Bronchoscopically-visible massive central airway cancer cavitation is associated with metastatic disease, lack of actionable mutations and poor prognosis: a case series.

Cavitating lung tumors occur in approximately 10-15% of the patients, are more commonly associated with squamous histology, and are typically located in the lung parenchyma. Herein we describe an exceedingly rare series of 5 patients, 4 of whom treatment-naïve, whose tumor caused the disruption of the normal airway anatomy at the level of lobar or segmental bronchi, leading to the formation of an endoscopically-visible cavity which ended up in the lung parenchyma or even into the pleural space. Sex (3 males, 2 females), smoking habit (2 never smokers, 2 former smokers, 1 current smoker), and histology (3 adenocarcinoma, 2 squamous cell carcinoma) were heterogeneous, but the 4 patients treatment-naïve presented with metastatic disease, poor ECOG performance status, similar clinical complaints of long duration, and lack of actionable mutations. The only patient who exhibited a meaningful response to treatment had the lowest symptoms' duration, the smallest size of the cavitated mass, and the best performance status at the time of diagnosis. This series provides the first comprehensive description of a rare presentation of lung cancer characterized by similar clinical complaints, delayed diagnosis and poor prognosis.

Diagnosis and Molecular Profiling of Lung Cancer by Percutaneous Ultrasound-Guided Biopsy of Superficial Metastatic Sites Is Safe and Highly Effective.

BACKGROUND: Diagnosis, staging, and molecular profiling of lung cancer are mostly carried out with bronchoscopy or CT-guided aspiration/biopsy. However, patients with locally advanced or advanced disease often harbor "superficial" metastases for which a percutaneous, ultrasound-assisted needle aspiration/biopsy (US-NAB) might represent an equally effective yet less invasive and costly alternative. PATIENTS AND METHODS: We reviewed a prospectively collected database of consecutive patients with known/suspected lung cancer who underwent a US-NAB of a suspected "superficial" metastasis. Cancer genotyping was carried out with next-generation sequencing using the Oncomine™ Focus DNA and RNA fusion panels. PD-L1 immunohistochemistry was performed with the SP263 antibody. Feasibility, diagnostic yield for tissue diagnosis, sensitivity for malignancy, diagnostic yield for the molecular profiling, and complications were the study endpoints. RESULTS: A total of 98 lesions were evaluated, and 93 were biopsied (95% feasibility). The spectrum of sampled sites included lymph nodes (63 patients), bone (11), subcutaneous tissue (8), muscle (7), and the pleura (4). The diagnostic yield for a tissue diagnosis was 93% (91/98). US-NAB correctly identified 85 of the 87 patients finally diagnosed with malignancy (98% sensitivity). Cancer genotyping and PDL1 testing were successfully completed in 41/42 patients (98%) and in 40/50 patients (80%) for whom these tests were requested, respectively. No complications were observed. CONCLUSION: US-NAB of "superficial" metastasis of lung cancer is safe and is associated with high success for diagnosis and molecular profiling. In this clinical setting, using US-NAB as a first-step technique would significantly limit the use of more invasive and costly diagnostic procedures.

Interobserver agreement between pathologist, pulmonologist and molecular pathologist to estimate the tumour burden in rapid on-site evaluation smears from endosonography and guided bronchoscopy.

