ALK immunohistochemistry is highly sensitive and specific for the detection of ALK translocated lung adenocarcinomas: lessons from an audit of lung cancer molecular testing.

Background The approval of novel targeted treatments for epidermal growth factor receptor (EGFR)-positive and anaplastic lymphoma kinase (ALK)-positive non-small cell lung cancer has led to the increased requirement for mutation testing. Results We report our experience of ALK testing with immunohistochemistry (IHC) and fluorescence in-situ hybridisation (FISH) and present the prevalence of EGFR, Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) and ALK mutations. From January 2011 to May 2014, we found mutation rates of EGFR, KRAS and ALK to be 10.4% (67/643), 35.8% (86/240) and 2.3% (7/304), respectively. ALK-rearrangements were found to be associated with never smokers (p < 0.001) and younger patients (≤ 50 years old) (p < 0.001). ALK IHC protein expression in tumour cells is 100% sensitive (7 IHC+/7 FISH+) and 96.6% specific (113 IHC-/117 FISH-) for ALK-rearrangements by FISH. ALK-rearranged tumours were wildtype for EGFR and KRAS. Conclusion Our findings support the use of ALK protein expression and KRAS mutation testing as part of the molecular diagnostic algorithm for lung adenocarcinomas.

Isolated mediastinal lymphadenopathy - performance of EBUS-TBNA in clinical practice.

Background Isolated mediastinal lymphadenopathy is an increasingly common finding as a result of the increasing use of cross-sectional thoracic imaging. We investigated the performance of endobronchial ultrasoundguided transbronchial needle-aspiration (EBUS-TBNA) in establishing a pathological diagnosis in patients with isolated mediastinal lymphadenopathy. Methods We retrospectively analysed all consecutive EBUS-TBNA examinations performed over a 4-year period at a single tertiary referral centre. Final diagnoses were made using pathology reports, correlated with clinical features and the results of any other investigations. Results In total, 126 EBUS-TBNA examinations were performed to investigate isolated mediastinal lymphadenopathy. A positive pathological diagnosis was made following EBUSTBNA in 54 cases (43%). When the results of further investigations and variable radiological follow up were included, the final sensitivity of EBUS-TBNA for making a diagnosis in isolated mediastinal lymphadenopathy was 80% (95% CI 69%-89%). Conclusions This study confirms that EBUS-TBNA has acceptable sensitivity for detecting both benign and malignant pathologies underlying isolated mediastinal lymphadenopathy.

James Craufurd Gregory, 19th century Scottish physicians, and the link between occupation as a coal miner and lung disease.

By the mid-19th century about 200,000 miners were employed in a UK coal mining industry still growing with the advances of the Industrial Revolution. Coal miners were long known to suffer poor health but the link to inhaling dust in the mines had not been made. In 1813 George Pearson was the first to suggest that darkening of lungs seen in normal individuals as they aged was caused by inhaled soot from burning oil, candles and coal, which were the common domestic sources of heat and light. In 1831 Dr James Craufurd Gregory first described black pigmentation and disease in the lungs of a deceased coal miner and linked this to pulmonary accumulation of coal mine dust. Gregory hypothesised that the black material seen at autopsy in the collier's lungs was inhaled coal dust and this was confirmed by chemical analysis carried out by Professor Sir Robert Christison. Gregory suggested that coal dust was the cause of the disease and warned physicians in mining areas to be vigilant for the disease. This first description of what came to be known as 'coal worker's pneumoconiosis' sparked a remarkable intellectual effort by physicians in Scotland, culminating in a large body of published work that led to the first understandings of this disease and its link to coalblackened lungs. This paper sets out the history of the role of Scottish physicians in gaining this understanding of coal worker's pneumoconiosis. It describes Gregory's case and the lung - recently discovered in the pathology collection of the Surgeons' Hall Museums, Edinburgh, where it has lain unnoticed for over 180 years - on which Gregory based his landmark paper.

