Lung adenocarcinoma (LUAD) is the most common histologic subtype of lung cancer and has a high risk of distant metastasis at every disease stage. We aimed to characterize the genomic landscape of ...LUAD and identify mutation signatures associated with tumor progression.
We performed an integrative genomic analysis, incorporating whole exome sequencing (WES), determination of DNA copy number and DNA methylation, and transcriptome sequencing for 101 LUAD samples from the Environment And Genetics in Lung cancer Etiology (EAGLE) study. We detected driver genes by testing whether the nonsynonymous mutation rate was significantly higher than the background mutation rate and replicated our findings in public datasets with 724 samples. We performed subclonality analysis for mutations based on mutant allele data and copy number alteration data. We also tested the association between mutation signatures and clinical outcomes, including distant metastasis, survival, and tumor grade. We identified and replicated two novel candidate driver genes, POU class 4 homeobox 2 (POU4F2) (mutated in 9 8.9% samples) and ZKSCAN1 (mutated in 6 5.9% samples), and characterized their major deleterious mutations. ZKSCAN1 was part of a mutually exclusive gene set that included the RTK/RAS/RAF pathway genes BRAF, EGFR, KRAS, MET, and NF1, indicating an important driver role for this gene. Moreover, we observed strong associations between methylation in specific genomic regions and somatic mutation patterns. In the tumor evolution analysis, four driver genes had a significantly lower fraction of subclonal mutations (FSM), including TP53 (p = 0.007), KEAP1 (p = 0.012), STK11 (p = 0.0076), and EGFR (p = 0.0078), suggesting a tumor initiation role for these genes. Subclonal mutations were significantly enriched in APOBEC-related signatures (p < 2.5×10-50). The total number of somatic mutations (p = 0.0039) and the fraction of transitions (p = 5.5×10-4) were associated with increased risk of distant metastasis. Our study's limitations include a small number of LUAD patients for subgroup analyses and a single-sample design for investigation of subclonality.
These data provide a genomic characterization of LUAD pathogenesis and progression. The distinct clonal and subclonal mutation signatures suggest possible diverse carcinogenesis pathways for endogenous and exogenous exposures, and may serve as a foundation for more effective treatments for this lethal disease. LUAD's high heterogeneity emphasizes the need to further study this tumor type and to associate genomic findings with clinical outcomes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Background There is little information on the trajectory and developmental fate of Lin - CD34 + DNAM-1 bright CXCR4 + progenitors exiting bone marrow during systemic inflammation. Objective To study ...Lin - CD34 + DNAM-1 bright CXCR4 + cell circulation in cancer patients, to characterize their entry into involved lung tissue and to characterize their progenies. Methods Flow cytometric analysis of PBMC from 18 patients with lung cancer on samples collected immediately before the first and the second treatment was performed to study Lin - CD34 + DNAM-1 bright CXCR4 + precursors. Precursors were purified (>99%) and cultured in vitro from all patients. Paired PBMC and tissue samples from patients undergoing tumor resection were analyzed by flow cytometry to assess tissue entry and compare phenotype and developmental potential of Lin - CD34 + DNAM-1 bright CXCR4 + cells in both compartments. Results Significant circulation of Lin - CD34 + DNAM-1 bright CXCR4 + precursors was observed 20d after the first treatment. Precursors express CXC3CR1, CXCR3, CXCR1 consistent with travel towards inflamed tissues. Flowcytometric analysis of lung tissue samples showed precursor presence in all patients in tumor and neighboring uninvolved areas. Successful purification and in vitro culture from both blood and lung tissue generates a minor proportion of maturing NK cells (<10%) and a predominant proportion (>85%) of α/β T-progenies with innate-like phenotype expressing NKG2D,NKp30,DNAM-1. Innate-like maturing T-cells in vitro are cytotoxic, can be triggered via NKR/TCR co-stimulation and display broad spectrum Th1,Th2 and Th1/Th17 cytokine production. Conclusion In advanced stage lung cancer CD34 + DNAM-1 bright CXCR4 + inflammatory precursors increase upon treatment, enter involved tissues, generate functional progenies and may thus represent an additional player contributing to immune balance in the highly SDF-1/CXCR4-biased pro-metastatic tumor microenvironment.
