The Role of Biomarkers in Lung Cancer Screening.

BACKGROUND: Lung Cancer Screening (LCS) is an evolving field with variations in its implementation in various countries. There are only scarce data from National LCS programs. AIM: We aim to provide an up-to-date overview of the current evidence regarding the use of biomarkers in LCS. MATERIALS AND METHODS: A multidisciplinary Task Force experts' panel collaborated and conducted a systematic literature search, followed by screening, review and synthesis of available evidence. RESULTS: Biomarkers in LCS could be used to improve risk stratification in high-risk participants, improve clarification regarding indeterminate lung nodules and avoid overdiagnosis in suspicious lung findings. Currently, there seem to be promising biomarkers (blood/serum/breath) that have been studied in various trials; however, there is still a lack of solid evidence in clinical validation that would pave the way for their integration into LCS programs. CONCLUSIONS: Biomarkers are the next logical step in improving the LCS pathway and its efficiency by playing an adjuvant role in a minimally invasive way. National LCS programs and pilot studies should integrate biomarkers to validate their accuracy in real-life LCS participants.

The Effectiveness of Atezolizumab in Metastatic Large Cell Neuroendocrine Carcinoma of the Lungs: Insights from the LANCE Pilot Study.

BACKGROUND: Large cell neuroendocrine carcinoma (LCNEC) presents significant treatment challenges due to its rarity and limited therapeutic options. The LANCE study was designed to explore the survival benefits of incorporating atezolizumab in chemotherapy for metastatic LCNEC. METHODS: In this non-randomized study, patients with metastatic LCNEC were prospectively enrolled and assigned to receive either standard chemotherapy plus atezolizumab followed by maintenance with atezolizumab or standard chemotherapy alone. The primary outcomes measured were 12- and 24-month survival rates, progression-free survival (PFS), and overall survival (OS) between the two groups. RESULTS: Of the 22 patients screened, 17 met the inclusion criteria and received either atezolizumab plus platinum-based chemotherapy (n = 10) or chemotherapy alone (n = 7). After a median follow-up of 23.3 months, the 12-month survival rate was 57.1% (95% CI: 32.6-100%) and 14.3% (95% CI: 2.33-87.7%) for the atezolizumab and the chemotherapy-only groups, respectively. The survival benefit for the atezolizumab group was sustained at 24 months (45.7% vs. 14.3%). Overall survival was significantly higher for the atezolizumab group, and PFS was non-significantly associated with the addition of atezolizumab (log-rank p = 0.04 and 0.05, respectively). CONCLUSIONS: This pilot study suggests that the addition of atezolizumab to standard platinum-based chemotherapy may provide a substantial survival benefit compared with chemotherapy alone in the first-line treatment of metastatic LCNEC.

Real-World Data and Evidence in Lung Cancer: A Review of Recent Developments.

Conventional cancer clinical trials can be time-consuming and expensive, often yielding results with limited applicability to real-world scenarios and presenting challenges for patient participation. Real-world data (RWD) studies offer a promising solution to address evidence gaps and provide essential information about the effects of cancer treatments in real-world settings. The distinction between RWD and data derived from randomized clinical trials lies in the method of data collection, as RWD by definition are obtained at the point of care. Experimental designs resembling those used in traditional clinical trials can be utilized to generate RWD, thus offering multiple benefits including increased efficiency and a more equitable balance between internal and external validity. Real-world data can be utilized in the field of pharmacovigilance to facilitate the understanding of disease progression and to formulate external control groups. By utilizing prospectively collected RWD, it is feasible to conduct pragmatic clinical trials (PCTs) that can provide evidence to support randomized study designs and extend clinical research to the patient's point of care. To ensure the quality of real-world studies, it is crucial to implement auditable data abstraction methods and develop new incentives to capture clinically relevant data electronically at the point of care. The treatment landscape is constantly evolving, with the integration of front-line immune checkpoint inhibitors (ICIs), either alone or in combination with chemotherapy, affecting subsequent treatment lines. Real-world effectiveness and safety in underrepresented populations, such as the elderly and patients with poor performance status (PS), hepatitis, or human immunodeficiency virus, are still largely unexplored. Similarly, the cost-effectiveness and sustainability of these innovative agents are important considerations in the real world.

