Thoracoscopic Assessment of Pleural Tumor Burden in Patients with Malignant Pleural Effusion: Prognostic and Therapeutic Implications

Background:Malignant pleural effusion (MPE) is encountered at an advanced stage of disease progression and often heralds a poor prognosis. The most reliable predictive factor of survival in such patients is the primary tumor. Thoracoscopy is often performed for accurate diagnosis and/or thoracoscopic talc insufflation as a therapeutic modality. It remains unknown whether pleural tumor burden, as visualized on thoracoscopy, has potential prognostic value. The objective of this study was to determine the prognostic accuracy of pleural tumor extent and localization (parietal, visceral, or diaphragmatic involvement), as assessed during medical thoracoscopy.Methods:Medical records of all patients who underwent thoracoscopy for suspicion of MPE between 2001 and 2008 at a tertiary care referral hospital were reviewed. Patients were included if pleural metastatic invasion was confirmed on tissue biopsy and survival status ascertained.Results:Four hundred twenty-one patients underwent diagnostic or therapeutic medical thoracoscopy at our referral center. Among them, 122 had confirmed metastatic pleural spread, but survival data were lacking in 15. Primary tumor consisted of non-mall cell lung cancer in 56, breast cancer in 23, melanoma in eight, and other malignancies in 20. Median survival of the entire population was 9.4 months. On univariate analysis, the following variables were significantly associated with reduced median overall survival: pleural metastatic melanoma, age less than 60 years, bloody MPE, extensive pleural adhesions, and widespread visceral pleural nodules (p < 0.05). On multivariate analysis, only melanoma as a primary tumor, pleural fluid appearance and extent of pleural adhesions remained independent and significant predictors of survival.Conclusion:No significant association was found between the extent or localization of pleural tumor burden and overall survival

Phenotypic heterogeneity of potentially curable non-small cell lung cancer: cohort study with cluster analysis

Background: The Tumor, Node, Metastasis (TNM) staging system in non-small cell lung cancer (NSCLC) is currently the most reliable prognostic tool. However, significant differences in clinical course and outcome are observed among patients with apparent curable disease by TNM staging. A more elaborate classification system that simultaneously incorporates the various facets of NSCLC may help identify specific disease patterns, therefore providing a more reliable prediction of outcome. Objectives: 1) to classify patients with potentially curable NSCLC into distinct phenotypic groups using cluster analysis, a multivariate statistical technique. 2) To validate the clinical relevance of these phenotypic clusters by assessing their differences with regard to outcome. Methods: A review of prospectively-collected data from stage I-III NSCLC patients, seen in a single hospital-based centre between January 2004 and October 2010, was conducted. Multiple correspondence analysis (MCA) was applied on a number of baseline variables, and followed by hierarchical clustering using Ward's linkage method. . Overall and disease-free survival estimates were compared among clusters using Kaplan-Meier curves and Cox proportional hazards modeling. Results: The total cohort (n=367) and a surgical sub-cohort (n=169) of patients with early-stage surgically resected NSCLC were analysed. In the total cohort, four and three-cluster models were identified to classify the patients. Clusters were distinct from each other, mainly with respect to gender distribution, smoking status, disease stage, degree of histologic differentiation- and to some extent histologic subtype- tumour metabolic activity on PET, and thyroid transcription factor 1 staining on immunohistochemistry. The surgical sub-cohort was also best classified using four or three-cluster algorithms. Clusters were determined on the basis of the previously cited variables, as well as EGFR mutational status and microscopic vascular and visceral pleural invasion. Overall and disease-free survival estimates differed significantly among various clusters in both the total cohort and surgical sub-cohort. Adjustment for age did not affect results significantly. Conclusion: Cluster analysis allowed the identification of distinct NSCLC phenotypes that exhibit differences in disease presentation, clinical course and outcome.Contexte: La classification TNM dans le cancer bronchique non à petites cellules (CBNPC) est actuellement le meilleur outil pronostique. Cependant, une hétérogénéité significative quant à la présentation et l'évolution clinique de la maladie est observée chez les patients dont le stade est potentiellement curable. Un système de classification plus élaboré, incorporant de façon simultanée plusieurs aspects de la maladie, permettrait d'identifier certains profils distincts du CBNPC, et ainsi offrir une meilleure prédiction de l'évolution clinique. Objectifs : 1) Classifier les patients avec CPNPC en phénotypes distincts, à l'aide de l'analyse de partitionnement de données (APD)- une technique statistique multi-variée. 2) Valider la pertinence clinique de ces phénotypes en comparant l'évolution clinique de chacun. Méthodes : Une revue de données prospectives sur les patients avec CBNPC stades I- III, diagnostiqué entre Janvier 2004 et Octobre 2010, a été effectuée. L'analyse des correspondances multiples a été appliquée sur un ensemble de variables de base, et suivie d'une APD hiérarchique utilisant la méthode de Ward. Des analyses de survie ont été effectuées à l'aide de la technique Kaplan-Meier. Les paramètres de survie globale et de survie sans progression ont été comparés entre les différents phénotypes, en ayant recours au modèle à risques proportionnels de Cox. Résultats: La cohorte complète (n= 367), ainsi qu'une sous-cohorte chirurgicale (n=169), ont été analysés. Dans la cohorte complète, un modèle de partitionnement de données à 3 ou 4 groupes est illustré. Les phénotypes se distinguaient par la distribution des sexes, tabagisme, stade de la maladie, degré de différentiation- et parfois le sous-type histologique- activité métabolique de la tumeur, et l'expression du facteur de transcription thyroïdienne en analyse immunohistochimique. La sous-cohorte chirurgicale était également représentée par un modèle de partition en 3 ou 4 groupes, se démarquant par les facteurs décrits ci-haut, en plus du statut de l'EGFR et l'invasion microscopique vasculaire et de la plèvre viscérale. Les paramètres de survie globale et sans progression différaient de façon significative entre les phénotypes établis, et ce, dans les deux cohortes. L'ajustement pour l'âge n'a pas modifié les résultats de façon notable. Conclusion: L'APD permet l'identification de phénotypes distincts de CBNPC, ayant des différences importantes quant à la présentation et l'évolution clinique de la maladie

