Two years progression-free survival under vinorelbine metronomic therapy of a patient with metastatic epithelioid hemangioendothelioma.

Epithelioid hemangioendothelioma (EHE) is a very rare vascular tumor, originating from endothelial cells. The etiology of EHE is unknown, yet at the molecular level, different angiogenic stimulators may act as promoters of endothelial cell proliferation. The tumor affects more commonly the lung, the liver and the bones but it can affect any other organ. Due to its heterogeneous presentation and its rarity it is often misdiagnosed. No treatment is proved to be efficient in metastatic EHE and the median survival of patients with metastatic pleural disease is generally poor, less than one year. we report a case of a 57-year-old female with multiple metastatic EHE including pleural, diagnosed by medical thoracoscopy, with a progression-free survival of 24 months with oral vinorelbine as maintenance therapy after combination of cisplatin-vinorelbine. We believe that this therapy might be of value to test in this patient population as it has never been tested before.

Burden of Comorbidities in Patients with OSAS and COPD-OSAS Overlap Syndrome.

Background and Objectives: Obstructive sleep apnea syndrome (OSAS) and chronic obstructive pulmonary disease (COPD) are usually associated with multi-morbidity. The aim of this study was to retrospectively investigate the prevalence of comorbidities in a cohort of patients with OSAS and COPD-OSAS overlap syndrome (OS) patients and to explore differences between these two groups. Materials and Methods: Included were consecutive OS patients and OSAS patients who had been referred to our sleep laboratory, and were matched in terms of sex, age, BMI, and smoking history. Presence of comorbidities was recorded based on their medical history and after clinical and laboratory examination. Results: The two groups, OS patients (n = 163, AHI > 5/h and FEV1/FVC < 0.7) and OSAS patients (n = 163, AHI > 5/h, and FEV1/FVC > 0.7), did not differ in terms of apnea hypopnea index (p = 0.346), and oxygen desaturation index (p = 0.668). Compared to OSAS patients, OS patients had lower average SpO2 (p = 0.008) and higher sleep time with oxygen saturation <90% (p = 0.002) during sleep, and lower PaO2 (p < 0.001) and higher PaCO2 (p = 0.04) in wakefulness. Arterial hypertension was the most prevalent comorbidity for both OS and OSAS, followed by dyslipidemia, cardiovascular disease (CVD) and diabetes. OS was characterized by a higher prevalence of total comorbidities (median (IQR):2 (1-3) vs. 2 (1-2), p = 0.033), which was due to the higher prevalence of CVD (p = 0.016) than OSAS. No differences were observed in other comorbidities. Conclusions: In OS patients, nocturnal hypoxia and impaired gas exchange in wakefulness are more overt, while a higher burden of CVD is observed among them in comparison to sex-, age- and BMI-matched OSAS patients.

Lung cancer in patients with Idiopathic Pulmonary Fibrosis. A retrospective multicenter study in Greece.

BACKGROUND: Abundant evidence supports an association between Idiopathic Pulmonary Fibrosis (IPF) and lung cancer development. Data on diagnosis and management of patients with IPF and lung cancer are still scarce. PATIENTS AND METHODS: This was a retrospective multicenter study, enrolling 1016 patients with IPF from eight different centers between 2011 and 2018 in Greece. Our aim was to estimate prevalence of lung cancer in patients with IPF in Greece. RESULTS: We identified 102 cases of patients with IPF and lung cancer (prevalence = 10.03% n = 102/1016, mean age±SD = 71.8 ± 6.9, 96 males, mean FVC±SD = 72.7 ± 19.7, mean DLCO±SD = 44.5 ± 16.3). We identified 85 cases (83.3%) of non-small cell lung cancer (35 squamous, 28 adenocarcinoma), and 15 cases (14.7%) of small cell lung cancer. Primary lesion was localized in lower lobes in 57.1% of cases. Lung cancer was diagnosed post IPF diagnosis (mean latency time + SD = 33.2 + 36.1 months) in 57.6% of patients and synchronously in 36.5% of patients. Chemotherapy was applied in 26.7% of cases, while 34.7% of patients underwent surgery. Median survival of patients with IPF and lung cancer was 27.4 months (95% CI: 20.6 to 36.8). CONCLUSIONS: IPF is a risk factor for lung cancer development. In line with current literature, squamous cell carcinoma is the most common histologic subtype in patients with IPF. Large randomized controlled studies on the management of patients with IPF and lung cancer are sorely needed.

