Perioperative identifications of non-palpable pulmonary nodules: a narrative review.

Early detection of lung cancer is the key to improving treatment and prognosis of this disease, and the advent of advances in computed tomography (CT) imaging and national screening programs have improved the detection rate of very small pulmonary lesions. As such, the management of this sub-centimetric and often sub-solid lesions has become quite challenging for clinicians, especially for choosing the most suitable diagnostic method. In clinical practice, to fulfill this diagnostic yield, transthoracic needle biopsy (TTNB) is often the first choice especially for peripheral nodules. For lesions for which TTNB could present technical difficulties or failed, other diagnostic strategies are needed. In this case, video-assisted thoracic surgery (VATS) is the gold standard to reach the diagnosis of lung nodules suspect of being malignant. Nonetheless it's often not easy the identification of such lesions during VATS because of their little dimensions, non-firm consistency, deep localization. In literature various marking techniques have been described, in order to improve intraoperative nodules detection and to reduce conversion rate to thoracotomy: CT-guided hookwire positioning, methylene blue staining, intra-operative ultrasound and electromagnetic navigation bronchoscopy are the most used. The scientific evidence on this matter is weak because there are no randomized clinical trials but only case series on single techniques with no comparison on efficacy, so there are no guidelines to refer. From this standing, in this article we conducted a narrative review of the existing literature on the subject, with the aim of outlining a framework as complete as possible. We analyzed strengths and weaknesses of the main techniques reported, so as to allow the clinician to orient himself with greater ease.

Prognostic Value of 18F-FDG PET/CT Metabolic Parameters in Surgically Treated Stage I Lung Adenocarcinoma Patients.

PURPOSE OF THE REPORT: This article aims to explore the prognostic role of 18F-FDG PET/CT metabolic parameters in stage I lung adenocarcinoma patients. PATIENTS AND METHODS: One hundred eighty pathological stage I lung adenocarcinoma patients were retrospectively reviewed. Semiquantitative analysis of FDG tumor uptake was performed with TrueD software on the Siemens Leonardo workstation. SUVmean and MTV were calculated using SUV threshold of 41% of SUVmax; the total lesion glycolysis (TLG) was calculated as the product of SUVmean and MTV. Correlation was evaluated using Spearman correlation coefficient. Maximally selected rank statistics was performed to detect the optimal cutoff used for dichotomizing each PET parameter (6.5 for SUVmean, 9.6 for SUVmax, and 19.1 for TLG). RESULTS: Our main finding was the significant correlation between 18F-FDG PET/CT parameters (SUVmean, SUVmax, and TLG) and disease-free survival in pathologic stage I non-small cell lung cancer. SUVmean has the greatest accuracy in recurrence prediction (integrated area under the curve, 0.803; 95% confidence interval, 0.689-0.918). We run the maximally selected rank statistics to provide the classification of observations in 2 groups by a continuous predictor parameter; the free from recurrence rate was significantly greater in patients with SUVmean ≤6.5, SUVmax ≤9.6, and TLG ≤19.1. CONCLUSIONS: Our research supports the hypothesis that SUVmean, SUVmax, and TLG are well correlated with free from recurrence rate in stage I adenocarcinoma patients, subjected to pulmonary lobectomy. Our findings also indicate these markers as promising prognostic indicators.

Energy devices safety and impact on video-assisted thoracoscopic lung lobectomy postoperative course: monopolar electrocautery versus ultrasonic dissector.

BACKGROUND: This study aims to compare safety and impact of monopolar electrocautery and ultrasonic dissector (Harmonic ACE Plus®) on postoperative short-term outcomes after video-assisted thoracoscopic (VATS) lobectomy and lymphadenectomy for lung cancer. METHODS: We analyzed the prospectively collected data of 140 consecutive patients [59% male; median age: 71(IQR:62-76) years] undergoing VATS lobectomy and lymphadenectomy in our institution between October 2016 and November 2019. Patients were divided in two groups based on device used: monopolar electric hook in 79 cases (Group A); ultrasonic dissector in 61(Group B). Energy instrument-related intraoperative accidents, hemothorax/chylothorax incidence, total pleural effusion volume at 48 postoperative hours and chest tube duration were compared between groups. Multivariable analysis was performed to test energy device as possible independent risk factor either for increased pleural effusion volume or for prolonged chest tube duration. RESULTS: No intraoperative accidents due to energy device occurred. No hemothorax was recorded. Postoperative chylothorax incidence was slightly higher in Group A (2.5% vs 0%; p-value = 0.21). Total pleural effusion volume at 48 h was significantly higher in Group B: 400 (285-500) vs 255 (150-459) ml (p-value = 0.005). Chest tube duration was similar in the two groups: 5 (3-9) vs 5 (3-8) days (p-value = 0.77). At multivariable analysis the energy device used was not associated with increased pleural effusion volume (p-value = 0.43) nor with prolonged chest tube duration (p-value = 0.28). CONCLUSIONS: Monopolar electrocautery and Harmonic ACE Plus® were safe and had a similar impact on short-term outcomes after VATS lobectomy and lymphadenectomy, suggesting that energy devices choice could be left to surgeon's preference.