OBJECTIVE: A growing number of studies have suggested that non-pathologists can reliably assess the adequacy and malignancy in rapid on-site evaluation (ROSE) smears prepared during endoscopic sampling procedures. However, no study has verified whether they can also consistently estimate the tumour burden, which is critical for the molecular profiling of lung cancer. We aimed to assess the interobserver agreement (IOA) between a pathologist, a pulmonologist (previously trained in lung and lymph node cytopathology) and a molecular pathologist for the tumour burden in ROSE smears. METHODS: The ROSE smears of consecutive patients with suspected lung cancer undergoing endosonography or guided bronchoscopy were assessed independently by a pathologist, a pulmonologist and a molecular pathologist (gold standard). The IOA for the tumour burden, assessed through k-statistics, was the primary outcome. RESULTS: A total of 322 ROSE smears obtained from 162 patients were evaluated. The IOA between the molecular pathologist and pulmonologist was very good (moderate to substantial), although slightly inferior to the IOA between the molecular pathologist and pathologist in the whole slide set (k: 0.707, 95% confidence interval [CI]: 0.677-0.739 vs 0.793, 95% CI: 0.762-0.815), as well as in smears prepared from lymphadenopathy (k: 0.783, 95% CI: 0.760-0.855 vs 0.827, 95% CI: 0.728-0.892) or from pulmonary nodules/masses (k: 0.558, 95% CI: 0.416-0.686 vs 0.715, 95% CI: 0.621-0.767). CONCLUSIONS: A professionally trained pulmonologist can reliably estimate the tumour burden in bronchoscopically derived ROSE smears, especially in the setting of lymphadenopathy. This can be particularly useful in institutions where a cytopathologist is not available regularly.

A Trained Pulmonologist Can Reliably Assess Endosonography-Derived Lymph Node Samples during Rapid On-Site Evaluation.

BACKGROUND: The widespread use of rapid on-site evaluation is hampered by constraints related to time and resources, inadequate reimbursement, and evidence from randomized trials that show a lack of increase in diagnostic yield and specimen adequacy associated with its usage. OBJECTIVE: We aimed to verify whether a pulmonologist can assess endosonography-derived lymph node samples after a comprehensive and reproducible training provided by a specialist pathologist. METHODS: Prospective, observational trial structured in three phases. In the first (training) phase, a pathologist critically evaluated the smears from 150 archival endosonography cases with a pulmonologist. In the second (test) phase, the pulmonologist was asked to assess 50 archival endosonography-derived samples. In the last (real-life) phase, the pulmonologist classified the samples from 200 patients during the endosonography. The overall agreement between pulmonologist and pathologist (gold standard), assessed through κ-statistics, was the primary outcome. The agreement for the identification of specific cytological categories was the secondary outcome. RESULTS: The overallagreement between pulmonologist and pathologist was 84% (κ0.765, 95% CI 0.732-0.826) in the test phase and 89.7% (κ 0.844, 95% CI 0.799-0.881) in the real-life phase. The agreement for specific cytological categories was 92.7% (95% CI 0.824-0.980) for inadequate samples, 90.3% (95% CI 84.5-94.5%) for reactive lymphadenopathies, 90.5% (95% CI 0.845-0.946) for malignancy, and 73% (95% CI 0.515-0.897) for granulomatous samples. CONCLUSIONS: A trained pulmonologist can reliably assess adequacy and malignancy for endosonography-derived samples, which could be useful in institutions where a cytopathologist/cytotechnician is not available regularly.

Intrathoracic Lymph Node Microcalcifications are Associated With a High Prevalence of Malignancy and Anaplastic Lymphoma Kinase Rearrangement: The "Calce" Study.

BACKGROUND: Microcalcifications are acknowledged as a malignancy risk factor in multiple cancers. However, the prevalence and association of intrathoracic lymph node (ILN) calcifications with malignancy remain unexplored. METHODS: In this cross-sectional study, we enrolled patients with known/suspected malignancy and an indication for endosonography for diagnosis or ILN staging. We assessed the prevalence and pattern of calcified ILNs and the prevalence of malignancy in ILNs with and without calcifications. In addition, we evaluated the genomic profile and PD-L1 expression in lung cancer patients, stratifying them based on the presence or absence of ILN calcifications. RESULTS: A total of 571 ILNs were sampled in 352 patients. Calcifications were detected in 85 (24.1%) patients and in 94 (16.5%) ILNs, with microcalcifications (78/94, 83%) being the predominant type. Compared with ILNs without calcifications (214/477, 44.9%), the prevalence of malignancy was higher in ILNs with microcalcifications (73/78, 93.6%; P<0.0001) but not in those with macrocalcifications (7/16, 43.7%; P=0.93). In patients with lung cancer, the high prevalence of metastatic involvement in ILNs displaying microcalcifications was independent of lymph node size (< or >1 cm) and the clinical stage (advanced disease; cN2/N3 disease; cN0/N1 disease). The anaplastic lymphoma kinase (ALK) rearrangement was significantly more prevalent in patients with than in those without calcified ILNs (17.4% vs. 1.7%, P<0.001), and all of them exhibited microcalcifications. CONCLUSION: ILN microcalcifications are common in patients undergoing endosonography for suspected malignancy, and they are associated with a high prevalence of metastatic involvement and ALK rearrangement.