Robotic Bronchoscopy in Lung Cancer Diagnosis.

BACKGROUND: The widespread use of chest CT has increased the number of detected pulmonary nodules. Nodules with intermediate risk of malignancy warrant further evaluation with PET-CT or sampling. Although sampling with conventional bronchoscopy presents lower complication rates compared to transthoracic needle biopsy (TTNB), it is limited by the inability to reach distal airways. To overcome this shortcoming, a new bronchoscopic technique named robotic bronchoscopy (RB) has emerged. METHODS: A literature review was used to clarify the rationale behind RB emergence, describe RB procedure, and summarize data regarding its efficacy and safety. RESULTS: The FDA has approved three RB platforms for clinical use. RB is safe, presenting a mortality and complication rate of 0% and 0-8.1%, respectively. Common complications include pneumothorax (0-5.7%) and minor bleeding (0-3.2%). However, its diagnostic yield remains lower than that of TTNB. CONCLUSIONS: RB is a promising bronchoscopic technique that aims to overcome the limitations of conventional bronchoscopy and improve upon the current techniques of guided bronchoscopy for the investigation of pulmonary nodules. Despite the lower complication rate, current evidence suggests a lower diagnostic yield compared to TTNB. Additional studies are required to adequately evaluate the role of RB in the diagnosis of pulmonary nodules.

Lung Cancer Proteogenomics: Shaping the Future of Clinical Investigation.

BACKGROUND: Lung cancer is associated with a high incidence of mortality worldwide. Molecular mechanisms governing the disease have been explored by genomic studies; however, several aspects remain elusive. The integration of genomic profiling with in-depth proteomic profiling has introduced a new dimension to lung cancer research, termed proteogenomics. The aim of this review article was to investigate proteogenomic approaches in lung cancer, focusing on how elucidation of proteogenomic features can evoke tangible clinical outcomes. METHODS: A strict methodological approach was adopted for study selection and key article features included molecular attributes, tumor biomarkers, and major hallmarks involved in oncogenesis. RESULTS: As a consensus, in all studies it becomes evident that proteogenomics is anticipated to fill significant knowledge gaps and assist in the discovery of novel treatment options. Genomic profiling unravels patient driver mutations, and exploration of downstream effects uncovers great variability in transcript and protein correlation. Also, emphasis is placed on defining proteogenomic traits of tumors of major histological classes, generating a diverse portrait of predictive markers and druggable targets. CONCLUSIONS: An up-to-date synthesis of landmark lung cancer proteogenomic studies is herein provided, underpinning the importance of proteogenomics in the landscape of personalized medicine for combating lung cancer.

Artificial Intelligence-Based Treatment Decisions: A New Era for NSCLC.

Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related mortality among women and men, in developed countries, despite the public health interventions including tobacco-free campaigns, screening and early detection methods, recent therapeutic advances, and ongoing intense research on novel antineoplastic modalities. Targeting oncogenic driver mutations and immune checkpoint inhibition has indeed revolutionized NSCLC treatment, yet there still remains the unmet need for robust and standardized predictive biomarkers to accurately inform clinical decisions. Artificial intelligence (AI) represents the computer-based science concerned with large datasets for complex problem-solving. Its concept has brought a paradigm shift in oncology considering its immense potential for improved diagnosis, treatment guidance, and prognosis. In this review, we present the current state of AI-driven applications on NSCLC management, with a particular focus on radiomics and pathomics, and critically discuss both the existing limitations and future directions in this field. The thoracic oncology community should not be discouraged by the likely long road of AI implementation into daily clinical practice, as its transformative impact on personalized treatment approaches is undeniable.

High-dose bevacizumab for radiation-induced brain necrosis: a case report.