Local Anesthesia Thoracoscopy with versus without Midazolam: A Randomized Controlled Trial.

BACKGROUND: Medical thoracoscopy is the gold standard for the diagnosis of pleural diseases. To date, no consensus exists regarding the choice of sedative and analgesic agents in patients undergoing local anesthetic thoracoscopy (LAT), and questions are raised as to whether sedatives may add to respiratory side effects. OBJECTIVE: The aim of the study was to test the hypothesis that administration of midazolam associated with lidocaine versus lidocaine alone in patients with LAT adds to respiratory side effects. METHODS: We randomly assigned 80 patients to a 1:1 study to 2 groups: local anesthesia by lidocaine (n = 40) versus lidocaine and midazolam (n = 40), with the primary end point being the mean lowest oxygen saturation. The secondary end points were cardiovascular parameters, complications, days of drainage, hospital stay, and patients' quality of life (QoL) as assessed by a visual analog scale (VAS). RESULTS: The mean age of all patients was 66.6 ± 13.1 years. The study comprised 50 males (62.5%). No difference was observed in the demographics between the 2 groups. No significant difference was observed between the 2 groups in oxygen saturation (primary end point). A significant difference was observed in favor of the midazolam group regarding the QoL assessed by VAS. CONCLUSION: Midazolam does not add to respiratory side effects when it is used with lidocaine for LAT, while patients' QoL is actually improved in this group. Therefore, in our department, we changed our startegy in favor of the association of lidocaine and midazolam.

Safety and efficacy of nintedanib in idiopathic pulmonary fibrosis: A real-life observational study in Greece.

BACKGROUND: Nintedanib represents an antifibrotic compound able to slow down disease progression of patients with idiopathic pulmonary fibrosis (IPF). OBJECTIVE: To investigate the safety and efficacy of nintedanib in patients with IPF in a real-life setting. METHODS: This was a multicentre, retrospective, observational, real-life study for patients with IPF receiving nintedanib between October 2014 and October 2016. RESULTS: We identified 94 patients with IPF receiving nintedanib (72 males, mean age±SD: 73.8 ±â€¯7.5, mean%FVC±SD = 68.1 ±â€¯18.3, mean%DLCo±SD = 44.4 ±â€¯14.5). Diarrhea (n = 52, 55.3%) was the most commonly reported adverse event. Twenty patients (21.2%) had to permanently discontinue nintedanib due to severe adverse events. In the 6-months follow-up, median decline in %FVC predicted and %DLCO predicted were 1.36 (95%Cl: 0 to 2.97) and 4.00 (95%Cl: 2.01 to 6.20), respectively, when deaths were censored and excluded from the analysis. At 12 months, mean%FVC±SD and mean%DLCo±SD were 64.5 ±â€¯19.1 and 43.7 ±â€¯15.4, respectively. With regards to mortality, 17 patients (18.1%) died over a study period of 730 days. CONCLUSION: Nintedanib demonstrated an acceptable safety and efficacy profile in our real-world observational study. Prospective observational studies in the context of registries that collect well-defined supporting data over time are sorely needed to answer residual questions on drug's performance.

Safety and efficacy of pirfenidone in severe Idiopathic Pulmonary Fibrosis: A real-world observational study.

BACKGROUND: Pirfenidone is a novel anti-fibrotic drug that has shown efficacy in five randomized multicenter clinical trials enrolling patients with Idiopathic Pulmonary Fibrosis of mild-to-moderate disease severity. Scarce data supports the use of pirfenidone in IPF patients with more advanced disease. OBJECTIVE: To investigate the safety and efficacy profile of pirfenidone in IPF patients with severe lung function impairment. PATIENTS AND METHODS: This was a retrospective study enrolling patients with advanced IPF (FVC%predicted < 50% and/or (DLco%predicted <35%) receiving pirfenidone for at least 6 months. RESULTS: Between September 2011 and March 2013, we identified 43 patients with severe IPF (baseline meanFVC%predicted±SD: 63.8 ± 20.3, meanDLCO%predicted: 27.3 ± 8.2), of mean age±SD: 66.3 + 9.7, 34 males (81%) that received pirfenidone (2.403 mg/daily) for one year. Pirfenidone treatment was associated with a trend towards decrease in functional decline compared to 6-months before treatment initiation but failed to show any benefit after one year of treatment (ΔFVC: -3.3 ± 4.6 vs 0.49 ± 11.4 and vs. -5.8 ± 11.8, p = 0.06 and p = 0.04, respectively and ΔDLCO: -13.3 ± 15.2 vs. -10.1 ± 16.6 and vs. 28.3 ± 19.2, p = 0.39 and p = 0.002, respectively). Gastrointestinal disorders (34.9%), fatigue (23.2%) and photosensitivity (18.6%) were the most common adverse events. Adverse events led to treatment discontinuation in 9 patients (20.9%) and dose reduction in 14 (32.5%). CONCLUSION: Pirfenidone appears to be safe when administered in patients with advanced IPF. Pirfenidone efficacy in IPF patients with severe lung function impairment may diminish after 6 months of treatment.

