Molecular testing in stage I–III non-small cell lung cancer : approaches and challenges

Precision medicine in non-small cell lung cancer (NSCLC) is a rapidly evolving area, with the development of targeted therapies for advanced disease and concomitant molecular testing to inform clinical decision-making. In contrast, routine molecular testing in stage I–III disease has not been required, where standard of care comprises surgery with or without adjuvant or neoadjuvant chemotherapy, or concurrent chemoradiotherapy for unresectable stage III disease, without the integration of targeted therapy. However, the phase 3 ADAURA trial has recently shown that the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI), osimertinib, reduces the risk of disease recurrence by 80% versus placebo in the adjuvant setting for patients with stage IB–IIIA EGFR mutation-positive NSCLC following complete tumor resection with or without adjuvant chemotherapy, according to physician and patient choice. Treatment with adjuvant osimertinib requires selection of patients based on the presence of an EGFR-TKI sensitizing mutation. Other targeted agents are currently being evaluated in the adjuvant and neoadjuvant settings. Approval of at least some of these other agents is highly likely in the coming years, bringing with it in parallel, a requirement for comprehensive molecular testing for stage I–III disease. In this review, we consider the implications of integrating molecular testing into practice when managing patients with stage I–III non-squamous NSCLC. We discuss best practices, approaches and challenges from pathology, surgical and oncology perspectives

Histological inflammation in the endoscopically uninflamed mucosa is associated with worse outcomes in limited ulcerative colitis

Background: The Montreal classification categorizes patients with ulcerative colitis (UC) based on their macroscopic disease extent. Independent of endoscopic extent, biopsies through all colonic segments should be retrieved during index colonoscopy. However, the prognostic value of histological inflammation at diagnosis in the inflamed and uninflamed regions of the colon has never been assessed.Methods: This was a multicenter retrospective cohort study of newly diagnosed patients with treatment-naïve proctitis and left-sided UC. Biopsies from at least 2 colonic segments (endoscopically inflamed and uninflamed mucosa) were retrieved and reviewed by 2 pathologists. Histological features in the endoscopically inflamed and uninflamed mucosa were scored using the Nancy score. The primary outcomes were disease complications (proximal disease extension, need for hospitalization or colectomy) and higher therapeutic requirements (need for steroids or for therapy escalation).Results: Overall, 93 treatment-naïve patients were included, with a median follow-up of 44 months (range, 2-329). The prevalence of any histological inflammation above the endoscopic margin was 71%. Proximal disease extension was more frequent in patients with histological inflammation in the endoscopically uninflamed mucosa at diagnosis (21.5% vs 3.4%, P = 0.04). Histological involvement above the endoscopic margin was the only predictor associated with an earlier need for therapy escalation (adjusted hazard ratio, 3.69; 95% confidence interval, 1.05- 13.0); P = 0.04) and disease complications (adjusted hazard ratio, 4.79; 95% confidence interval, 1.10-20.9; P = 0.04).Conclusions: The presence of histological inflammation in the endoscopically uninflamed mucosa at the time of diagnosis was associated with worse outcomes in limited UC.peer-reviewe

Contribuição para o conhecimento da cancerigénese na colite ulcerosa de longa evolução : fenótipo aberrante de mucinas e mecanismos relacionados com a sua expresão

