An unusual case of recurrent haemoptysis after ablation for atrial fibrillation requiring pneumonectomy: a case report.

Background: Pulmonary vein (PV) stenosis is a rare complication after catheter ablation for atrial fibrillation (AF). While there have been reported anecdotal cases of complete PV stenosis requiring pulmonary lobectomy, only one case of pneumonectomy has been documented so far. Case summary: A 42-year-old man was referred to our Thoracic Surgery Unit for recurrent haemoptysis and exertional dyspnoea over the past 4 years and a recent finding of left PV occlusion. He suffered of relapsing AF that had almost five recurrences and that underwent a total of two percutaneous catheter ablations within a 7-year period. He also experienced a hospitalization for multifocal lobar pneumonia. Two attempts of percutaneous transluminal angioplasty (PTA) were unsuccessful. Due to the severity and the duration of PV occlusion, the previous PTA failure, the patient's age, and his symptoms, a left pneumonectomy was performed. During the postoperative period, the patient experienced only mild anaemia effectively managed with blood transfusions. Five months after surgery, he has no recurrence of symptoms. Discussion: When the PV stenosis is complete, PTA may face high failure and recurrence rates. In this setting, anatomical pulmonary resections may represent a valid option to allow symptom relief and resolution.

Hybrid epithelial-mesenchymal status of lung cancer dictates metastatic success through differential interaction with NK cells.

BACKGROUND: Epithelial to mesenchymal transition (EMT) endows cancer cells with pro-metastatic properties, which appear most effective when cells enter an intermediate hybrid (H) state, characterized by integrated mesenchymal (M) and epithelial (E) traits. The reasons for this advantage are poorly known and, especially, it is totally unexplored whether the interplay between H-cells and NK cells could have a role. Here we characterize the pro-metastatic mechanics of non-small cell lung cancer (NSCLC) H-cells and their subset of cancer-initiating cells (CICs), dissecting crucial interactions with NK cells. METHODS: Human lung cancer cell lines and sublines representative of E, M, or H states, assessed by proteomics, were analyzed in vivo for their tumor-forming and disseminating capabilities. Interactions with NK cells were investigated in vitro using migration assays, cytotoxic degranulation assays, and evaluation of CD133+ CICs modulation after coculture, and validated in vivo through NK cell neutralization assays. Correlation between EMT status, NK cell infiltration, and survival data, was evaluated in a cohort of surgically resected NSCLC cases (n=79). RESULTS: We demonstrated that H-cells, have limited dissemination capability but show the highest potential to initiate metastases in vivo. This property was related to their ability to escape NK cell surveillance. Mechanistically, H-cells expressed low levels of NK-attracting chemokines (CXCL1 and CXCL8), generating poorly infiltrated metastases. Accordingly, proteomics and GO enrichment analysis of E, H, M cell lines showed that the related secretory processes could change during EMT.Furthermore, H-CICs uniquely expressed high levels of the inhibitory ligand B7-H3, which protected H-CIC from NK cell-mediated clearance. In vivo neutralization assays confirmed that, indeed, the pro-metastatic properties of H-cells are poorly controlled by NK cells.Finally, the analysis of patients revealed that detection of hybrid phenotypes associated with low NK infiltration in NSCLC clinical specimens could identify a subset of patients with poor prognosis. CONCLUSIONS: Our study demonstrates that H-cells play a central role in the metastatic spread in NSCLC. Such pro-metastatic advantage of H-cells is supported by their altered interaction with NK cells and by the critical role of B7-H3 in preserving their H-CIC component, indicating B7-H3 as a potential target in combined NK-based therapies.

Characterization of two transcriptomic subtypes of marker-null large cell carcinoma of the lung suggests different origin and potential new therapeutic perspectives.