Radiation-induced brain necrosis (RIBN) is a common adverse event from radiation therapy. We present a case of a 56-year-old man, diagnosed with non-small-cell lung cancer with brain metastases 2 years prior, for which he had received whole brain radiotherapy and brain stereotactic radiosurgery, who presented to the oncology unit with headache, dizziness and abnormal gait. MRI of the brain revealed radiological worsening of a cerebellar mass, including edema and mass effect. After a multidisciplinary tumor board meeting, the patient was diagnosed with RIBN and received 4 cycles of high-dose bevacizumab, with complete symptom resolution and significant radiological response. We report the successful use of a high-dose, shorter-duration treatment protocol of bevacizumab for RIBN.

Radiation therapy, which is commonly used in the treatment of cancer, often causes cells to die. We report the case of a 56-year-old man with lung cancer that had spread to his brain, who received radiation therapy, but later experienced symptoms like headache, dizziness and difficulty walking. Scans showed that the radiation had caused damage to his brain, specifically a mass in the cerebellum. The patient received bevacizumab, a drug that inhibits the growth of new blood vessels, in a higher dose than usual but for fewer times overall. After treatment, the patient was completely symptom-free, while the scans showed significant improvement.

Radiomics/Radiogenomics in Lung Cancer: Basic Principles and Initial Clinical Results.

Lung cancer is the leading cause of cancer-related deaths worldwide, and elucidation of its complicated pathobiology has been traditionally targeted by studies incorporating genomic as well other high-throughput approaches. Recently, a collection of methods used for cancer imaging, supplemented by quantitative aspects leading towards imaging biomarker assessment termed "radiomics", has introduced a novel dimension in cancer research. Integration of genomics and radiomics approaches, where identifying the biological basis of imaging phenotypes is feasible due to the establishment of associations between molecular features at the genomic-transcriptomic-proteomic level and radiological features, has recently emerged termed radiogenomics. This review article aims to briefly describe the main aspects of radiogenomics, while discussing its basic limitations related to lung cancer clinical applications for clinicians, researchers and patients.

Malignant Superior Vena Cava Syndrome: State of the Art.

Superior vena cava syndrome (SVCS) is a clinical entity characterized by signs and symptoms arising from the obstruction or occlusion of the thin-walled superior vena cava (SVC) and can result in significant morbidity and mortality. Despite the rise of benign cases of SVCS, as a thrombotic complication of intravascular devices, it is most commonly seen secondary to malignancy as a consequence of thrombosis, direct invasion of tumor cells inside the vessel, or external compression. SVCS can be the initial presentation of a previously undiagnosed tumor in up to 60% of cases. Lung cancer and non-Hodgkin lymphoma (NHL) are responsible for up to 85%-90% of malignancy-related SVCS, while metastatic cancers account for approximately 10%. Herein, we review the pathophysiology, etiology, clinical presentation, diagnosis, and management of malignancy-related SVCS.

Risk Factors for Venous Thromboembolism in Patients With Small Cell Lung Cancer.

BACKGROUND/AIM: Small cell lung cancer (SCLC) accounts for 13% of all lung cancers. Venous thromboembolism (VTE) is a frequent complication. The purpose of this study was to investigate the incidence and risk factors for VTE in SCLC patients. PATIENTS AND METHODS: Retrospective analysis of patients with histologically confirmed SCLC treated between January 2015 and June 2018 at Sotiria General Hospital, Athens, Greece. RESULTS: Two hundred and seventeen patients were included in the analysis. The incidence of VTE was 4.1%. Increased body mass index (BMI) was correlated with the development of VTE. Moreover, VTE appeared more frequently in patients with major vessel infiltration and with poor Eastern Cooperative Oncology Group Performance Status. Other factors, including gender, age, stage, presence of metastasis, treatment, immobilization, anticoagulation, comorbidities, and laboratory values did not correlate with the development of VTE. CONCLUSION: Factors associated with the development of VTE were BMI, major vessel infiltration and PS. Identifying factors that predispose to VTE could help physicians detect high-risk patients who would benefit from prophylactic anticoagulation therapy.