Death in the New Town: Edinburgh's hidden story of stonemasons' silicosis.

The building of the Edinburgh New Town, from the mid-18th to the mid-19th centuries, was a major advance in harmonious and elegant town planning. However, there is anecdotal evidence that it led to the occurrence of an epidemic of silicosis/tuberculosis among the stonemasons. We have reviewed contemporary accounts of the episode and early records of the understanding of silicosis. We have also studied the lung of a contemporary stonemason, preserved in the museum of the Royal College of Surgeons of Edinburgh, and confirmed the presence of silico-tuberculosis in it. The evidence shows that a major epidemic did occur, caused by a combination of factors. The size of the undertaking attracted many stonemasons to Edinburgh over a period of almost 100 years, intensively cutting and dressing stone. The principal stone worked was a very high-quartz sandstone, derived from the local Craigleith quarry, having properties that made it desirable for prestige buildings. However, even before the construction of the New Town, Craigleith sandstone was notorious for its dustiness and the Edinburgh stonemasons worked the stone in unventilated sheds. Stonemasons appeared to be aware of the risk of their trade, but little was known about preventive measures. It appears it was assumed that the risks to stonemasons disappeared after the Craigleith quarry closed, the employers emphasising (without evidence) the lack of health risks in other quarries, and the tragic episode appears to have been forgotten. However, we point to the continuing occurrence of silicosis among stonemasons to the present day; the importance of remembering such episodes is stressed lest the lessons of the past be forgotten.

A new classification of glenoid bone loss to help plan the implantation of a glenoid component before revision arthroplasty of the shoulder.

AIMS: Glenoid bone loss can be a challenging problem when revising a shoulder arthroplasty. Precise pre-operative planning based on plain radiographs or CT scans is essential. We have investigated a new radiological classification system to describe the degree of medialisation of the bony glenoid and that will indicate the amount of bone potentially available for supporting a glenoid component. It depends on the relationship between the most medial part of the articular surface of the glenoid with the base of the coracoid process and the spinoglenoid notch: it classifies the degree of bone loss into three types. It also attempts to predict the type of glenoid reconstruction that may be possible (impaction bone grafting, structural grafting or simple non-augmented arthroplasty) and gives guidance about whether a pre-operative CT scan is indicated. PATIENTS AND METHODS: Inter-method reliability between plain radiographs and CT scans was assessed retrospectively by three independent observers using data from 39 randomly selected patients. Inter-observer reliability and test-retest reliability was tested on the same cohort using Cohen's kappa statistics. Correlation of the type of glenoid with the Constant score and its pain component was analysed using the Kruskal-Wallis method on data from 128 patients. Anatomical studies of the scapula were reviewed to explain the findings. RESULTS: Excellent inter-method reliability, inter-observer and test-retest reliability were seen. The system did not correlate with the Constant score, but correlated well with its pain component. TAKE HOME MESSAGE: Our system of classification is a helpful guide to the degree of glenoid bone loss when embarking on revision shoulder arthroplasty.

Acromioclavicular joint reconstruction using the LockDown synthetic implant: a study with cadavers.

Dislocation of the acromioclavicular joint is a relatively common injury and a number of surgical interventions have been described for its treatment. Recently, a synthetic ligament device has become available and been successfully used, however, like other non-native solutions, a compromise must be reached when choosing non-anatomical locations for their placement. This cadaveric study aimed to assess the effect of different clavicular anchorage points for the Lockdown device on the reduction of acromioclavicular joint dislocations, and suggest an optimal location. We also assessed whether further stability is provided using a coracoacromial ligament transfer (a modified Neviaser technique). The acromioclavicular joint was exposed on seven fresh-frozen cadaveric shoulders. The joint was reconstructed using the Lockdown implant using four different clavicular anchorage points and reduction was measured. The coracoacromial ligament was then transferred to the lateral end of the clavicle, and the joint re-assessed. If the Lockdown ligament was secured at the level of the conoid tubercle, the acromioclavicular joint could be reduced anatomically in all cases. If placed medial or 2 cm lateral, the joint was irreducible. If the Lockdown was placed 1 cm lateral to the conoid tubercle, the joint could be reduced with difficulty in four cases. Correct placement of the Lockdown device is crucial to allow anatomical joint reduction. Even when the Lockdown was placed over the conoid tubercle, anterior clavicle displacement remained but this could be controlled using a coracoacromial ligament transfer.

