Table_1_Minimally invasive sleeve lobectomy for centrally located lung cancer: A real-world study with propensity-score matching.docx

BackgroundThe safety, feasibility, and prognosis of sleeve lobectomy by minimally invasive surgery (MIS) remain to be validated. The purpose of this study was to investigate outcomes in real-world patients receiving minimally invasive sleeve lobectomy in a balanced large cohort.MethodsBetween January 2013 and December 2018, 578 consecutive patients undergoing sleeve resection at a high-volume center were retrospectively analyzed. Surgical and oncologic outcomes were compared between MIS and thoracotomy patients after propensity-score matching (PSM).ResultsMIS sleeve lobectomy was increasingly used as a time-trend in real-world. Before PSM, the MIS group had smaller tumor size, more T2-stage cases, and more right upper lobe sleeve lobectomies compared to the Open group. After 1:4 PSM by patient demographics and tumoral characteristics, 100 cases of MIS and 338 cases of Open sleeve lobectomy were further analyzed. Although median operation time was longer in the MIS group than in the Open group (170.5 minutes vs.149.5 minutes, P ConclusionsMIS sleeve lobectomy is associated with similar or even better perioperative results and oncologic outcomes to open thoracotomy. Conversion to thoracotomy does not compromise perioperative outcomes. Robot surgery may be preferable for more complex sleeve resections.</p

Data_Sheet_1.DOCX

<p>Experimental models closely representing in vivo conditions allow investigating mechanisms of resistance. Our aims were to establish a live-cell biobank of malignant pleural mesothelioma (MPM) samples and to obtain proof of principle that primary culture chemoresistant models, mimicking tumor progression observed in patients, can be obtained in vitro, providing a useful tool to investigate underlying mechanisms. Primary mesothelioma cultures were established from 235 samples between 2007 and 2014. Of two MPM patients, primary cultures obtained at different time points: at initial diagnosis, after neoadjuvant treatment at surgery and/or after tumor recurrence, were deeply investigated. Cells and corresponding tumor tissue were characterized by mesothelial protein and gene expression analysis. In addition, primary cultures from chemo naive patients were exposed to increasing doses of cisplatin/pemetrexed during three months and compared with non-treated cells in a cytotoxicity assay, and by selected profiling of senescence markers. In vitro chemoresistance in the primary mesothelioma cell cultures was associated with increased Thy1 (CD90) expression. Thy1 expression in MPM samples was significantly associated with poor overall survival in the TCGA MPM cohort. Our results illustrate that the establishment of a large live-cell MPM biobank contributes to a better understanding of therapy resistance observed in vivo, which eventually may lead to a more logical approach for developing new treatment strategies.</p

Kaplan-Meier curves.

<p>Survival curves presented for nestin expression in chemo-naïve biopsies (A) and the combination of nestin and histology in chemo-treated surgical specimens (B).</p

IHC examples for nestin and periostin.

<p>Upper left: Sarcomatoid MPM and the biphasic mesothelioma cell line SPC212 (insert). Upper right: Biphasic MPM tissue core with >10% epithelioid moiety (triangle) and predominant sarcomatoid differentiation (asterisk). Arrow = nestin-positive vessel endothelia. Lower left: Arrow = tumor cell-associated cytosolic periostin, triangle = stromal periostin. Lower right: Arrow = tumor cell-associated periostin, triangle = stromal periostin along vessel structures. Original magnifications 100x (upper right), 200x (other 3 panels) and400x (insert).</p

Change of nestin and periostin expression after neo-adjuvant chemotherapy.

<p>Neo-adj. CT: Comparison of nestin and periostin H-scores in chemo-naïve biopsies (Chemo-) with surgical specimens after neo-adjuvant chemotherapy (Chemo +) (paired samples Wilcoxon signed rank test). CT regimen: Comparison of marker expression after application of two different chemotherapy regimens: Pla/Gem, platinum + gemcitabine versus Pla/Pem, platinum + pemetrexed (Mann-Whitney U test for independent samples). IQR: interquartile range; CT: chemotherapy.</p><p>Change of nestin and periostin expression after neo-adjuvant chemotherapy.</p

Association of markers with histology in cohort 1.

<p>H-scores of nestin (A) were significantly higher in sarcomatoid MPM whereas the diagnostic epithelioid markers podoplanin/D2-40 (B) and calretinin (C) were significantly decreased in sarcomatoid MPM; Mann-Whitney U tests.</p

Univariate analysis of overall survival.