Pulmonary large cell carcinoma (LCC) is an undifferentiated neoplasm lacking morphological, histochemical, and immunohistochemical features of small cell lung cancer, adenocarcinoma (ADC), or squamous cell carcinoma (SCC). The available molecular information on this rare disease is limited. This study aimed to provide an integrated molecular overview of 16 cases evaluating the mutational asset of 409 genes and the transcriptomic profiles of 20,815 genes. Our data showed that TP53 was the most frequently inactivated gene (15/16; 93.7%) followed by RB1 (5/16; 31.3%) and KEAP1 (4/16; 25%), while CRKL and MYB genes were each amplified in 4/16 (25%) cases and MYC in 3/16 (18.8%) cases; transcriptomic analysis identified two molecular subtypes including a Pure-LCC and an adenocarcinoma like-LCC (ADLike-LCC) characterized by different activated pathways and cell of origin. In the Pure-LCC group, POU2F3 and FOXI1 were distinctive overexpressed markers. A tuft cell-like profile and the enrichment of a replication stress signature, particularly involving ATR, was related to this profile. Differently, the ADLike-LCC were characterized by an alveolar-cell transcriptomic profile and association with AIM2 inflammasome complex signature. In conclusion, our study split the histological marker-null LCC into two different transcriptomic entities, with POU2F3, FOXI1, and AIM2 genes as differential expression markers that might be probed by immunohistochemistry for the differential diagnosis between Pure-LCC and ADLike-LCC. Finally, the identification of several signatures linked to replication stress in Pure-LCC and inflammasome complex in ADLike-LCC could be useful for designing new potential therapeutic approaches for these subtypes.

The International Association for the Study of Lung Cancer Early Lung Imaging Confederation Open-Source Deep Learning and Quantitative Measurement Initiative.

INTRODUCTION: With global adoption of computed tomography (CT) lung cancer screening, there is increasing interest to use artificial intelligence (AI) deep learning methods to improve the clinical management process. To enable AI research using an open-source, cloud-based, globally distributed, screening CT imaging data set and computational environment that are compliant with the most stringent international privacy regulations that also protect the intellectual properties of researchers, the International Association for the Study of Lung Cancer sponsored development of the Early Lung Imaging Confederation (ELIC) resource in 2018. The objective of this report is to describe the updated capabilities of ELIC and illustrate how this resource can be used for clinically relevant AI research. METHODS: In this second phase of the initiative, metadata and screening CT scans from two time points were collected from 100 screening participants in seven countries. An automated deep learning AI lung segmentation algorithm, automated quantitative emphysema metrics, and a quantitative lung nodule volume measurement algorithm were run on these scans. RESULTS: A total of 1394 CTs were collected from 697 participants. The LAV950 quantitative emphysema metric was found to be potentially useful in distinguishing lung cancer from benign cases using a combined slice thickness more than or equal to 2.5 mm. Lung nodule volume change measurements had better sensitivity and specificity for classifying malignant from benign lung nodules when applied to solid lung nodules from high-quality CT scans. CONCLUSIONS: These initial experiments revealed that ELIC can support deep learning AI and quantitative imaging analyses on diverse and globally distributed cloud-based data sets.

Long-Term Survival Analysis of Pleural Mesothelioma Patients Undergoing Surgery: Brief Report From a Tertiary Referral Centre.

OBJECTIVES: to date, no consensus has been reached on the surgical gold-standard in pleural mesothelioma (PM). We retrospectively reviewed our experience as a tertiary referral centre, to compare short- and long-term survival of PM patients undergoing different types of surgery. METHODS: in retrospective, observational, single-centre study, we analysed all the patients histologically diagnosed with PM undergoing surgical procedures with palliative or curative intent at IRCCS Istituto Nazionale dei Tumori of Milan, Italy, from January 2003 to December 2020. The primary study endpoint was 10-year overall survival (OS) in three different types of resections: extra-pleural-pneumonectomy (EPP), pleurectomy/decortication (P/D), partial-pleurectomy/pleural-biopsy (PP/B). Secondary endpoints were postoperative hospital stay and postoperative 30-day and 90-day mortality rates. The survival function was estimated using Kaplan-Meier, and the Log-rank test was used for testing differences. Univariable and Multivariable Cox regression models were implemented to estimate Hazard Ratio (HR) for all variables of interest. RESULTS: 243 consecutive patients were enrolled, EPP was performed in 49 (20.2%), P/D in 58 (23.8%), PP/B in 136 (56.0%) patients. The median follow-up time was 19.8 months. 10-year OS was significantly better for P/D group (16%, Log-Rank test p<0.0001) compared to PP/B (1.8%) and EPP (0%). No statistically significant differences were found among the 3 surgical groups in 30- and 90-day mortality rates. At multivariable analysis, gender (male, HR=1.58), type of resection (P/D, HR=0.55) and surgery date (recent years, HR=0.61) were found to be independent prognostic factors for OS. CONCLUSIONS: in PM, lung-sparing curative approach (e.g. P/D) should be preferred in highly selected patients and in highly experienced centres, whenever appropriate. Anyway, when P/D is not indicated, adopting palliative/conservative management (e.g. PP/B) could ensure comparable results as extremely aggressive surgeries (e.g. EPP). The aim of surgery in PM should not be reaching complete resection, but rather accomplishing significant resection allowing to complete the multimodality treatment in highly selected patients in experienced centers.

