Radiological-pathological correlation in diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH): imaging and histopathology.

AIM: To review histologically confirmed diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH) cases and carry out a detailed pathological-radiological correlation to see if computed tomography (CT) can be used to confidently identify DIPNECH. MATERIALS AND METHODS: Twenty-three histologically confirmed DIPNECH patients in the shared database of two NHS Trusts were reviewed. CT images were reviewed by two independent radiologists, each of them with >10 years of experience in thoracic imaging. All histological specimens were reviewed by a single pathologist with >25 years of experience. The diagnosis of DIPNECH was made according to the current World Health Organization (WHO) definition included in the WHO 2015 classification of pulmonary tumours. The results on histology were compared to the presence of nodules and air trapping on CT. Demographic information and, when available, molecular imaging studies and pulmonary function tests were also considered. RESULTS: There are prototypal clinical and radiological findings reflecting the presence of underlying histological DIPNECH: middle-aged women with multiple small and scattered nodules due to the clustering and proliferation of neuroendocrine cells. At least one larger, dominant, lung nodule reflecting a carcinoid tumour is very common and mosaic attenuation/air trapping is seen approximately in 50% of cases in inspiratory scans. Airflow obstruction is rarely associated with histological bronchial or peribronchial fibrosis, which suggests other mechanisms must be involved in its development. CONCLUSION: CT can be used to predict pathological DIPNECH in the appropriate clinical setting. It is important to consider DIPNECH to avoid overdiagnosis of more sinister conditions such as lung cancer or metastases.

Pathologist-initiated reflex testing for biomarkers in non-small-cell lung cancer: expert consensus on the rationale and considerations for implementation.

Biomarker tests in lung cancer have been traditionally ordered by the treating oncologist upon confirmation of an appropriate pathological diagnosis. The delay this introduces prolongs yet further what is already a complex, multi-stage, pre-treatment pathway and delays the start of first-line systemic treatment, which is crucially informed by the results of such analysis. Reflex testing, in which the responsibility for testing for an agreed range of biomarkers lies with the pathologist, has been shown to standardise and expedite the process. Twelve experts discussed the rationale and considerations for implementing reflex testing as standard clinical practice.

Clinical and molecular practice of European thoracic pathology laboratories during the COVID-19 pandemic. The past and the near future.

BACKGROUND: This study evaluated the consequences in Europe of the COVID-19 outbreak on pathology laboratories orientated toward the diagnosis of thoracic diseases. MATERIALS AND METHODS: A survey was sent to 71 pathology laboratories from 21 European countries. The questionnaire requested information concerning the organization of biosafety, the clinical and molecular pathology, the biobanking, the workload, the associated research into COVID-19, and the organization of education and training during the COVID-19 crisis, from 15 March to 31 May 2020, compared with the same period in 2019. RESULTS: Questionnaires were returned from 53/71 (75%) laboratories from 18 European countries. The biosafety procedures were heterogeneous. The workload in clinical and molecular pathology decreased dramatically by 31% (range, 3%-55%) and 26% (range, 7%-62%), respectively. According to the professional category, between 28% and 41% of the staff members were not present in the laboratories but did teleworking. A total of 70% of the laboratories developed virtual meetings for the training of residents and junior pathologists. During the period of study, none of the staff members with confirmed COVID-19 became infected as a result of handling samples. CONCLUSIONS: The COVID-19 pandemic has had a strong impact on most of the European pathology laboratories included in this study. Urgent implementation of several changes to the organization of most of these laboratories, notably to better harmonize biosafety procedures, was noted at the onset of the pandemic and maintained in the event of a new wave of infection occurring in Europe.

ALK immunohistochemistry positive, FISH negative NSCLC is infrequent, but associated with impaired survival following treatment with crizotinib.