Chronic chest pain and paresthesia after video-assisted thoracoscopy for primary pneumothorax.

BACKGROUND: This study aims to identify clinical and surgical risk factors for chronic chest pain and paresthesia after video thoracoscopic surgery for primary spontaneous pneumothorax. METHODS: We retrospectively collected the data of 1,178 consecutive patients <40-years-old undergoing video thoracoscopic surgery for primary spontaneous pneumothorax in 9 Italian centers in 2007-2017. Cases with <2-month follow-up were excluded, leaving 920 patients [80% male; median age: 21 (IQR, 18-27) years] for statistical analysis. The following risk factors for chronic chest pain and chronic paresthesia were assessed by univariable and multivariable Cox regression model: age, gender, cannabis smoking, video thoracoscopy ports number, pleurodesis technique (partial pleurectomy/pleural electrocauterization/pleural abrasion/talc poudrage), chest tube size (24/28 F), postoperative chest tube stay. RESULTS: Blebs/bullae resection with pleurodesis was performed in 732 (80%) cases; pleurodesis alone in 188 (20%). During a median follow-up of 68 (IQR: 42-95) months, chronic chest pain developed in 8% of patients, chronic chest paresthesia in 22%; 0.5% of patients regularly assumed painkillers. Chronic chest pain was independently associated with partial pleurectomy/pleura abrasion (P<0.001) and postoperative chest tube stay (P=0.019). Chronic chest paresthesia was independently associated with pleurodesis by partial pleurectomy (P<0.001), chest tube stay (P=0.035) and 28 F chest tube (P<0.001). CONCLUSIONS: After video thoracoscopic surgery for primary spontaneous pneumothorax, the incidence of chronic chest pain and paresthesia was significantly lower when pleurodesis was performed by pleural electrocauterization or talc poudrage, and chest tube was removed early. A 24 F chest tube was associated with lower risk of chronic chest paresthesia.

Serum miR-223: A Validated Biomarker for Detection of Early-Stage Non-Small Cell Lung Cancer.

BACKGROUND: The published circulating miRNA signatures proposed for early-stage non-small cell lung cancer (NSCLC) detection are inconsistent and difficult to replicate. Reproducibility and validation of an miRNA simple signature of NSCLC are prerequisites for translation to clinical application. METHODS: The serum level of miR-223 and miR-29c, emerging from published studies, respectively, as a highly sensitive and a highly specific biomarker of early-stage NSCLC, was measured with droplet digital PCR (ddPCR) technique in an Italian cohort of 75 patients with stage I-II NSCLC and 111 tumor-free controls. By ROC curve analysis we evaluated the miR-223 and miR-29c performance in discerning NSCLC cases from healthy controls. RESULTS: Reproducibility and robust measurability of the two miRNAs using ddPCR were documented. In a training set (40 stage I-II NSCLCs and 56 controls), miR-223 and miR-29c, respectively, showed an AUC of 0.753 [95% confidence interval (CI), 0.655-0.836] and 0.632 (95% CI, 0.527-0.729) in identifying NSCLC. Combination of miR-223 with miR-29c yielded an AUC of 0.750, not improved over that of miR-223 alone. Furthermore, in an independent blind set (35 stage I-II NSCLCs and 55 controls), we validated serum miR-223 as an effective biomarker of stage I-II NSCLC (AUC = 0.808; 95% CI, 0.712-0.884), confirming the miR-223 diagnostic performance reported by others in Chinese cohorts. CONCLUSIONS: Using ddPCR technology, miR-223 was externally validated as a reproducible, effective serum biomarker of early-stage NSCLC in ethnically different subjects. Combination with miR-29c did not improve the miR-223 diagnostic performance. IMPACT: Serum miR-223 determination may be proposed as a tool for refining NSCLC risk stratification, independent of smoking habit and age.

