To explore the relationship between nodule count and lung cancer probability in baseline low-dose... more To explore the relationship between nodule count and lung cancer probability in baseline low-dose CT lung cancer screening. Included were participants from the NELSON trial with at least one baseline nodule (3392 participants [45% of screen-group], 7258 nodules). We determined nodule count per participant. Malignancy was confirmed by histology. Nodules not diagnosed as screen-detected or interval cancer until the end of the fourth screening round were regarded as benign. We compared lung cancer probability per nodule count category. 1746 (51.5%) participants had one nodule, 800 (23.6%) had two nodules, 354 (10.4%) had three nodules, 191 (5.6%) had four nodules, and 301 (8.9%) had>4 nodules. Lung cancer in a baseline nodule was diagnosed in 134 participants (139 cancers; 4.0%). Median nodule count in participants with only benign nodules was 1 (Inter-quartile range [IQR]: 1-2), and 2 (IQR 1-3) in participants with lung cancer (p=NS). At baseline, malignancy was detected mostly in the largest nodule (64/66 cancers). Lung cancer probability was 62/1746 (3.6%) in case a participant had one nodule, 33/800 (4.1%) for two nodules, 17/354 (4.8%) for three nodules, 12/191 (6.3%) for four nodules and 10/301 (3.3%) for>4 nodules (p=NS). In baseline lung cancer CT screening, half of participants with lung nodules have more than one nodule. Lung cancer probability does not significantly change with the number of nodules. Baseline nodule count will not help to differentiate between benign and malignant nodules. Each nodule found in lung cancer screening should be assessed separately independent of the presence of other nodules.
Background: In computed tomography lung cancer screening programs, up to 30% of all resections ar... more Background: In computed tomography lung cancer screening programs, up to 30% of all resections are futile. Objective: To investigate whether a preoperative positron emission tomography (PET) after a conclusive or inconclusive nonsurgical workup will reduce the resection rate for benign disease in testpositive participants of a lung cancer screening program. Methods: (18)F-Fluorodeoxyglucose-PET scans were made in 220 test positives. Nodules were classified as positive, indeterminate, or negative based on visual comparison with background activity. Gold standard for a positive PET was the presence of cancer in the resection specimen or the detection of cancer during more than 2 years follow-up. Sensitivity, specificity, positive predictive value, and negative predictive value (NPV) were calculated at participant level and 95% confidence intervals (CIs) constructed. Results: The sensitivity of PET to detect cancer was 84.2% (95% CI: 77.6-90.7%), the specificity 75.2% (95% CI: 67.1-83.3), the positive predictive value 78.9% (95% CI: 71.8-86.0), and the NPV 81.2% (95% CI: 73.6-88.8). The resection rate for benign disease was 23%, but 26% of them had a diagnosis with clinical consequences. A preoperative PET after an inconclusive nonsurgical workup reduced the resection rate for benign lesions by 11 to 15%, at the expense of missing 12 to 18% lung cancer cases. A preoperative PET after a conclusive nonsurgical workup reduced the resection rate by 78% at the expense of missing 3% lung cancer cases. Conclusion: A preoperative PET scan in participants with an inconclusive nonsurgical workup is not recommended because of the very low NPV, but after a conclusive nonsurgical workup, the resection rate for benign disease can be decreased by 72%.
