Gene Mutational Status. Sex Med 2022;10:100465.

Longitudinal effects of ivacaftor and medicine possession ratio in people with the Gly551Asp mutation: a 5-year study.

INTRODUCTION: Ivacaftor was the first therapy licensed to address the underlying defect in cystic fibrosis (CF). The improvements in lung function, nutritional status and pulmonary exacerbations in patients carrying a Gly551Asp mutation were greater than previously seen in clinical trials for other therapies. Limited data are available regarding long-term outcomes and adherence to ivacaftor outside clinical trials. METHODS: We conducted a 5-year single-centre retrospective study of people with CF carrying the Gly551Asp mutation who received ivacaftor. Clinical outcome data were extracted from medical notes and databases. Drug delivery data were used to assess medicine possession ratio (MPR). RESULTS: 35 people were included. After commencing ivacaftor, FEV1 improved by 9.6% (SE±1.59%) predicted by 6 months. Thereafter, FEV1 declined, and at 5 years had returned to pre-ivacaftor baseline. Ivacaftor did not alter annual rate of FEV1 decline (1.57% pre vs 1.82% post, p=0.74). Body mass index (BMI) increased for 4 years. There was a significant reduction in inpatient and total intravenous antibiotic days sustained over 5 years. MPR remained high but declined over time (-2.5±0.9% per year, p=0.007). FEV1 was better maintained in patients with higher MPRs. CONCLUSION: The addition of ivacaftor provides acute benefits for people with the Gly551Asp mutation and established lung disease. We report a sustained reduction in intravenous antibiotic use but following acute improvement in lung function, decline continues, and patients will continue to require medical observation and optimisation. Strategies to maintain high adherence should be a priority to prolong the benefits of ivacaftor.

Change in blood eosinophils following treatment with inhaled corticosteroids may predict long-term clinical response in COPD.

There is an emerging role for blood eosinophil count (EOS) as a biomarker to guide inhaled corticosteroid (ICS) therapy in COPD. Since ICS administration could influence EOS, we hypothesised that change in EOS following treatment with ICS may predict outcomes of long-term therapy.In a post hoc analysis of ISOLDE, a 3-year, double-blind trial comparing 500 µg fluticasone propionate twice daily with placebo in 751 patients with moderate-to-severe COPD, we evaluated whether the initial changes in EOS during ICS treatment were predictive of ICS treatment response.EOS change within 1 year after the introduction of ICS was strongly predictive of treatment response. A suppressed EOS was associated with treatment effect. Characteristically, in patients with EOS suppression of ≥200 cells·µL-1, ICS use was associated with a decelerated rate of decline of forced expiratory volume in 1 s (FEV1), by 32 mL·year-1, and a 30% reduction in the exacerbation rate. In contrast, in patients experiencing an increase in EOS of ≥200 cells·µL-1, ICS use was associated with an accelerated rate of decline of FEV1, by 37 mL·year-1 and an 80% increase in the exacerbation rate (p<0.0001). EOS change was not predictive of clinical response with regards to health status evaluated using the St George's Respiratory Questionnaire.These findings suggest that EOS change after ICS administration may predict clinical response to ICS therapy in patients with moderate-to-severe COPD at risk of exacerbations. ICS administration may be associated with more frequent exacerbations and an accelerated lung function decline in the 20% of patients in whom EOS increases after the administration of ICS. These hypothesis-generating observations will need validation in prospectively designed studies.The ISOLDE trial was conducted before the ICJME recommended a prospective registration of RCT protocols.

The Ellipse modification of the Friedman method for measuring glenoid version.

AIMS: Accurate measurement of the glenoid version is important in performing total shoulder arthroplasty (TSA). Our aim was to evaluate the Ellipse method, which involves formally defining the vertical mid-point of the glenoid prior to measuring the glenoid version and comparing it with the 'classic' Friedman method. METHODS: This was a retrospective study which evaluated 100 CT scans for patients who underwent a primary TSA. The glenoid version was measured using the Friedman and Ellipse methods by two senior observers. Statistical analyses were performed using the paired t-test for significance and the Bland-Altman plot for agreement. RESULTS: The mean glenoid version was -3.11° (-23.8° to 17.9°) using the Friedman method and -1.95° (-29.8° to 24.6°) using the Ellipse method (p = 0.002). In 16 patients the difference between methods was greater than 5°, which we considered to be clinically significant. There was poor agreement between methods with relatively large 95% limits of agreement. There was excellent inter-rater agreement between the observers for the Ellipse method and similarly, the intrarater agreement was excellent with a repeatability coefficient of 0.94. CONCLUSION: We recommend the use of the Ellipse modification to define the mid glenoid point prior to measuring the glenoid version in patients undergoing TSA. Cite this article: Bone Joint J 2020;102-B(2):232-238.

