A TIAM1-TRIM28 complex mediates epigenetic silencing of protocadherins to promote migration of lung cancer cells.

Lung cancer is the leading cause of cancer deaths. Its high mortality is associated with high metastatic potential. Here, we show that the RAC1-selective guanine nucleotide exchange factor T cell invasion and metastasis-inducing protein 1 (TIAM1) promotes cell migration and invasion in the most common subtype of lung cancer, non-small-cell lung cancer (NSCLC), through an unexpected nuclear function. We show that TIAM1 interacts with TRIM28, a master regulator of gene expression, in the nucleus of NSCLC cells. We reveal that a TIAM1-TRIM28 complex promotes epithelial-to-mesenchymal transition, a phenotypic switch implicated in cell migration and invasion. This occurs through H3K9me3-induced silencing of protocadherins and by decreasing E-cadherin expression, thereby antagonizing cell-cell adhesion. Consistently, TIAM1 or TRIM28 depletion suppresses the migration of NSCLC cells, while migration is restored by the simultaneous depletion of protocadherins. Importantly, high nuclear TIAM1 in clinical specimens is associated with advanced-stage lung adenocarcinoma, decreased patient survival, and inversely correlates with E-cadherin expression.

Rheumatoid nodule on the anterior mitral valve leaflet.

Symptomatic cardiac rheumatoid nodules are a rare but recognized manifestation of rheumatoid arthritis. We describe the surgical management of a rheumatic nodule involving the anterior leaflet of the mitral valve.

Interrogating the precancerous evolution of pathway dysfunction in lung squamous cell carcinoma using XTABLE.

Lung squamous cell carcinoma (LUSC) is a type of lung cancer with a dismal prognosis that lacks adequate therapies and actionable targets. This disease is characterized by a sequence of low- and high-grade preinvasive stages with increasing probability of malignant progression. Increasing our knowledge about the biology of these premalignant lesions (PMLs) is necessary to design new methods of early detection and prevention, and to identify the molecular processes that are key for malignant progression. To facilitate this research, we have designed XTABLE (Exploring Transcriptomes of Bronchial Lesions), an open-source application that integrates the most extensive transcriptomic databases of PMLs published so far. With this tool, users can stratify samples using multiple parameters and interrogate PML biology in multiple manners, such as two- and multiple-group comparisons, interrogation of genes of interests, and transcriptional signatures. Using XTABLE, we have carried out a comparative study of the potential role of chromosomal instability scores as biomarkers of PML progression and mapped the onset of the most relevant LUSC pathways to the sequence of LUSC developmental stages. XTABLE will critically facilitate new research for the identification of early detection biomarkers and acquire a better understanding of the LUSC precancerous stages.

Lung squamous cell carcinoma is the second most common lung cancer. However, very little is known about how normal tissues in the lung develop in to these tumours. Like many cancers, this transformation comprises of an intermediate phase where healthy cells begin to form lesions that may (or may not) progress in to tumours. Understanding the biology of these lesions in lung squamous cell carcinoma may help clinicians detect them before they become cancerous. Knowing which genes are switched on and off during this intermediary phase can provide clues as to how these lesions form. There are already some publicly available transcriptional datasets showing the activity of tens of thousands of genes in pre-cancerous lesions extracted from patients with lung squamous cell carcinoma. But not every laboratory has the bioinformatic tools and skills required to interrogate these extensive databases. To address this, Roberts et al. built an open-source platform called XTABLE (short for Exploring Transcriptomes of Bronchial Lesions) which can analyse transcriptional datasets in multiple ways depending on the needs of the user. For instance, the tool can stratify the data into groups based on different parameters, such as the lesions potential to progress in to cancer, to see how the genes of the groups compare. It can also analyse the activity of individual genes and sets of genes involved in the same biological processes. Using XTABLE, Roberts et al. showed that a biological process linked to lung squamous cell carcinoma is also involved in the formation of pre-cancerous lesions. This suggests that molecules and genes associated with this process could potentially help scientists design prevention strategies. XTABLE will help researchers to better understand the biology of pre-cancerous lesions and how they develop in to tumours. Moreover, it will make it easier for scientists to validate their hypotheses using data collected from patients. The tool could also be useful for scientists interested in other types of lung cancers that share a similar biology.