<p>Association of histologic variant as well as nestin and periostin H-scores (alone or in combination) in chemo-naïve biopsies and chemo-treated surgical specimens with patient’s overall survival (OS) indicated. Median OS was calculated in months from the date of diagnosis for chemo-naïve and from the date of surgery for chemo-treated samples. P-value was determined by log rank test. CI: confidence interval.</p><p>Univariate analysis of overall survival.</p

Multivariate analysis of overall survival.

<p>Categorized histology and dichotomized H-scores of nestin and periostin were included in the multivariate Cox regression analysis for both chemo-naïve biopsies and chemo-treated surgical specimens. HR: hazard ratio; CI: confidence interval.</p><p>Multivariate analysis of overall survival.</p

Influence of inter-observer delineation variability on radiomics stability in different tumor sites

<p><b>Background:</b> Radiomics is a promising methodology for quantitative analysis and description of radiological images using advanced mathematics and statistics. Tumor delineation, which is still often done manually, is an essential step in radiomics, however, inter-observer variability is a well-known uncertainty in radiation oncology. This study investigated the impact of inter-observer variability (IOV) in manual tumor delineation on the reliability of radiomic features (RF).</p> <p><b>Methods:</b> Three different tumor types (head and neck squamous cell carcinoma (HNSCC), malignant pleural mesothelioma (MPM) and non-small cell lung cancer (NSCLC)) were included. For each site, eleven individual tumors were contoured on CT scans by three experienced radiation oncologists. Dice coefficients (DC) were calculated for quantification of delineation variability. RF were calculated with an in-house developed software implementation, which comprises 1404 features: shape (<i>n</i> = 18), histogram (<i>n</i> = 17), texture (<i>n</i> = 137) and wavelet (<i>n</i> = 1232). The IOV of RF was studied using the intraclass correlation coefficient (ICC). An ICC >0.8 indicates a good reproducibility. For the stable RF, an average linkage hierarchical clustering was performed to identify classes of uncorrelated features.</p> <p><b>Results:</b> Median DC was high for NSCLC (0.86, range 0.57–0.90) and HNSCC (0.72, 0.21–0.89), whereas it was low for MPM (0.26, 0–0.9) indicating substantial IOV. Stability rate of RF correlated with DC and depended on tumor site, showing a high stability in NSCLC (90% of total parameters), acceptable stability in HNSCC (59% of total parameters) and low stability in MPM (36% of total parameters). Shape features showed the weakest stability across all tumor types. Hierarchical clustering revealed 14 groups of correlated and stable features for NSCLC and 6 groups for both HNSCC and MPM.</p> <p><b>Conclusion:</b> Inter-observer delineation variability has a relevant influence on radiomics analysis and is strongly influenced by tumor type. This leads to a reduced number of suitable imaging features.</p

Combined Genetic and Genealogic Studies Uncover a Large BAP1 Cancer Syndrome Kindred Tracing Back Nine Generations to a Common Ancestor from the 1700s

<div><p>We recently discovered an inherited cancer syndrome caused by BRCA1-Associated Protein 1 (<i>BAP1</i>) germline mutations, with high incidence of mesothelioma, uveal melanoma and other cancers and very high penetrance by age 55. To identify families with the BAP1 cancer syndrome, we screened patients with family histories of multiple mesotheliomas and melanomas and/or multiple cancers. We identified four families that shared an identical <i>BAP1</i> mutation: they lived across the US and did not appear to be related. By combining family histories, molecular genetics, and genealogical approaches, we uncovered a BAP1 cancer syndrome kindred of ~80,000 descendants with a core of 106 individuals, whose members descend from a couple born in Germany in the early 1700s who immigrated to North America. Their descendants spread throughout the country with mutation carriers affected by multiple malignancies. Our data show that, once a proband is identified, extended analyses of these kindreds, using genomic and genealogical studies to identify the most recent common ancestor, allow investigators to uncover additional branches of the family that may carry <i>BAP1</i> mutations. Using this knowledge, we have identified new branches of this family carrying BAP1 mutations. We have also implemented early-detection strategies that help identify cancers at early-stage, when they can be cured (melanomas) or are more susceptible to therapy (MM and other malignancies).</p></div