Philip V. Barber

Are We Achieving the Current Waiting Time Targets in Lung Cancer Treatment? Result of a Prospective Study from a Large United Kingdom Teaching Hospital

Background: Recent United Kingdom National Cancer Plan guidelines have specified a number of waiting time targets to prevent delays in the treatment of lung cancer. This study was performed to compare our waiting times with national recommendations. Methods: All newly diagnosed cases of lung cancer presenting to our institution were entered into a prospective tracking study by a dedicated audit officer. From September 2003 to December 2005, a total of 342 patients were entered into the study. Of these, 193 (56%) were referred by general practitioners; the remaining 114 (46%) were internal referrals. The Cancer Plan waiting time targets are mainly applicable to general practitioners referrals, which formed the study group. Results: All the patients were seen in chest outpatient clinics within the recommended 2-week period. However, there was a delay in starting all forms of treatment. The median waiting time to any form of treatment was 60 days (recommendation, 62 days for all patients). From specialist referrals, the median waiting times for radiotherapy, surgery, and chemotherapy were 43, 25, and 16.5 days compared with recommended maximums of 28, 28, and 7 days, respectively. Conclusion: These data demonstrate that although patients receive outpatient consultation in the recommended time period, the National Cancer Plan treatment target of 62 days for patients referred by general practitioners is not being achieved. A concerted effort by all clinicians is required to meet the prescribed target times.

Association between lung cancer risk and single nucleotide polymorphisms in the first intron and codon 178 of the DNA repair gene, O6-alkylguanine–DNA alkyltransferase

The association between lung cancer risk and 2 polymorphisms, rs12268840 and rs2308327 (codon K178R), in the DNA repair protein, O6‐alkylguanine–DNA alkyltransferase, which are associated with interindividual differences in activity, have been investigated in 3 hospital‐based case–control studies. Genotyping was carried out on 617 subjects of whom 255 had lung cancer. In 2 of the 3 series, there was a significant inverse association between the 178R allele and case status (p < 0.05). In a meta‐analysis, the odds ratio (95% CI) associated with the 178R allele relative to the 178K allele was 0.64 (0.45–0.92, p = 0.01) and 0.51 (0.24–1.11, p = 0.09) in fixed effects and random effects models, respectively. In a pooled analysis, after adjustment for sex, age, pack years and series, the OR (95% CI) for a heterozygote was 0.67 (0.45–1.01) and for a 178R homozygote was 0.10 (0.01–0.94); the trend for a decreased risk with the number of R alleles was significant (p = 0.008). This trend was particularly pronounced in heavy smokers (trend test p = 0.003), but not significant in light smokers (p = 0.73). There was no evidence of an association between rs12268840 and lung cancer risk. These results suggest that the R allele may protect against lung cancer, specifically in heavy smokers, an effect that may result from this polymorphism affecting the function of the MGMT protein and/or levels in MGMT activity.

UK waiting time targets in lung cancer treatment: are they achievable? Results of a prospective tracking study

BackgroundRecent guidelines have specified a number of waiting time targets to prevent delay in the treatment of lung cancer. This study was carried out to assess the quality of lung cancer services and compare with national recommendations.MethodsAll newly diagnosed cases of lung cancer presenting to our institution via general practitioner referral were entered into a prospective tracking study by a dedicated audit officer. From September 2003 to March 2005 a total of 247 patients were entered into the study. Of these 133 (54%) were referred by general practitioners and the remainder 114 (46%) were internal referrals. The Cancer Plan waiting time targets are mainly applicable to GP referrals, which formed the study group.ResultsAll the patients were seen in chest out-patients clinic within the recommended two weeks period. However there was a delay in starting all forms of treatment. The median waiting time to any form of treatment was 60 days (recommendation 62 days for all patients).ConclusionThis data demonstrates that although patients receive out patient consultation in the recommended time period, the National Cancer Plan 62 days GP referral to treatment target is not being achieved. A concerted effort by all clinicians is required to meet the prescribed target times.

Can Computed Tomography Characteristics Predict Outcomes in Patients Undergoing Radial Endobronchial Ultrasound-Guided Biopsy of Peripheral Lung Lesions?