Tese de doutoramento, Medicina (Anatomia Patológica), Universidade de Lisboa, Faculdade de Medicina, 2009A colite ulcerosa (CU) é uma das poucas condições pré-neoplásicasconhecidas do intestino, pelo que a escolhemos como modelo de investigaçãoda cancerigénese do cancro colorectal (CCR) em contexto de inflamaçãocrónica.Objectivos:a) Esclarecer alguns mecanismos da sequência inflamação-displasiacarcinoma,investigando populações celulares metaplásicas reveladas pelaexpressão de apomucinas gástricas e estabelecendo a sua relação com a presençade displasia/neoplasia em doentes com colite ulcerosa; b) Avaliar o papel degenes homeobox envolvidos na diferenciação gástrica.Materiais e metodologia:Estudámos a expressão das apomucinas MUC5AC e MUC6 e dosfactores de transcrição SOX2 e Pdx1 em amostras de mucosa intestinal numasérie de 130 doentes com CU, subdivididos em dois grupos: grupo I, semdisplasia/neoplasia (n = 105) e grupo II, com displasia/adenocarcinoma (n= 25). Avaliámos a metilação dos genes SOX2 e Pdx1 em 30 casos. Usámosmétodos imunohistoquímicos e de PCR (QMSP).Resultados:Demonstrámos haver expressão de MUC5AC (72,1%) e MUC6 (21%),predominantemente no grupo II. MUC5AC correlacionou-se com distorçãoe com inflamação (actividade, intensidade) e duração da doença. MUC6correlacionou-se com expressão de MUC5AC, extensão da doença e displasia/neoplasia. Observou-se expressão de SOX2 (18%) e Pdx1 (73,3%). SOX2foi detectado em neoplasias nas áreas com menor diferenciação ou padrãomucocelular e correlacionou-se com MUC6 e displasia/neoplasia. Pdx1correlacionou-se com MUC5AC.Identificou-se metilação do SOX2 (n = 6), correlacionando-se coma presença de displasia/neoplasia e também de Pdx1 (n = 4). Não haviadiferenças significativas quando comparados os dois grupos, nem correlaçãocom as variáveis estudadas.Being one of the few pre-neoplastic conditions affecting the colon,we selected ulcerative colitis (UC) as a model within the carcinogenesis ofcolorectal cancer (CRC), in the setting of chronic inflammation.Aims:To clarify: a) Some of the mechanisms implicated in the sequenceinflammation-carcinoma, investigating the role of metaplastic gastric celllineages and their relation to dysplasia/neoplasia in patients with UC; b) Therelationship between aberrant gastric mucins and homeobox genes SOX2 andPdx1, trying to explain some aspects responsible for cellular differentiation inUC.Patients and methods:Demographic/morphological parameters of 130 patients (group I - 105patients without dysplasia/neoplasia; group II - 25 patients with dysplasia/invasive adenocarcinoma) were evaluated. Differentiation studies includedevaluation of immunoexpression of gastric apomucins (MUC5AC e MUC6)and transcription factors SOX2 and Pdx1 in colonic mucosa samples. DNAmethylation of SOX2 and Pdx1 genes was determined by PCR (QMSP) in30 cases.Results:Both apomucinas were expressed. MUC5AC (72.1%) correlated withcrypt distortion, inflammation and disease duration. MUC6 (21%), correlatedwith MUC5AC, disease extension and dysplasia/carcinoma.SOX2 (18%) and Pdx1 (73.3%) were present in regenerative and neoplasticmucosa. SOX2 was more common in neoplasia, in areas less differentiatedor with a mucocellular pattern. SOX2 correlated with MUC6 and dysplasia.Pdx1 correlated with crypt distortion and MUC5AC.Methylation of SOX2 (n = 6) and Pdx1 (n = 4) was detected, with nosignificant differences amongst groups; SOX2 correlated with dysplasia/neoplasia

Unusual cause for smoldering dysphagia

A 30-year-old black woman presented with heartburn and odynophagia. She had a 2-year history of Behçet’s disease and systemic lupus erythematosus and had been treated with colchicine, hydroxychloroquine, and sucralfate. Odynophagia was not related to the presence of oral ulcers as they were painless and when they were in remission the patient would still intermittently complain of substernal pain. The patient underwent upper digestive endoscopy that revealed only small mucosal irregularities in the upper third of the esophagus. Biopsies of these segments showed marked acanthosis and papillomatosis of the squamous epithelium as well as intense lymphoplasmacytic infiltrate with an increased number of intraepithelial lymphocytes (IEL). There were neither granulocytes nor signs of viral infection. The endoscopic findings were then attributed to regenerative changes of the epithelium and the patient was started on a proton pump inhibitor (PPI), assuming gastroesophageal reflux disease (GERD). During the following years there were flare-ups of rheumatologic disease activity due to the patient’s lack of adherence to therapy. However, there was no correlation of the patient’s maintained (although scarce) complaints of transitory dysphagia and substernal pain

Biópsias Transtraqueais em Neoplasia do Mediastino: Um Método Diagnóstico Viável

O diagnóstico de lesões pulmonares e mediastínicas pode ser realizado através de procedimentos minimamente invasivos dos quais se destaca a broncoscopia flexível e a ecoendoscopia brônquica. Descreve-se o caso de uma doente de 65 anos com lesão sólida no mediastino superior e médio em que o diagnóstico de cancro de pulmão de pequenas células foi alcançado por biópsia transtraqueal, um método não convencional mas viável. Recebido: 30/04/2017 - Aceite: 29/07/201

Biópsias Transtraqueais em Neoplasia do Mediastino: Um Método Diagnóstico Viável

O diagnóstico de lesões pulmonares e mediastínicas pode ser realizado através de procedimentos minimamente invasivos dos quais se destaca a broncoscopia flexível e a ecoendoscopia brônquica. Descreve-se o caso de uma doente de 65 anos com lesão sólida no mediastino superior e médio em que o diagnóstico de cancro de pulmão de pequenas células foi alcançado por biópsia transtraqueal, um método não convencional mas viável. Recebido: 30/04/2017 - Aceite: 29/07/201