The biological response to a failed extra-articular polyester ligament used for AC Joint reconstruction at the shoulder girdle: a retrieval analysis of five cases.

The LockDown device (previously called Surgilig) is a braided polyester mesh which is mostly used to reconstruct the dislocated acromioclavicular joint. More than 11,000 have been implanted worldwide. Little is known about the tissue reaction to the device nor to its wear products when implanted in an extra-articular site in humans. This is of importance as an adverse immunological reaction could result in osteolysis or damage to the local tissues, thereby affecting the longevity of the implant. We analysed the histology of five LockDown implants retrieved from five patients over the last seven years by one of the senior authors. Routine analysis was carried out in all five cases and immunohistochemistry in one. The LockDown device acts as a scaffold for connective tissue which forms an investing fibrous pseudoligament. The immunological response at the histological level seems favourable with a limited histiocytic and giant cell response to micron-sized wear particles. The connective tissue envelope around the implant is less organised than a native ligament.

A cautionary lesson on the use of targeted methods for EGFR mutation analysis: a case report.

Epidermal growth factor receptor (EGFR) mutation analysis is recommended for lung cancer patients prior to the prescription of first-line EGFR tyrosine kinase inhibitors in order to predict response to treatment. There are many methods available to identify mutations in the EGFR gene; a large number of clinical laboratories use the therascreen EGFR RGQ PCR kit (Qiagen). We report a case where this kit detected an exon 19 deletion, predicting sensitivity to tyrosine kinase inhibitors (TKIs), which on further analysis was found to be a 2 bp indel (c.2239_2240delinsCC, p.(Leu747Pro)). Two of four published cases with this mutation were found to be associated with resistance to EGFR TKI. The sample was also tested using two other commercial kits, one of which indicated a deletion. This is a rare mutation making the erroneous detection of a deletion unlikely; however, it is important that clinical laboratories are aware of the potential failings of two commercial kits for EGFR mutation analysis.

Evaluation of adjunct immunohistochemistry on reporting patterns of non-small cell lung carcinoma diagnosed histologically in a regional pathology centre.

Morphological sub-classification of non-small cell carcinoma in small biopsy specimens presents difficulties for pathologists and recent advances in chemotherapy have resulted in increased pressure to more robustly differentiate between squamous carcinoma and adenocarcinoma. The results of audits examining classification of non-small cell lung carcinoma by pathologists working in a specialist team within a regional centre and the effect of introducing adjunct immunohistochemistry into the reporting pathway are presented. It is concluded that the use of a limited immunohistochemical panel substantially reduces the number of cases when a specific cell type cannot be identified or 'favoured' (34% to 6%) and that the classification obtained correlates well with that found in subsequent resection specimens. In addition the introduction of immunohistochemistry substantially reduces the variability in reporting practice between pathologists.

Cytological recognition of herpes simplex virus infection in bronchoscopic samples from the respiratory tract.

Cytological features suggesting herpes simplex virus (HSV) infection in samples obtained at bronchoscopy have been described only very rarely in routinely processed samples. We report four cases where evidence of HSV infection was identified morphologically in samples processed using thin-layer techniques, with polymerase chain reaction confirmation of the presence of virus in three cases. We suggest that the increased morphological clarity provided by this technique for processing these cytology samples may result in the morphological features of viral infection being seen more frequently. Pathologists reporting such samples need to be aware of this possibility in order to avoid potential misinterpretations. In addition, however, respiratory and intensive care physicians unused to receiving cytology reports indicating 'HSV infection' need to be aware that the significance is uncertain and in most cases it is likely to indicate the reactivation of a latent infection.