Introduction: Percutaneous computed tomography (CT)-guided lung biopsy is a standard minimally invasive technique for sampling peripheral lung lesions. Radial endobronchial ultrasound (EBUS) offers an alternative approach but it has yet to be defined which patients are most suited to this procedure. The primary aim of this study was to investigate whether CT characteristics could predict the success of radial EBUS-guided sampling. Methods: The University Hospital South Manchester provides a radial EBUS service, under conscious sedation without fluoroscopy, double-hinged curettes, or guide sheaths, to a large cancer Network in the United Kingdom. This retrospective analysis of a prospectively maintained database included all patients undergoing radial EBUS from January 2011 to June 2013. Lesion size, structure, location, and presence of a bronchus sign on thoracic CT were analyzed against predefined outcomes using multivariate analysis. Results: One-hundred and seventeen patients underwent radial EBUS in the study period (mean age 69.5, mean lesion size 36.6 mm). The presence of a bronchus sign on CT was the only independent predictor of all predefined outcomes: (1) lesion identification with radial EBUS, (2) positioning of probe within the center of the lesion, and (3) accurate pathological diagnosis; odds ratio (OR) 31.1 (7.8–123.9, p < 0.0001), OR 44.8 (5.6–354.9, p < 0.0001) and OR 46.6 (11.1–195.3, p < 0.0001) respectively. The sensitivity and diagnostic accuracy for those patients with a bronchus sign on CT was 87.3% and 86.7% compared with 12.5% and 11.1% for those lacking the bronchus sign. Discussion: The patients most likely to benefit from radial EBUS, without the use of adjuncts, are those with a bronchus sign on CT.

Nodal staging in lung cancer: a risk stratification model for lymph nodes classified as negative by EBUS-TBNA.

Background: Over the last 10 years, endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has become established as the first-line nodal staging procedure of choice for lung cancer patients. However, the pathway for patients following a negative EBUS-TBNA has not been clearly defined. The primary aim of this study was to develop and validate a risk stratification model to categorize lymph nodes deemed negative by EBUS-TBNA into “low-risk” and “high-risk” groups, where “risk” refers to the risk of false negative sampling. Methods: A retrospective analysis of a prospectively maintained database at a UK tertiary EBUS-TBNA centre was performed. Only patients with primary lung cancer and only negative lymph nodes by EBUS-TBNA were included in the analysis. A risk stratification model was built from a derivation set using independent predictors of malignancy and the validation set used to evaluate the constructed model. The study period was from March 2010 to August 2013. Results: Three hundred twenty-nine lymph nodes were included in the analysis (derivation set n = 196, validation set n = 133). Lymph node standardized uptake value, the standardized uptake value ratio between the lymph node and primary tumor, and heterogeneous echogenicity during sonographic assessment were the only independent predictors of malignancy. Using a simplified scoring system based on the natural logs of the odds ratios from the multivariable analysis on the derivation sample, lymph nodes can be stratified into low risk (score ⩽1) and high risk (score ≥2). One hundred forty-one of 142 and 94 of 96 lymph nodes classified as low risk in the derivation and validation set, respectively, were ultimately proven to be benign and 35 of 54 and 24 of 37 lymph nodes classified as high risk were proven malignant. The negative predictive value of the risk stratification model for the derivation set and validation set was 99.3% (95% confidence interval 96.1%–99.6%) and 97.9% (95% confidence interval 92%–99.6%), respectively. Conclusion: This risk stratification model may assist lung cancer multidisciplinary teams in deciding which patients need further staging procedures and which may proceed directly to treatment after a negative EBUS.

A study of patients with isolated mediastinal and hilar lymphadenopathy undergoing EBUS-TBNA

Background Isolated mediastinal and/or hilar lymphadenopathy (IMHL) may be caused by benign and malignant disorders or be ‘reactive’. Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) has a reported low negative predictive value (NPV) in IMHL, necessitating mediastinoscopy in selected patients. The aim of this study was to examine the NPV of EBUS-TBNA in an IMHL population and determine whether clinical variables differentiate between pathological and reactive IMHL. Methods Analysis of a prospectively maintained database of consecutive patients with IMHL referred to a single UK centre for EBUS-TBNA. Results 100 patients with IMHL had EBUS-TBNA during the study (March 2010–February 2013), mean age 58.6±15.7 years, 63% men, 70% white British and mean follow-up 16.8±8.6 months. Pathological cause of IMHL established in 52 patients (sarcoidosis n=20, tuberculosis n=18, carcinoma n=7, lymphoma n=6, benign cyst n=1), 43 from EBUS-TBNA. 48/57 negative EBUS-TBNA samples were true negatives reflecting reactive lymphadenopathy in 48%. The diagnostic accuracy of EBUS-TBNA was 91% and NPV was 84.2% (95% CI 72.6% to 91.5%). Multivariate analysis of clinical covariates showed age (odds ratio (OR) 1.07, 95% CI 1.01 to 1.13; p=0.033), the presence of a relevant comorbidity (OR 9.49, 95% CI 2.20 to 41.04; p=0.003) and maximum lymph node size (OR 0.70, 95% CI 0.59 to 0.83; p=0.00004) to differentiate between reactive and pathological IMHL. Stratification of the study population according to comorbidity and maximum lymph node size (<20 mm) identified a low-risk cohort (n=32) where the NPV of EBUS-TBNA was 93.8% (95% CI 79.9% to 98.3%). Conclusions Reactive lymphadenopathy accounts for a significant proportion of patients with IMHL. In carefully selected patients with IMHL and a negative EBUS-TBNA, surveillance rather than further invasive sampling may be an appropriate strategy.