Both direct and indirect effects account for the pro-inflammatory activity of enteropathogenic mycotoxins on the human intestinal epithelium: stimulation of interleukin-8 secretion, potentiation of interleukin-1beta effect and increase in the transepithelial passage of commensal bacteria.

International audienceMycotoxins are fungal secondary metabolites responsible of food-mediated intoxication in animals and humans. Deoxynivalenol, ochratoxin A and patulin are the best known enteropathogenic mycotoxins able to alter intestinal functions resulting in malnutrition, diarrhea, vomiting and intestinal inflammation in vivo. Although their effects on intestinal barrier and transport activities have been extensively characterized, the mechanisms responsible for their pro-inflammatory effect are still poorly understood. Here we investigated if mycotoxin-induced intestinal inflammation results from a direct and/or indirect pro-inflammatory activity of these mycotoxins on human intestinal epithelial cells, using differentiated Caco-2 cells as model and interleukin 8 (IL-8) as an indicator of intestinal inflammation. Deoxynivalenol was the only mycotoxin able to directly increase IL-8 secretion (10- to 15-fold increase). We also investigated if these mycotoxins could indirectly stimulate IL-8 secretion through: (i) a modulation of the action of pro-inflammatory molecules such as the interleukin-1beta (IL-1beta), and/or (ii) an increase in the transepithelial passage of non-invasive commensal Escherichia coli. We found that deoxynivalenol, ochratoxin A and patulin all potentiated the effect of IL-1beta on IL-8 secretion (ranging from 35% to 138% increase) and increased the transepithelial passage of commensal bacteria (ranging from 12- to 1544-fold increase). In addition to potentially exacerbate established intestinal inflammation, these mycotoxins may thus participate in the induction of sepsis and intestinal inflammation in vivo. Taken together, our results suggest that the pro-inflammatory activity of enteropathogenic mycotoxins is mediated by both direct and indirect effects

The Impact of COVID-19 on the Diagnosis and Treatment of Lung Cancer at a Canadian Academic Center: A Retrospective Chart Review

The large burden of COVID-19 on health care systems worldwide has raised concerns among medical oncologists about the impact of COVID-19 on the diagnosis and treatment of lung cancer patients. In this retrospective cohort study, we investigated the impact of COVID-19 on lung cancer diagnosis and treatment before and during the COVID-19 era. New lung cancer diagnoses decreased by 34.7% during the pandemic with slightly more advanced stages of disease, there was a significant increase in the utilization of radiosurgery as the first definitive treatment, and a decrease in both systemic treatment as well as surgery compared to the pre-COVID-19 era. There was no significant delay in starting chemotherapy and radiation treatment during the pandemic compared to pre-COVID-19 time. However, we observed a delay to lung cancer surgery during the pandemic time. COVID-19 seems to have had a major impact at our lung cancer center on the diagnoses and treatment patterns of lung cancer patients. Many oncologists fear that they will see an increase in newly diagnosed lung cancer patients in the coming year. This study is still ongoing and further data will be collected and analyzed to better understand the total impact of the COVID-19 pandemic on our lung cancer patient population

The Impact of COVID-19 on the Diagnosis and Treatment of Lung Cancer at a Canadian Academic Center: A Retrospective Chart Review

The large burden of COVID-19 on health care systems worldwide has raised concerns among medical oncologists about the impact of COVID-19 on the diagnosis and treatment of lung cancer patients. In this retrospective cohort study, we investigated the impact of COVID-19 on lung cancer diagnosis and treatment before and during the COVID-19 era. New lung cancer diagnoses decreased by 34.7% during the pandemic with slightly more advanced stages of disease, there was a significant increase in the utilization of radiosurgery as the first definitive treatment, and a decrease in both systemic treatment as well as surgery compared to the pre-COVID-19 era. There was no significant delay in starting chemotherapy and radiation treatment during the pandemic compared to pre-COVID-19 time. However, we observed a delay to lung cancer surgery during the pandemic time. COVID-19 seems to have had a major impact at our lung cancer center on the diagnoses and treatment patterns of lung cancer patients. Many oncologists fear that they will see an increase in newly diagnosed lung cancer patients in the coming year. This study is still ongoing and further data will be collected and analyzed to better understand the total impact of the COVID-19 pandemic on our lung cancer patient population

