The Early Diagnosis of Lung Cancer: Critical Gaps in the Discovery of Biomarkers.

Lung cancer remains the leading cause of cancer-related mortality worldwide. The main issue is the absence of a screening test available in clinical practice; the identification of noninvasive biomarkers is thus an urgent clinical necessity. Currently, low-dose computed tomography (LD-CT) demonstrates a 20% reduction in lung cancer mortality. However, it is not particularly suitable for clinical practice because of its costs, radiation, and false-positive rate. Several studies have therefore focused on research into biomarkers in body fluids. Despite the power of certain molecules to distinguish lung cancer patients from healthy subjects, no biomarker has yet been shown to significantly and reliably influence clinical decisions or to be translated from the laboratory to clinical practice. In this paper, we provide an overview of the peer-reviewed biomedical literature published in the last 10 years on the research regarding biomarkers for the early diagnosis of lung cancer via a comprehensive analysis of the reviews published this past year. Our main objective is to highlight the limitations and strengths of studies on predictive lung cancer biomarkers to stimulate further investigation for early diagnosis. Finally, we discuss future perspectives on managing clinical trials for biomarker research and their integration into clinical practice.

Sniffer dogs performance is stable over time in detecting COVID-19 positive samples and agrees with the rapid antigen test in the field.

Rapid antigen diagnostic (RAD) tests have been developed for the identification of the SARS-CoV-2 infection. However, they require nasopharyngeal or nasal swab, which is invasive, uncomfortable, and aerosolising. The use of saliva test was also proposed but has not yet been validated. Trained dogs may efficiently smell the presence of SARS-CoV-2 in biological samples of infected people, but further validation is needed both in laboratory and in field. The present study aimed to (1) assess and validate the stability over a specific time period of COVID-19 detection in humans' armpit sweat by trained dogs thanks to a double-blind laboratory test-retest design, and (2) assess this ability when sniffing people directly. Dogs were not trained to discriminate against other infections. For all dogs (n. 3), the laboratory test on 360 samples yielded 93% sensitivity and 99% specificity, an 88% agreement with the Rt-PCR, and a moderate to strong test-retest correlation. When sniffing people directly (n. 97), dogs' (n. 5) overall sensitivity (89%) and specificity (95%) were significantly above chance level. An almost perfect agreement with RAD results was found (kappa 0.83, SE 0.05, p = 0.001). Therefore, sniffer dogs met appropriate criteria (e.g., repeatability) and WHO's target product profiles for COVID-19 diagnostics and produced very promising results in laboratory and field settings, respectively. These findings support the idea that biodetection dogs could help reduce the spread of the virus in high-risk environments, including airports, schools, and public transport.

Serum proteomics profiling identifies a preliminary signature for the diagnosis of early-stage lung cancer.

PURPOSE: Lung cancer is the most common cause of death from cancer worldwide, largely due to late diagnosis. Thus, there is an urgent need to develop new approaches to improve the detection of early-stage lung cancer, which would greatly improve patient survival. EXPERIMENTAL DESIGN: The quantitative protein expression profiles of microvesicles isolated from the sera from 46 lung cancer patients and 41 high-risk non-cancer subjects were obtained using a mass spectrometry method based on a peptide library matching approach. RESULTS: We identified 33 differentially expressed proteins that allow discriminating the two groups. We also built a machine learning model based on serum protein expression profiles that can correctly classify the majority of lung cancer cases and that highlighted a decrease in the levels of Arysulfatase A (ARSA) as the most discriminating factor found in tumors. CONCLUSIONS AND CLINICAL RELEVANCE: Our study identified a preliminary, non-invasive protein signature able to discriminate with high specificity and selectivity early-stage lung cancer patients from high-risk healthy subjects. These results provide the basis for future validation studies for the development of a non-invasive diagnostic tool for lung cancer.

The Overweight Paradox: Impact of Body Mass Index on Patients Undergoing VATS Lobectomy or Segmentectomy.

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.