In the last decade, the emergence of effective systemic therapies (ESTs) in the form of both targeted and immuno-based therapies has revolutionized the treatment of patients with advanced stage III ...and stage IV melanoma. Even though lungs represent the most frequent site of melanoma metastases, only limited data are available on the role of surgery in isolated pulmonary metastases from malignant melanoma (PmMM) in the era of ESTs. The aim of this study is to describe the outcomes of patients who underwent metastasectomy of PmMM in the era of ESTs, in order to identify prognostic factors affecting survival and to provide a framework for more informed patient selection of treatmeant with lung surgery in the future. Clinical data of 183 patients who underwent metastasectomy of PmMM between June 2008 and June 2021 were collected among four Italian Thoracic Centers. The main clinical, surgical and oncological variables reviewed were: sex, comorbidities, previous oncological history, melanoma histotypes and primary site, date of primary cancer surgical treatment, melanoma growth phase, Breslow thickness, mutation pattern disease, stage at diagnosis, metastatic sites, DFI (Disease Free Interval), characteristics of lung metastases (number, side, dimension, type of resection), adjuvant therapy after lung metastasectomy, site of recurrence, disease-free survival (DFS) and cancer-specific survival (CSS; defined as the time interval between the first melanoma resection or lung metastasectomy and death from cancer). All patients underwent surgical resection of the primary melanoma before lung metastasectomy. Twenty-six (14.2%) patients already had a synchronous lung metastasis at the time of primary melanoma diagnosis. A wedge resection was performed in 95.6% of cases to radically remove the pulmonary localizations, while an anatomical resection was necessary in the remaining cases. The incidence of major post-operative complications was null, while only 21 patients (11.5%) developed minor complications (mainly air leakage followed by atrial fibrillation). The mean in-hospital stay was 4.46 ± 2.8 days. Thirty- and sixty-day mortality were null. After lung surgery, 89.6% of the population underwent adjuvant treatments (47.0% immunotherapy, 42.6% targeted therapy). During a mean FUP of 107.2 ± 82.3 months, 69 (37.7%) patients died from melanoma disease, 11 (6.0%) from other causes. Seventy-three patients (39.9%) developed a recurrence of disease. Twenty-four (13.1%) patients developed extrapulmonary metastases after pulmonary metastasectomy. The CSS from melanoma resection was: 85% at 5 years, 71% at 10 years, 54% at 15 years, 42% at 20 years and 2% at 25 years. The 5- and 10-year CSS from lung metastasectomy were 71% and 26%, respectively. Prognostic factors negatively affecting CSS from lung metastasectomy at multivariable analysis were: melanoma vertical growth (
= 0.018), previous metastatic sites other than lung (
< 0.001) and DFI < 24 months (
= 0.007). Our results support the evidence that surgical indication confirms its important role in stage IV melanoma with resectable pulmonary metastases, and selected patients can still benefit from pulmonary metastasectomy in terms of overall cancer specific survival. Furthermore, the novel systemic therapies may contribute to prolonged survival after systemic recurrence following pulmonary metastasectomy. Patients with long DFI, radial growth melanoma phase and no site of metastatization other than lung seem to be the best candidate cases for lung metastasectomy; however, to drive stronger conclusions, further studies evaluating the role of metastasectomy in patients with iPmMM are needed.