GSTM1 copy number and lung cancer risk

The GSTM1 null genotype is associated with a small increased lung cancer risk when compared to controls with at least one copy of the GSTM1 gene. As two copies of the GSTM1 gene might provide more protection than a single copy, we have determined GSTM1 copy number in a lung cancer case-control study. Cases with incident lung cancer were identified through a Bronchoscopy Unit and two separate hospital based control groups with non-malignant disease were selected with one from the same Bronchoscopy Unit and the other from a chest clinic at the same hospital. Subjects with at least one GSTM1 copy had a decreased lung cancer risk whatever the control group: the odds ratio (95% CI), after adjustment for age, gender and smoking duration, was 0.64 (0.41-0.98) and 0.54 (0.32-0.91) with bronchoscopy and chest clinic controls, respectively. Lung cancer risk varied with GSTM1 copy number with chest clinic controls only: the OR was 0.56 (0.32-0.97) for one copy of the GSTM1 gene and with two copies 0.43 (0.15-1.22), a trend that was significant (p=0.02): with bronchoscopy controls the trend was not significant (p=0.07). Results then confirm that the presence of GSTM1 provides protection against the risk of lung cancer. In addition there is equivocal evidence that this protection varies with the number of gene copies.

Topographical study of O6-alkylguanine DNA alkyltransferase repair activity and N7-methylguanine levels in resected lung tissue

BACKGROUND Tobacco specific nitrosamines such as 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are genotoxic alkylating agents found within cigarette smoke that induce lung adenocarcinomas in animal models. In humans, adenocarcinomas originate most frequently in the lung periphery. The aim of this study was to determine whether peripheral lung has increased susceptibility to the genotoxic effects of alkylating agents by comparing DNA alkylation damage (N7-methylguanine: N7-meG) and repair (O(6)-alkylguanine DNA alkyltransferase: MGMT) in peripheral relative to central lung tissue. METHODS Macroscopically normal lung tissue, resected from patients undergoing surgery for lung cancer, was sampled at equidistant points from central to peripheral lung along a bronchus. N7-meG levels were determined using an immunoslotblot technique and MGMT activity with a [32P]-labelled oligodeoxynucleotide cleavage assay. RESULTS A total of 20 subjects were recruited, 12 males and 8 females with a mean age of 68.7±5.8years. There were 14 former and 6 current smokers with a mean smoking exposure of 34.0±18.3packyears. N7-meG (mean 0.75±0.57/10(6)dG, n=65 samples from 14 patients) and MGMT repair (geometric mean 9.57±1.62fmol/μg DNA, n=79 samples from 16 patients) were detected in all samples assayed. MGMT activity increased towards the lung periphery (r=0.28, p=0.023; n=16) with a highly significant association in current (r=0.53, p=0.008; n=6) but not former smokers (r=0.13; p=0.41; n=10). No correlation was seen with N7-meG levels and lung position (r=-0.18; p=0.21; n=14). N7-meG levels were higher in current compared to former smokers reaching significance in two lung positions including peripheral lung (p=0.047). CONCLUSIONS The findings in this study do not support the hypothesis that peripheral tissue is more susceptible to the genotoxic effects of alkylating agents than central lung tissue. In addition exposure to cigarette smoke reduced the level of MGMT in central bronchial tissue possibly through increased alkylating agent exposure.

Can EBUS-TBNA provide an accurate diagnosis in patients found to have enlarged or FDG-avid lymph nodes during surveillance of previously treated lung cancer? A retrospective study.

Background:Reliable pathologic sampling methods are pivotal in the management of lung cancer patients who have undergone either curative intent or palliative treatment previously. Early diagnosis of localized disease recurrence may facilitate further curative treatment and rebiopsy at the point of disease progression during palliative treatment can inform further management. This study assessed the performance of endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) lymph node sampling in a cohort of such patients. Methods:A retrospective analysis of a prospectively maintained database of EBUS-TBNA procedures at the University Hospital of South Manchester from August 2010 to August 2013. All patients with previously treated lung cancer and suspected nodal metastases (defined as nodal enlargement on CT>10 mm in the short axis or abnormal FDG avidity on PET-CT) were included. Results:The sensitivity of EBUS-TBNA, on a per patient and per lymph node basis, was 91.4% and 91.8%, respectively (CI, 80.8%-96.5%). The corresponding NPV was 87.5% and 89.7%, respectively (CI, 76.4%-95.9%). There were no major complications and 3 (5.4%) minor complications. From the malignant EBUS-TBNA samples, the NSCLC-NOS rate was 3.2% and adequate tissue for molecular testing was provided in 100% of the cases (16/16). Conclusions:EBUS-TBNA is a safe and highly effective diagnostic procedure in suspected nodal metastases after previous treatment for lung cancer. The sensitivity and NPV are equivalent to EBUS-TBNA in the diagnosis of “new” lung cancer.

Development of cryptogenic fibrosing alveolitis during pregnancy.

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