Clinical utility of thoracic endosonography (EBUS/EUS-b) in mediastinal staging of patients with non-small cell lung cancer: comparison with integrated PET/CT-a real-life prospective study in Greece.

BACKGROUND: Accurate mediastinal staging in patients with non-small cell lung cancer (NSCLC) is crucial for the determination of optimal treatment management. METHODS: This was a real-life prospective study enrolling 140 patients between December 2016 and August 2018. We aimed to determine the clinical utility of EBUS/EUS-b in mediastinal staging of patients with NSCLC in comparison with integrated PET/CT. Furthermore, SUVmax cut-off value with the highest specificity/accuracy was evaluated. Subgroup analysis according to histological type was performed. RESULTS: One hundred and thirty patients were eligible for analysis (mean age ± SD: 67.6±7.6, males 97). Three hundred different lymph node stations were sampled (272 through EBUS-TBNA and 28 through EUS-b FNA). Mean SUVmax of all malignant lymph nodes was 7.46 (SD =5.54). Sensitivity, specificity, PPV and NPV of EBUS/EUS-b for the identification of mediastinal malignant lymph nodes was 93.8%, 100%, 100%, and 93.4%, respectively. Accordingly, PET/CT yielded 92.2% sensitivity, 43.9% specificity, 64.8% PPV and 83.3% NPV. For adenocarcinoma (n=76) NPV were 86.2% with EBUS/EUS-b and 75% with PET/CT. NPV for squamous cell (n=46) was 100% with EBUS/EUS-b and 90.9% with PET/CT. EBUS/EUS-b staging yielded excellent agreement with final staging (97.5%, Tau 0.94, P<0.001). ROC curve analysis identified the value 4.95 as the optimal SUVmax cut-off value with the best specificity (87.4%) and accuracy (79%) (AUC 0.69; 95% CI: 0.73-0.84, P<0.001). CONCLUSIONS: Thoracic endosonography is an excellent, minimally invasive tool yielding high sensitivity and diagnostic accuracy in mediastinal staging of patients with NSCLC. Implementation of both EBUS/EUS-b and PET/CT is necessary before any surgical intervention.

Modern radiopharmaceuticals for lung cancer imaging with positron emission tomography/computed tomography scan: A systematic review.

INTRODUCTION: In this study, we evaluated the use and the contribution of radiopharmaceuticals to the field of lung neoplasms imaging using positron emission tomography/computed tomography. METHODS: We conducted review of the current literature at PubMed/MEDLINE until February 2020. The search language was English. RESULTS: The most widely used radiopharmaceuticals are the following:Experimental/pre-clinical approaches: (18)F-Misonidazole (18F-MISO) under clinical development, D(18)F-Fluoro-Methyl-Tyrosine (18F-FMT), 18F-FAMT (L-[3-18F] (18)F-Fluorothymidine (18F-FLT)), (18)F-Fluoro-Azomycin-Arabinoside (18F-FAZA), (68)Ga-Neomannosylated-Human-Serum-Albumin (68Ga-MSA) (23), (68)Ga-Tetraazacyclododecane (68Ga-DOTA) (as theranostic agent), (11)C-Methionine (11C-MET), 18F-FPDOPA, ανß3 integrin, 68Ga-RGD2, 64Cu-DOTA-RGD, 18F-Alfatide, Folate Radio tracers, and immuno-positron emission tomography radiopharmaceutical agents.Clinically approved procedures/radiopharmaceuticals agents: (18)F-Fluoro-Deoxy-Glucose (18F-FDG), (18)F-sodium fluoride (18F-NaF) (bone metastases), and (68)Ga-Tetraazacyclododecane (68Ga-DOTA). The quantitative determination and the change in radiopharmaceutical uptake parameters such as standard uptake value, metabolic tumor volume, total lesion glycolysis, FAZA tumor to muscle ratio, standard uptake value tumor to liver ratio, standard uptake value tumor to spleen ratio, standard uptake value maximum ratio, and the degree of hypoxia have prognostic and predictive (concerning the therapeutic outcome) value. They have been associated with the assessment of overall survival and disease free survival. With the positron emission tomography/computed tomography radiopharmaceuticals, the sensitivity and the specificity of the method have increased. CONCLUSION: In terms of lung cancer, positron emission tomography/computed tomography may have clinical application and utility (a) in personalizing treatment, (b) as a biomarker for the estimation of overall survival, disease free survival, and (c) apply a cost-effective patient approach because it reveals focuses of the disease, which are not found with the other imaging methods.