Cytisine as a smoking cessation aid: Preliminary observations with a modified therapeutic scheme in real life.

INTRODUCTION: Cigarette smoke accounts for over 90,000 deaths each year in Italy. Tobacco dependence treatment guidelines suggest adopting an integrated pharmacological-behavioral model of intervention. Cytisine is a partial agonist of nicotinic receptors. Trials conducted to date have demonstrated its good efficacy in promoting smoking cessation. The cytisine scheme of treatment consists of 25 days of treatment. A 40-day regimen, with an escalating dose and an extended duration of the treatment, has been in use in many anti-smoking centers in Italy for several years, but to date there are no reports on the use of cytisine with this scheme. METHODS: A retrospective, real-life, observational study was conducted between January 2016 and September 2022. The 300 patients who had received at least one dose of study medication were selected. Continuous variables were compared by the Wilcoxon-Mann-Whitney test. Univariate and multivariate logistic regression models were implemented for self-reported seven-day point prevalence for abstinence at three, six and 12 months. RESULTS: The median age of the patients was 59 years, 57% were women. The median smoking exposure was 33.8 pack-years. Self-reported smoking abstinence at three, six and 12 months was 68.7%, 56.3% and 47.3% respectively. 84% completed the cytisine treatment, 31.3% reported adverse events and in 8.3% these led to dropping out of the treatment. CONCLUSION: Cytisine, administered with a novel therapeutic scheme in the real-life setting of a specialized anti-smoking center, significantly promotes smoking abstinence. However, more studies are needed to assess the tolerability and efficacy of this new regimen.

Long-term outcomes of lung cancer screening in males and females.

BACKGROUND: This study explored female and male overall mortality and lung cancer (LC) survival in two LC screening (LCS) populations, focusing on the predictive value of coronary artery calcification (CAC) at baseline low-dose computed tomography (LDCT). METHODS: This retrospective study analysed data of 6495 heavy smokers enrolled in the MILD and BioMILD LCS trials between 2005 and 2016. The primary objective of the study was to assess sex differences in all-cause mortality and LC survival. CAC scores were automatically calculated on LDCT images by a validated artificial intelligence (AI) software. Sex differences in 12-year cause-specific mortality rates were stratified by age, pack-years and CAC score. RESULTS: The study included 2368 females and 4127 males. The 12-year all-cause mortality rates were 4.1 % in females and 7.7 % in males (p < 0.0001), and median CAC score was 8.7 vs. 41 respectively (p < 0.0001). All-cause mortality increased with rising CAC scores (log-rank test, p < 0.0001) for both sexes. Although LC incidence was not different between the two sexes, females had lower rates of 12-year LC mortality (1.0 % vs. 1.9 %, p = 0.0052), and better LC survival from diagnosis (72.3 % vs. 51.7 %; p = 0.0005), with a similar proportion of stage I (58.1 % vs. 51.2 %, p = 0.2782). CONCLUSIONS: Our findings demonstrate that female LCS participants had lower rates of all-cause mortality at 12 years and better LC survival than their male counterparts, with similar LC incidence rates and stage at diagnosis. The lower CAC burden observed in women at all ages might contribute to explain their lower rates of all-cause mortality and better LC survival.

Routine perioperative blood tests predict survival of resectable lung cancer.