Múltiplas Recidivas Oligometastáticas em Doente com Tumor de Pulmão Não-Pequenas Células

O tumor de pulmão não-pequenas células apresenta-se em estádio precoce, claramente cirúrgico, apenas em cerca de 20% dos casos. No entanto, até metade destes doentes vêm a recidivar sistemicamente, com rápida progressão de doença. Nalguns casos, no entanto, o padrão de metastização é limitado a um órgão, com um pequeno número de lesões (1-5) correspondendo ao conceito de recidiva oligometastática ou oligoprogressiva. Com tratamento local agressivo, têm sido documentadas longas sobrevivências nestes doentes, sugerindo uma biologia particular. Apresenta-se o caso de uma doente jovem, com recidiva de adenocarcinoma primário do pulmão oligoprogressiva, mas múltipla, na mama, pele e sistema nervoso central, dois, 12 e 27 meses após cirurgia curativa, tratada localmente com cirurgia e gamma knife, com longa sobrevivência e mantendo-se clinicamente assintomática. Recebido: 09/05/2017 - Aceite: 31/08/201

Clinicopathological and molecular specificities of inflammatory bowel disease-related colorectal neoplastic lesions: the role of inflammation

Compared to the general population, patients with inflammatory bowel disease (IBD) have an increased risk of developing colorectal cancer. Molecular mechanisms underlying colorectal carcinogenesis in the setting of IBD are not well understood. However, modern molecular investigative tools have facilitated the identification of features that help distinguish IBD-related carcinoma from sporadic. Moreover, with advances in endoscopic technology and improved understanding of the natural history, the management of colorectal neoplastic lesions in IBD patients has evolved. This review discusses the clinicopathological and molecular features of colorectal neoplastic lesions complicating IBD. Chronic inflammation is believed to promote the development of neoplasia, partly by producing reactive oxygen and nitrogen species (ROS and NOS) which may interact with genes involved in carcinogenetic pathways. Furthermore, alterations in microbiota and in the innate and adaptive immune responses might contribute, particularly by initiating, regulating and sustaining chronic inflammation. Earlier detection and better characterization of neoplastic colorectal lesions complicating IBD and a better knowledge of molecular mechanisms underlying carcinogenesis in this setting should facilitate improvements in the risk stratification of patients with longstanding IBD and in the management of dysplastic and malignant colorectal lesions that arise in this setting

Tumor-Infiltrating T Cells in Skin Basal Cell Carcinomas and Squamous Cell Carcinomas: Global Th1 Preponderance with Th17 Enrichment—A Cross-Sectional Study

Basal cell carcinomas (BCCs) and squamous cell carcinomas (SCCs) are high-incidence, non-melanoma skin cancers (NMSCs). The success of immune-targeted therapies in advanced NMSCs led us to anticipate that NMSCs harbored significant populations of tumor-infiltrating lymphocytes with potential anti-tumor activity. The main aim of this study was to characterize T cells infiltrating NMSCs. Flow cytometry and immunohistochemistry were used to assess, respectively, the proportions and densities of T cell subpopulations in BCCs (n = 118), SCCs (n = 33), and normal skin (NS, n = 30). CD8+ T cells, CD4+ T cell subsets, namely, Th1, Th2, Th17, Th9, and regulatory T cells (Tregs), CD8+ and CD4+ memory T cells, and γδ T cells were compared between NMSCs and NS samples. Remarkably, both BCCs and SCCs featured a significantly higher Th1/Th2 ratio (~four-fold) and an enrichment for Th17 cells. NMSCs also showed a significant enrichment for IFN-γ-producing CD8+T cells, and a depletion of γδ T cells. Using immunohistochemistry, NMSCs featured denser T cell infiltrates (CD4+, CD8+, and Tregs) than NS. Overall, these data favor a Th1-predominant response in BCCs and SCCs, providing support for immune-based treatments in NMSCs. Th17-mediated inflammation may play a role in the progression of NMSCs and thus become a potential therapeutic target in NMSCs

Definitions of histological abnormalities in inflammatory bowel disease : an ECCO position paper

Abstract: Histological assessment of endoscopic biopsies in inflammatory bowel disease [IBD] plays an important role in clinical management, investigative studies, and clinical trials. Scoring schemes consisting of multiple histological items and offering considerable precision are widely available. However, definitions of histological abnormalities are often inconsistent. Furthermore, interobserver variability for their recognition and assessment may be high.The European Crohn's and Colitis Organisation [ECCO] formed an expert panel to explore definitions of histological abnormalities in IBD, with the aim of improving the quality of diagnosis and facilitating development of scoring schemes. The process confirmed that the current definitions often have no evidence base and vary between sources. Using available evidence and expert knowledge, the panel produced a series of ECCO consensus position statements on histological features in IBD