Background The clinical relevance of epidermal growth factor receptor (EGFR) copy number gain in ... more Background The clinical relevance of epidermal growth factor receptor (EGFR) copy number gain in patients with EGFR mutated advanced non-small cell lung cancer on first-line tyrosine kinase inhibitor treatment has not been fully elucidated. Objective We aimed to estimate EGFR copy number gain using amplicon-based next generation sequencing data and explored its prognostic value. Patients and Methods Next generation sequencing data were obtained for 1566 patients with non-small cell lung cancer. EGFR copy number gain was defined based on an increase in EGFR read counts relative to internal reference amplicons and normal controls in combination with a modified z-score ≥ 3.5. Clinical follow-up data were available for 60 patients treated with first-line EGFR-tyrosine kinase inhibitors. Results Specificity and sensitivity of next generation sequencing-based EGFR copy number estimations were above 90%. EGFR copy number gain was observed in 27.9% of EGFR mutant cases and in 7.4% of EGFR wild-type cases. EGFR gain was not associated with progression-free survival but showed a significant effect on overall survival with an adjusted hazard ratio of 3.14 (95% confidence interval 1.46-6.78, p = 0.003). Besides EGFR copy number gain, osimertinib in second or subsequent lines of treatment and the presence of T790M at relapse revealed significant effects in a multivariate analysis with adjusted hazard ratio of 0.43 (95% confidence interval 0.20-0.91, p = 0.028) and 0.24 (95% confidence interval 0.1-0.59, p = 0.001), respectively. Conclusions Pre-treatment EGFR copy number gain determined by amplicon-based next generation sequencing data predicts worse overall survival in EGFR-mutated patients treated with first-line EGFR-tyrosine kinase inhibitors. T790M at relapse and subsequent treatment with osimertinib predict longer overall survival. Jiacong Wei and Pei Meng contributed equally to the article.
Take-down policy If you believe that this document breaches copyright please contact us providing... more Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
BackgroundNowadays, the detection of therapy-guiding aberrations such as EGFR mutations and ALK f... more BackgroundNowadays, the detection of therapy-guiding aberrations such as EGFR mutations and ALK fusion genes in tumor tissue is common practice for lung cancer patients. The aim of this study is to explore the feasibility of detecting common therapy-guiding aberrations in RNA isolated from platelets.MethodsWe applied a single primed enrichment-based targeted next generation sequencing (NGS) approach on 10 platelet RNA samples isolated from patients with active disease. In parallel, we applied RNA-based ddPCR focusing on EGFR p.(T790M), p.(L858R) and E19del, on KRAS codon 12 and 13 and on ALK-EML4/KIF5B fusions on 22 platelet RNA samples from patients with tumors known to harbor one of these drivers. For 11 cases ddPCR analysis of circulating cell free (cf)DNA from the same blood sample was performed in parallel.ResultsDespite having good quality NGS data, none of the variants detected in the tumor biopsy were observed in platelet-derived RNA samples. Using the more sensitive ddPCR, ...
1730 Rationale: Cigarette smoking is the main risk factor for both development of squamous cell ... more 1730 Rationale: Cigarette smoking is the main risk factor for both development of squamous cell lung carcinoma (SCC) and chronic obstructive pulmonary disease (COPD). Additionally, COPD itself is an independent risk factor for SCC. This suggests a common genetic background of COPD and SCC. Objectives: To analyze smoke-induced and COPD-related gene expression changes in histologically normal bronchial epithelium and compare the expression levels of the differentially expressed genes to the levels in SCC. Methods: Gene expression profiles were generated using Agilent whole human genome microarray for 28 laser microdissected bronchus epithelial samples of current and ex-smokers from patients with and without COPD, and 35 laser microdissected SCC samples. Results: Gene expression analysis revealed 246 genes that were significantly different between current and ex-smokers, independent of smoking history. Despite the important role of epithelium in pathogenesis of COPD we found no ...
PURPOSE Molecular tumor boards (MTBs) provide physicians with a treatment recommendation for comp... more PURPOSE Molecular tumor boards (MTBs) provide physicians with a treatment recommendation for complex tumor-specific genomic alterations. National and international consensus to reach a recommendation is lacking. In this article, we analyze the effectiveness of an MTB decision-making methodology for patients with non–small-cell lung cancer (NSCLC) with rare or complex mutational profiles as implemented in the University Medical Center Groningen (UMCG). METHODS The UMCG-MTB comprises (pulmonary) oncologists, pathologists, clinical scientists in molecular pathology, and structural biologists. Recommendations are based on reported actionability of variants and molecular interpretation of pathways affected by the variant and supported by molecular modeling. A retrospective analysis of 110 NSCLC cases (representing 106 patients) with suggested treatment of complex genomic alterations and corresponding treatment outcomes for targeted therapy was performed. RESULTS The MTB recommended targe...