A prospective, non-randomized, no placebo-controlled, phase Ib clinical trial to study the safety of the adipose derived stromal cells-stromal vascular fraction in idiopathic pulmonary fibrosis.

INTRODUCTION: Regenerative medicine and particular adult stem cells represent an alternative option with several fruitful therapeutic applications in patients suffering from chronic lung diseases including idiopathic pulmonary fibrosis (IPF). Nevertheless, lack of knowledge regarding the origin and the potential of mesenchymal stem cells (MSCs) to differentiate into fibroblasts has limited their use for the treatment of this dismal disease. PATIENTS AND METHODS: To this end, we conducted a phase Ib, non-randomized, clinical trial to study the safety of three endobronchial infusions of autologous adipose derived stromal cells (ADSCs)-stromal vascular fraction (SVF) (0.5 million cells per kgr of body weight per infusion) in patients with IPF (n=14) of mild to moderate disease severity (forced vital capacity -FVC>50% predicted value and diffusion lung capacity for carbon monoxide-DLCO>35% of predicted value). Our primary end-point was incidence of treatment emergent adverse events within 12 months. Alterations of functional, exercise capacity and quality of life parameters at serial time points (baseline, 6 and 12 months after first infusion) were exploratory secondary end-points. RESULTS: No cases of serious or clinically meaningful adverse events including short-term infusional toxicities as well as long-term ectopic tissue formation were recorded in all patients. Detailed safety monitoring through several time-points indicated that cell-treated patients did not deteriorate in both functional parameters and indicators of quality of life. CONCLUSIONS: The clinical trial met its primary objective demonstrating an acceptable safety profile of endobronchially administered autologous ADSCs-SVF. Our findings accelerate the rapidly expanded scientific knowledge and indicate a way towards future efficacy trials.

Stem cell treatment for chronic lung diseases.

Chronic lung diseases such as idiopathic pulmonary fibrosis and cystic fibrosis or chronic obstructive pulmonary disease and asthma are leading causes of morbidity and mortality worldwide with a considerable human, societal and financial burden. In view of the current disappointing status of available pharmaceutical agents, there is an urgent need for alternative more effective therapeutic approaches that will not only help to relieve patient symptoms but will also affect the natural course of the respective disease. Regenerative medicine represents a promising option with several fruitful therapeutic applications in patients suffering from chronic lung diseases. Nevertheless, despite relative enthusiasm arising from experimental data, application of stem cell therapy in the clinical setting has been severely hampered by several safety concerns arising from the major lack of knowledge on the fate of exogenously administered stem cells within chronically injured lung as well as the mechanisms regulating the activation of resident progenitor cells. On the other hand, salient data arising from few 'brave' pilot investigations of the safety of stem cell treatment in chronic lung diseases seem promising. The main scope of this review article is to summarize the current state of knowledge regarding the application status of stem cell treatment in chronic lung diseases, address important safety and efficacy issues and present future challenges and perspectives. In this review, we argue in favor of large multicenter clinical trials setting realistic goals to assess treatment efficacy. We propose the use of biomarkers that reflect clinically inconspicuous alterations of the disease molecular phenotype before rigid conclusions can be safely drawn.

Relationship Between Intra-Abdominal pressure and microaspiration of gastric contents in critically ill mechanically ventilated patients.