ACTH-producing tumorlets and carcinoids of the lung: clinico-pathologic study of 63 cases and review of the literature.

Adrenocorticotropic hormone (ACTH)-secreting lung carcinoids represent the principal cause of ectopic Cushing syndrome, but the prevalence of ACTH expression and the association between ACTH production and Cushing syndrome in lung carcinoids have scarcely been investigated. In addition, available information on the prognostic meaning of ACTH production is controversial. The aims of this multicentric retrospective study, also including a review of the literature, were to describe the clinico-pathologic features of ACTH-producing lung carcinoids, to assess recurrence and specific survival rates, and to evaluate potential prognostic factors. To identify ACTH production in 254 unselected and radically resected lung carcinoids, we used a double approach including RT-PCR (mRNA encoding for pro-opiomelanocortin) and immunohistochemistry (antibodies against ACTH and ß-endorphin). Sixty-three (24.8%) tumors produced ACTH and 11 of them (17.4%), representing 4.3% of the whole series, were associated with Cushing syndrome. The median follow-up time was 71 months. The 10-year overall and specific survival rates were 88.5% and 98.2%, respectively, with difference neither between functioning and nonfunctioning tumors nor between ACTH-positive and ACTH-negative carcinoids. At univariate analysis, histological type (typical or atypical) and Ki67 index significantly correlated with tumor recurrence. The literature review identified 172 previously reported patients with functioning ACTH-secreting lung carcinoids, and the meta-analysis of survival showed that 92% of them were alive after a mean follow-up time of 50 months. Our results demonstrate that ACTH-producing lung carcinoids are not rare, are not always associated with Cushing syndrome, and do not represent an aggressive variant of lung carcinoid.

Video-assisted thoracoscopic resection of lung nodules localized with a hydrogel plug.

OBJECTIVES: Computed tomography (CT)-guided hydrogel plug deployment was recently proposed for lung nodule preoperative localization and simultaneous prevention of pneumothorax. We analysed our initial experience with CT-guided hydrogel plug localization of lung nodules in patients undergoing video-assisted thoracoscopic (VATS) resection. METHODS: We retrospectively evaluated the medical notes from 27 consecutive patients (mean age 68 ± 11 SD years; men 74%) undergoing VATS lung wedge resection for biopsy or definitive treatment of 28 small pulmonary nodules (malignant 82%) at a single institution between October 2017 and July 2018. Difficult intraoperative nodule localization was anticipated with a lesion <10 mm, a depth from pleura:size ratio >1, ground-glass opacity or the judgement of the operating surgeon. All lesions were preoperatively marked by deployment of a CT-guided hydrogel plug. Study end points were frequency of postlocalization pneumothorax; feasibility of delayed surgery; rate of localization of intraoperative nodule and rate of successful VATS resection. RESULTS: The mean sizes of the solid nodules (n = 24) and of the ground-glass opacities (n = 4) were, respectively, 10.4 ± 3.4 mm and 16.0 ± 6.2 mm. One (4%) hydrogel plug marking procedure caused a clinically relevant pneumothorax. Nodule resection was scheduled flexibly as required by patient management/operating room scheduling: same day (11 nodules) or delayed [median 6 days (range 1-60 days)]; (17 nodules). All nodules were localized intraoperatively: 25 (89%) by hydrogel plug; 3 (11%) by palpation and pleural puncture hole visible after plug displacement. All nodules were completely excised by VATS, without complications. CONCLUSIONS: CT-guided hydrogel plug marking was valuable for VATS localization and resection of challenging lung nodules. The plug minimized clinically relevant pneumothoraxes and allowed flexible surgical schedules.

Natural Killer Cells from Malignant Pleural Effusion Are Endowed with a Decidual-Like Proangiogenic Polarization.

Natural killer (NK) cells are crucial in tumor recognition and eradication, but their activity is impaired in cancer patients, becoming poorly cytotoxic. A particular type of NK cells, from the decidua, has low cytotoxicity and shows proangiogenic functions. We investigated whether NK cells from peripheral blood (PB) and pleural effusions of patients develop decidual-like NK phenotype and whether exposure to IL-2 can restore their killing ability in the presence of pleural fluids. NK cells from pleural effusion of patients with inflammatory conditions (iPE, n = 18), primary tumor (ptPE, n = 18), and metastatic tumor (tmPE, n = 27) acquired the CD56brightCD16- phenotype. NK cells from both ptPE and tmPE showed increased expression for the CD49a and CD69 decidual-like (dNK) markers and decreased levels of the CD57 maturation marker. NK from all the PE analyzed showed impaired degranulation capability and reduced perforin release. PE-NK cells efficiently responded to IL-2 stimulation in vitro. Addition of TGFß or cell-free pleural fluid to IL-2 in the culture medium abrogated NK cell CD107a and IFNγ expression even in healthy donors (n = 14) NK. We found that tmPE-NK cells produce VEGF and support the formation of capillary-like structures in endothelial cells. Our results suggest that the PE tumor microenvironment can shape NK cell polarization towards a low cytotoxic, decidual-like, highly proangiogenic phenotype and that IL-2 treatment is not sufficient to limit this process.

Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer.

NK cells are effector lymphocytes involved in tumor immunosurveillance; however, in patients with solid malignancies, NK cells have compromised functions. We have previously reported that lung tumor-associated NK cells (TANKs; peripheral blood) and tumor-infiltrating NK cells (TINKs) show proangiogenic, decidual NK-like (dNK) phenotype. In this study, we functionally and molecularly investigated TINKs and TANKs from blood and tissue samples of patients with colorectal cancer (CRC), a neoplasm in which inflammation and angiogenesis have clinical relevance, and compared them to NK cells from controls and patients with nononcologic inflammatory bowel disease. CRC TINKs/TANKs showed decreased expression for the activatory marker NKG2D, impaired degranulation activity, a decidual-like NK polarization toward the CD56brightCD16dim/-CD9+CD49+ subset. TINKs and TANKs secreted cytokines with proangiogenic activities, and induce endothelial cell proliferation, migration, adhesion, and the formation of capillary-like structures in vitro. dNK cells release specific proangiogenic factors; among which, angiogenin and invasion-associated enzymes related to the MMP9-TIMP1/2 axis. Here, we describe, for the first time, to our knowledge, the expression of angiogenin, MMP2/9, and TIMP by TANKs in patients with CRC. This phenotype could be relevant to the invasive capabilities and proangiogenic functions of CRC-NK cells and become a novel biomarker. STAT3/STAT5 activation was observed in CRC-TANKs, and treatment with pimozide, a STAT5 inhibitor, reduced endothelial cell capability to form capillary-like networks, inhibiting VEGF and angiogenin production without affecting the levels of TIMP1, TIMP2, and MMP9, indicating that STAT5 is involved in cytokine modulation but not invasion-associated molecules. Combination of Stat5 or MMP inhibitors with immunotherapy could help repolarize CRC TINKs and TANKs to anti-tumor antimetastatic ones.-Bruno, A., Bassani, B., D'Urso, D. G., Pitaku, I., Cassinotti, E., Pelosi, G., Boni, L., Dominioni, L., Noonan, D. M., Mortara, L., Albini, A. Angiogenin and the MMP9-TIMP2 axis are up-regulated in proangiogenic, decidual NK-like cells from patients with colorectal cancer.

Quantitative computed tomography detects interstitial lung diseases proven by biopsy.

Background: The Quantitative chest CT (QCT) is emerging as a promising tool in the assessment of interstitial lung disease (ILD). However, the precise relationship between QCT parameters and the fibrosis detectable in lung tissue, remains to be established. Objectives: The aim of this study was to compare QCT and histopathological features in patients with ILD. Moreover we verified if the QCT assessment is similar in patients with or without a ILD diagnosis proven by a biopsy. Methods: Twenty patients affected by ILD who underwent a chest CT and, later, a lung biopsy, were enrolled. Patients were divided according to the histopathological findings (IPF vs sarcoidosis) in two groups (respectively bIPF and bSarc). Other 20 patients with a radiological diagnosis of IPF were included in a control group (rIPF). All CTs were post-processed with a free software (Horos) in order to obtain an ILD quantitative assessment. Results: There were no differences in terms of gender, smoking habit and spirometric values between patients' groups. rIPF subjects were older than the other: 70 vs 59 and 47 years (p<0.001). A different distribution of QCT parameters was observed between bIPF and bSarc (p<0.01) while it was comparable within bIPF and rIPF. Conclusions: QCT parameters were similar in subjects affected by the same type of ILD detected with biopsy and with CT alone. These findings make stronger the assumption that QCT can identify the presence of pulmonary fibrosis and, ultimately, that it can represent an useful and effective tool to assess ILD. (Sarcoidosis Vasc Diffuse Lung Dis 2018; 35: 16-20).

Surgical site infections after lung resection: a prospective study of risk factors in 1,091 consecutive patients.