OBJECTIVE: Metastasized non-small cell lung cancer (NSCLC) with an anaplastic lymphoma kinase (ALK) rearrangement is usually sensitive to a range of ALK-tyrosine kinase inhibitors. ALK-positive NSCLC have been identified in pivotal phase III trials with fluorescence in situ hybridization (ALK FISH+). These tumors are also expressing the fusion product (ALK immunohistochemistry (IHC)+). However, discrepant cases occur, including ALK IHC + FISH-. The aim of this study was to collect ALK IHC + cases and compare within this group response to crizotinib treatment of ALK FISH + cases with ALK FISH- cases. MATERIALS AND METHODS: In this European prospective multicenter research study patients with Stage IV ALK IHC + NSCLC treated with crizotinib were enrolled. Tumor slides were validated centrally for ALK IHC and ALK FISH. RESULTS: Registration of 3523 ALK IHC tests revealed a prevalence of 2.7% (n = 94) ALK IHC + cases. Local ALK FISH analysis resulted in 48 concordant (ALK IHC+/FISH+) and 16 discordant (ALK IHC+/FISH-) cases. Central validation revealed 37 concordant and 7 discordant cases, 5 of which had follow-up. Validation was hampered by limited amount of tissue in biopsy samples. The PFS at 1 year for ALK concordant and discordant was 58% and 20%, respectively (HR = 2.4; 95% CI: 0.78-7.3; p = 0.11). Overall survival was significantly better for concordant cases than discordant cases after central validation (HR=4.5; 95% CI= 1.2-15.9; p=0.010. CONCLUSION: ALK IHC + FISH- NSCLC is infrequent and associated with a worse outcome on personalized treatment. A suitable predictive testing strategy may be to screen first with IHC and then confirm with FISH instead of considering ALK IHC equivalent to ALK FISH according to the current guidelines.

UK Lung Cancer RCT Pilot Screening Trial: baseline findings from the screening arm provide evidence for the potential implementation of lung cancer screening.

BACKGROUND: Lung cancer screening using low-dose CT (LDCT) was shown to reduce lung cancer mortality by 20% in the National Lung Screening Trial. METHODS: The pilot UK Lung Cancer Screening (UKLS) is a randomised controlled trial of LDCT screening for lung cancer versus usual care. A population-based questionnaire was used to identify high-risk individuals. CT screen-detected nodules were managed by a pre-specified protocol. Cost effectiveness was modelled with reference to the National Lung Cancer Screening Trial mortality reduction. RESULTS: 247 354 individuals aged 50-75 years were approached; 30.7% expressed an interest, 8729 (11.5%) were eligible and 4055 were randomised, 2028 into the CT arm (1994 underwent a CT). Forty-two participants (2.1%) had confirmed lung cancer, 34 (1.7%) at baseline and 8 (0.4%) at the 12-month scan. 28/42 (66.7%) had stage I disease, 36/42 (85.7%) had stage I or II disease. 35/42 (83.3%) had surgical resection. 536 subjects had nodules greater than 50 mm(3) or 5 mm diameter and 41/536 were found to have lung cancer. One further cancer was detected by follow-up of nodules between 15 and 50 mm(3) at 12 months. The baseline estimate for the incremental cost-effectiveness ratio of once-only CT screening, under the UKLS protocol, was £8466 per quality adjusted life year gained (CI £5542 to £12 569). CONCLUSIONS: The UKLS pilot trial demonstrated that it is possible to detect lung cancer at an early stage and deliver potentially curative treatment in over 80% of cases. Health economic analysis suggests that the intervention would be cost effective-this needs to be confirmed using data on observed lung cancer mortality reduction. TRIAL REGISTRATION: ISRCTN 78513845.

A microRNA-based prediction algorithm for diagnosis of non-small lung cell carcinoma in minimal biopsy material.

BACKGROUND: Diagnosis is jeopardised when limited biopsy material is available or histological quality compromised. Here we developed and validated a prediction algorithm based on microRNA (miRNA) expression that can assist clinical diagnosis of lung cancer in minimal biopsy material to improve clinical management. METHODS: Discovery utilised Taqman Low Density Arrays (754 miRNAs) in 20 non-small cell lung cancer (NSCLC) tumour/normal pairs. In an independent set of 40 NSCLC patients, 28 miRNA targets were validated using qRT-PCR. A prediction algorithm based on eight miRNA targets was validated blindly in a third independent set of 47 NSCLC patients. The panel was also tested in formalin-fixed paraffin-embedded (FFPE) specimens from 20 NSCLC patients. The genomic methylation status of highly deregulated miRNAs was investigated by pyrosequencing. RESULTS: In the final, frozen validation set the panel had very high sensitivity (97.5%), specificity (96.3%) and ROC-AUC (0.99, P=10(-15)). The panel provided 100% sensitivity and 95% specificity in FFPE tissue (ROC-AUC=0.97 (P=10(-6))). DNA methylation abnormalities contribute little to the deregulation of the miRNAs tested. CONCLUSION: The developed prediction algorithm is a valuable potential biomarker for assisting lung cancer diagnosis in minimal biopsy material. A prospective validation is required to measure the enhancement of diagnostic accuracy of our current clinical practice.