Background Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored trea... more Background Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored treatment recommendations. Worldwide, MTBs differ in terms of scope, composition, methods, and recommendations. This study aimed to assess differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands. Materials and Methods MTBs from all tertiary cancer referral centers in The Netherlands were invited to participate. A survey assessing scope, value, logistics, composition, decision-making method, reporting, and registration of the MTBs was completed through on-site interviews with members from each MTB. Targeted therapy recommendations were compared using 10 anonymized cases. Participating MTBs were asked to provide a treatment recommendation in accordance with their own methods. Agreement was based on which molecular alteration(s) was considered actionable with the next line of targeted therapy. Results Interviews with ...
Background: Survival problems in hepatocellular carcinoma (HCC) challenge the clinical practice, ... more Background: Survival problems in hepatocellular carcinoma (HCC) challenge the clinical practice, and drug resistance is one of the major obstacles. Microvascular invasion (MVI) is a histological feature of HCC related to aggressive biological behavior. Its influence on sorafenib sensitivity has been reported. But the mechanism was unclear. This study aimed to investigate the regulatory mechanisms and functional roles of lncRNAs as ceRNAs in MVI genesis, HCC progression, and sorafenib resistance. Methods: We systematically studied the RNA-seq data of HCC. First established an MVI related network of dysregulated ceRNAs. Then, developed a lncRNA signature with prognostic lncRNAs. Finally, HCC's sensitivity to sorafenib was tested by this lncRNA signature with an extensive bioinformatics method.
Background The detection of driver aberrations such as EGFR and ALK, in tumour tissue or plasma h... more Background The detection of driver aberrations such as EGFR and ALK, in tumour tissue or plasma has become important for treating lung cancer patients. The aim of this study is to explore the feasibility of detecting therapy-guiding aberrations in RNA, isolated from platelet and plasma samples. Methods We applied a hybridization capture-based NGS approach on 10 platelet-derived RNA samples with 13 known variants. For validation, we applied RNA-based ddPCR focussing on T790M, L858R and E19del in EGFR, codon 12 and 13 of KRAS and the ALK-EML4/KIF5B fusions on both cell free plasma RNA and platelet RNA. Results For none of the platelet-derived RNA samples we detected the known variant with targeted RNA sequencing despite having sufficient unique reads (1.23x10^5 to 1.4x10^6). We next applied ddPCR to determine presence of mutated transcripts at a higher sensitivity (sensitivity of the assays reached down to 0.07%). No ALK fusion droplets were detected in platelet and plasma samples der...
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Background: To present and evaluate a new respiratory level biofeedback system that aids the pati... more Background: To present and evaluate a new respiratory level biofeedback system that aids the patient to return to a consistent breath-hold level with potential application in image-guided interventions. Methods: The study was approved by the local ethics committee and written informed consent was waived. Respiratory motion was recorded in eight healthy volunteers in the supine and prone positions, using a depth camera that measures the mean distance to thorax, abdomen and back. Volunteers were provided with real-time visual biofeedback on a screen, as a ball moving up and down with respiratory motion. For validation purposes, a conversion factor from mean distance (in mm) to relative lung volume (in mL) was determined using spirometry. Subsequently, without spirometry, volunteers were given breathing instructions and were asked to return to their initial breath-hold level at expiration ten times, in both positions, with and without visual biofeedback. For both positions, the median and interquartile range (IQR) of the absolute error in lung volume from initial breath-hold were determined with and without biofeedback and compared using Wilcoxon signed rank tests. Results: Without visual biofeedback, the median difference from initial breath-hold was 124.6 mL (IQR 55.7-259.7 mL) for the supine position and 156.3 mL (IQR 90.9-334.7 mL) for the prone position. With the biofeedback, the difference was significantly decreased to 32.7 mL (IQR 12.8-59.6 mL) (p < 0.001) and 22.3 mL (IQR 7.7-47.0 mL) (p < 0.001), respectively. Conclusions: The use of a depth camera to provide visual biofeedback increased the reproducibility of breath-hold expiration level in healthy volunteers, with a potential to eliminate targeting errors caused by respiratory movement during lung image-guided procedures.