Breast cancer risk status influences uptake, retention and efficacy of a weight loss programme amongst breast cancer screening attendees: two randomised controlled feasibility trials.

BACKGROUND: Excess body weight and sub-optimal lifestyle are modifiable causes of breast cancer and other diseases. There is little evidence that behaviour change is possible within screening programmes and whether this is influenced by prior knowledge of disease risk. We determined whether breast cancer risk influences uptake, retention and efficacy of a weight control programme in the UK National Health Service Breast Screening Programme, and whether additional cardiovascular disease and type 2 diabetes risk information improves uptake and retention further. METHOD: Overweight/obese women in the UK National Health Service Breast Screening Programme identified at high, moderately increased, average and low-risk of breast cancer were randomised to receive individualised breast cancer risk information (breast cancer prevention programme), or individualised breast cancer, cardiovascular disease (QRISK2) and type 2 diabetes (QDiabetes, HbA1c) information (multiple disease prevention programme). Personalised breast cancer risk feedback was given before randomisation in Study-1, and after randomisation in Study-2. RESULTS: Recruitment was 9% (126/1356) in Study-1 and 7% (52/738) in Study-2. With respect to breast cancer risk, odds ratio of uptake for high/moderately increased vs low risk women was 1.99 (95% CI 1.24-3.17, P = 0.004) in Study-1 and 3.58 (95% CI 1.59-8.07, P = 0.002) in Study-2. Odds ratio of retention for high/moderately increased -risk vs. low risk women was 2.98 (95% CI 1.05-8.47, P = 0.041) in Study-1 and 3.88 (95% CI 1.07-14.04, P = 0.039) in Study-2. Weight loss of ≥5% at 12 months was achieved by 63% high/moderate vs. 43% low-risk women in Study-1 (P = 0.083) and 39% vs. 8% in Study-2 (P = 0.008). Uptake, retention and weight loss were equivalent in both the breast cancer prevention programme and the multiple disease prevention programme in both studies. CONCLUSIONS: Women who are informed that they are at increased breast cancer risk were significantly more likely to join and remain in the programmes and consequently lose more weight across both studies. High risk women are more likely engage in a lifetyle prevention programme and also have the greatest potential benefit fom risk reduction strategies. TRIAL REGISTRATION: ISRCTN91372184 Registered 28 September 2014.

Functional Testing of a Skin Topical Formulation In Vivo: Objective and Quantitative Evaluation in Human Skin Scarring Using a Double-Blind Volunteer Study with Sequential Punch Biopsies.

Objective: Many topicals claim an efficacious role in skin scar management with limited evidence. Our aim is to present a clear format for functional testing of a skin scarring ointment, using noninvasive and invasive measurements, categorizing findings under the physiological, structural, and mechanical parameters of a scar. Approach: A double-blinded, randomized volunteer research study of 45 subjects receiving an ointment composing of natural ingredients against a widely used antiscarring topical used as a positive control with temporal sequential punch biopsies (up to 16 weeks) was evaluated using noninvasive quantitative devices and validated by gene and protein studies. Results: Outcome measures included physiological, mechanical, and structural features of scars. Significant non-invasive findings included an increase in skin hydration (p < 0.05) at week (W) 4, 8, and 12, and elasticity (W16; p = 0.009). These findings were validated by immunohistochemistry (IHC) and quantitative real-time PCR (qRT-PCR). Hyaluronic acid IHC (W4 p = 0.014, W12 p = 0.034, and W16 p = 0.042), qRT-PCR (W16 p = 0.049); Collagen I (W16 p = 0.034, and 0.049) IHC and qRT-PCR, respectively. Collagen III qRT-PCR (W12 p = 0.035, and W16 p = 0.32); elastin IHC (W12 p = 0.044); and fibronectin IHC (W4 p = 0.009, W12 p = 0.038, and W16 p = 0.026). Innovation: Utilizing this model allows for quantitative, objective evaluation of any topical, where previously there has been a paucity of relevant methods to evaluate their effect. Conclusions: The positive effect of a topical formulation with an unknown mechanism of action on early cutaneous scar maturation over progressive sequential time points is now evidenced using noninvasive and invasive techniques with the findings categorized on the basis of scarring parameters.