Spinal cord injury-related chronic pain in victims of the 2008 Sichuan earthquake: a prospective cohort study.

STUDY DESIGN: Prospective cohort. OBJECTIVES: To characterize spinal cord injury (SCI)-related pain and treatment in victims of the 2008 Sichuan earthquake. SETTING: Mianzhu County, China. METHODS: Twenty-six patients who sustained SCI in the 2008 Sichuan earthquake and who were treated in the same hospital were enrolled. Data was collected on pain severity with a visual analog scale, depression with Patient Health Questionnaire-9, quality of life (QoL) with World Health Organization Quality of Life-BREF and social participation with the Craig Hospital Handicap Assessment and Reporting Technique Short Form at three assessment points. Detailed pain descriptions including therapeutic interventions were elicited at the fourth assessment. Pain determinants were analyzed with a longitudinal Tobit regression, and Pearson's correlations of pain severity with depression, QoL and social participation stratified by measurement point were calculated. RESULTS: SCI-related pain was highly prevalent and prevalence of neuropathic pain was nearly twice that of nociceptive pain. Most patients reported pain since the onset and severity was not significantly reduced over time. Cervical injury, complete lesions and education level were significant pain determinants. Depression and QoL scores were highly correlated with pain at the first two assessments points but not at the third measurement. Most patients did not seek treatment because they regarded pain as either a normal condition after SCI or were afraid of drug dependency. CONCLUSION: This initial longitudinal assessment and characterization of SCI-related pain in earthquake victims provides a foundation for further exploration of the biological and psychosocial determinants of pain severity and of the correlation of chronic pain with other outcomes of interest in this population. Patient pain-treatment-seeking behavior and therapeutic interventions should be evaluated concurrently.

Medical rehabilitation of spinal cord injury following earthquakes in rehabilitation resource-scarce settings: implications for disaster research.

STUDY DESIGN: Narrative literature review. OBJECTIVES: To (1) summarize epidemiological and scientific research on spinal cord injury (SCI) populations from three severe earthquakes (EQs) in rehabilitation resource-scarce settings; (2) summarize SCI rehabilitation services by local and foreign providers in response to these EQs and (3) provide implications including research gaps for a supporting global scientific research agenda. SETTING: International. METHODS: A literature review was conducted using PubMed to identify epidemiological studies reporting data on SCI survivors of the 2005 Kashmir EQ in Pakistan, the Sichuan EQ of 2008 in China and the 2010 Haiti EQ. A follow-up review on the SCI rehabilitation services provided by local and foreign providers in response to these EQs was also performed. RESULTS: Review of the scientific literature revealed the qualitative trends in focused EQ victim epidemiological data, including SCI classification and types of medical complications. Selected EQ country narratives showed that post-disaster SCI rehabilitation services were expanded by adapting local resources with international assistance to manage the significant numbers of SCI survivors. The resulting SCI research was limited. CONCLUSION: A global disaster research agenda for SCI in EQs in rehabilitation resource-scarce settings is needed to strengthen the evidence base for improvement of clinical management and outcomes for SCI EQ survivors. Expansion of this limited narrative review into a systematic review to identify additional research gaps is a proposed next step. Effective disaster setting data management and research collaborations of foreign and local SCI disability and rehabilitation stakeholders will be required for agenda implementation.

A massive pleural-based tumour: the challenge of diagnosis.

Liposarcomas of the mediastinum and chest wall have been previously described; however, primary pleural liposarcoma is extremely rare. We report an exceedingly rare case of a well-differentiated sclerosing pleural liposarcoma in a 47-year-old male that was resected. We emphasise the importance of careful inspection of the origin of these tumours to allow accurate diagnosis.