There is growing evidence that inflammatory, immunologic, and metabolic status is associated with cancer patients survival. Here, we built a simple algorithm to predict lung cancer outcome. Perioperative routine blood tests (RBT) of a cohort of patients with resectable primary lung cancer (LC) were analysed. Inflammatory, immunologic, and metabolic profiles were used to create a single algorithm (RBT index) predicting LC survival. A concurrent cohort of patients with resectable lung metastases (LM) was used to validate the RBT index. Charts of 2088 consecutive LC and 1129 LM patients undergoing lung resection were evaluated. Among RBT parameters, C-reactive protein (CRP), lymphocytes, neutrophils, hemoglobin, albumin and glycemia independently correlated with survival, and were used to build the RBT index. Patients with a high RBT index had a higher 5-year mortality than low RBT patients (adjusted HR 1.93, 95% CI 1.62-2.31). High RBT patients also showed a fourfold higher risk of 30-day postoperative mortality (2.3% vs. 0.5%, p 0.0019). The LM analysis validated the results of the LC cohort. We developed a simple and easily available multifunctional tool predicting short-term and long-term survival of curatively resected LC and LM. Prospective external validation of RBT index is warranted.

Extracellular vesicles from subjects with COPD modulate cancer initiating cells phenotype through HIF-1α shuttling.

Chronic obstructive pulmonary disease (COPD) is a risk factor for lung cancer development. COPD induces activation of hypoxia-induced signaling, causing remodeling of surrounding microenvironmental cells also modulating the release and cargo of their extracellular vesicles (EVs). We aimed to evaluate the potential role of circulating EVs from COPD subjects in lung cancer onset. Plasma-EVs were isolated by ultracentrifugation from heavy smoker volunteers with (COPD-EVs) or without (heavy smoker-EVs, HS-EV) COPD and characterized following MISEV guidelines. Immortalized human bronchial epithelial cells (CDK4, hTERT-HBEC3-KT), genetically modified with different oncogenic alterations commonly found in lung cancer (sh-p53, KRASV12), were used to test plasma-EVs pro-tumorigenic activity in vitro. COPD-EVs mainly derived from immune and endothelial cells. COPD-EVs selectively increased the subset of CD133+CXCR4+ metastasis initiating cells (MICs) in HBEC-sh-p53-KRASV12high cells and stimulated 3D growth, migration/invasion, and acquisition of mesenchymal traits. These effects were not observed in HBEC cells bearing single oncogenic mutation (sh-p53 or KRASV12). Mechanistically, hypoxia-inducible factor 1-alpha (HIF-1α) transferred from COPD-EVs triggers CXCR4 pathway activation that in turn mediates MICs expansion and acquisition of pro-tumorigenic effects. Indeed, HIF-1α inhibition or CXCR4 silencing prevented the acquisition of malignant traits induced by COPD-EVs alone. Hypoxia recapitulates the effects observed with COPD-EVs in HBEC-sh-p53-KRASV12high cells. Notably, higher levels of HIF-1α were observed in EVs from COPD subjects who subsequently developed cancer compared to those who remained cancer-free. Our findings support a role of COPD-EVs to promote the expansion of MICs in premalignant epithelial cells through HIF-1α-CXCR4 axis activation thereby potentially sustaining lung cancer progression.

Prior CT Improves Deep Learning for Malignancy Risk Estimation of Screening-detected Pulmonary Nodules.

Background Prior chest CT provides valuable temporal information (eg, changes in nodule size or appearance) to accurately estimate malignancy risk. Purpose To develop a deep learning (DL) algorithm that uses a current and prior low-dose CT examination to estimate 3-year malignancy risk of pulmonary nodules. Materials and Methods In this retrospective study, the algorithm was trained using National Lung Screening Trial data (collected from 2002 to 2004), wherein patients were imaged at most 2 years apart, and evaluated with two external test sets from the Danish Lung Cancer Screening Trial (DLCST) and the Multicentric Italian Lung Detection Trial (MILD), collected in 2004-2010 and 2005-2014, respectively. Performance was evaluated using area under the receiver operating characteristic curve (AUC) on cancer-enriched subsets with size-matched benign nodules imaged 1 and 2 years apart from DLCST and MILD, respectively. The algorithm was compared with a validated DL algorithm that only processed a single CT examination and the Pan-Canadian Early Lung Cancer Detection Study (PanCan) model. Results The training set included 10 508 nodules (422 malignant) in 4902 trial participants (mean age, 64 years ± 5 [SD]; 2778 men). The size-matched external test sets included 129 nodules (43 malignant) and 126 nodules (42 malignant). The algorithm achieved AUCs of 0.91 (95% CI: 0.85, 0.97) and 0.94 (95% CI: 0.89, 0.98). It significantly outperformed the DL algorithm that only processed a single CT examination (AUC, 0.85 [95% CI: 0.78, 0.92; P = .002]; and AUC, 0.89 [95% CI: 0.84, 0.95; P = .01]) and the PanCan model (AUC, 0.64 [95% CI: 0.53, 0.74; P < .001]; and AUC, 0.63 [95% CI: 0.52, 0.74; P < .001]). Conclusion A DL algorithm using current and prior low-dose CT examinations was more effective at estimating 3-year malignancy risk of pulmonary nodules than established models that only use a single CT examination. Clinical trial registration nos. NCT00047385, NCT00496977, NCT02837809 © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Horst and Nishino in this issue.