Background: Pulmonary LCNEC is a rare tumor. Two mutually exclusive subtypes of LCNEC are recogni... more Background: Pulmonary LCNEC is a rare tumor. Two mutually exclusive subtypes of LCNEC are recognized, the co-mutated TP53 and RB1 and the STK11/KEAP1 (predominantly RB1 wildtype) group. We investigated PD-L1 expression in a well characterized stage IV LCNEC cohort and compared expression in the two subtypes. Methods: Panel-consensus pathology revision was performed along with targeted next generation sequencing (TNGS) for genes TP53, RB1, STK11 and KEAP1 and immunohistochemical (IHC) analysis of RB1, on pretreatment tumor samples of stage IV LCNEC treated with chemotherapy (Derks et al. CCR 2018). IHC staining for PD-L1 (DAKO 28-8) was performed according to standard protocols on the DAKO autostainer and evaluated by an experienced screener. Tumors were scored positive if > 1% of tumor cells showed any membranous staining. Overall survival (OS) was evaluated by Kaplan Meier analysis and differences estimated with Log-Rank test. Cox-regression analysis included PD-L1, age and gender. Results: PD-L1 IHC expression data could be generated in 98/147 confirmed LCNEC samples along with RB1 IHC (n ¼ 97) of which 77 passed quality control for TNGS. PD-L1 expression was positive in 16/98 cases (16%); n ¼ 5 (5%) with >50%, n ¼ 11 (11%) having >1-50% and n ¼ 82 (82%) with 1% membranous staining, respectively. No significant correlation of PD-L1 expression with molecular subtyping of LCNEC was identified (Table). PD-L1 expression was correlated with a superior OS, hazard ratio (HR) 0.54 ((95% Confidence interval (CI), 0.31-0.96) P ¼ 0.034.
To determine survival in afatinib-treated patients after treatment with first-generation EGFR tyr... more To determine survival in afatinib-treated patients after treatment with first-generation EGFR tyrosine kinase inhibitors (TKIs) and to study resistance mechanisms in afatinib-resistant tumors. Methods Characteristics and survival of patients treated with afatinib after resistance to erlotinib or gefitinib in two large Dutch centers were collected. Whole exome sequencing (WES) and pathway analysis was performed on available pre-and post-afatinib tumor biopsies and normal tissue. Results A total of 38 patients were treated with afatinib. T790M mutations were identified in 22/29 (76%) pre-afatinib treatment tumor samples. No difference in median progression-free-survival (2.8 months (95% CI 2.3-3.3) and 2.7 months (95% CI 0.9-4.6), p = 0.55) and median overall-survival (8.8 months (95% CI 4.2-13.4) and 3.6 months (95% CI 2.3-5.0), p = 0.14) were observed in T790M+ patients compared to T790M-mutations. Somatic mutations in TP53, ADAMTS2, CNN2 and multiple genes in the Wnt and PI3K-AKT pathway were observed in post-afatinib tumors of six afatinib-responding and in one non-responding patient. No new EGFR mutations were found in the post-afatinib samples of the six responding patients. Further analyses of post-afatinib progressive tumors revealed 28 resistant specific mutations in six genes (HLA-DRB1,