BACKGROUND: To assess incidence and risk factors of surgical site infections (SSI) (wound infection, pneumonia, empyema) in a monocentric series of patients undergoing lung resection over a decade. METHODS: All patients undergoing lung resection at our institution in 2006-2015 [wedge resection, n=579; lobectomy, n=472 (12% after chemo/radiotherapy); pneumonectomy, n=40 (47% after chemo/radiotherapy)], were prospectively enrolled. Perioperative SSI risk factors were recorded: age, gender, blood haemoglobin, lymphocyte count, serum albumin, forced expiratory volume in 1 second percentage (FEV1%) of predicted, antibiotic prophylaxis, length of stay, diabetes, malignancy, steroid therapy, induction chemo/radiotherapy, resection in 2006-2010/2011-2015, urgent/elective procedure, videothoracoscopic/open approach, resection type, operative time. SSIs diagnosed within 30 days from surgery were prospectively recorded and association with risk factors was evaluated. RESULTS: Of the 1,091 resected patients [median age, 65 (range, 13-91) years; male, 74%; malignancy, 65%], 124 (11.4%) developed one or more SSI. Wound infection, pneumonia and empyema rates were respectively 3.2%, 8.3% and 1.9%, stable through the decade. Overall infection rates after wedge resection, lobectomy and pneumonectomy were 4.8%, 17.4% and 35.0%, respectively. Thirty-day postoperative mortality was 0.6%; of the 7 deaths, 4 were causally related with SSI. Multivariable analysis showed that male gender, diabetes, preoperative steroids, induction chemo/radiotherapy, missed antibiotic prophylaxis and resection type were independent risk factors for overall SSI. CONCLUSIONS: SSI rates after lung resection were stable over the decade. The observed 11.4% frequency of SSI indicates that postoperative infections remain a relevant issue and a predominant cause of mortality after lung surgery. Focusing on SSI risk factors that are perioperatively modifiable may improve surgical results.

Systematic review and critique of circulating miRNAs as biomarkers of stage I-II non-small cell lung cancer.

Selected circulating microRNAs (miRNAs) have been suggested for non-invasive screening of non-small cell lung cancer (NSCLC), however the numerous proposed miRNA signatures are inconsistent. Aiming to identify miRNAs suitable specifically for stage I-II NSCLC screening in serum/plasma samples, we searched the databases "Pubmed", "Medline", "Scopus", "Embase" and "WOS" and systematically reviewed the publications reporting quantitative data on the efficacy [sensitivity, specificity and/or area under the curve (AUC)] of circulating miRNAs as biomarkers of NSCLC stage I and/or II. The 20 studies fulfilling the search criteria included 1110 NSCLC patients and 1009 controls, and were of medium quality according to Quality Assessment of Diagnostic Accuracy Studies checklist. In these studies, the patient cohorts as well as the control groups were heterogeneous for demographics and clinicopathological characteristics; moreover, numerous pre-analytical and analytical variables likely influenced miRNA determinations, and potential bias of hemolysis was often underestimated. We identified four circulating miRNAs scarcely influenced by hemolysis, each featuring high sensitivity (> 80%) and AUC (> 0.80) as biomarkers of stage I-II NSCLC: miR-223, miR-20a, miR-448 and miR-145; four other miRNAs showed high specificity (> 90%): miR-628-3p, miR-29c, miR-210 and miR-1244. In a model of two-step screening for stage I-II NSCLC using first the above panel of serum miRNAs with high sensitivity and high AUC, and subsequently the panel with high specificity, the estimated overall sensitivity is 91.6% and overall specificity is 93.4%. These and other circulating miRNAs suggested for stage I-II NSCLC screening require validation in multiple independent studies before they can be proposed for clinical application.

LINE-1 hypomethylation is associated to specific clinico-pathological features in Stage I non-small cell lung cancer.