Volatolomic urinary profile analysis for diagnosis of the early stage of lung cancer.

Currently, in clinical practice there is a pressing need for potential biomarkers that can identify lung cancer at early stage before becoming symptomatic or detectable by conventional means. Several researchers have independently pointed out that the volatile organic compounds (VOCs) profile can be considered as a lung cancer fingerprint useful for diagnosis. In particular, 16% of volatiles contributing to the human volatilome are found in urine, which is therefore an ideal sample medium. Its analysis through non-invasive, relatively low-cost and straightforward techniques could offer great potential for the early diagnosis of lung cancer. In this study, urinary VOCs were analysed with a gas chromatography-ion mobility spectrometer (GC-IMS) and an electronic nose (e-nose) made by a matrix of twelve quartz microbalances complemented by a photoionization detector. This clinical prospective study involved 127 individuals, divided into two groups: 46 with lung cancer stage I-II-III confirmed by computerized tomography or positron emission tomography-imaging techniques and histology (biopsy), and 81 healthy controls. Both instruments provided a multivariate signal which, after being analysed by a machine learning algorithm, identified eight VOCs that could distinguish lung cancer patients from healthy ones. The eight VOCs are 2-pentanone, 2-hexenal, 2-hexen-1-ol, hept-4-en-2-ol, 2-heptanone, 3-octen-2-one, 4-methylpentanol, 4-methyl-octane. Results show that GC-IMS identifies lung cancer with respect to the control group with a diagnostic accuracy of 88%. Sensitivity resulted as being 85%, and specificity was 90%-Area Under the Receiver Operating Characteristics: 0.91. The contribution made by the e-nose was also important, even though the results were slightly less sensitive with an accuracy of 71.6%. Moreover, of the eight VOCs identified as potential biomarkers, five VOCs had a high sensitivity (p⩽ 0.06) for early stage (stage I) lung cancer.

Early Diagnosis of Lung Cancer: The Urgent Need of a Clinical Test.

Globally, lung cancer continues to be the leading cause of cancer death in men and women [...].

Urinary Biomarkers for Early Diagnosis of Lung Cancer.

Lung cancer is the leading cause of cancer deaths worldwide. Its early detection has the potential to significantly impact the burden of the disease. The screening and diagnostic techniques in current use suffer from limited specificity. The need therefore arises for a reliable biomarker to identify the disease earlier, which can be integrated into a test. This test would also allow for the recurrence risk after surgery to be stratified. In this context, urine could represent a non-invasive alternative matrix, with the urinary metabolomic profile offering a potential source for the discovery of diagnostic biomarkers. This paper aims to examine the current state of research and the potential for translation into clinical practice.

Results of Surgical Resection of Locally Advanced Pulmonary Neuroendocrine Tumors.

BACKGROUND: Pulmonary neuroendocrine tumors include well-differentiated and poorly differentiated histology for which cell type has proved to be a determinant of survival in many studies. In patients diagnosed with bronchial carcinoid and large cell neuroendocrine carcinoma (LCNEC), surgery is the treatment of choice even in the case of locally advanced disease with lymph node involvement. METHODS: We retrospectively analyzed patients undergoing anatomic lung resection for bronchial carcinoid or LCNEC with lymph node involvement (N1/N2) at the final pathologic examination (pN+). Characteristics of patients and differences in overall survival and disease-free survival are presented according to tumor type. Overall survival of distinct histologic groups was compared with survival in our institutional experience in stage I patients, without nodal involvement (pN0). RESULTS: In all, 325 patients underwent surgical resection for neuroendocrine tumors; 89 patients had nodal involvement. Five-year survival was 89% in pN+ bronchial carcinoid both for typical carcinoid and atypical carcinoid but worse for pN+ LCNEC (47%). Cell type did not influence the prognosis in N0 disease, and no differences in survival were evident between N0 and N+ in the bronchial carcinoid group. In the group of LCNEC, 5-year overall survival was much worse for pN+ LCNEC (47%) compared with pN0 LCNEC (91%). CONCLUSIONS: Bronchial carcinoids have the best prognosis, and surgery remains the treatment of choice for both early and locally advanced disease. On the contrary, aggressive forms (LCNEC) with lymph nodal metastasis have a poor prognosis, and they need to be treated with an aggressive multidisciplinary approach.