PD-L1 testing and immunotherapy selection - early laboratory experience and its potential role in head and neck cancer management.

Anti-programmed cell death protein-1 (PD-1) therapy has been relatively recently approved in a defined context by NICE in adults in the management of recurrent and metastatic head and neck squamous cell carcinomas (HNSCC). In this context, companion diagnostic programmed cell death ligand-1 (PD-L1) testing, previously established at our center for lung and bladder tumors, was undertaken in a few head and neck cancer cases. The scope of this study was to audit the relevant PD-L1 data and integrate the findings in our current clinical practice, with a view to promote improved routine laboratory biomarkers in HNSCC. Histopathology reports documenting tumor type, PD-L1 result and type of clone/assay were included in this study. Over a 5-year period, PD-L1 testing was undertaken in 199 cancer cases, including 3 with head and neck squamous carcinoma with low focal positive staining. Immunotherapy treatment in HNSCC demonstrates a discreet but still significant improvement in the overall survival of PD-L1 positive subjects.

An evaluation of the effect of ozone therapy on tissues surrounding dental implants.

BACKGROUND: Dental implant surgery despite its growing popularity poses several challenges like include tissue inflammation, pain discomfort and tissue injury. OBJECTIVE: To evaluate the effect of ozone therapy on inflammation, pain and wound healing after implant surgery. METHODS: A clinical study was conducted on 60 systematically healthy patients- 30 patients treated with ozone (Experimental group) and 30 patients without ozone treatment (control group). In the control group osteotomy procedure was performed with saline irrigation and in the experimental group irrigation was done with ozonated water at 25 µg/mL concentration, along with ozone gas. Clinical assessment was done by evaluating C-reactive Protein (CRP) for inflammation, pain using Visual Analogue Scale (VAS) score and tissue wound healing using wound healing index. Side effects, if any, were noted. RESULTS: Postoperative increment in CRP levels was 0.10 and 0.63 mg/dl in Experimental and control groups respectively (p < 0.001). At 24-hr, 48-hr and 7 day post-operative intervals mean VAS scores for pain were significantly higher in Control group as compared to that in Experimental Group (p < 0.001). At day 7, mean VAS scores for pain were 3.50 ± 0.63 and 37.70 ± 4.17 in Experimental and Control groups respectively (p < 0.001). Mean tissue healing indices were significantly higher on Day 7 and Day 14 in Experimental Group (4.23 ± 0.43 and 4.97 ± 0.18) as compared to that in control group (3.07 ± 0.45 and 4.03 ± 0.18) (p < 0.001). No potential side effects were noted in either of two groups. CONCLUSION: Ozone therapy accelerated the tissue wound healing, minimized tissue inflammation and decreased pain.

E-Cadherin Expression in Blastic Plasmacytoid Dendritic Cell Neoplasms: An Unrecognized Finding and Potential Diagnostic Pitfall.

E-cadherin is expressed in hematopoietic erythroid precursors, but to our knowledge, its expression in blastic plasmacytoid dendritic cell neoplasm (BPDCN) has not been described. We report a case of BPDCN showing strong expression of E-cadherin, arising in a patient with history of primary myelofibrosis. Four more cases of BPDCN tested all showed strong expression of E-cadherin. Lack of awareness of this pattern of expression may lead to erroneous diagnosis of acute erythroid leukemia. It is increasingly becoming important to correctly identify this group of neoplasms, as approved new anti-CD123-targeted therapies are becoming available.

Soluble guanylate cyclase signalling mediates etoposide resistance in progressing small cell lung cancer.