A Double-Blind, Randomized Trial Shows the Role of Zonal Priming and Direct Topical Application of Epigallocatechin-3-Gallate in the Modulation of Cutaneous Scarring in Human Skin.

BACKGROUND: Epigallocatechin-3-gallate (EGCG), a polyphenol, influences cutaneous wound healing because of its antiangiogenic, anti-inflammatory, and antioxidant properties. We previously showed the role of EGCG in scarring in ex vivo human scar models. Here, we evaluate direct application of topical EGCG compared with zonal priming, a unique concept in the immediate treatment of the zone of injury at the time of wounding before scar formation. TRIAL DESIGN: Double-blind randomized controlled trial. METHODS: We assessed EGCG application compared with placebo over 1-6 weeks in scars created in 62 human volunteers using quantitative noninvasive devices, immunohistochemical analysis, mRNA sequencing, and quantitative real-time reverse transcriptase-PCR of tissue biopsy samples. RESULTS: EGCG reduced mast cells at weeks 1-3, as evidenced by gene and protein analyses (P ≤ 0.01). M2 macrophages were increased with EGCG compared with placebo. EGCG application by zonal priming significantly down-regulated VEGFA and CD31 at week 1 and at 1-2 weeks after direct application (P ≤ 0.01). Direct EGCG application also reduced scar thickness at weeks 1-3 (P = 0.001) and increased scar elasticity at week 4 (P = 0.01). Increased hydration was evident both noninvasively and by increased hyaluronic acid levels (P < 0.01) at week 3. CONCLUSIONS: We show the beneficial role of both zonal priming and direct EGCG application in scar therapy with positive effects on scar thickness, erythema, hydration, and elasticity. Trial register: International standard randomized controlled trial, registration number ISRCTN 18643079; July 16, 2018.

Innovative intelligent insole system reduces diabetic foot ulcer recurrence at plantar sites: a prospective, randomised, proof-of-concept study.

BACKGROUND: Prevention of diabetic foot ulcer recurrence in high risk patients, using current standard of care methods, remains a challenge. We hypothesised that an innovative intelligent insole system would be effective in reducing diabetic foot ulcer recurrence in such patients. METHODS: In this prospective, randomised, proof-of-concept study, patients with diabetes, and with peripheral neuropathy and a recent history of plantar foot ulceration were recruited from two multidisciplinary outpatient diabetic foot clinics in the UK, and were randomly assigned to either intervention or control. All patients received an insole system, which measured plantar pressure continuously during daily life. The intervention group received audiovisual alerts via a smartwatch linked to the insole system and offloading instructions when aberrant pressures were detected; the control group did not receive any alerts. The primary outcome was plantar foot ulcer occurrence within 18 months. This trial is registered with ISRCTN, ISRCTN05585501, and is closed to accrual and complete. FINDINGS: Between March 18, 2014, and Dec 20, 2016, 90 patients were recruited and consented to the study, and 58 completed the study. At follow-up, ten ulcers from 8638 person-days were recorded in the control group and four ulcers from 11 835 person-days in the intervention group: a 71% reduction in ulcer incidence in the intervention group compared with the control group (incidence rate ratio 0·29, 95% CI, 0·09-0·93; p=0·037). The number of patients who ulcerated was similar between groups (six of 26 [control group] vs four of 32 [intervention group]; p=0·29); however, individual plantar sites ulcerated more often in the control group (ten of 416) than in the intervention group (four of 512; p=0·047). In an exploratory analysis of good compliers (n=40), ulcer incidence was reduced by 86% in the intervention group versus control group (incidence rate ratio 0·14, 95% CI 0·03-0·63; p=0·011). In the exploratory analysis, plantar callus severity (change from baseline to 6 months) was greater in re-ulcerating patients (6·5, IQR 4·0-8·3) than non-re-ulcerating patients (2·0, 0·0-4·8; p=0·040). INTERPRETATION: To our knowledge, this study is the first to show that continuous plantar pressure monitoring and dynamic offloading guidance, provided by an innovative intelligent insole system, can lead to a reduction in diabetic foot ulcer site recurrence. FUNDING: Diabetes UK and Orpyx Medical Technologies.