Biomarkers in Early Diagnosis and Early Stage Lung Cancer: The Clinician's Point of View.

Starting from the work of Ulivi and colleagues, we aim to summarize the research area of biomarkers for early diagnosis and early stage lung cancer.

Clinical Application of Mass Spectrometry-Based Proteomics in Lung Cancer Early Diagnosis.

The current knowledge on proteomic biomarker analysis for the early diagnosis of lung cancer is summarized, underlining the diversity among the results and the current interest in translating research results into clinical practice. A MEDLINE/PubMed literature search to retrieve all the papers published in the last 10 years is performed. Proteomics studies on lung cancer have gathered evidence on the potential role of biomarkers in early diagnosis. Although promising, none of them have proved to be sufficiently reliable to achieve validation. Future research should evolve toward a multipanel analysis of proteins, considering the possibility that individual biomarkers might not be specific enough to diagnose lung cancer, but could be related to oncological conditions.

Two-step investigation of lung cancer detection by sniffer dogs.

Early detection of lung cancer (LC) is a priority since LC is characterized by symptoms mimicking other respiratory conditions, but it remains the leading cause of oncological disease death. Properly trained dogs can perceive the volatile organic compounds (VOCs) related to cancer thanks to their acute sense of smell. The use of dogs for LC detection could be advantageous: reliably trained dogs would represent a valuable, cost-effective, non-invasive method of screening, which gives a clear-cut yes/no response. However, whether sniffer dogs are able to maintain their discriminative capacity under long-term control, and in different types of environments, needs further investigation. In this study, we sought to test two hypotheses: firstly, if dogs can be trained to perceive LC-related VOCs in human urine, a substrate which is not influenced by the carrier materials and may thus be a good candidate for large-number screening; and secondly, whether trained dogs retain their performance stability over time, even if the environment in which the tests are carried out varies. We have selected three family dogs that underwent a one-year training period (two weekly training sessions) by the clicker training method. At the end of the training, the dogs underwent two separate test phases, in two different locations, one year apart. All the other procedures had been maintained unchanged. The donors of the samples submitted to the dogs were recruited by the European Institute of Oncology (IEO), Milan, Italy. The results show that the dogs had different sensitivity (range: 45%-73%) and specificity rates (range: 89%-91%), and were deceived neither by lung conditions (that the dogs did not consider) nor by the existence of tumors in the beginning stage, that were correctly reported by the dogs. The one-year interruption of the research work and the changes in the test environment did not induce statistically significant differences in the dogs' perceptive capacity. To our knowledge, so far, these issues have never been highlighted.

When a Differential Diagnosis Is Fundamental: Choriocarcinoma Mimicking Lung Carcinoma.

Background: Choriocarcinoma is a rare malignant disease that is usually associated with a gestational event. Lung metastasis with no evident primary origin and choriocarcinoma, which mimics features of non-small-cell lung cancer, might be misdiagnosed as adenocarcinoma or large-cell carcinoma. This is a pivotal clinical concern since the tumor can lead to various symptoms, seriously affecting the quality of life and can escalate rapidly, with a high mortality rate, compared to lung cancer. Methods: We reported a case of a 37-year-old woman with a history of one-year enhancement of beta-human chorionic gonadotropin levels and only a single nodule in the right upper lobe, with no abnormal findings on the gynecological investigation. Then we retrospectively examined all cases treated in the Division of Thoracic Surgery at the European Institute of Oncology in the last twenty years (from 1998 to 2018). Results: This was the first time in our experience that choriocarcinoma presentation was with a single nodule without a gynecological finding. Moreover, the differential diagnosis between lung carcinoma and choriocarcinoma was achieved only after surgical removal. Conclusions: As confirmed by our literature search, precise and expedited differential diagnosis is essential in choriocarcinoma care (both with single or multiple metastases), to successfully remove the tumor and increase the patient's chances of survival.