Small cell lung cancer (SCLC) has a 5-year survival rate of <7%. Rapid emergence of acquired resistance to standard platinum-etoposide chemotherapy is common and improved therapies are required for this recalcitrant tumour. We exploit six paired pre-treatment and post-chemotherapy circulating tumour cell patient-derived explant (CDX) models from donors with extensive stage SCLC to investigate changes at disease progression after chemotherapy. Soluble guanylate cyclase (sGC) is recurrently upregulated in post-chemotherapy progression CDX models, which correlates with acquired chemoresistance. Expression and activation of sGC is regulated by Notch and nitric oxide (NO) signalling with downstream activation of protein kinase G. Genetic targeting of sGC or pharmacological inhibition of NO synthase re-sensitizes a chemoresistant CDX progression model in vivo, revealing this pathway as a mediator of chemoresistance and potential vulnerability of relapsed SCLC.

Tubulo-squamous polyp of the vagina with sebaceous glands: novel features in an uncommon recently described entity.

Tubulo-squamous polyp of the vagina is a recently described histopathologic entity. This case report describes an as yet unreported morphologic feature of sebaceous glands in an example of this lesion. Further knowledge of the morphologic spectrum of this lesion should be of aid to histopathologists in its recognition. A brief review of currently available literature on this topic is also given.

Immunohistochemistry in surgical pathology practice: a current perspective of a simple, powerful, yet complex, tool.

Immunohistochemistry (IHC) is a powerful tool in the surgical pathologists' armamentarium. The requests for IHC and the list of monoclonal antibodies have increased tremendously in the past decade. Issues concerning technical reproducibility, uniformity of interpretation, inter-laboratory comparability, and quality assurance are assuming greater importance due to the increased availability of IHC and its impact on diagnosis and therapy. An attempt has been made to give a current perspective of this simple and yet, in some aspects, a complex tool.

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.

Somatic cancer genetics in the UK: real-world data from phase I of the Cancer Research UK Stratified Medicine Programme.

INTRODUCTION: Phase I of the Cancer Research UK Stratified Medicine Programme (SMP1) was designed to roll out molecular pathology testing nationwide at the point of cancer diagnosis, as well as facilitate an infrastructure where surplus cancer tissue could be used for research. It offered a non-trial setting to examine common UK cancer genetics in a real-world context. METHODS: A total of 26 sites in England, Wales and Scotland, recruited samples from 7814 patients for genetic examination between 2011 and 2013. Tumour types involved were breast, colorectal, lung, prostate, ovarian cancer and malignant melanoma. Centralised molecular testing of surplus material from resections or biopsies of primary/metastatic tissue was performed, with samples examined for 3-5 genetic alterations deemed to be of key interest in site-specific cancers by the National Cancer Research Institute Clinical Study groups. RESULTS: 10 754 patients (98% of those approached) consented to participate, from which 7814 tumour samples were genetically analysed. In total, 53% had at least one genetic aberration detected. From 1885 patients with lung cancer, KRAS mutation was noted to be highly prevalent in adenocarcinoma (37%). In breast cancer (1873 patients), there was a striking contrast in TP53 mutation incidence between patients with ductal cancer (27.3%) and lobular cancer (3.4%). Vast inter-tumour heterogeneity of colorectal cancer (1550 patients) was observed, including myriad double and triple combinations of genetic aberrations. Significant losses of important clinical information included smoking status in lung cancer and loss of distinction between low-grade and high-grade serous ovarian cancers. CONCLUSION: Nationwide molecular pathology testing in a non-trial setting is feasible. The experience with SMP1 has been used to inform ongoing CRUK flagship programmes such as the CRUK National Lung MATRIX trial and TRACERx.

Well-differentiated adenocarcinoma of the rectosigmoid colon associated with psammoma bodies: a case report.

This report documents an unusualfinding of scattered psammomatous-type calcification in a well-differentiated adenocarcinoma of the rectosigmoid colon in a 54-year-old woman. The clinical relevance of this histologic feature is discussed, in light of review of the literature.