To explore the relationship between nodule count and lung cancer probability in baseline low-dose... more To explore the relationship between nodule count and lung cancer probability in baseline low-dose CT lung cancer screening. Included were participants from the NELSON trial with at least one baseline nodule (3392 participants [45% of screen-group], 7258 nodules). We determined nodule count per participant. Malignancy was confirmed by histology. Nodules not diagnosed as screen-detected or interval cancer until the end of the fourth screening round were regarded as benign. We compared lung cancer probability per nodule count category. 1746 (51.5%) participants had one nodule, 800 (23.6%) had two nodules, 354 (10.4%) had three nodules, 191 (5.6%) had four nodules, and 301 (8.9%) had&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;4 nodules. Lung cancer in a baseline nodule was diagnosed in 134 participants (139 cancers; 4.0%). Median nodule count in participants with only benign nodules was 1 (Inter-quartile range [IQR]: 1-2), and 2 (IQR 1-3) in participants with lung cancer (p=NS). At baseline, malignancy was detected mostly in the largest nodule (64/66 cancers). Lung cancer probability was 62/1746 (3.6%) in case a participant had one nodule, 33/800 (4.1%) for two nodules, 17/354 (4.8%) for three nodules, 12/191 (6.3%) for four nodules and 10/301 (3.3%) for&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;4 nodules (p=NS). In baseline lung cancer CT screening, half of participants with lung nodules have more than one nodule. Lung cancer probability does not significantly change with the number of nodules. Baseline nodule count will not help to differentiate between benign and malignant nodules. Each nodule found in lung cancer screening should be assessed separately independent of the presence of other nodules.
Background: In computed tomography lung cancer screening programs, up to 30% of all resections ar... more Background: In computed tomography lung cancer screening programs, up to 30% of all resections are futile. Objective: To investigate whether a preoperative positron emission tomography (PET) after a conclusive or inconclusive nonsurgical workup will reduce the resection rate for benign disease in testpositive participants of a lung cancer screening program. Methods: (18)F-Fluorodeoxyglucose-PET scans were made in 220 test positives. Nodules were classified as positive, indeterminate, or negative based on visual comparison with background activity. Gold standard for a positive PET was the presence of cancer in the resection specimen or the detection of cancer during more than 2 years follow-up. Sensitivity, specificity, positive predictive value, and negative predictive value (NPV) were calculated at participant level and 95% confidence intervals (CIs) constructed. Results: The sensitivity of PET to detect cancer was 84.2% (95% CI: 77.6-90.7%), the specificity 75.2% (95% CI: 67.1-83.3), the positive predictive value 78.9% (95% CI: 71.8-86.0), and the NPV 81.2% (95% CI: 73.6-88.8). The resection rate for benign disease was 23%, but 26% of them had a diagnosis with clinical consequences. A preoperative PET after an inconclusive nonsurgical workup reduced the resection rate for benign lesions by 11 to 15%, at the expense of missing 12 to 18% lung cancer cases. A preoperative PET after a conclusive nonsurgical workup reduced the resection rate by 78% at the expense of missing 3% lung cancer cases. Conclusion: A preoperative PET scan in participants with an inconclusive nonsurgical workup is not recommended because of the very low NPV, but after a conclusive nonsurgical workup, the resection rate for benign disease can be decreased by 72%.