Predicting survival following surgical resection of lung cancer using clinical and pathological variables: The development and validation of the LNC-PATH score.

INTRODUCTION: The aim of this study was to develop and validate a simple prognostic scoring system using readily available clinical and pathological variables that could stratify patients according to the risk of death following lung cancer resection. We hypothesized that by using additional pathological variables not accounted for by pathological stage alone coupled with markers of overall fitness a new prognostic tool could be developed. METHODS: Multivariable logistic regression analysis of pathological and other clinical variables from patients undergoing surgical resection of non-small cell lung cancer (NSCLC) were used to determine factors independently associated with 2-year overall survival and so derive the scoring system. The model was then validated in an external multi-centre dataset. RESULTS: Using multivariable logistic regression on a large dataset (n = 1,421) the 'LNC-PATH' (Lymphovascular invasion, N-stage, adjuvant Chemotherapy, Performance status, Age, T-stage, Histology) prognostic score was devised and then validated using an external dataset (n = 402). This can be used to risk stratify patients into low, moderate and high-risk groups with a statistically significant difference between the three groups in their survival distributions. 83.8% of patients in the low-risk group survived two years after surgery compared to 55.6% in the moderate-risk group and 26.2% in the high-risk group. The score was shown to perform moderately well with an Area Under the Receiver Operating Characteristic curve (AUROC) value of 0.76 (95% CI: 0.73-0.79) and 0.70 (95% CI: 0.64-0.76) in the derivation and validation cohorts respectively. DISCUSSION: The LNC-PATH score predicts 2-year overall survival after surgery for NSCLC. This may allow the development of risk stratified follow-up protocols in survivorship clinics which could be the subject of future prospective studies.

Clinical characteristics and survival in cardiogenic shock admissions to a UK heart transplant unit.

AIM: We describe the characteristics and outcomes of cardiogenic shock (CS) admissions to a UK transplant unit, which is previously unreported. PATIENTS & METHODS: Fifty-nine unselected, consecutive patients over a 38-month period in CS (INTERMACS ≤2) and potentially eligible for transplant were retrospectively reviewed. RESULTS: Patients were predominantly male (76.3%), young (mean age 42.2 years) and with severe end-organ dysfunction (acute liver/kidney injury 83%, mean lactate 3.5 mmol/l). 57.6% required mechanical support and 28.8% cardiac transplant. 30 days, discharge and 1-year survival were 78, 68 and 63%, respectively. Predictors of death included no transplant, increasing age and increasing creatinine. CONCLUSION: Patients with CS and potential for transplant require significant resource input but demonstrate favorable outcomes in our experience.

Explanations for less small fibre neuropathy in South Asian versus European subjects with type 2 diabetes in the UK.

BACKGROUND: Low foot ulcer risk in South Asian, compared with European, people with type 2 diabetes in the UK has been attributed to their lower levels of neuropathy. We have undertaken a detailed study of corneal nerve morphology and neuropathy risk factors, to establish the basis of preserved small nerve fibre function in South Asians versus Europeans. METHODS: In a cross-sectional, population-based study, age- and sex-matched South Asians (n = 77) and Europeans (n = 78) with type 2 diabetes underwent neuropathy assessment using corneal confocal microscopy, symptoms, signs, quantitative sensory testing, electrophysiology and autonomic function testing. Multivariable linear regression analyses determined factors accounting for ethnic differences in small fibre damage. RESULTS: Corneal nerve fibre length (22.0 ± 7.9 vs. 19.3 ± 6.3 mm/mm2 ; P = 0.037), corneal nerve branch density (geometric mean (range): 60.0 (4.7-246.2) vs. 46.0 (3.1-129.2) no./mm2 ; P = 0.021) and heart rate variability (geometric mean (range): 7.9 (1.4-27.7) vs. 6.5 (1.5-22.0); P = 0.044), were significantly higher in South Asians vs. Europeans. All other neuropathy measures did not differ, except for better sural nerve amplitude in South Asians (geometric mean (range): 10.0 (1.3-43.0) vs. 7.2 (1.0-30.0); P = 0.006). Variables with the greatest impact on attenuating the P value for age- and HbA1C -adjusted ethnic difference in corneal nerve fibre length (P = 0.032) were pack-years smoked (P = 0.13), BMI (P = 0.062) and triglyceride levels (P = 0.062). CONCLUSIONS: South Asians have better preserved small nerve fibre integrity than equivalent Europeans; furthermore, classic, modifiable risk factors for coronary heart disease are the main contributors to these ethnic differences. We suggest that improved autonomic neurogenic control of cutaneous blood flow in Asians may contribute to their protection against foot ulcers.