A review of exhaled breath: a key role in lung cancer diagnosis.

One of the main causes of the high mortality rate in lung cancer is the late-stage tumor detection. Early diagnosis is therefore essential to increase the chances of obtaining an effective treatment quickly thus increasing the survival rate. Current screening techniques are based on imaging, with low-dose computed tomography (LDCT) as the pivotal approach. Even if LDCT has high accuracy, its invasiveness and high false positive rate limit its application to high-risk population screening. A non-invasive, cost-efficient, and easy-to-use test should instead be designed as an alternative. Exhaled breath contains thousands of volatile organic compounds (VOCs). Since ancient times, it has been understood that changes in the VOCs' mixture may be directly related to the presence of a disease, and recent studies have quantified the change in the compounds' concentration. Analyzing exhaled breath to achieve lung cancer early diagnosis represents a non-invasive, low-cost, and user-friendly approach, thus being a promising candidate for high-risk lung cancer population screening. This review discusses technological solutions that have been proposed in the literature as tools to analyze exhaled breath for lung cancer diagnosis, together with factors that potentially affect the outcome of the analysis. Even if research on this topic started many years ago, and many different technological approaches have since been adopted, there is still no validated clinical application of this technique. Standard guidelines and protocols should be defined by the medical community in order to translate exhaled breath analysis to clinical practice.

Pneumonectomy in Stage IIIA-N2 NSCLC: Should It Be Considered After Neoadjuvant Chemotherapy?

BACKGROUND: Owing to the expected poor long-term outcomes and high postoperative morbidity and mortality, patients with stage IIIA-N2 tumors candidate to pneumonectomy (PN) are usually excluded from surgery. This study aims to analyze the outcome of patients who underwent PN to prove its safety and feasibility. PATIENTS AND METHODS: We retrospectively analyzed data from 233 patients who underwent PN for N2 non-small-cell lung cancer (NSCLC) between 1998 and 2015. Eighty-five patients were occult N2 disease (group 1), whereas 148 patients underwent induction therapy (IT) for stage IIIA-N2 (group 2). RESULTS: Overall morbidity, postoperative mortality, and 90-day mortality rates were 46.8%, 2.6%, and 8.6%, respectively. The 2 groups (group 1 vs. 2) had similar postoperative and 90-day mortality rates: 2.4% versus 2.7% (P = 1.00), and 9.4% versus 8.1% (P = .81), respectively. The incidence of major morbidity was higher and statistically significant in group 2 compared with group 1: 23% versus 12.9% (P = .1). Postoperative bronchopleural fistula occurred in 4.7% (4/85) of patients with occult N2 (group 1) and in 10.1% (15/148) of patients undergoing IT (group 2) (P = .10). Median overall survival (OS) was 2.2 years, with a 3 and 5-year OS of 43.4% and 31.6%, respectively. Disease-free survival (DFS) was 1.5 years, with 3 and 5-year DFS of 41.6% and 32%, respectively; no difference in OS and DFS between the 2 groups was found. CONCLUSIONS: Considering the acceptable morbidity and mortality rate and the long-term survival, PN should not be excluded for selected patients with stage IIIA-N2 NSCLC as a matter of principle.

A Metal Oxide Gas Sensors Array for Lung Cancer Diagnosis Through Exhaled Breath Analysis.