Thirty-Day Complications, Unplanned Hospital Encounters, and Mortality after Endosonography and/or Guided Bronchoscopy: A Prospective Study.

BACKGROUND AND OBJECTIVE: Limited data exist regarding the adverse events of advanced diagnostic bronchoscopy, with most of the available information derived from retrospective datasets that primarily focus on early complications. METHODS: We conducted a 15-month prospective cohort study among consecutive patients undergoing endosonography and/or guided bronchoscopy under general anesthesia. We evaluated the 30-day incidence of severe complications, any complication, unplanned hospital encounters, and deaths. Additionally, we analyzed the time of onset (immediate, within 1 h of the procedure; early, 1 h-24 h; late, 24 h-30 days) and identified risk factors associated with these events. RESULTS: Thirty-day data were available for 697 out of 701 (99.4%) enrolled patients, with 85.6% having suspected malignancy and multiple comorbidities (median Charlson Comorbidity Index (IQR): 4 (2-5)). Severe complications occurred in only 17 (2.4%) patients, but among them, 10 (58.8%) had unplanned hospital encounters and 2 (11.7%) died within 30 days. A significant proportion of procedure-related severe complications (8/17, 47.1%); unplanned hospital encounters (8/11, 72.7%); and the two deaths occurred days or weeks after the procedure. Low-dose attenuation in the biopsy site on computed tomography was independently associated with any complication (OR: 1.87; 95% CI 1.13-3.09); unplanned hospital encounters (OR: 2.17; 95% CI 1.10-4.30); and mortality (OR: 4.19; 95% CI 1.74-10.11). CONCLUSIONS: Severe complications arising from endosonography and guided bronchoscopy, although uncommon, have significant clinical consequences. A substantial proportion of adverse events occur days after the procedure, potentially going unnoticed and exerting a negative clinical impact if a proactive surveillance program is not implemented.

Ultrasound-Guided Needle Aspiration Biopsy of Superficial Metastasis of Lung Cancer with and without Rapid On-Site Evaluation: A Randomized Trial.

BACKGROUND AND OBJECTIVE: Studies which evaluated the role of an ultrasound-guided needle aspiration biopsy (US-NAB) of metastases from lung cancer located in "superficial" organs/tissues are scant, and none of them assessed the possible impact of rapid on-site evaluation (ROSE) on diagnostic accuracy and safety outcomes. METHODS: Consecutive patients with suspected superficial metastases from lung cancer were randomized 1:1 to US-NAB without (US-NAB group) or with ROSE (ROSE group). The diagnostic yield for a tissue diagnosis was the primary outcome. Secondary outcomes included the diagnostic yield for cancer genotyping, the diagnostic yield for PD-L1 testing, and safety. RESULTS: During the study period, 136 patients were randomized to receive an US-NAB with (n = 68) or without ROSE (n = 68). We found no significant differences between the ROSE group and the US-NAB group in terms of the diagnostic yields for tissue diagnosis (94.1% vs. 97%, respectively; p = 0.68), cancer genotyping (88% vs. 91.8%, respectively; p = 0.56), and PD-L1 testing (93.5% vs. 90.6%, respectively; p = 0.60). Compared to the diagnostic US-NAB procedures, the non-diagnostic procedures were characterized by less common use of a cutting needle (66.6% vs. 96.9%, respectively; p = 0.0004) and less common retrieval of a tissue core (37.5% vs. 98.5%; p = 0.0001). Only one adverse event (vasovagal syncope) was recorded. CONCLUSION: US-NAB of superficial metastases is safe and has an excellent diagnostic success regardless of the availability of ROSE. These findings provide a strong rationale for using US-NAB as the first-step method for tissue acquisition whenever a suspected superficial metastatic lesion is identified in patients with suspected lung cancer.