OBJECTIVES: We hypothesize that selected genetic and/or epigenetic changes associated with advanced tumours may help identifying early non-small cell lung cancers (NSCLCs) that recur after resection. Among epigenetic changes, long interspersed nuclear element-1 (LINE-1) hypomethylation is seen early during carcinogenesis and may act in concert with genetic alterations to cancer progression. LINE-1 hypomethylation and gene mutations frequently involved in lung cancer, were analysed to evaluate their prognostic role in resected stage I NSCLC. METHODS: Gene mutations and LINE-1 methylation were analysed in 167 Caucasian patients with stage I NSCLC, namely 100 adenocarcinomas (ADC) and 67 squamous-cell carcinomas (SqCC), using mass-spectrometry and pyrosequencing. We evaluated the correlation between molecular results and clinico-pathological data: age, gender, smoking status, period of surgery, histology, grading, pathological stage, p53 expression, LINE-1 hypomethylation. These variables have been assessed as possible predictors of cancer related survival by regression analysis. RESULTS: Frequency and spectrum of gene mutations were significantly different in ADCs compared with SqCCs. p53 positivity was more common in SqCC, while EGFR or KRAS mutations were mainly detected in ADC. LINE1 hypomethylation was associated with SqCC histology, p53 immunoreactivity and smoking habit. Stage IB, LINE-1 hypomethylation and PIK3CA mutation independently predicted a worse cancer-related survival. When combined into a scoring system, their prognostic power was strengthened. CONCLUSIONS: In many stage I NSCLC a mutation pattern of advanced disease was observed. Stage IB, LINE-1 hypomethylation and PIK3CA mutation were associated to poor prognosis. Genetic and epigenetic events occurring in early carcinogenesis may help identifying stage I NSCLC patients who deserve adjuvant therapy.

Multicentric study of endobronchial ultrasound-transbronchial needle aspiration for lung cancer staging in Italy.

BACKGROUND: Multi-institutional studies of endobronchial-ultrasound transbronchial needle aspiration (EBUS-TBNA) for mediastinal staging in lung cancer are scarce. It is unclear if the high diagnostic performance of EBUS-TBNA reported by experts' guidelines can be generally achieved. METHODS: This is a retrospective study performed in five tertiary referral centers of thoracic surgery in Italy, to assess the EBUS-TBNA diagnostic performance in patients with non-small cell lung cancer (NSCLC). Patient inclusion criteria were: both genders; >18 years old; with suspect/confirmed NSCLC; undergoing EBUS-TBNA for mediastinal node enlargement at computed tomography (size >1 cm, ≤3 cm) and/or pathological uptake at positron emission tomography. Altogether we included 485 patients [male, 366; female, 119; median age, 68 years (IQR, 61-74 years)] undergoing mediastinal staging between January 2011 and July 2016. All EBUS-TBNAs were performed by experienced bronchoscopists, without pre-defined quality standards. Depending on usual practice in each center, EBUS-TBNA was done under conscious sedation, with 21- or 22-Gauge (G) needle, and specimen preparation was cell-block, or cytology slides, or core-tissue. Sampling was classified inadequate in absence of lymphocytes, or when sample was insufficient. We analyzed the EBUS-TBNA procedural steps likely to influence the rate of adequate samplings (diagnostic yield). RESULTS: EBUS-TBNA sensitivity, negative predictive value (NPV) and accuracy respectively were 90%, 78% and 93% in the whole cohort. At multivariate analysis, use of 21-G needle was associated with better diagnostic yield (P<0.001). Center and specimen processing technique were not independent factors affecting EBUS-TBNA diagnostic yield. CONCLUSIONS: In this multicentric study, EBUS-TBNA was a highly sensitive and accurate method for NSCLC mediastinal node staging. Results indicate better performance of EBUS-TBNA with 21-G needle, and suggest that specimen processing technique could be chosen according to the local practice preference.

Comparison of multiple techniques for endobronchial ultrasound-transbronchial needle aspiration specimen preparation in a single institution experience.

BACKGROUND: The optimal method for specimen preparation of endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) is still controversial. This study aims to compare several techniques available for EBUS-TBNA specimen acquisition and processing, in order to identify the best performing technique. METHODS: We retrospectively reviewed the data of 199 consecutive patients [male, 73%; median age, 64 years (IQR: 52-74 years)] undergoing EBUS-TBNA at our institution from 2012 through 2014 for diagnosis of hilar-mediastinal lymph node enlargement suspect of neoplastic (n=139) or granulomatous (n=60) disease. All procedures were performed by two experienced bronchoscopists, under conscious sedation and local anaesthesia, using 21/22-Gauge (G) needle, without rapid on-site evaluation (ROSE). Five specimen-processing techniques were used: cytology slides in 42 cases (21%); cell-block in 25 (13%); core-tissue in 60 (30%); combination of cytology slides and core-tissue in 51 (26%); combination of cytology slides and cell-block in 21 (10%). To assess the diagnostic accuracy of each tissue-processing technique we compared the EBUS-TBNA results to those obtained with surgical lymphadenectomy, or 1-year follow-up in non-operated patients. RESULTS: Diagnostic yield, accuracy and area under the curve (AUC) were as follows. Cytology slides: 81%, 80%, 0.90; cell-block: 48%, 33%, 0.67; core-tissue: 87%, 99%, 0.96; cytology slides + core-tissue: 80%, 100%, 1.00; cytology slides + cell-block: 86%, 100%, 1.00. Cytology slides and core-tissue method showed non-significantly different diagnostic yield (P=0.435) and AUC (P=0.152). CONCLUSIONS: In our single-institution experience, cytology slides and core-tissue preparations demonstrated high and similar diagnostic performance. Cytology slides combination with core-tissue or cell-block showed the highest performance, however these combination methods were more resource-consuming.