Lung cancer high mortality rate is mainly related to late-stage tumor diagnosis. Survival rates and treatments could be greatly improved with an effective early diagnosis. Volatile organic compounds (VOCs) in exhaled breath have been known for long to be linked to the presence of a disease. Exhaled breath analysis for early diagnosis of lung cancer represents a non-invasive, low-cost and user-friendly approach. In this paper we present the design and development of an electronic nose based on a metal oxide sensors array for the early diagnosis of lung cancer. Breath samples collected from healthy controls (n=10) and lung cancer subjects (n=6) were analyzed by the electronic nose, and classification was performed using an artificial neural network (ANN). A sensitivity of 85.7%, specificity of 100%, and accuracy of 93.8% were reached with leave one out cross validation (LOOCV). The presented device demonstrates that a simple, cost-effective, and non-invasive approach based on exhaled breath analysis has the potential to be of great help in decreasing lung cancer mortality.

The Electronic Nose's Emerging Role in Respiratory Medicine.

New interest has grown in the respiratory disorder diagnosis and monitoring, throughout electronic nose technologies. This technology has several advantages compared to classic approach. In this short letter, we aim to emphasize electronic nose role in respiratory medicine.

A single-institution retrospective analysis of metachronous and synchronous metastatic bronchial neuroendocrine tumors.

BACKGROUND: Broncho-pulmonary neuroendocrine tumors (bpNETs) are rare malignancies and there is no consensus on therapeutical management of metastatic disease and follow-up after radical resection. METHODS: Clinical records of patients with a cytological or histological diagnosis of bpNETs and distant metastases (metachronous or synchronous), evaluated at the European Institute of Oncology between 1997 and 2014, were retrospectively analyzed. Data on patient demographics, pathology, imaging exams, surgical and non-surgical treatments were collected. P value descriptive data, uni- and multi-variate survival analysis were generated for all variables. RESULTS: With a median follow-up of 53 [9-215] months, 61 patients with metachronous and 47 with synchronous metastases were analysed. The most common tool of first recurrence detection was computed tomography. Liver (67%), lymph node (25%), bone (22%) and lung (16%) were the most common sites of relapse. Median time to recurrence was 5 years. Median overall survival (OS) was 72 months for the whole population, with no significant difference between patients with synchronous and metachronous metastases. Age, bone metastases, liver metastases and Ki-67 as a continuous variable all significantly correlated with prognosis at the multivariate analysis. CONCLUSIONS: This is one of the largest, single-centre, series of metastatic bpNETs. Among patients with metachronous metastases the pattern of recurrences was heterogeneous as were the follow-up exams used to detect them. The results of our analysis may represent solid bases for designing prospective clinical trials in homogeneous settings of bpNETs.

Pleural catheters after thoracoscopic treatment of malignant pleural effusion: a randomized comparative study on quality of life.

BACKGROUND: Malignant pleural effusion (MPE) complicates many neoplasms and its incidence is expected to rise in parallel with the aging population and longer survival of cancer patients. Although a clear consensus exists on indwelling catheters in patients with poor performance status, no study has hitherto compared different devices in patients requiring temporary or definitive drainage following talc poudrage. METHODS: This is a prospective, two-arm, pilot study on patients with MPE undergoing talc poudrage, comparing two different catheters (PleurX® versus Pleurocath®) positioned because of the inefficacy of the procedure or the high risk of short-term failure. End points of the study were quality of life (QoL), median dyspnea and chest pain assessment by EORTC questionnaires and a 100 mm visual analog scale, total in-hospital length of stay and frequency of serious adverse events. RESULTS: No difference was observed between the two groups in in mean dyspnea and mean chest pain in any questions of the EORTC QLQ-C30 and QLQ-LC13 questionnaires. Duration of the procedure was significantly longer in the PleurX® group versus the Pleurocath® group (72±33 versus 44±13 minutes; P=0.03). No difference was observed between the two groups in total length of hospital stay (P=1.00) or complication rate (P=1.00). CONCLUSIONS: For the cohort of patients still needing indwelling pleural catheters (PC) after thoracoscopic talc poudrage, PleurX® is suggested when drain removal is unlikely due to short life expectancy or the high chance of pleurodesis failure. Conversely, Pleurocath® should be recommended in all other patients as it is faster to place and easier to remove. KEYWORDS: Malignant pleural effusion (MPE); talc poudrage; indwelling pleural catheter (indwelling PC).