Background The clinical relevance of epidermal growth factor receptor (EGFR) copy number gain in ... more Background The clinical relevance of epidermal growth factor receptor (EGFR) copy number gain in patients with EGFR mutated advanced non-small cell lung cancer on first-line tyrosine kinase inhibitor treatment has not been fully elucidated. Objective We aimed to estimate EGFR copy number gain using amplicon-based next generation sequencing data and explored its prognostic value. Patients and Methods Next generation sequencing data were obtained for 1566 patients with non-small cell lung cancer. EGFR copy number gain was defined based on an increase in EGFR read counts relative to internal reference amplicons and normal controls in combination with a modified z-score ≥ 3.5. Clinical follow-up data were available for 60 patients treated with first-line EGFR-tyrosine kinase inhibitors. Results Specificity and sensitivity of next generation sequencing-based EGFR copy number estimations were above 90%. EGFR copy number gain was observed in 27.9% of EGFR mutant cases and in 7.4% of EGFR wild-type cases. EGFR gain was not associated with progression-free survival but showed a significant effect on overall survival with an adjusted hazard ratio of 3.14 (95% confidence interval 1.46-6.78, p = 0.003). Besides EGFR copy number gain, osimertinib in second or subsequent lines of treatment and the presence of T790M at relapse revealed significant effects in a multivariate analysis with adjusted hazard ratio of 0.43 (95% confidence interval 0.20-0.91, p = 0.028) and 0.24 (95% confidence interval 0.1-0.59, p = 0.001), respectively. Conclusions Pre-treatment EGFR copy number gain determined by amplicon-based next generation sequencing data predicts worse overall survival in EGFR-mutated patients treated with first-line EGFR-tyrosine kinase inhibitors. T790M at relapse and subsequent treatment with osimertinib predict longer overall survival. Jiacong Wei and Pei Meng contributed equally to the article.
Take-down policy If you believe that this document breaches copyright please contact us providing... more Take-down policy If you believe that this document breaches copyright please contact us providing details, and we will remove access to the work immediately and investigate your claim.
BackgroundNowadays, the detection of therapy-guiding aberrations such as EGFR mutations and ALK f... more BackgroundNowadays, the detection of therapy-guiding aberrations such as EGFR mutations and ALK fusion genes in tumor tissue is common practice for lung cancer patients. The aim of this study is to explore the feasibility of detecting common therapy-guiding aberrations in RNA isolated from platelets.MethodsWe applied a single primed enrichment-based targeted next generation sequencing (NGS) approach on 10 platelet RNA samples isolated from patients with active disease. In parallel, we applied RNA-based ddPCR focusing on EGFR p.(T790M), p.(L858R) and E19del, on KRAS codon 12 and 13 and on ALK-EML4/KIF5B fusions on 22 platelet RNA samples from patients with tumors known to harbor one of these drivers. For 11 cases ddPCR analysis of circulating cell free (cf)DNA from the same blood sample was performed in parallel.ResultsDespite having good quality NGS data, none of the variants detected in the tumor biopsy were observed in platelet-derived RNA samples. Using the more sensitive ddPCR, ...
1730 Rationale: Cigarette smoking is the main risk factor for both development of squamous cell ... more 1730 Rationale: Cigarette smoking is the main risk factor for both development of squamous cell lung carcinoma (SCC) and chronic obstructive pulmonary disease (COPD). Additionally, COPD itself is an independent risk factor for SCC. This suggests a common genetic background of COPD and SCC. Objectives: To analyze smoke-induced and COPD-related gene expression changes in histologically normal bronchial epithelium and compare the expression levels of the differentially expressed genes to the levels in SCC. Methods: Gene expression profiles were generated using Agilent whole human genome microarray for 28 laser microdissected bronchus epithelial samples of current and ex-smokers from patients with and without COPD, and 35 laser microdissected SCC samples. Results: Gene expression analysis revealed 246 genes that were significantly different between current and ex-smokers, independent of smoking history. Despite the important role of epithelium in pathogenesis of COPD we found no ...
PURPOSE Molecular tumor boards (MTBs) provide physicians with a treatment recommendation for comp... more PURPOSE Molecular tumor boards (MTBs) provide physicians with a treatment recommendation for complex tumor-specific genomic alterations. National and international consensus to reach a recommendation is lacking. In this article, we analyze the effectiveness of an MTB decision-making methodology for patients with non–small-cell lung cancer (NSCLC) with rare or complex mutational profiles as implemented in the University Medical Center Groningen (UMCG). METHODS The UMCG-MTB comprises (pulmonary) oncologists, pathologists, clinical scientists in molecular pathology, and structural biologists. Recommendations are based on reported actionability of variants and molecular interpretation of pathways affected by the variant and supported by molecular modeling. A retrospective analysis of 110 NSCLC cases (representing 106 patients) with suggested treatment of complex genomic alterations and corresponding treatment outcomes for targeted therapy was performed. RESULTS The MTB recommended targe...