Prior subclinical histoplasmosis revealed in Nigeria using histoplasmin skin testing.

OBJECTIVES: Disseminated histoplasmosis is an AIDS-defining illness. Histoplasmosis is commonly misdiagnosed as tuberculosis. Nigeria has the second highest number of people living with HIV/AIDS in Africa. The present study was carried out to investigate the prevalence of skin sensitivity amongst Nigerians to histoplasmin. DESIGN: A cross-sectional study was conducted in six centres across five geopolitical zones of Nigeria. METHODS: We recruited both healthy non-HIV and HIV-positive adults with CD4 count ≥ 350 cells/mm3 regardless of their ART status from March to May 2017. Skin tests were performed intradermally; induration ≥5 mm were considered to be histoplasmin positive. RESULTS: 750 participants were recruited from Lagos (n = 52), Yola (n = 156), Ilorin (n = 125), Calabar (n = 120), Ibadan (n = 202) and Benin (n = 95). 467 (62.3%) were HIV negative, 247 (32.9%) were HIV positive and 36 (4.8%) did not know their HIV status. A total of 32/735 (4.4%) participants had a positive skin test. Study centre (p<0.001), education (p = 0.002) and age (p = 0.005) appeared to be significantly associated with positive skin reactivity at the 0.5% significance level, while sex (p = 0.031) and occupation (p = 0.031) would have been significant at the 5% significance level. Males had a higher rate of reactivity than females (p = 0.031, 7% vs 3%). The highest positive rates were recorded from Benin City (13/86 (15%)) and Calabar (7/120 (6%)) and no positives were recorded in Lagos (p<0.001). HIV status was not statistically significant (p = 0.70). CONCLUSION: Histoplasmosis diagnostics should be included in the Nigerian HIV guidelines. Epidemiological vigilance of progressive disseminated histoplasmosis should be considered by local health authorities.

Diagnosis of asthma in symptomatic children based on measures of lung function: an analysis of data from a population-based birth cohort study.

BACKGROUND: Concerns have been expressed about asthma overdiagnosis. The UK National Institute of Health and Care Excellence (NICE) proposed a new diagnostic algorithm applying four lung function measures sequentially (ratio of forced expiratory volume in 1 s [FEV1] to forced vital capacity [FVC] <70%, bronchodilator reversibility ≥12%, fractional exhaled nitric oxide [FeNO] ≥35 parts per billion, and peak expiratory flow variability >20%). We aimed to assess the diagnostic value of three of the tests individually, and then test the proposed algorithm in symptomatic children. METHODS: We used follow-up data at age 13-16 years from the Manchester Asthma and Allergy Study, a prospective, population-based, birth cohort study. We initially present results for the whole population, then by subgroup of disease. To simulate the situation in primary care, we included participants reporting symptoms of wheeze, cough, or breathlessness in the previous 12 months and who were not on regular inhaled corticosteroids. We used an epidemiological definition of current asthma, defined as all three of physician-diagnosed asthma, current wheeze, and current use of asthma treatment, reported by parents in a validated questionnaire. We assigned children with negative answers to all three questions as non-asthmatic controls. We also measured spirometry, bronchodilator reversibility, and FeNO at follow-up; data for peak expiratory flow variability were not available. We calculated the proportion of participants with a current positive lung function test at each step of the algorithm, and recorded the number of participants that met our definition of asthma. FINDINGS: Of 1184 children born into the cohort, 772 attended follow-up at age 13-16 years between July 22, 2011, and Nov 11, 2014. Among 630 children who completed spirometry, FEV1:FVC was less than 70% in ten (2%) children, of whom only two (20%) had current asthma. Bronchodilator reversibility was positive in 54 (9%) of 624 children, of whom only 12 (22%) had current asthma. FeNO was 35 or more parts per billion in 115 (24%) of 485 children, of whom 29 (25%) had current asthma. Only four of 56 children with current asthma had positive results for all three tests (spirometry, bronchodilator reversibility, and FeNO). Conversely, 24 (43%) of the 56 children with current asthma were negative on all three tests. FEV1:fvc (p=0·0075) and FeNO (p<0·0001), but not bronchodilator reversibility (p=0·97), were independently associated with asthma in multivariable logistic regression models. Among children who reported recent symptoms, the diagnostic accuracy of the algorithm was poor. INTERPRETATION: Our findings challenge the proposed cutoff values for spirometry, the order in which the lung function tests are done, and the position of bronchodilator reversibility within the algorithm sequence. Until better evidence is available, the proposed NICE algorithm on asthma diagnosis should not be implemented in children. FUNDING: UK Medical Research Council.