Performance characteristics and predictors of yield from transbronchial needle aspiration in the diagnosis of peripheral pulmonary lesions.

BACKGROUND AND OBJECTIVE: Transbronchial needle aspiration (TBNA) is useful for diagnosing peripheral pulmonary lesions (PPL). However, TBNA is largely underused and the variables that may be related to its diagnostic usefulness have not been specifically studied. The aim of the present study was to evaluate the performance characteristics and predictors of yield from TBNA of PPL, and to compare the performance characteristics of different bronchoscopic sampling methods. METHODS: Consecutive patients with PPL were prospectively enrolled, and during the same examination, TBNA, transbronchial lung biopsy (TBLB) and bronchial washing (BW) were performed. RESULTS: Two hundred and eighteen PPL in 218 patients were sampled. TBNA was more sensitive (65%) than either TBLB (45%, P<0.001) or BW (22%, P<0.001). TBNA was the only diagnostic procedure in 42/196 patients (21%) with malignant lesions, and was more likely to be the only diagnostic procedure for lesions lacking (23/85 patients, 27%) than for lesions with the bronchus sign (19/111 patients, 17%). In multivariate analysis, a lesion size >2cm, malignancy and location in the middle lobe were independent predictors of a positive TBNA result. CONCLUSIONS: TBNA is the single best contributor to the success of bronchoscopy in the diagnosis of PPLs, and should be routinely used especially in the presence of lesions lacking the bronchus sign. Lesion size of > 2cm, location in the middle lobe, and malignant nature are strong predictors of a positive TBNA result.

Pattern of cancer patient referral and organisational model of an interventional pulmonology programme during the COVID-19 pandemic.

An interventional pulmonary programme can be carried out safely for both cancer patients and HCWs during the #COVID19 pandemic. However, a worrisome reduction of new cancer patient referral occurs during periods of high community spread of the virus. https://bit.ly/2PRWNXo.

The "Polonium In Vivo" Study: Polonium-210 in Bronchial Lavages of Patients with Suspected Lung Cancer.

Few studies have reported on polonium-210, a decay breakdown product of radon-222 and lead-210, in human lungs and there has been no study in patients with suspected lung cancer. The main aim of this "Polonium in vivo" study was to evaluate polonium-210 radioactivity in bronchopulmonary systems of smoker, ex-smoker and never smoker patients with suspected lung cancer. Alpha-spectrometric analyses were performed on bronchial lavage (BL) fluids from two Italian hospitals in 2013-2016. Socio-demographic, smoking, occupational and spirometric characteristics, lung cancer confirmation and histologic type and radon-222 concentration in patients' homes were collected. Seventy BL samples from never (n = 13), former (n = 35) and current smokers (n = 22) were analyzed; polonium-210 was detected in all samples from current and former smokers and in 54% of samples from never smokers (p < 0.001; median values: 1.20, 1.43 and 0.40 mBq, respectively). Polonium-210 levels were significantly higher in COPD versus no COPD patients (median value: 3.60 vs. 0.97 mBq; p = 0.007); former and current smokers, without and with COPD, had significantly increased polonium-210 levels (p = 0.012); 96% of confirmed versus 69% of non-confirmed lung cancer patients recorded detectable polonium-210 levels (p = 0.018). A polonium-210 detectable activity was measured in BL samples from all current and former smokers. Polonium-210 in the lungs could be the result of lead-210 entrapment, which, with its half-life of 22 years, could provide a continuous emission of alpha radioactivity, even many years after quitting, thus proposing a possible explanation for the onset of lung cancer, particularly in former smokers.

Pulmonary adenocarcinoma with psammoma bodies is associated with a specific endobronchial ultrasound pattern and a high prevalence of actionable driver mutations.