Real-World Pattern of Treatment and Clinical Outcomes of EGFR-Mutant Non-Small Cell Lung Cancer in a Single Academic Centre in Quebec

The discovery of EGFR tyrosine kinase inhibitors (TKI) for the treatment of EGFR mutant (EGFRm) metastatic NSCLC is regarded as a landmark in lung cancer. EGFR-TKIs have now become a standard first-line treatment for EGFRm NSCLC. The aim of this retrospective cohort study is to describe real-world patterns of treatment and treatment outcomes in patients with EGFRm metastatic NSCLC who received EGFR-TKI therapy outside of clinical trials. One hundred and seventy EGFRm metastatic NSCLC patients were diagnosed and initiated on first-line TKI therapy between 2004 and 2018 at the Peter Brojde Lung Cancer Centre in Montreal. Following progression of the disease, 137 (80%) patients discontinued first-line treatment. Moreover, 80/137 (58%) patients received second-line treatment, which included: EGFR-TKIs, platinum-based, or single-agent chemotherapy. At the time of progression on first-line treatment, 73 patients were tested for the T790M mutation. Moreover, 30/73 (41%) patients were found to be positive for the T790M mutation; 62/80 patients progressed to second-line treatment and 20/62 were started on third-line treatment. The median duration of treatment was 11.5 (95% CI; 9.62–13.44) months for first-line treatment, and 4.4 (95% CI: 1.47–7.39) months for second-line treatment. Median OS from the time of diagnosis of metastatic disease was 23.5 months (95% CI: 16.9–30.1) and median OS from the initiation of EGFR-TKI was 20.6 months (95% CI: 13.5–27.6). We identified that ECOG PS ≤ 2, presence of exon 19 deletion mutation, and absence of brain metastases were associated with better OS. A significant OS benefit was observed in patients treated with osimertinib in second-line treatment compared to those who never received osimertinib. Overall, our retrospective observational study suggests that treatment outcomes in EGFRm NSCLC in real-world practice, such as OS and PFS, reflect the result of RCTs. However, given the few observational studies on real-world treatment patterns of EGFR-mutant NSCLC, this study is important for understanding the potential impact of EGFR-TKIs on survival outside of clinical trials. Further real-world studies are needed to characterize patient outcomes for emerging therapies, including first-line osimertinib use and combination of osimertinib with chemotherapy and potential future combination of osimertinib and novel anticancer drug, outside of a clinical trial setting

Cell-Free Tumor DNA (ctDNA) Utility in Detection of Original Sensitizing and Resistant EGFR Mutations in Non-Small Cell Lung Cancer (NSCLC)

Background: Recent studies have demonstrated the utility of cell-free tumor DNA (ctDNA) from plasma as an alternative source of genomic material for detection of sensitizing and resistance mutations in NSCLC. We hypothesized that the plasma level of ctDNA is an effective biomarker to provide a non-invasive and thus a less risky method to determine new resistance mutations and to monitor response to treatment and tumor progression in lung cancer patients. Methods: This prospective cohort study was approved and conducted at the Peter Brojde Lung Cancer Centre, Montreal. Blood was collected in STRECK tubes at four time points. DNA was extracted from plasma, and ctDNA was analyzed for the presence of mutations in the EGFR gene using the COBAS® EGFR v2 qPCR (Roche) test. Results: Overall, 75 pts were enrolled in the study. In total, 23 pts were TKI-naïve, and 52 were already receiving first-line TKI treatment. ctDNA detected the original mutations (OM) in 35/75 (48%) patients. Significantly higher detection rates were observed in TKI-naïve patients compared to the TKI-treated group, 70% versus 37%, respectively (p = 0.012). The detection of the original mutation at the study baseline was a negative predictor of progression-free survival (PFS) and overall survival (OS). The resistance mutation (T790M) was detected in 32/74 (43%) patients. In 27/32 (84%), the T790M was detected during treatment with TKI: in 25/27 patients, T790M was detected at the time of radiologic progression, in one patient, T790M was detected before radiologic progression, and in one patient, T790M was detected four weeks after starting systemic chemotherapy post progression on TKI. At the time of progression, the detection of T790M significantly correlates with the re-appearance of OM (p = 0.001). Conclusion: Plasma ctDNA is a noninvasive patient-friendly test that can be used to monitor response to treatment, early progression, and detection of acquired resistant mutations. Monitoring of clearance and re-emergence of driver mutations during TKI treatment effectively identifies progression of the disease. As larger NGS panels are available for ctDNA testing, these findings may also have implications for other biomarkers. The results from ongoing and prospective studies will further determine the utility of plasma testing to diagnose, monitor for disease progression, and guide treatment decisions in NSCLC