The relationship between increased intra-abdominal pressure (IAP) and microaspiration of oro-gastric content in mechanically-ventilated patients has not yet been established. Microaspiration is proposed as one of the causes of ventilator-associated pneumonia (VAP). We aimed to investigate whether mechanically-ventilated patients with increased IAP present evidence of lung microaspiration by assessing pepsin levels in bronchial secretions and evaluated the relationship between pepsin and VAP. 68 mechanically-ventilated patients and 10 control subjects were recruited from an academic ICU in Greece. IAP, pH, pepsin and total protein levels, in bronchial secretions, were assessed within 14 days. Patients underwent assessment for timely VAP diagnosis based on clinical, radiological and laboratory criteria. Pepsin and total protein levels were significantly elevated in patients compared to controls. Pepsin values correlated significantly with IAP (r = 0.61, ***p < 0.001). Multivariate regression analysis showed that IAP was an independent risk factor for increased pepsin values in bronchial secretions [OR95%CI 1.463(1.061-1.620), *p = 0.014]. Pepsin values were higher in patients with VAP, while IAP was independently associated with VAP. There was an indication towards increased VAP in patients with increased pepsin. In conclusion, our results show that pepsin in bronchial secretions may be elevated when IAP is increased, indicating microaspiration and potentially VAP.

Into the matrix: targeting fibroblasts in pulmonary fibrosis.

PURPOSE OF REVIEW: This review describes the challenges created by the existence of multiple molecular pathways leading to fibrosis and proposes that attention be focused on targeting the fibroblasts and myofibroblasts which themselves produce multiple cytokines and growth factors as well as the extracellular matrix, which is the hallmark of fibrotic lung disease. RECENT FINDINGS: The last 20 years have seen remarkable progress in our understanding of the molecular pathogenesis of pulmonary fibrosis leading to multiple programmes in drug discovery, and there are currently 15 actively recruiting trials registered on http://www.clinicaltrials.gov. Unfortunately, at this time only one new drug, pirfenidone, has progressed to approval for use in patients. Part of the frustration is that drugs that are effective in targeting inflammatory pathways have been ineffective in lung fibrosis. This may result from the inability to treat patients early in the disease process but it is also likely that pathways independent of inflammation can drive fibrosis. SUMMARY: We further propose that this approach should inhibit fibrosis independent of cell type or the signalling cascade that is activating these cells. We are hopeful that the next 20 years will see many more therapeutic options for patients suffering with fibrotic lung disease.

Hypersensitivity pneumonitis in a slaughterhouse worker: A case report.

This case report describes a 60-year-old male, who presented to the Respiratory Outpatient Unit due to dyspnea on exertion and persistent dry cough, worsened during the preceding 6 months. He was nonsmoker with an otherwise unremarkable medical history and had been working in a sheep/goat slaughterhouse for the last 25 years. He recalled a number of episodes of flu-like symptoms in the past that subsided without any specific treatment. Given the compatible occupational history, the radiologic pattern in chest High-Resolution Computed Tomography and the Bronchoalveolar Lavage subpopulation analysis, hypersensitivity pneumonitis was diagnosed, and the patient was advised to leave temporarily his current occupational activity. Four weeks later, clinical and functional improvement was observed. A permanent job change was subsequently suggested, and sustained improvement was confirmed during his follow-up at 3 months.

Stem cell therapy for idiopathic pulmonary fibrosis: a protocol proposal.

BACKGROUND: Idiopathic pulmonary fibrosis represents a lethal form of progressive fibrotic lung disorder with gradually increasing incidence worldwide. Despite intense research efforts its pathogenesis is still elusive and controversial reflecting in the current disappointing status regarding its treatment. PATIENTS AND METHODS: We report the first protocol proposal of a prospective, unicentric, non-randomized, phase Ib clinical trial to study the safety and tolerability of the adipose-derived stem cells (ADSCs) stromal vascular fraction (SVF) as a therapeutic agent in IPF. After careful patient selection based on functional criteria (forced vital capacity-FVC > 50%, diffuse lung capacity for carbon monoxide-DLCO > 35% of the predicted values) all eligible subjects will be subjected to lipoaspiration resulting in the isolation of approximately 100- 500 gr of adipose tissue. After preparation, isolation and labelling ADSCs-SVF will be endobronchially infused to both lower lobes of the fibrotic lungs. Procedure will be repeated thrice at monthly intervals. Primary end-point represent safety and tolerability data, while exploratory secondary end-points include assessment of clinical functional and radiological status. RESULTS: Preliminary results recently presented in the form of an abstract seem promising and tantalizing since there were no cases of clinically significant allergic reactions, infections, disease acute exacerbations or ectopic tissue formation. In addition 6 months follow-up data revealed a marginal improvement at 6-minute walking distance and forced vital capacity. CONCLUSIONS: Adipose tissue represents an abundant, safe, ethically uncontested and potentially beneficial source of stem cells for patients with IPF. Larger multicenter phase II and III placebo-controlled clinical trials are sorely needed in order to prove efficacy. However, pilot safety studies are of major importance and represent the first hamper that should be overcome to establish a rigid basis for larger clinical trials.