Background Despite ongoing efforts to improve therapy in malignant pleural mesothelioma, few patients undergoing extrapleural pneumonectomy experience long-term survival (LTS). This study aims to ...explore predictors of LTS after extrapleural pneumonectomy and to define a prognostic score. Methods From January 2000 to December 2010, we retrospectively reviewed clinicopathologic and oncological factors in a multicenter cohort of 468 malignant pleural mesothelioma patients undergoing extrapleural pneumonectomy. LTS was defined as survival longer than 3 years. Associations were evaluated using χ2 , Student’s t , and Mann-Whitney U tests. Logistic regression, Cox regression hazard model, and bootstrap analysis were applied to identify outcome predictors. Survival curves were calculated by the Kaplan-Meier method. Receiver operating characteristic analyses were used to estimate optimal cutoff and area under the curve for accuracy of the model. Results Overall, 107 patients (22.9%) survived at least 3 years. Median overall, cancer-specific, and disease-free survival times were 60 (95% confidence interval CI, 51 to 69), 63 (95% CI, 54 to 72), and 49 months (95% CI, 39 to 58), respectively. At multivariate analysis, age (odds ratio, 0.51; 95% CI, 0.31 to 0.82), epithelioid histology (odds ratio, 7.07; 95% CI, 1.56 to 31.93), no history of asbestos exposure (odds ratio, 3.13; 95% CI, 1.13 to 8.66), and the ratio between metastatic and resected lymph nodes less than 22% (odds ratio, 4.12; 95% CI, 1.68 to 10.12) were independent predictors of LTS. According to these factors, we created a scoring system for LTS that allowed us to correctly predict overall, cancer-specific, and disease-free survival in the total sample, obtaining two different groups with favorable or poor prognosis (area under the curve, 0.74; standard error, 0.04; p < 0.0001). Conclusions Our prognostic model facilitates the prediction of LTS after surgery for malignant pleural mesothelioma and can help to stratify the outcome and, eventually, tailor postoperative treatment.
A significant gap in our knowledge of how to manage pulmonary ground-glass opacities (GGOs) still exists. Accordingly, there is a lack of consensus among clinicians on this topic. The Italian Society ...of Thoracic Surgery (Società Italiana di Chirurgia Toracica, SICT) promoted a national expert meeting to provide insightful guidance for clinical practice. Our goal was to publish herein the final consensus document from this conference.
The working panel of the PNR group (Pulmonary Nodules Recommendation Group, a branch of the SICT) together with 5 scientific supervisors (nominated by the SICT) identified a jury of expert thoracic surgeons who organized a multidisciplinary meeting to propose specific statements (n = 29); 73 participants discussed and voted on statements using a modified Delphi process (repeated iterations of anonymous voting over 2 rounds with electronic support) requiring 70% agreement to reach consensus on a statement.
Consensus was reached on several critical points in GGO management, in particular on the definition of GGO, radiological and radiometabolic evaluation, indications for a non-surgical biopsy, GGO management based on radiological characteristics, surgical strategies (extension of pulmonary resection and lymphadenectomy) and radiological surveillance. A list of 29 statements was finally approved.
The participants at this national expert meeting analysed this challenging topic and provided a list of suggestions for health institutions and physicians with practical indications for GGO management.
Abstract
OBJECTIVES: The potential benefit of surgery for malignant pleural mesothelioma (MPM), especially concerning pleurectomy/decortication (P/D), is unclear from the literature. The aim of this ...study was to evaluate the outcome after multimodality treatment of MPM involving different types of P/D and to analyse the prognostic factors.
METHODS: We reviewed 314 patients affected by MPM who were operated on in 11 Italian centres from 1 January 2007 to 11 October 2014.