INTRODUCTION: Pulmonary adenocarcinoma with psammoma bodies (PAPBs) is a rare histological variant whose association with a high prevalence of targetable mutations has been suggested by scant literature reports describing small series. We aim to describe the endobronchial ultrasound (EBUS) pattern and the molecular profile by next-generation sequencing of an Italian series of patients with PAPBs. MATERIAL AND METHODS: Over a 8-year period (2012-2019), we identified 15 patients with a very uncommon endobronchial ultrasound (EBUS) heterogeneity pattern characterized by the presence of multiple to countless, punctate non-shadowing foci ("starry sky" sign) which were not evident at CT and corresponded to psammoma bodies at pathological examination. The clinical, radiological, pathological and molecular findings of these patients were retrieved and analyzed. RESULTS: Pathological examination of the EBUS-TBNA specimens revealed malignancy (12 pulmonary adenocarcinoma, 2 breast carcinoma, 1 colonic carcinoma) and showed the presence of psammoma bodies in all of the 15 patients with the starry sky sign. Among the 12 patients with pulmonary adenocarcinoma with psammoma bodies, female sex (8/12, 66.7 %) and never-smoking habit (6/12, 50 %) were prevalent. Molecular tumor profiling using the Oncomine™ Focus DNA and RNA fusion panels was successfully performed in 11/12 patients and revealed 10 genetic alterations (BRAF mutation, 4; EGFR mutation, 2; ALK rearrangement, RET rearrangement, PIK3CA mutation, CDK4 amplification 1) in 7 patients (63.6 %). CONCLUSION: The present series suggests that pulmonary adenocarcinoma with psammoma bodies is associated with a readily identifiable EBUS pattern and with a high prevalence of different, often uncommon and actionable, driver mutations.

"Melting Lymph Node Sign": The Endobronchial Ultrasound Pattern Of Cystic Mediastinal Nodal Metastases.

Cystic change in metastatic lymph nodes occurs in certain types of tumors (ie, papillary thyroid carcinoma and squamous cell carcinoma of the Waldeyer's ring) and it is usually observed in the head and neck region. We report on a series of 6 patients with mediastinal metastasis from lung cancer in whom the endobronchial ultrasound showed that most of the lymph node tissue had "melted," leading to the formation of a single, anechoic, avascular cavity. Besides the unique endobronchial ultrasound pattern, we describe the imaging and pathology findings of this unusual presentation of malignant mediastinal lymphadenopathy to facilitate its recognition.

Adequacy of endosonography-derived samples from peribronchial or periesophageal intrapulmonary lesions for the molecular profiling of lung cancer.

INTRODUCTION AND OBJECTIVES: Endosonography is increasingly used for the diagnosis of centrally located, bronchoscopically invisible intrapulmonary lesions, but data regarding its utility for molecular profiling are lacking. We aimed to assess the suitability of endosonography samples obtained from intrapulmonary lesions for cancer genotyping and programmed-death ligand 1 (PD-L1) testing. METHODS: A prospectively collected database regarding 99 consecutive patients undergoing endosonography for the diagnosis of an intrapulmonary lesion was retrospectively reviewed. Genotyping ± PD-L1 testing was carried out in the 53 patients with advanced lung cancer and was classified as complete if all clinically indicated tests could be performed, incomplete if at least one test could not be carried out, and unsuccessful if the sample was unsuitable for molecular analysis. RESULTS: All clinically indicated biomarkers could be tested in 44 (83%) patients, whereas the molecular profiling was classified as incomplete in 6 (11.3%), and unsuccessful in 3 (5.7%). Thirty-seven genetic alterations (KRAS mutation, 17; EGFR mutation, 17; ALK rearrangement, 3) and 2 cases of PD-L1 expression >50% were found in 31 (58%) patients. EGFR was successfully analysed in 94.1% of cases, KRAS in 93.9%, ALK in 89%, ROS1 in 90% and PD-L1 in 63.1%. CONCLUSION: Endosonography-derived samples from intrapulmonary lesions were suitable for a thorough molecular profiling in most patients. The few cases of incomplete accomplishment of the testing algorithm were related to the failure of PD-L1 analysis due to the exhaustion of the sample or the lack of sufficient tumour cells in the paraffin-embedded material.