Lung Nodules and Hypoxemia: Any Association?

Pulmonary arteriovenous malformations (PAVMs) consist of aberrant circulation between pulmonary arteries and veins causing right-to-left shunt, uncommon and asymptomatic in the general population. We presented two patients, one presented with unexplained dyspnea and disease limited to the lung and the other with neurologic signs and systematic disease. Both patients were diagnosed with arteriovenous malformations and received embolization treatment successfully. Both patients received embolization treatment successfully.

The Role of Microbiome and Virome in Idiopathic Pulmonary Fibrosis.

The interest in the lung microbiome and virome and their contribution to the pathogenesis, perpetuation and progression of idiopathic pulmonary fibrosis (IPF) has been increasing during the last decade. The utilization of high-throughput sequencing to detect microbial and/or viral genetic material in bronchoalveolar lavage fluid or lung tissue samples has amplified the ability to identify and quantify specific microbial and viral populations. In stable IPF, higher microbial burden is associated with worse prognosis but no specific microbe has been identified to contribute to this. Additionally, no causative relation has been established. Regarding viral infections, although in the past they have been associated with IPF, causation has not been proved. Although in the past the diagnosis of acute exacerbation of IPF (AE-IPF) was not considered in patients with overt infection, this was amended in the last few years and infection is considered a cause for exacerbation. Besides this, a higher microbial burden has been found in the lungs of patients with AE-IPF and an association with higher morbidity and mortality has been confirmed. In contrast, an association of AE-IPF with viral infection has not been established. Despite the progress during the last decade, a comprehensive knowledge of the microbiome and virome in IPF and their role in disease pathogenesis are yet elusive. Although association with disease severity, risk for progression and mortality has been established, causation has not been proven and the potential use as a biomarker or the benefits of antimicrobial therapeutic strategies are yet to be determined.

Chemotherapy-induced changes in bronchoalveolar lavage fluid CD4 + and CD8 + cells of the opposite lung to the cancer.

Published articles support the effect of chemotherapy in the immune environment of tumors, including lung carcinomas. The role of CD4 + T-cells is crucial for expansion and accumulation of other antigen-specific immune cells, and the participation of CD8 + cells in tumor killing activity has been confirmed by many studies. However, little is known about the effect of chemotherapy on the healthy lung parenchyma from lung cancer patients, and whether there are differences between the different chemotherapy compounds used to treat this patient population. The aim of our study was to explore the effect of chemotherapy on CD4 + and CD8 + cells in the bronchoalveolar lavage fluid (BALF) of the healthy lung in patients treated with standard chemotherapy regimens. Fifteen patients underwent BAL, in the healthy lung before and after six chemotherapy courses. Platinum-based regimens included vinolerbine (VN) in 6 patients, gemcitabine (GEM) in 4 patients and etoposide (EP) in 5 patients. All patients but one were males and smokers (93%). The median age of patients was 56 years (42-75). No significant difference was noted in the patients' age between the three treated groups. Furthermore, between the three groups, no significant changes in the means of CD4 + and CD8 + cells were noted. However, when we compared the mean CD4 + cells before and after chemotherapy within each group, changes were noted when comparing VN before versus after (p = 0.05), GEM before versus after (p = 0.03), and EP before versus after (p = 0.036). In our pilot study, changes were noted in BALF CD4 + cells for the three most applied regimens at the normal lung parenchyma.

Solitary glandular papilloma of the lung with molecular analysis: A case report and literature review.

BACKGROUND: Solitary papillomas of the lung are rare. One of their subtypes is glandular papilloma with only a very few cases described in the literature. We describe a case of pulmonary glandular papilloma with emphasis in its differential diagnosis and its molecular analysis. CASE DESCRIPTION: A 64-years old former smoker was incidentally found to have an endobronchial tumor of the right main bronchus. Microscopic and immunohistochemical findings revealed a glandular papilloma. EGFR, KRAS and BRAF V600E mutation analysis, as well as HPV detection analysis revealed no mutation or HPV infection. Detailed differential diagnosis and literature review are presented. CONCLUSION: Glandular papillomas of the lung are usually central, affecting older patients than squamous or mixed squamous cell and glandular papillomas. In previously reported cases, one glandular papilloma with KRAS mutation and another one with BRAF mutation have been reported. The present case harbored no mutation or HPV infection.