RESULTS: The characteristics of the population were male/female ratio: 3.7/1, and median age at operation was 67.8 years. The epithelioid histotype was observed in 79.9% of patients; neoadjuvant chemotherapy was given to 57% of patients and Stage III disease was found following a pathological analysis in 62.3% of cases. A total of 162 (51.6%) patients underwent extended P/D (EP/D); 115 (36.6%) patients had P/D and 37 (11.8%) received only a partial pleurectomy. Adjuvant radiotherapy was delivered in 39.2% of patients. Median overall survival time after surgery was 23.0 95% confidence interval (CI): 19.6–29.1 months. On multivariable (Cox) analysis, pathological Stage III–IV P = 0.004, hazard ratio (HR):1.34; 95% CI: 1.09–1.64, EP/D and P/D (P = 0.006, HR for EP/D: 0.46; 95% CI: 0.29–0.74; HR for P/D: 0.52; 95% CI: 0.31–0.87), left-sided disease (P = 0.01, HR: 1.52; 95% CI: 1.09–2.12) and pathological status T4 (P = 0.0003, HR: 1.38; 95% CI: 1.14–1.66) were found to be independent significant predictors of overall survival.
CONCLUSIONS: Whether the P/D is extended or not, it shows similarly good outcomes in terms of early results and survival rate. In contrast, a partial pleurectomy, which leaves gross tumour behind, has no impact on survival.
There is little information on the trajectory and developmental fate of Lin
CD34
DNAM-1
CXCR4
progenitors exiting bone marrow during systemic inflammation.
To study Lin
CD34
DNAM-1
CXCR4
cell ...circulation in cancer patients, to characterize their entry into involved lung tissue and to characterize their progenies.
Flow cytometric analysis of PBMC from 18 patients with lung cancer on samples collected immediately before the first and the second treatment was performed to study Lin
CD34
DNAM-1
CXCR4
precursors. Precursors were purified (>99%) and cultured
from all patients. Paired PBMC and tissue samples from patients undergoing tumor resection were analyzed by flow cytometry to assess tissue entry and compare phenotype and developmental potential of Lin
CD34
DNAM-1
CXCR4
cells in both compartments.
Significant circulation of Lin
CD34
DNAM-1
CXCR4
precursors was observed 20d after the first treatment. Precursors express CXC3CR1, CXCR3, CXCR1 consistent with travel towards inflamed tissues. Flowcytometric analysis of lung tissue samples showed precursor presence in all patients in tumor and neighboring uninvolved areas. Successful purification and
culture from both blood and lung tissue generates a minor proportion of maturing NK cells (<10%) and a predominant proportion (>85%) of α/β T-progenies with innate-like phenotype expressing NKG2D,NKp30,DNAM-1. Innate-like maturing T-cells
are cytotoxic, can be triggered via NKR/TCR co-stimulation and display broad spectrum Th1,Th2 and Th1/Th17 cytokine production.
In advanced stage lung cancer CD34
DNAM-1
CXCR4
inflammatory precursors increase upon treatment, enter involved tissues, generate functional progenies and may thus represent an additional player contributing to immune balance in the highly SDF-1/CXCR4-biased pro-metastatic tumor microenvironment.
The aim of this study was to assess the impact of BMI on perioperative outcomes in patients undergoing VATS lobectomy or segmentectomy. Data from 5088 patients undergoing VATS lobectomy or ...segmentectomy, included in the VATS Group Italian Registry, were collected. BMI (kg/m2) was categorized according to the WHO classes: underweight, normal, overweight, obese. The effects of BMI on outcomes (complications, 30-days mortality, DFS and OS) were evaluated with a linear regression model, and with a logistic regression model for binary endpoints. In overweight and obese patients, operative time increased with BMI value. Operating room time increased by 5.54 minutes (S.E. = 1.57) in overweight patients, and 33.12 minutes (S.E. = 10.26) in obese patients (P < 0.001). Compared to the other BMI classes, overweight patients were at the lowest risk of pulmonary, acute cardiac, surgical, major, and overall postoperative complications. In the overweight range, a BMI increase from 25 to 29.9 did not significantly affect the length of stay, nor the risk of any complications, except for renal complications (OR: 1.55; 95% CI: 1.07–2.24; P = 0.03), and it reduced the risk of prolonged air leak (OR: 0.8; 95% CI: 0.71–0.90; P < 0.001). 30-days mortality is higher in the underweight group compared to the others. We did not find any significant difference in DFS and OS. According to our results, obesity increases operating room time for VATS major lung resection. Overweight patients are at the lowest risk of pulmonary, acute cardiac, surgical, major, and overall postoperative complications following VATS resections. The risk of most postoperative complications progressively increases as the BMI deviates from the point at the lowest risk, towards both extremes of BMI values. Thirty days mortality is higher in the underweight group, with no differences in DFS and OS.