Psychological correlates of sleep quality in lung cancer patients under chemotherapy: A single-center cross-sectional study.

OBJECTIVES: Disturbed sleep is a common complaint of lung cancer patients undergoing active oncologic treatment. We aimed to clarify the extent to which psychological symptoms, coping strategies, and social support interfere with sleep quality and whether they mediate the relationship between sleep quality and fatigue or functional capacity in a sample of chemotherapy treated lung cancer patients. METHODS: Lung cancer patients attending an oncology unit for scheduled chemotherapy cycles completed questionnaires assessing their sleep quality, fatigue, depression, anxiety, stress, coping, social support, symptoms of pain, dyspnea, and cough, and sleep hygiene practices. Demographic and disease-related characteristics were obtained from patients' medical records and treating physicians rated their functional status. Multivariate regression and mediation analyses were applied to test the study's hypotheses. RESULTS: One hundred nineteen patients were enrolled, 58.2% of whom were identified as poor sleepers. After adjusting for age, gender, comorbidities, concomitant medications, cancer stage, prior and ongoing treatment, sleep hygiene, and symptoms, there was a statistically significant association between poor sleep quality and anxiety (odd`s ratio [OR] 1.17 [95% CI, 1.01-1.35]), stress (OR 1.14 [95% CI, 1.04-1.25]), and positive coping (OR 1.15 [95% CI, 1.02-1.31]). Poor sleep quality was an independent correlate of fatigue (B 1.56 [95% CI, 0.61-2.50]) and low performance status (OR 5.17 [95% CI, 1.60-16.72]); stress symptoms partially mediated the relationship between sleep quality and fatigue (P = .030). CONCLUSIONS: Higher psychological burden predict sleep disturbances and contribute to increased fatigue in lung cancer patients undergoing chemotherapy. Effective psychoeducational interventions may benefit these populations.

Sarcoidosis-Like Reactions Induced by Checkpoint Inhibitors.

Immune checkpoint inhibitors (ICIs) are a newly developed component of cancer care that expands the treatment possibilities for patients. Their use has been associated with several immune-related adverse events, including ICI-induced sarcoidosis-like reactions. This article reviews the data concerning ICI-induced sarcoidosis-like reactions currently available in the medical literature. These reactions have been reported in three classes of ICIs: anti-cytotoxic T-lymphocyte associated protein 4 antibodies, programmed death 1 inhibitors and programmed death ligand 1 inhibitors. These reactions are indistinguishable from sarcoidosis with a similar histology, pattern of organ involvement, and pattern of clinical manifestations. The most common locations to observe granulomatous inflammation from these reactions is in intrathoracic locations (the lung and/or mediastinal lymph nodes) and the skin. The median time between initiation of an ICI and the development of a sarcoidosis-like reaction averaged 14 weeks. Clinicians have opted to use corticosteroids and/or discontinue the ICI, or take no action when these reactions have developed. Regardless of whether the clinician performed an intervention or not, these reactions have uniformly improved or resolved after ICI-treatment, which provides additional temporal evidence supporting the presence of a sarcoidosis-like reaction as opposed to sarcoidosis. There is even evidence that the development of an ICI-induced sarcoidosis-like reaction suggests that the ICI is effective as an anti-tumor agent and should be continued. As is the case for sarcoidosis, sarcoidosis-like reactions do not mandate antisarcoidosis therapy, especially if the condition is asymptomatic. When treatment of sarcoidosis-like reaction is required, it may be prudent to continue ICI therapy and add antisarcoidosis therapy because standard antisarcoidosis regimens seem to be effective. Further research into the mechanisms involved in the development of ICI-induced sarcoidosis-like reactions may give insights into the immunopathogenesis of sarcoidosis.