Large pulmonary masses containing varicose veins: a rare presentation of benign metastasising leiomyomas.

A 48-year-old woman presented with cough and chest pain. A chest radiograph and CT scans showed bilateral lung masses containing massive venous varices. A core biopsy specimen revealed benign metastasising leiomyoma with strong expression of progesterone receptors. A review of her medical history revealed a hysterectomy 11 years earlier. The lung masses showed significant reduction in size after induction of artificial menopause, although the pulmonary varices persisted.

EUELC project: a multi-centre, multipurpose study to investigate early stage NSCLC, and to establish a biobank for ongoing collaboration.

The European Early Lung Cancer (EUELC) project aims to determine if specific genetic alterations occurring in lung carcinogenesis are detectable in the respiratory epithelium. In order to pursue this objective, nonsmall cell lung cancer (NSCLC) patients with a very high risk of developing progressive lung cancer were recruited from 12 centres in eight European countries: France, Germany, southern Ireland, Italy, the Netherlands, Poland, Spain and the UK. In addition, NSCLC patients were followed up every 6 months for 36 months. A European Bronchial Tissue Bank was set up at the University of Liverpool (Liverpool, UK) to optimise the use of biological specimens. The molecular-pathological investigations were subdivided into specific work packages that were delivered by EUELC Partners. The work packages encompassed mutational analysis, genetic instability, methylation profiling, expression profiling utilising immunohistochemistry and chip-based technologies, as well as in-depth analysis of FHIT and RARbeta genes, the telomerase catalytic subunit hTERT and genotyping of susceptibility genes in specific pathways. The EUELC project engendered a tremendous collaborative effort, and it enabled the EUELC Partners to establish protocols for assessing molecular biomarkers in early lung cancer with the view to using such biomarkers for early diagnosis and as intermediate end-points in future chemopreventive programmes.

Interobserver variation in the classification of thymic tumours--a multicentre study using the WHO classification system.

AIMS: To test the reproducibility of the current World Health Organization (WHO) classification of thymic epithelial tumours and to determine the level of interobserver variation within a group of pathologists, all with experience and expertise in thoracic pathology. METHODS AND RESULTS: Ninety-five thymic tumours were circulated to a group of 17 pathologists in the UK and The Netherlands over a 1-year period. Participants were asked to classify them according to WHO criteria. The diagnoses were subjected to statistical analysis and kappa values calculated. The overall level of agreement was moderate (kappa 0.45). When the categories were reduced in number by creating two groups, (A + AB + B1 + B2 and B3 + C), the level of agreement increased to 0.62. An alternative grouping (A + AB + B1 and B2 + B3 + C) increased it slightly further. The best agreement was in tumour types A and AB. Difficulties arose in distinguishing B1 tumours from B2 tumours and B2 tumours from B3 tumours. CONCLUSIONS: Although the WHO system describes a number of well-defined tumour types with clear diagnostic criteria, the overall level of agreement was moderate and improved if some groups were amalgamated.

Effect of exercise training on quality of life in multiple sclerosis: a meta-analysis.

Using meta-analytic procedures, this study examined the overall effect of exercise training interventions on quality of life (QOL) among individuals with multiple sclerosis (MS). We searched MEDLINE, PSYCHINFO and CURRENT CONTENTS PLUS for the period of 1960 to November 2006 using the key words exercise, physical activity and physical fitness in conjunction with QOL and MS. We further conducted a manual search of bibliographies of the retrieved papers as well as literature reviews and contacted study authors about additional studies. Twenty-five journal articles were located and reviewed, and only 13 provided enough data to compute effect sizes expressed as Cohen's d. One hundred and nine effect sizes were retrieved from the 13 studies with 484 MS participants and yielded a weighted mean effect size of g=0.23 (95% CI=0.15, 0.31). There were larger effects associated with MS-specific measures of QOL and fatigue as an index of QOL. The nature of the exercise stimulus further influenced the magnitude of the mean effect size. The cumulative evidence supports that exercise training is associated with a small improvement in QOL among individuals with MS.

Expression of p53, pRB, and p16 in lung tumours: a validation study on tissue microarrays.