Fully automated calcium scoring predicts all-cause mortality at 12 years in the MILD lung cancer screening trial.

Coronary artery calcium (CAC) is a known risk factor for cardiovascular (CV) events and mortality but is not yet routinely evaluated in low-dose computed tomography (LDCT)-based lung cancer screening (LCS). The present analysis explored the capacity of a fully automated CAC scoring to predict 12-year mortality in the Multicentric Italian Lung Detection (MILD) LCS trial. The study included 2239 volunteers of the MILD trial who underwent a baseline LDCT from September 2005 to January 2011, with a median follow-up of 190 months. The CAC score was measured by a commercially available fully automated artificial intelligence (AI) software and stratified into five strata: 0, 1-10, 11-100, 101-400, and > 400. Twelve-year all-cause mortality was 8.5% (191/2239) overall, 3.2% with CAC = 0, 4.9% with CAC = 1-10, 8.0% with CAC = 11-100, 11.5% with CAC = 101-400, and 17% with CAC > 400. In Cox proportional hazards regression analysis, CAC > 400 was associated with a higher 12-year all-cause mortality both in a univariate model (hazard ratio, HR, 5.75 [95% confidence interval, CI, 2.08-15.92] compared to CAC = 0) and after adjustment for baseline confounders (HR, 3.80 [95%CI, 1.35-10.74] compared to CAC = 0). All-cause mortality significantly increased with increasing CAC (7% in CAC ≤ 400 vs. 17% in CAC > 400, Log-Rank p-value <0.001). Non-cancer at 12 years mortality was 3% (67/2239) overall, 0.8% with CAC = 0, 1.0% with CAC = 1-10, 2.9% with CAC = 11-100, 3.6% with CAC = 101-400, and 8.2% with CAC > 400 (Grey's test p < 0.001). In Fine and Gray's competing risk model, CAC > 400 predicted 12-year non-cancer mortality in a univariate model (sub-distribution hazard ratio, SHR, 10.62 [95% confidence interval, CI, 1.43-78.98] compared to CAC = 0), but the association was no longer significant after adjustment for baseline confounders. In conclusion, fully automated CAC scoring was effective in predicting all-cause mortality at 12 years in a LCS setting.

Ultra-low dose computed tomography protocols using spectral shaping for lung cancer screening: Comparison with low-dose for volumetric LungRADS classification.