Background Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored trea... more Background Molecular tumor boards (MTBs) provide rational, genomics-driven, patient-tailored treatment recommendations. Worldwide, MTBs differ in terms of scope, composition, methods, and recommendations. This study aimed to assess differences in methods and agreement in treatment recommendations among MTBs from tertiary cancer referral centers in The Netherlands. Materials and Methods MTBs from all tertiary cancer referral centers in The Netherlands were invited to participate. A survey assessing scope, value, logistics, composition, decision-making method, reporting, and registration of the MTBs was completed through on-site interviews with members from each MTB. Targeted therapy recommendations were compared using 10 anonymized cases. Participating MTBs were asked to provide a treatment recommendation in accordance with their own methods. Agreement was based on which molecular alteration(s) was considered actionable with the next line of targeted therapy. Results Interviews with ...
Background: Survival problems in hepatocellular carcinoma (HCC) challenge the clinical practice, ... more Background: Survival problems in hepatocellular carcinoma (HCC) challenge the clinical practice, and drug resistance is one of the major obstacles. Microvascular invasion (MVI) is a histological feature of HCC related to aggressive biological behavior. Its influence on sorafenib sensitivity has been reported. But the mechanism was unclear. This study aimed to investigate the regulatory mechanisms and functional roles of lncRNAs as ceRNAs in MVI genesis, HCC progression, and sorafenib resistance. Methods: We systematically studied the RNA-seq data of HCC. First established an MVI related network of dysregulated ceRNAs. Then, developed a lncRNA signature with prognostic lncRNAs. Finally, HCC's sensitivity to sorafenib was tested by this lncRNA signature with an extensive bioinformatics method.
Background The detection of driver aberrations such as EGFR and ALK, in tumour tissue or plasma h... more Background The detection of driver aberrations such as EGFR and ALK, in tumour tissue or plasma has become important for treating lung cancer patients. The aim of this study is to explore the feasibility of detecting therapy-guiding aberrations in RNA, isolated from platelet and plasma samples. Methods We applied a hybridization capture-based NGS approach on 10 platelet-derived RNA samples with 13 known variants. For validation, we applied RNA-based ddPCR focussing on T790M, L858R and E19del in EGFR, codon 12 and 13 of KRAS and the ALK-EML4/KIF5B fusions on both cell free plasma RNA and platelet RNA. Results For none of the platelet-derived RNA samples we detected the known variant with targeted RNA sequencing despite having sufficient unique reads (1.23x10^5 to 1.4x10^6). We next applied ddPCR to determine presence of mutated transcripts at a higher sensitivity (sensitivity of the assays reached down to 0.07%). No ALK fusion droplets were detected in platelet and plasma samples der...
This is a PDF file of an article that has undergone enhancements after acceptance, such as the ad... more This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
Background: To present and evaluate a new respiratory level biofeedback system that aids the pati... more Background: To present and evaluate a new respiratory level biofeedback system that aids the patient to return to a consistent breath-hold level with potential application in image-guided interventions. Methods: The study was approved by the local ethics committee and written informed consent was waived. Respiratory motion was recorded in eight healthy volunteers in the supine and prone positions, using a depth camera that measures the mean distance to thorax, abdomen and back. Volunteers were provided with real-time visual biofeedback on a screen, as a ball moving up and down with respiratory motion. For validation purposes, a conversion factor from mean distance (in mm) to relative lung volume (in mL) was determined using spirometry. Subsequently, without spirometry, volunteers were given breathing instructions and were asked to return to their initial breath-hold level at expiration ten times, in both positions, with and without visual biofeedback. For both positions, the median and interquartile range (IQR) of the absolute error in lung volume from initial breath-hold were determined with and without biofeedback and compared using Wilcoxon signed rank tests. Results: Without visual biofeedback, the median difference from initial breath-hold was 124.6 mL (IQR 55.7-259.7 mL) for the supine position and 156.3 mL (IQR 90.9-334.7 mL) for the prone position. With the biofeedback, the difference was significantly decreased to 32.7 mL (IQR 12.8-59.6 mL) (p < 0.001) and 22.3 mL (IQR 7.7-47.0 mL) (p < 0.001), respectively. Conclusions: The use of a depth camera to provide visual biofeedback increased the reproducibility of breath-hold expiration level in healthy volunteers, with a potential to eliminate targeting errors caused by respiratory movement during lung image-guided procedures.