Laryngeal chondrometaplasia: a great mimic of chondrosarcoma.

Chondrometaplasia of larynx is a rare entity with an unknown etiopathogenesis. The lesion remains asymptomatic unless it reaches a large size and a history of trauma is usually elicited. It is a known pitfall in diagnostic evaluation and a clinically significant differential considered in evaluation of cartilaginous tumors of the larynx. A 66-year-old man presented with a nodular mass of right side of neck, progressive hoarseness of voice and pain, and a suspicious growth in the right glottic region. A CT followed by an MRI one month later revealed a slow growing ill defined thickening and enhancement of the supraglottic soft tissues, predominantly involving the submucosa, along the greater cornu on the left side of the thyroid cartilage, with extra-chondral enhancement and was suggested to be of infectious etiology. On neck exploration a lesion clinically suspected to be a chondrosarcoma was excised along with the right ala of the thyroid cartilage. The tissue processed entirely, revealed features consistent with chondrometaplasia of larynx. The importance of distinguishing this lesion from cartilaginous tumors is emphasized.

High-grade Neuroendocrine Carcinoma of the Lung With Carcinoid Morphology: A Study of 12 Cases.

Twelve lung neuroendocrine tumors with morphologic features of carcinoid tumors but with mitotic count >10/2 mm are reported. There were 7 males and 5 females, with age ranging from 56 to 78 years. Four cases were from never-smokers. All tumors showed architectural and cytomorphologic features of carcinoid tumor, including organoid nesting, insular, trabecular, or acinar growth, and tumor cells with low nucleocytoplasmic ratio, abundant cytoplasm, ovoid to round nuclei, and salt and pepper chromatin. Angulated or confluent nesting, insular or lobular growth pattern was also seen. Nuclear irregularities and anisonucleosis were focally present. Mitotic count ranged from 11 to 61/2 mm. Punctate-type necrosis was present in 8 tumors. Anaplastic cytology, large infarct-type necrosis, desmoplasia, or marked inflammatory infiltrate was not found in any of the tumors. One tumor occurred in the background of diffuse idiopathic pulmonary neuroendocrine hyperplasia. All tumors were treated by resection, and all but 1 patient subsequently developed metastasis, and 7 died of the tumor. For metastatic tumors, 4 patients were treated by platinum-based chemotherapy with no apparent response, whereas 3 other patients were treated by combined capecitabine and temozolomide-novel chemotherapy for well-differentiated neuroendocrine tumor/carcinoid tumor-2 of them responded. This subset of tumor would be classified as large cell neuroendocrine carcinoma according to the current WHO classification scheme, but their clinical and pathologic features appear to have more in common with the carcinoid tumor group than large cell neuroendocrine carcinoma, therefore, identification of this subset may be relevant for further therapeutic management.

CD10 in diffuse uterine leiomyomatosis: a case report along with a few comments on histogenesis.

Diffuse uterine leiomyomatosis (DUL) is a rare entity with an unknown etiopathogenesis. A 24 years old female presented with abdominal discomfort and menorrhagia. Clinical and ultrasonographic examination revealed an enlarged uterus. The hysterectomy specimen showed a symmetrically enlarged uterus with a bosselated external surface. The cut surface showed multiple nodules of varying sizes diffusely involving the myometrium. Microscopically, the nodules were leiomyomas of varying degrees of cellularity. Some of the leiomyomas showed an increased vascularity either in the form of congeries of blood vessels with a lobular arrangement or occasionally as foci of 2-3 vessels. The vessels were surrounded by whorls of spindle cells. On immunohistochemistry the leiomyomas expressed vimentin, smooth muscle actin (SMA), desmin and CD10: the cells whorling around the blood vessels expressed vimentin, SMA and focally desmin and were negative for CD10 and HMB-45. The aim of this paper is to document that CD10 is expressed in diffuse uterine leiomyomatosis and discuss the histogenesis of DUL.