PURPOSE: To compare Low-Dose Computed Tomography (LDCT) with four different Ultra-Low-Dose Computed Tomography (ULDCT) protocols for PN classification according to the Lung Reporting and Data System (LungRADS). METHODS: Three hundred sixty-one participants of an ongoing lung cancer screening (LCS) underwent single-breath-hold double chest Computed Tomography (CT), including LDCT (120kVp, 25mAs; CTDIvol 1,62 mGy) and one ULDCT among: fully automated exposure control ("ULDCT1"); fixed tube-voltage and current according to patient size ("ULDCT2"); hybrid approach with fixed tube-voltage ("ULDCT3") and tube current automated exposure control ("ULDCT4"). Two radiologists (R1, R2) assessed LungRADS 2022 categories on LDCT, and then after 2 weeks on ULDCT using two different kernels (R1: Qr49ADMIRE 4; R2: Br49ADMIRE 3). Intra-subject agreement for LungRADS categories between LDCT and ULDCT was measured by the k-Cohen Index with Fleiss-Cohen weights. RESULTS: LDCT-dominant PNs were detected in ULDCT in 87 % of cases on Qr49ADMIRE 4 and 88 % on Br49ADMIRE 3. The intra-subject agreement was: κULDCT1 = 0.89 [95 %CI 0.82-0.96]; κULDCT2 = 0.90 [0.81-0.98]; κULDCT3 = 0.91 [0.84-0.99]; κULDCT4 = 0.88 [0.78-0.97] on Qr49ADMIRE 4, and κULDCT1 = 0.88 [0.80-0.95]; κULDCT2 = 0.91 [0.86-0.96]; κULDCT3 = 0.87 [0.78-0.95]; and κULDCT4 = 0.88 [0.82-0.94] on Br49ADMIRE 3. LDCT classified as LungRADS 4B were correctly identified as LungRADS 4B at ULDCT3, with the lowest radiation exposure among the tested protocols (median effective doses were 0.31, 0.36, 0.27 and 0.37 mSv for ULDCT1, ULDCT2, ULDCT3, and ULDCT4, respectively). CONCLUSIONS: ULDCT by spectral shaping allows the detection and characterization of PNs with an excellent agreement with LDCT and can be proposed as a feasible approach in LCS.

Long term outcome of complex surgical resection and reconstruction for rare thoracic cancers.

BACKGROUND: Complex surgical resection and reconstruction for rare thoracic cancers (RTCs) represent a major challenge, given their very low frequency, extreme variability of presentation, multi-modality treatment options and inadequate outcome prediction. We analysed the experience of a tertiary referral centre on a consecutive series of patients with thoracic germ cell tumours, thymomas and sarcomas, with the aim of reporting the long-term outcome by cancer type and complexity of surgical procedures. METHODS: From Jan 2003 to Dec 2018, 768 surgical procedures were performed with curative intent on 644 RTC patients. Study endpoints were: post-operative hospital stay (Pod), 30-day and 90-day mortality, 5-year and 10-year overall survival (OS). Median follow-up of alive patients was 7.2 years. RESULTS: Median Pod was 7 days, with a 1.2% 30-day and 2.9% 90-day mortality. OS was 90.8% at one year, 74.2% at five years and 62.8% at 10 years. Ten-year OS was 73.0% in low, 65.3% in intermediate, and 55.6% in high complexity score (Log-rank tests p<0.0001); 66.6% in patients with one or two reconstructions and 46.4% in patients with three or more reconstructions (p<0.0001); 46.0% with vascular and 50.0% with chest wall reconstruction; 71.8% in germ cell tumours, 64.6% in thymoma and 51.3% in sarcoma (p<0.0001). CONCLUSION: Complex surgical resection and reconstruction was associated with acceptable 90-day mortality and good 10-year survival in all RTC types. A predictive score based on surgical complexity and cancer type can help the clinical decision making.

Automated Coronary Artery Calcium and Quantitative Emphysema in Lung Cancer Screening: Association With Mortality, Lung Cancer Incidence, and Airflow Obstruction.