Endobronchial ultrasound-transbronchial needle aspiration for mediastinal staging of non-small cell lung cancer: variability of results and perspectives.

The remarkable value of endobronchial ultrasound-transbronchial needle aspiration (EBUS-TBNA) for mediastinal staging of non-small cell lung cancer (NSCLC) is recognized worldwide. Reports from different centers however show considerable variation of EBUS-TBNA performance in terms of diagnostic yield, sensitivity and negative predictive value (NPV). Interpretation of EBUS-TBNA diagnostic efficacy requires clarifying whether the technique is used for purely diagnostic purpose or mediastinal staging, recognizing that different study groups may be inherently heterogeneous and that numerous factors may impact on the procedure outcomes. Review of these factors indicates that the prevalence of N2/N3 disease, the thoroughness of mediastinal sampling and >3 needle passes per target lymph node (LN) [in the absence of rapid on-site evaluation (ROSE)] influence the procedure outcomes, while many details in the sample preparation technique are unlikely to impact on the results and should be left to the proceduralists' preference. Generalized use of a standardized database for prospective collection of relevant EBUS-TBNA data would allow reporting institutional results by sub-groups of N2/N3 disease prevalence and thoroughness of staging, and would help establishing quality standards for the procedure.

Thyroid cancer with tracheal invasion: a pathological estimation.

We review the clinical and pathologic features of seven cases of papillary carcinoma of the thyroid that invaded the trachea and were treated by thyroidectomy, airway resection with reconstructive surgery over an interval of 15 years. We depicted the peculiarity of invasion of well differentiated papillary thyroid carcinoma (PTC) cells is perpendicularly oriented to the tracheal lumen, in between cartilaginous rings, along blood vessels and collagen fibers. Tracheal rings appear non-infiltrated in all histological sections of well differentiated PTC infiltrating the trachea. Similar description of inter-cartilage PTC infiltration into the trachea was first provided by Shin et al. in 1993. Interestingly, our pathological revision support the estimation by Shin et al., though that cartilage rings infiltration did occur in poorly differentiated thyroid cancers with exiguous prognosis.

A comparison between quantitative PCR and droplet digital PCR technologies for circulating microRNA quantification in human lung cancer.

BACKGROUND: Selected microRNAs (miRNAs) that are abnormally expressed in the serum of patients with lung cancer have recently been proposed as biomarkers of this disease. The measurement of circulating miRNAs, however, requires a highly reliable quantification method. Quantitative real-time PCR (qPCR) is the most commonly used method, but it lacks reliable endogenous reference miRNAs for normalization of results in biofluids. When used in absolute quantification, it must rely on the use of external calibrators. Droplet digital PCR (ddPCR) is a recently introduced technology that overcomes the normalization issue and may facilitate miRNA measurement. Here we compared the performance of absolute qPCR and ddPCR techniques for quantifying selected miRNAs in the serum. RESULTS: In the first experiment, three miRNAs, proposed in the literature as lung cancer biomarkers (miR-21, miR-126 and let-7a), were analyzed in a set of 15 human serum samples. Four independent qPCR and four independent ddPCR amplifications were done on the same samples and used to estimate the precision and correlation of miRNA measurements obtained with the two techniques. The precision of the two methods was evaluated by calculating the Coefficient of Variation (CV) of the four independent measurements obtained with each technique. The CV was similar or smaller in ddPCR than in qPCR for all miRNAs tested, and was significantly smaller for let-7a (p = 0.028). Linear regression analysis of the miRNA values obtained with qPCR and ddPCR showed strong correlation (p < 0.001). To validate the correlation obtained with the two techniques in the first experiment, in a second experiment the same miRNAs were measured in a larger cohort (70 human serum samples) by both qPCR and ddPCR. The correlation of miRNA analyses with the two methods was significant for all three miRNAs. Moreover, in our experiments the ddPCR technique had higher throughput than qPCR, at a similar cost-per-sample. CONCLUSIONS: Analyses of serum miRNAs performed with qPCR and ddPCR were largely concordant. Both qPCR and ddPCR can reliably be used to quantify circulating miRNAs, however, ddPCR revealed similar or greater precision and higher throughput of analysis.