Tissue microarrays have been created from 326 lung tumours, including 173 squamous cell carcinomas (SCCs) and 132 adenocarcinomas (ADs). In order to evaluate the usefulness of this microarray series, the expression of p53, p16, and Rb proteins was compared by immunohistochemistry on both the tissue microarrays and the corresponding whole sections for all 326 tumours. The presence of replicate punches improved both the yield and the concordance of data relative to the whole section results, so that the consensus score from the replicates agreed with the whole section result in more than 90% of informative tumours. The large number of tumours in this series also allowed significant differences in protein expression patterns to be detected between SCC and AD, the major subtypes of non-small cell lung carcinoma (NSCLC). SCC had higher levels of p53 staining (67% vs 52% in AD) and substantially increased p16 loss (SCC 75%, AD 53%) combined with greater retention of pRB expression (SCC 86% vs 67% in AD). The strong inverse correlation between p16 and pRB seen in SCC was essentially absent in AD. This study represents the largest single immunohistochemical survey of protein expression for p53, p16, and RB in NSCLCs.

TP53 mutations in malignant and premalignant Barrett's esophagus.

In order to improve the efficacy of endoscopic surveillance of Barrett's esophagus, markers of neoplastic progression in addition to dysplasia are required. The aim of the present study was to assess TP53 mutational analysis as a method of identifying patients with Barrett's esophagus who are at greatest risk of adenocarcinoma, for whom endoscopic surveillance is most appropriate. TP53 mutational analysis was initially performed on premalignant and malignant tissue from 30 patients undergoing esophagectomy for adenocarcinoma, and on premalignant biopsies from 48 patients participating in a Barrett's surveillance program. Surveillance patients were followed up endoscopically and histologically for a median of 5 years following TP53 assessment. Mutational analysis was performed by single-strand conformation polymorphism analysis and direct DNA sequencing. TP53 mutations were detected in 10 of 30 esophageal adenocarcinomas, and were more common in well-differentiated carcinomas. An identical TP53 mutation was detected in carcinoma and adjacent dysplasia. Two patients with premalignant Barrett's esophagus had TP53 mutations and one of these patients developed adenocarcinoma on follow up whilst the other has not yet progressed beyond metaplasia. No patient without TP53 mutation developed high-grade dysplasia or adenocarcinoma. TP53 mutations are detected in 33% of esophageal adenocarcinomas and in 4% of premalignant Barrett's esophagus in patients undergoing endoscopic surveillance. TP53 mutation can be detected before the development of high-grade dysplasia or carcinoma, and may be useful in stratifying the risk of adenocarcinoma in patients with Barrett's esophagus.

Allelic imbalance at the DNA mismatch repair loci, hMSH2, hMLH1, hPMS1, hPMS2 and hMSH3, in squamous cell carcinoma of the head and neck.

BACKGROUND: Squamous cell carcinoma of the head and neck (SCCHN) is one of the 10 most frequently occurring cancers in the world. Defective mismatch repair, as exhibited by the phenomenon of microsatellite instability, has been observed in SCCHN although no reports of mismatch repair gene mutations or altered protein expression have been published. In a variety of microsatellite instability (MSI) positive cancers where mutations in the mismatch repair (MMR) genes were not observed, allelic imbalance at the loci of the MMR genes was prevalent. OBJECTIVE: To investigate whether allelic imbalance at the MMR genetic loci contributes to the development of SCCHN. MATERIALS AND METHODS: 35 matched normal/tumour SCCHN pairs were studied using 29 microsatellite markers located within and adjacent to six known DNA mismatch repair genes. In addition, mutational analysis and protein expression of hMSH2 and hMLH1 were investigated. RESULTS AND CONCLUSIONS: We demonstrated that 36 and 17% of the analysed SCCHN specimens exhibited allele imbalance at the hMLH1 and hMSH3 genetic loci, respectively. Allelic instability at these two loci was found to be correlated with the MSI status of the SCCHN tumours. Allelic instability was found to be uncommon at the other MMR gene loci analysed. One mutation was found in hMSH2 and none in hMLH1 in this series of tumours. 23 of 24 (96%) of the examined SCCHN tumours showed reduced expression of either hMSH2 or hMCH1 genes. Allelic instability in the MMR genes, hMLH1 and hMSH3, is proposed to be involved in the aetiology of SCCHN tumours.