PURPOSE: To assess automated coronary artery calcium (CAC) and quantitative emphysema (percentage of low attenuation areas [%LAA]) for predicting mortality and lung cancer (LC) incidence in LC screening. To explore correlations between %LAA, CAC, and forced expiratory value in 1 second (FEV 1 ) and the discriminative ability of %LAA for airflow obstruction. MATERIALS AND METHODS: Baseline low-dose computed tomography scans of the BioMILD trial were analyzed using an artificial intelligence software. Univariate and multivariate analyses were performed to estimate the predictive value of %LAA and CAC. Harrell C -statistic and time-dependent area under the curve (AUC) were reported for 3 nested models (Model survey : age, sex, pack-years; Model survey-LDCT : Model survey plus %LAA plus CAC; Model final : Model survey-LDCT plus selected confounders). The correlations between %LAA, CAC, and FEV 1 and the discriminative ability of %LAA for airflow obstruction were tested using the Pearson correlation coefficient and AUC-receiver operating characteristic curve, respectively. RESULTS: A total of 4098 volunteers were enrolled. %LAA and CAC independently predicted 6-year all-cause (Model final hazard ratio [HR], 1.14 per %LAA interquartile range [IQR] increase [95% CI, 1.05-1.23], 2.13 for CAC ≥400 [95% CI, 1.36-3.28]), noncancer (Model final HR, 1.25 per %LAA IQR increase [95% CI, 1.11-1.37], 3.22 for CAC ≥400 [95%CI, 1.62-6.39]), and cardiovascular (Model final HR, 1.25 per %LAA IQR increase [95% CI, 1.00-1.46], 4.66 for CAC ≥400, [95% CI, 1.80-12.58]) mortality, with an increase in concordance probability in Model survey-LDCT compared with Model survey ( P <0.05). No significant association with LC incidence was found after adjustments. Both biomarkers negatively correlated with FEV 1 ( P <0.01). %LAA identified airflow obstruction with a moderate discriminative ability (AUC, 0.738). CONCLUSIONS: Automated CAC and %LAA added prognostic information to age, sex, and pack-years for predicting mortality but not LC incidence in an LC screening setting. Both biomarkers negatively correlated with FEV 1 , with %LAA enabling the identification of airflow obstruction with moderate discriminative ability.

Ascl1 and OTP tumour expressions are associated with disease-free survival in lung atypical carcinoids.

According to World Health Organization guidelines, atypical carcinoids (ACs) are well-differentiated lung neuroendocrine tumours with 2-10 mitoses/2 mm2 and/or foci of necrosis (usually punctate). Besides morphological criteria, no further tools in predicting AC clinical outcomes are proposed. The aim of this work was to identify novel factors able to predict AC disease aggressiveness and progression. METHODS AND RESULTS: Three hundred-seventy lung carcinoids were collected and centrally reviewed by two expert pathologists. Morphology and immunohistochemical markers (Ki-67, TTF-1, CD44, OTP, SSTR2A, Ascl1, p53, and Rb1) were studied and correlated with disease-free survival (DFS) and overall survival (OS). Fifty-eight of 370 tumours were defined as AC. Survival analysis showed that patients with Ascl1 + ACs and those with OTP-ACs had a significantly worse DFS than patients with Ascl1-ACs and OTP + ACs, respectively. Combining Ascl1 and OTP expressions, groups were formed reflecting the aggressiveness of disease (P = 0.0005). Ki-67 ≥10% patients had a significantly worse DFS than patients with Ki-67 <10%. At multivariable analysis, Ascl1 (present versus absent, hazard ratio [HR] = 3.42, 95% confidence interval [CI] 1.35-8.65, P = 0.009) and OTP (present versus absent, HR = 0.26, 95% CI 0.10-0.68, P = 0.006) were independently associated with DFS. The prognosis of patients with Ki-67 ≥10% tended to be worse compared to that with Ki-67 <10%. On the contrary, OTP (present versus absent, HR = 0.28, 95% CI 0.09-0.89, P = 0.03), tumour stage (III-IV versus I-II, HR = 4.25, 95% CI 1.42-12.73, P = 0.01) and increasing age (10-year increase, HR = 1.67, 95% CI 1.04-2.68, P = 0.03) were independently associated with OS. CONCLUSION: This retrospective analysis of lung ACs showed that Ascl1 and OTP could be the main prognostic drivers of postoperative recurrence.

Lung metastasectomy for osteosarcoma in children, adolescents, and young adults: proof of permanent cure.

INTRODUCTION: Surgical resection of pulmonary metastases has been associated with increased survival at 5 years for osteosarcoma, but limited information is available on long-term outcome, role of repeated metastasectomies, and surgical sequelae in a pediatric population. We analyzed a consecutive series of children, adolescents, and young adults (AYA) treated by repeated lung metastasectomies during a period >40 years to estimate the clinical benefit and potential cure rate of salvage surgery. METHODS: All patients who underwent lung metastasectomy for osteosarcoma at the IRCCS Istituto Ortopedico Rizzoli of Bologna, University of Modena, and IRCCS Istituto Nazionale Tumori of Milan from May 1973 to January 2014 were included. Overall survival (OS) at 20 years from the first metastasectomy was calculated. RESULTS: A total of 463 consecutive children and AYA were analyzed. Median age was 15.9 years (range 0.2-23.2 years) and median follow-up 18.6 years. The 5- and 20-year OS were 34.0% and 29.7% (95% CI 25.5-34.0%). Among the 138 (29.8%) alive patients, 42 (30.4%) had disease recurrence cured by repeated metastasectomies. Disease-free interval from primary tumor, number of metastases, and complete resection were the most relevant survival predictors at multivariable model analysis. DISCUSSION: The extended follow-up of this consecutive series shows that repeated lung metastasectomy can achieve a permanent cure when offered to properly selected patients with metastases from osteosarcoma.