Adequacy of Intraoperative Nodal Staging during Surgical Resection of NSCLC: Influencing Factors and Its Relationship to Survival.

INTRODUCTION: Adequate intraoperative lymph node sampling is a fundamental part of lung cancer surgery, but adherence to standards is not well known. This study sought to measure the adequacy of intraoperative lymph node sampling at a regional Thoracic Surgery Centre and a tertiary lung cancer center in the United Kingdom. METHODS: This retrospective study analyzed the pathological reports from NSCLC resections over the 4-year period 2011-2014. Adequacy of sampling was assessed against International Association for the Study of Lung Cancer recommendations of at least three mediastinal lymph node stations: station 7 in all patients, station 5 or 6 in left upper lobe tumors, and station 9 in lower lobe tumors. The influence of clinical variables (age, tumor T stage, type of surgery, and laterality) on adequacy of sampling and the effect of adequacy on overall survival were also assessed. RESULTS: A total of 1301 NSCLC resections were performed from January 11, 2011, to December 31, 2014. Adequate intraoperative lymph node sampling increased significantly from 14% (22 of 160) in 2011 to 53% (206 of 390) in 2014 (p = 0.001). Secondary analysis of clinical variables also revealed that patients with T1a or T4 tumors, those undergoing sublobar resections, those undergoing video-assisted thoracic surgery resections, and those undergoing left-sided resections have significantly higher rates of inadequate lymph node sampling. Overall, there was no statistically significant difference in survival between patients with adequate versus inadequate intraoperative lymph node sampling or when survival was stratified according to overall stage. There was worse survival in inadequate sampling for patients with pN2 disease than for patients with pN2 disease and adequate sampling. CONCLUSION: This study provides a much-needed benchmark of current thoracic surgical practice in lung cancer in the United Kingdom and important granularity to facilitate changes to improve adequacy of staging.

Comparative performance of Aspergillus galactomannan ELISA and PCR in sputum from patients with ABPA and CPA.

OBJECTIVES: Galactomannan (GM) and Aspergillus DNA detection are useful tools for the diagnosis of invasive pulmonary aspergillosis (IPA), primarily in blood and bronchoscopy samples. This study aimed to evaluate the utility of both markers for detection of Aspergillus in sputum from patients with allergic bronchopulmonary aspergillosis (ABPA) and chronic pulmonary aspergillosis (CPA). METHODS: ABPA or CPA demographic patient data were retrieved. This retrospective observational audit included 159 patients with at least one sputum pair. 223 sputum sample pairs were analysed, as well as six control samples for GM only. Real time PCR was performed following sputum DNA extraction using the MycAssay™ Aspergillus kit and cycle thresholds were subtracted from 38 to give positive values (transformed Ct, TCt). RESULTS: The mean age of the patients was 61.81years (SD: ±11.06; range 29-100). One hundred and twenty-six (79.2%) had CPA. Cultures were positive for fungi in 13.1% of the samples, and A. fumigatus was the commonest (11.9%) fungus isolated. Receiver operating characteristic (ROC curve) analysis of sputum GM comparing TCt of >0.0, and >2.0 to derive GMI cut-off values showed a cut-off of 6.5. About 50% of sputa with strongly positive PCR values had GM values>6.5. Two of six (33%) control samples had GM indices>6.5. CONCLUSION: It is not clear that GM determinations in sputum are useful for diagnosis of either CPA or ABPA, or following therapy.