Accuracy of cell typing in nonsmall cell lung cancer by EBUS/EUS-FNA cytological samples.

Endoscopic ultrasound-guided transbronchial or transoesophageal lymph node aspiration is increasingly used as a method of diagnosing nonsmall cell carcinoma. Data validating the accuracy of cell typing of nonsmall cell carcinoma using these cytological samples has not been assessed. 23 samples were identified in Edinburgh, UK and a further 25 in Cambridge, UK, with matching histological samples. The morphological cell type, as assessed on the cytological preparations and cell blocks, was recorded and immunohistochemical staining was performed, where possible, as an adjunct. The final cell type, as assessed by morphology with or without immunohistochemistry, was correlated with that reported in the paired histological samples. Cell blocks with tumour were available in 39 out of 48 cases. The accuracy of cell typing when no cell block was available was four out of nine cases. This increased to 25 out of 39 when a cell block was available, increasing to 33 out of 39 with the addition of immunohistochemistry. The overall accuracy of classification was 37 out of 48 cases. Accurate cell typing of nonsmall cell carcinomas can be performed using endoscopically derived fine-needle aspirates. The importance of obtaining sufficient material for the production of cell blocks is critical in allowing optimal assessment.

Sarcoidosis complicating treatment with natalizumab for Crohn's disease.

Natalizumab is a humanised monoclonal antibody targeting the lymphocyte adhesion molecule a4 integrin, with proven efficacy in multiple sclerosis (MS) and Crohn's disease (CD). The development of sarcoidosis with extrapulmonary involvement is reported in two patients with refractory CD who had received maintenance therapy with natalizumab. This complication has not been previously reported. It is hypothesised that the effect of natalizumab in altering lymphocyte mucosal trafficking may underlie the development of sarcoidosis in these patients.

Catastrophic injuries in the Olympic styles of wrestling in Iran.

OBJECTIVES: In this study, a profile of direct catastrophic injuries in international styles of wrestling was developed, and the possible risk factors were described. DESIGN: Survey and retrospective review. SETTING: Catastrophic injuries that occurred in wrestling clubs in Iran from July 1998 to June 2005 were identified by contacting several sources. The cases were retrospectively reviewed. RESULTS: The injuries included were 29 direct injuries (12 fatalities, 11 non-fatal and 6 serious).The injury rate was 1.99 direct catastrophic injuries/100 000 wrestlers/year. The majority of direct injuries occurred during training sessions, with a trend towards more injuries in the low-weight and middle-weight classes and those who were competing at high performance and experience levels. The takedown position, especially for the attacking wrestler who faces a counterattack, was the most common activity at the time of injury. A list of risk factors was suggested, of which "performing the wrestling manoeuvre incorrectly", "inappropriate management of the injury", "lack of the coach supervision", "mat problems" and "lack of restraining the wrestlers in a precarious position" were the most common risk factors. CONCLUSIONS: Catastrophic wrestling injuries are rare and preventable. Coaches have an essential role in the prevention of these injuries.

Orthopaedic training experience in the UK and Ireland: an analysis using the eLogbook.

The eLogbook is used to collect and collate the operative experience of every orthopaedic trainee in the UK and Ireland. We describe the project and discuss the national data now emerging on elective and trauma training.

Diagnosis and staging of lung and pleural malignancy - an overview of tissue sampling techniques and the implications for pathological assessment.

Malignant diseases of the lungs and pleura are common causes of morbidity and mortality throughout the developed world. Determining the appropriate treatment strategies for an individual patient requires a multidisciplinary approach integrating input from many disciplines including pathology. In this overview, we discuss diagnosis of lung and pleural malignancy from the pathologist's perspective, placing particular emphasis on methods available to obtain material for pathological assessment, and their implications for diagnosis and provision of information to guide patient management.

A single ThinPrep slide may not be representative in all head and neck fine needle aspirate specimens.