Lung carcinoid tumours: histology and Ki-67, the eternal rivalry.

WHO classification of Thoracic Tumours defines lung carcinoid tumours (LCTs) as well-differentiated neuroendocrine neoplasms (NENs) classified in low grade typical (TC) and intermediate grade atypical carcinoids (AC). Limited data exist concerning protein expression and morphologic factors able to predict disease aggressiveness. Though Ki-67 has proved to be a powerful diagnostic and prognostic factor for Gastro-entero-pancreatic NENs, its role in lung NENs is still debated. A retrospective series of 370 LCT from two oncology centers was centrally reviewed. Morphology and immunohistochemical markers (Ki-67, TTF-1, CD44, OTP, SSTR-2A, Ascl1, and p53) were studied and correlated with Overall Survival (OS), Cancer-specific survival (CSS) and Disease-free survival (DFS). Carcinoid histology was confirmed in 355 patients: 297 (83.7%) TC and 58 (16.3%) AC. Ki-67 at 3% was the best value in predicting DFS. Ki-67 ≥ 3% tumours were significantly associated with AC histology, stage III-IV, smoking, vascular invasion, tumour spread through air spaces OTP negativity, and TTF-1, Ascl1 and p53 positivity. After adjustment for center and period of diagnosis, both Ki-67 (≥3 versus <3) and histology (AC versus TC) alone significantly added prognostic information to OS and CSS multivariable model with age, stage and OTP; addition of both variables did not provide further prognostic information. Conversely, an improved significance of the DFS prediction model at multivariate analysis was seen by adding Ki-67 (≥3 versus <3, P adj = 0.01) to TC and AC histological distinction, age, lymph node involvement, residual tumour and OTP. Ki-67 ≥ 3% plays a potentially pivotal role in LCT prognosis, irrespective of histological grade.

Prognostic Factors across Poorly Differentiated Neuroendocrine Neoplasms: A Pooled Analysis.

INTRODUCTION: Poorly differentiated neuroendocrine carcinomas (NECs) are characterized by aggressive clinical course and poor prognosis. No reliable prognostic markers have been validated to date; thus, the definition of a specific NEC prognostic algorithm represents a clinical need. This study aimed to analyze a large NEC case series to validate the specific prognostic factors identified in previous studies on gastro-entero-pancreatic and lung NECs and to assess if further prognostic parameters can be isolated. METHODS: A pooled analysis of four NEC retrospective studies was performed to evaluate the prognostic role of Ki-67 cut-off, the overall survival (OS) according to primary cancer site, and further prognostic parameters using multivariable Cox proportional hazards model and machine learning random survival forest (RSF). RESULTS: 422 NECs were analyzed. The most represented tumor site was the colorectum (n = 156, 37%), followed by the lungs (n = 111, 26%), gastroesophageal site (n = 83, 20%; 66 gastric, 79%) and pancreas (n = 42, 10%). The Ki-67 index was the most relevant predictor, followed by morphology (pure or mixed/combined NECs), stage, and site. The predicted RSF response for survival at 1, 2, or 3 years showed decreasing survival with increasing Ki-67, pure NEC morphology, stage III-IV, and colorectal NEC disease. Patients with Ki-67 <55% and mixed/combined morphology had better survival than those with pure morphology. Morphology pure or mixed/combined became irrelevant in NEC survival when Ki-67 was ≥55%. The prognosis of metastatic patients who did not receive any treatment tended to be worse compared to that of the treated group. The prognostic impact of Rb1 immunolabeling appears to be limited when multiple risk factors are simultaneously assessed. CONCLUSION: The most effective parameters to predict OS for NEC patients could be Ki-67, pure or mixed/combined morphology, stage, and site.