Background: Pulmonary LCNEC is a rare tumor. Two mutually exclusive subtypes of LCNEC are recogni... more Background: Pulmonary LCNEC is a rare tumor. Two mutually exclusive subtypes of LCNEC are recognized, the co-mutated TP53 and RB1 and the STK11/KEAP1 (predominantly RB1 wildtype) group. We investigated PD-L1 expression in a well characterized stage IV LCNEC cohort and compared expression in the two subtypes. Methods: Panel-consensus pathology revision was performed along with targeted next generation sequencing (TNGS) for genes TP53, RB1, STK11 and KEAP1 and immunohistochemical (IHC) analysis of RB1, on pretreatment tumor samples of stage IV LCNEC treated with chemotherapy (Derks et al. CCR 2018). IHC staining for PD-L1 (DAKO 28-8) was performed according to standard protocols on the DAKO autostainer and evaluated by an experienced screener. Tumors were scored positive if > 1% of tumor cells showed any membranous staining. Overall survival (OS) was evaluated by Kaplan Meier analysis and differences estimated with Log-Rank test. Cox-regression analysis included PD-L1, age and gender. Results: PD-L1 IHC expression data could be generated in 98/147 confirmed LCNEC samples along with RB1 IHC (n ¼ 97) of which 77 passed quality control for TNGS. PD-L1 expression was positive in 16/98 cases (16%); n ¼ 5 (5%) with >50%, n ¼ 11 (11%) having >1-50% and n ¼ 82 (82%) with 1% membranous staining, respectively. No significant correlation of PD-L1 expression with molecular subtyping of LCNEC was identified (Table). PD-L1 expression was correlated with a superior OS, hazard ratio (HR) 0.54 ((95% Confidence interval (CI), 0.31-0.96) P ¼ 0.034.
To determine survival in afatinib-treated patients after treatment with first-generation EGFR tyr... more To determine survival in afatinib-treated patients after treatment with first-generation EGFR tyrosine kinase inhibitors (TKIs) and to study resistance mechanisms in afatinib-resistant tumors. Methods Characteristics and survival of patients treated with afatinib after resistance to erlotinib or gefitinib in two large Dutch centers were collected. Whole exome sequencing (WES) and pathway analysis was performed on available pre-and post-afatinib tumor biopsies and normal tissue. Results A total of 38 patients were treated with afatinib. T790M mutations were identified in 22/29 (76%) pre-afatinib treatment tumor samples. No difference in median progression-free-survival (2.8 months (95% CI 2.3-3.3) and 2.7 months (95% CI 0.9-4.6), p = 0.55) and median overall-survival (8.8 months (95% CI 4.2-13.4) and 3.6 months (95% CI 2.3-5.0), p = 0.14) were observed in T790M+ patients compared to T790M-mutations. Somatic mutations in TP53, ADAMTS2, CNN2 and multiple genes in the Wnt and PI3K-AKT pathway were observed in post-afatinib tumors of six afatinib-responding and in one non-responding patient. No new EGFR mutations were found in the post-afatinib samples of the six responding patients. Further analyses of post-afatinib progressive tumors revealed 28 resistant specific mutations in six genes (HLA-DRB1,
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