OBJECTIVES: Ideally, head and neck aspiration should be performed by trained aspirators within the setting of a one-stop clinic, where smeared material is available for immediate assessment. However, this may not always be possible for practical reasons and the use of liquid-based techniques in head and neck cytology is increasing. Although liquid-based cytology has been extensively validated for use in gynaecological cytology, no studies have investigated whether or not a single ThinPrep slide is representative for head and neck aspirate specimens. We performed a prospective audit of head and neck fine needle aspiration specimens processed by the ThinPrep method to investigate whether a single ThinPrep slide was representative. METHODS: A prospective audit of 115 consecutive head and neck aspirates was carried out. A single ThinPrep slide was prepared and a diagnosis recorded. The remainder of the specimen was then spun down and prepared as a cell block. The ThinPrep and cell block diagnoses were compared. RESULTS: In 36 cases (31%), the cell block provided additional information that contributed to the diagnosis. In 14 (12%), the cell block was regarded as essential to the diagnosis. CONCLUSIONS: A single ThinPrep slide may not provide representative diagnostic material in all head and neck aspirates. This should be taken into consideration when contemplating the use of liquid-based methods for non-gynaecological cytology.

Non-small-cell lung cancer dimensions: CT-pathological correlation and interobserver variation.

The aim of the study was to identify the most accurate CT window level setting for the measurement of non-small-cell lung cancer to optimise CT planning for radiotherapy treatment. 27 patients who underwent resection for non-small-cell lung cancer in a single institution were studied. The maximal superior-inferior, anteroposterior and mediolateral dimensions of the resected tumours were measured by a consultant pathologist. Two radiologists made corresponding measurements using pre-operative CT scans independently of each other and of the pathologist's findings. The measurements were obtained using four different CT window settings. The mean pathological size of the superior-inferior tumours, the anteroposterior tumours and the mediolateral tumours was 32 mm, 28 mm and 25 mm, respectively. A total of 648 CT measurements were taken, of which 321 were within +/-5 mm of the pathological size (49.5%). There was significant interobserver variability between the two radiologists. There was poor correlation between the pathological and radiological measurements of tumour size. Significant interobserver variability was noted between the two radiologists and no window setting could be identified as being superior in accurately assessing the tumour size.

Trauma experience in the UK and Ireland: analysis of orthopaedic training using the FHI eLogbook.

Surgical trainees routinely provide evidence of their training and operative experience for assessment. National comparative data on the number of procedures performed during training was previously unavailable in the UK. Since 2003 every trainee in Trauma and Orthopaedics (T&O) in the UK and Ireland has submitted data recording their operative experience electronically via the Faculty of Health Informatics (FHI) eLogbook. This provides detailed data on trainee, trainer, hospital and training programme performance. This data has been analysed for trauma surgery. By March 2007 there were 1053 T&O Specialist Registrars with operations logged. Trauma operations performed and uploaded during the previous 3 years have been included. Each trainee's work is analysed by 'year-in-training' (YIT, 1-6). Data on levels of supervision and potentially missed opportunities (where the trainee was present but assisted rather than performed the operation) was analysed. The mean number of trauma operations performed annually by trainees was 109, 120, 110, 122, 98 and 84 (total 643) for YIT 1-6, respectively. 22% of the operations at which a trainee was present were potentially missed opportunities. A high level of experience is gained in hip fracture surgery (121 operations performed), intramedullary nailing (38) and ankle (47) stabilisation over the 6 years of training. However, the mean number of tendon repairs (18), tension band wires (13), external fixators (12) and children's supracondylar fracture procedures (9) performed is low. We also report figures for complex fracture stabilisation. The eLogbook remains a powerful tool which can provide accurate information to support in-depth analysis of trainees, trainers, and training programmes. Based on this analysis, we suggest 'standard setting' to identify trainees performing fewer operations than required during their training. We have also established a baseline which can be used to identify the consequences of changes to length of training and working hours.