Cell Therapy for Idiopathic Pulmonary Fibrosis: Rationale and Progress to Date.

Idiopathic pulmonary fibrosis (IPF) is a devastating disease characterized by progressive lung scarring due to unknown injurious stimuli ultimately leading to respiratory failure. Diagnosis is complex and requires a combination of clinical, laboratory, radiological, and histological investigations, along with exclusion of known causes of lung fibrosis. The current understanding of the disease etiology suggests an interaction between genetic factors and epigenetic alterations in susceptible, older individuals. Prognosis is dismal and current treatment options include anti-fibrotic agents that only slow down disease progression and carry considerable side effects that hamper patients' quality of life. Therefore, the need for new, more effective treatments, alone or in combination with existing pharmacotherapy, is sorely needed. Regenerative medicine, the potential use of cell therapies to treat destructive diseases that cause architectural distortion to the target organ, has also emerged as an alternative therapeutic for lung diseases with unfavorable prognosis such as IPF. Mesenchymal stem cells (MSCs) and type II alveolar epithelial cells (AEC2s) have been used and their safety has been demonstrated. In the case of MSCs, both homogenic and allogeneic sources have been used and both are considered viable options without immunosuppressive therapy, taking into consideration the absence of immunogenicity and HLA response. AEC2s have been used in one trial with promising results but their use requires a deceased donor and immunosuppressive pre-treatment. In this review, we briefly summarize the current state of knowledge regarding the pathogenesis of IPF, and the background and rationale for using MSCs or AEC2s as potential treatment options. We list and describe the clinical trials completed to date and provide a comparison of their methods and results as well as a possible way forward.

Clinical long-term outcome of non-specific pleuritis (NSP) after surgical or medical thoracoscopy.

BACKGROUND: Thoracoscopy, either "medical" or "surgical", is the gold standard to reveal the cause of pleural effusion by taking large biopsies. However, in some cases, the histology of pleural biopsies is inconclusive for a specific cause, describing a variable process of inflammation, encompassing for non-specific pleuritis (NSP). Questions are raised whether the surgical (or video-assisted thoracoscopic surgery, VATS) is doing better than the medical thoracoscopy (MT or pleuroscopy), but no direct comparison between the two techniques exist in the current bibliography. The aim of our retrospective study was to compare these two techniques to find whether there is any difference in the false negative cases of NSP. METHODS: We included in our study 295 patients with NSP, 179 patients who underwent VATS comparing to 116 patients who underwent MT for pleural effusion of initially undetermined cause, having a follow-up of at least one year. Analysis of patients' files, history, clinical examinations, further tests, and follow-up were recorded. RESULTS: The mean age of our patients was 58.5±19.1 and M/F gender was 216/79; no difference was observed between the two groups. The mean follow-up period was 47.3±20.7 months. After VATS, only one patient (0.55%) was finally diagnosed with pleural malignancy (false negative) while after MT 2 patients (1.7%). Negative predictive value for pleura-related malignancy for VATS was 0.994 and for MT 0.982. CONCLUSIONS: In patients with histological diagnosis of NSP both VATS and MT showed similar and excellent results of false negative cases and negative predictive value in excluding malignant pleural disease.

Deciphering the genomic, epigenomic, and transcriptomic landscapes of pre-invasive lung cancer lesions.

The molecular alterations that occur in cells before cancer is manifest are largely uncharted. Lung carcinoma in situ (CIS) lesions are the pre-invasive precursor to squamous cell carcinoma. Although microscopically identical, their future is in equipoise, with half progressing to invasive cancer and half regressing or remaining static. The cellular basis of this clinical observation is unknown. Here, we profile the genomic, transcriptomic, and epigenomic landscape of CIS in a unique patient cohort with longitudinally monitored pre-invasive disease. Predictive modeling identifies which lesions will progress with remarkable accuracy. We identify progression-specific methylation changes on a background of widespread heterogeneity, alongside a strong chromosomal instability signature. We observed mutations and copy number changes characteristic of cancer and chart their emergence, offering a window into early carcinogenesis. We anticipate that this new understanding of cancer precursor biology will improve early detection, reduce overtreatment, and foster preventative therapies targeting early clonal events in lung cancer.