Erlotinib-Associated Rash in Advanced Non-Small Cell Lung Cancer: Relation to Clinicopathological Characteristics, Treatment Response, and Survival.

Systematic treatment of advanced non-small cell lung cancer (NSCLC) includes targeted treatment with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs). The development of skin rash and its intensity have been associated with EGFR TKI's efficacy. The main purpose of this study was to further investigate the potential value of erlotinib-associated rash as a predictor of prognosis and treatment response in a real-world cohort of patients with advanced NSCLC. The medical records of all NSCLC patients treated with erlotinib at the Oncology Unit of GPP, Sotiria Athens General Hospital between January 1, 2014 and August 31, 2016 were retrospectively reviewed. Seventy-nine patient medical records fulfilled the criteria and were included in the study. Development of erlotinib-associated rash was correlated with clinicopathological characteristics of patients, treatment response, and overall survival (OS) using univariate and multivariate Cox regression analysis. The number of patients with rash was greater in the responders group (90% vs. 46.4%, p = 0.015). In univariate analysis, there was a statistically significant association between rash development and time to progression (TTP) [HR: 0.32 (0.17-0.57), p < 0.001]. With multivariate Cox regression analysis, it was found that PS ≥ 2 (HR: 2.01, 95% CI: 1.12-3.60, p = 0.018) and rash (HR: 0.34, 95% CI: 0.18-0.63, p = 0.001) were independently associated with TTP and also that the duration of treatment with erlotinib (HR: 0.58, 95% CI: 0.42-0.80, p = 0.001) and rash (HR: 0.10, 95% CI: 0.20-0.48, p = 0.004) was an independent predictor of survival. Our results suggest that erlotinib-associated rash may represent a clinically valuable biomarker for the prediction of treatment response and OS in patients with advanced NSCLC.

New data for venous thromboembolism in patients with small cell lung cancer: A review.

Malignancy is an important predisposing factor for thromboembolic disease. Patients with malignancy display 4 to 10 times greater risk than the general population. As for lung cancer, that risk seems to further increase and become up to 20 times higher. The aim of this article is to review the International literature in order to highlight for the first time, the correlation between thromboembolic disease and small cell lung cancer. PubMed, Medline and Embase databases were searched from 1990 up to 2016, for retrospective and prospective studies that investigate the correlation between thromboembolic disease and small cell lung cancer. The incidence rate of thromboembolic disease found in these studies ranged between 6.8% and 11.5%. Thromboembolic disease is associated with a reduced survival in patients with small cell lung cancer and six factors seemed to increase the risk of thromboembolism: chemotherapy, cisplatin treatment, smoking, extensive disease, the infiltration of the superior vena cava and multiple concomitant diseases. Thromboembolic disease shows an increased incidence in patients with small cell lung cancer and more research with well-designed studies is required in order to study in detail the anticoagulation treatment and the survival in small cell lung cancer patients.

PET/CT and brain MRI role in staging NSCLC: prospective assessment of the accuracy, reliability and cost-effectiveness.

AIM: To determine whether PET/CT and brain MRI used in staging NSCLC can be accurate, reliable and cost-effective tools. NSCLC represents 80-85% of lung cancer and adequate information on the initial tumor staging is critical for planning an optimal therapeutic strategy. PATIENTS & METHODS: Data from 30 newly diagnosed NSCLC patients in Greece were collected and prospectively recorded. Patients with potential resectable disease were evaluated to ensure that there are no detectable metastases that would rule out the possibility of a curative surgery. RESULTS: Divergence occurred in 50% of cases of staging with CT or PET/CT alone, while metastases undetectable by the CT were revealed using PET/CT. Unnecessary thoracotomies were avoided by 10% of patients and another 10% was operated on after chemotherapy with a better prognosis. CONCLUSION: PET/CT and brain MRI combined are reliable for correct staging, reducing avoidable thoracotomies, morbidity rates and costs.