Chest pain control with kinesiology taping after lobectomy for lung cancer: initial results of a randomized placebo-controlled study.

OBJECTIVES: Kinesiology taping (KT) is a rehabilitative technique performed by the cutaneous application of a special elastic tape. We tested the safety and efficacy of KT in reducing postoperative chest pain after lung lobectomy. METHODS: One-hundred and seventeen consecutive patients, both genders, age 18-85, undergoing lobectomy for lung cancer between January 2013 and July 2015 were initially considered. Lobectomies were performed by the same surgical team, with thoracotomy or video-assisted thoracoscopic surgery (VATS) access. Exclusion criteria (n = 25 patients) were: previous KT exposure, recent trauma, pre-existing chest pain, lack of informed consent, >24-h postoperative intensive care unit treatment. After surgery, the 92 eligible patients were randomized to KT experimental group (n = 46) or placebo control group (n = 46). Standard postoperative analgesia was administered in both groups (paracetamol/non-steroidal anti-inflammatory drugs, epidural analgesia including opioids), with supplemental analgesia boluses at patient request. On postoperative day 1 in addition, in experimental group patients a specialized physiotherapist applied KT, with standardized tape length, tension and shape, over three defined skin areas: at the chest access site pain trigger point; over the ipsilateral deltoid/trapezius; lower anterior chest. In control group, usual dressing tape mimicking KT was applied over the same areas, as placebo. Thoracic pain severity score [visual analogue scale (VAS) ranging 0-10] was self-assessed by all patients on postoperative days 1, 2, 5, 8, 9 and 30. RESULTS: The KT group and the control group had similar demographics, lung cancer clinico-pathological features and thoracotomy/VATS ratio. Postoperatively, the two groups also resulted similar in supplemental analgesia, complication rate, mean duration of chest drainage and length of stay. There were no adverse events with KT application. After tape application, KT patients reported overall less thoracic pain than the control group, the difference being significant on postoperative day 5 [median VAS, 2 (interquartile range, 1-3) vs 3 (2-5), P < 0.01] and day 8 [median VAS, 1 (0-2) vs 2 (1-3), P < 0.05]. Moreover, on postoperative day 30 persistence of chest pain (VAS ≥3) was reported less frequently by the KT group than by the control group (7 vs 24%; P = 0.03). CONCLUSIONS: KT after lung lobectomy is a safe and effective auxiliary technique for chest pain control. ISRCTN REGISTRY: ISRCTN37253470.

Resection rate of lung cancer in Teesside (UK) and Varese (Italy): a comparison after implementation of the National Cancer Plan.

BACKGROUND: In a lung cancer survey in 2000 we showed significantly less favourable stage distribution and lower resection rate in Teesside (UK) than in the comparable industrialised area of Varese (Italy). Lung cancer services in Teesside were subsequently reorganised according to National Cancer Plan recommendations. METHODS: For all new lung cancer cases diagnosed in Teesside (n=324) and Varese (n=260) during the 12 months October 2010 to September 2011 (hereafter 'the 2010 cohort'), demographic, clinico-pathological and disease management data were prospectively recorded using the same database and protocol as the 2000 survey. Findings were analysed focusing on resection rate. RESULTS: In the 2010 cohort compared with 2000, both in Teesside and Varese emergency referral decreased (p<0.001), performance status improved (p<0.001), but cancer stage shift was not seen; resection rate improved in Teesside, from 7% to 11% (p=0.054), and was unchanged in Varese (24%). Moreover, in Teesside compared with Varese the stage distribution remained less favourable, stage I-II non-small cell lung cancer (NSCLC) proportion being respectively 12% and 19% (p=0.040), and resection rate in all lung cancers remained lower (11% and 24%; p<0.001). On multivariate analysis, resection predictors in Teesside were as follows: stage I-II NSCLC (OR 86.14; 95% CI 31.80 to 233.37), performance status 0-1 (OR 5.02; 95% CI 1.48 to 17.07), belonging to 2010 cohort (OR 2.85; 95% CI 1.06 to 7.64). CONCLUSIONS: In Teesside the main independent predictor of resection was disease stage; in 2010-2011 compared with 2000, lung cancer service improved but stage shift did not occur, and resection rate increased but remained significantly lower than in Varese.