A Review of the Multidisciplinary Diagnosis of Interstitial Lung Diseases: A Retrospective Analysis in a Single UK Specialist Centre.

The accurate diagnosis and management of individuals with interstitial lung diseases (ILDs) poses an interesting challenge in clinical practice. A multidisciplinary team (MDT) approach is considered the gold standard. This is a single-centre retrospective review spanning a five-year period. We assessed the accuracy of prior ILD diagnosis, the methodology used to establish a correct diagnosis and how an MDT approach affected subsequent management. Our data supports an MDT approach in an experienced specialist ILD centre. We have demonstrated that diagnosis is often changed after an MDT review and that this impacts the subsequent management. Our results demonstrate that an MDT approach to diagnosis can establish a diagnosis in the majority of cases when prior diagnosis is uncertain (76%). We also show that a prior diagnosis of idiopathic pulmonary fibrosis is deemed inaccurate in over 50% of cases after MDT discussion. We have shown that during diagnostic uncertainty the considered gold standard of proceeding to a lung biopsy is not always feasible due to disease severity and comorbidities. In these circumstances, an MDT approach to diagnosis of ILDs combines clinical data with serial lung function and disease behavior, with or without responses to previous treatment trials to establish an accurate expert diagnosis.

Pulmonary artery sarcoma: a rare thoracic tumor frequently misdiagnosed at presentation.

This case illustrates a rare but important differential diagnosis of pulmonary emboli in the field of thoracic oncology, that of pulmonary artery sarcoma. It describes particular clinical features that may raise suspicion of this tumor in cases of suspected pulmonary emboli, and highlights novel radiological modalities and tissue sampling techniques in such cases. Surgical resection, as part of multi-modality therapy, is the cornerstone of treatment that has seen survival dramatically improve in recent years for patients with this rare cancer.

EBUS-TBNA in elderly patients with lung cancer: safety and performance outcomes.

BACKGROUND: Endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) enables minimally invasive lymph node sampling during bronchoscopy under conscious sedation. The primary purpose of this study was to investigate the safety profile of EBUS-TBNA in an elderly population. The secondary aim was to assess the efficacy of EBUS-TBNA for nodal staging and pathological diagnosis in elderly patients with primary lung cancer. METHODS: This was a prospective cohort study of patients undergoing EBUS-TBNA, between March 2010 and August 2012, at a single U.K. hospital site. Procedure and outcome data including 6-month follow-up were collected prospectively. Patients were divided into less than 70 (<70yrs) or 70 and older (≥70yrs) age categories for analysis. RESULTS: Four hundred and fifty-one patients underwent EBUS-TBNA during the study period. Mean age of the patients was 66.9 ± 11.9 years, 43.9% (n=198) of them were aged ≥70yrs. Older patients (≥70yrs) had a worse performance status (p=0.0001) and required significantly lower levels of sedation (p<0.000001) but had similar overall complication rates (<70yrs 8.7% versus ≥70yrs 5.1%; p=0.13) and tolerated the procedure better than younger patients (p=0.036). Sensitivity (92.9% versus 86.4%; p=0.12) was equivalent, but negative predictive value (91.8% versus 73.9%; p=0.001) and diagnostic accuracy (96.0% versus 90.2%; p=0.02) of nodal sampling in patients with confirmed or suspected lung cancer (n=273) was higher in the ≥70yrs cohort (n=131, 48.0%). However, the prevalence of nodal malignancy was significantly different between the two groups as was the proportion of patients subject to surgical lymph node sampling after negative EBUS-TBNA. EBUS-TBNA samples produced low non-small-cell lung cancer-not otherwise specified rates (6.9%) and high levels of successful epidermal growth factor receptor mutation analysis (97.5%) irrespective of age category. CONCLUSION: EBUS is a safe and well-tolerated procedure in elderly patients, which facilitates accurate pathological diagnosis and minimally invasive staging in patients with lung cancer.