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Abstract
OBJECTIVES
Inherent technical aspects of pulmonary lobectomy by video-assisted thoracoscopic surgery (VATS) may limit surgeons’ ability to deal with factors predisposing to complications. We ...analysed complication rates after VATS lobectomy in a prospectively maintained nationwide registry.
METHODS
The registry was queried for all consecutive VATS lobectomy procedures from 49 Italian Thoracic Units. Baseline condition, tumour features, surgical techniques, devices, postoperative care, complications, conversions and the reasons thereof were detailed. Univariable and multivariable regressions were used to assess factors potentially linked to complications.
RESULTS
Four thousand one hundred and ninety-one VATS lobectomies in 4156 patients (2480 men, 1676 women) were analysed. The median age-adjusted Charlson index of the patients was 4 (interquartile range 3–6). Grade 1 and 2 and Grade 3–5 complications were observed in 20.1% and in 5.8%, respectively. Ninety-day mortality was 0.55%. The overall conversion rate was 9.2% and significantly higher in low-volume centres (<100 cases, P < 0.001), but there was no significant difference between intermediate- and high-volume centres under this aspect. Low-volume centres were significantly more likely to convert due to issues with difficult local anatomy, but not significantly so for bleeding. Conversion, lower case-volume, comorbidity burden, male gender, adhesions, blood loss, operative time, sealants and epidural analgesia were significantly associated with increased postoperative morbidity.
CONCLUSIONS
VATS lobectomy is a safe procedure even in medically compromised patients. An improved classification system for conversions is proposed and prevention strategies are suggested to reduce conversion rates and possibly complications in less-experienced centres.
Thoracoscopic lobectomy (VATS-L) for non-small-cell lung cancer (NSCLC) is a well-established option for early stage NSCLC, but the evidences are limited for octogenarians.
The objectives of this ...multi-institutional study were to evaluate the post-operative outcomes of VATS-L in octogenarians and to estimate the post-operative quality of life (QoL) using a validated questionnaire (EuroQoL5D).
Data from patients underwent VATS-L between 2014 and 2019 were analysed and divided into two groups: Group A (younger patients) and Group B (octogenarians). To define predictors for complications, univariate and multivariable logistic regression analysis were performed.
7023 patients underwent VATS-L and 329 (4.6%) were octogenarians. 30-day and 90-day post-operative mortality were similar (0.95% vs 0.91%, p = 0.84 and 1.3% vs 1.2%, p = 0.58), whereas the percentage of patients who suffered from any complication (25.5% vs 31.9%, p = 0.012) and the complication rate (31.6% vs 45.2%, p=<0.01) were higher for octogenarians. At discharge, the values of EuroQoL5D were worse in group B, but after one month these levels became similar. Age >80 years had a significant influence on morbidity on both univariate and multivariable analyses (p = 0.025).
VATS-L for NSCLC can be performed in selected octogenarians without increased risk of post-operative death, acceptable not-life-threatening complications and a moderate impact on QoL.
•What are the outcomes thoracoscopic lobectomy for non-small-cell lung cancer?•What is the impact of VATS-lobectomy on Quality of Life (QoL) in octogenarian patients?•Post-operative complications were significantly more frequent, but not life-threatening.•Levels of QoL were worse for elderly patients, but after a month these levels became similar.•VATS-lobectomy can be safely performed in selected octogenarians, without worsening their QoL.
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