Endobronchial ultrasound-guided transbronchial needle aspiration with the flexible 19-gauge needle.

INTRODUCTION AND OBJECTIVES: Endosonography has become standard of care in the diagnostic work-up of mediastinal lymphadenopathy and peribronchial lung lesions, but its success rate in some specific settings/conditions may be hampered by limited needle flexibility and size. We report on our initial experience with the 19G Flex needle, characterized by larger size and greater flexibility as compared with the currently available cytology needles. METHODS: Retrospective review of prospectively collected data on the first 13 consecutive patients submitted to endosonography with the 19G Flex needle. Patients were included if they had: (a) suspicion of a histologically complex disease (ie, lymphoma); (b) suspicion of an advanced lung cancer possibly requiring extensive genotyping; (c) a lesion whose sampling with a 22G needle had failed because of lack of visibility when the needle was loaded into the scope. RESULTS: The 13 patients enrolled had a mean age of 58.15 ± 17 years and a male to female ratio of 8:5. Target lesions (mean size 18.6 ± 6.4 mm) were lymphadenopathies (9 patients), lung lesions (3 patients) and a pleural nodule (1 patient). Histology core/s and a definite diagnosis (adenocarcinoma, 4 cases; lymphoma, 2; mesothelioma, 2, metastases from extrathoracic tumors, 2; non-small-cell lung cancer not otherwise specifiable, 1; small cell carcinoma, 1; sarcoidosis, 1) were obtained in 100% of patients. A single case of self-resolving bleeding was the only complication we observed. CONCLUSIONS: Preliminary results obtained with the dedicated Flex 19G needle are promising, as sample size/quality is satisfactory and the needle influence on scope flexibility is minimal.

Utilization of noninvasive ventilation in acute care hospitals: a regional survey.

PURPOSES: Little information is available on the utilization of noninvasive positive-pressure ventilation (NPPV) in the United States. Accordingly, we performed a survey on the use of NPPV at acute care hospitals in a region of the United States to determine variations in utilization and between hospitals, the reasons for lower rates of utilization, and the techniques used for application. METHODS: Using survey methodology, we developed a questionnaire consisting of 19 questions and distributed it by mail to directors of respiratory care at all 82 acute care hospitals in Massachusetts and Rhode Island. Nonresponders were contacted by phone to complete the survey. Responses were analyzed using standard statistics, including t tests and Mann-Whitney U tests where appropriate. RESULTS: We obtained responses from 71 of the 82 hospitals (88%). The overall utilization rate for NPPV was 20% of ventilator starts, but we found enormous variation in the estimated utilization rates among different hospitals, from none to > 50%. The top two reasons given for lower utilization rates were a lack of physician knowledge and inadequate equipment. In the 19 hospitals that provided detailed information, COPD and congestive heart failure constituted 82% of the diagnoses of patients receiving NPPV, but NPPV was still used in only 33% of patients with these diagnoses receiving any form of mechanical ventilation. CONCLUSIONS: The utilization rates for NPPV vary enormously among different acute care hospitals within the same region. The perceived reasons for lower utilization rates include lack of physician knowledge, insufficient respiratory therapist training, and inadequate equipment. Educational programs directed at individual institutions may be useful to enhance utilization rates.

Randomized Trial of Endobronchial Ultrasound-Guided Transbronchial Needle Aspiration With and Without Rapid On-site Evaluation for Lung Cancer Genotyping.

BACKGROUND: Experts and scientific society guidelines recommend that rapid on-site evaluation (ROSE) be used with endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) to optimize lung cancer genotyping, but no comparative trial has been carried out to confirm and quantify its usefulness. METHODS: To assess the influence of ROSE on the yield of EBUS-TBNA for a multigene molecular analysis of lung cancer samples, consecutive patients with suspected or known advanced lung cancer were randomized to undergo EBUS-TBNA without ROSE (EBUS arm) or with ROSE (ROSE arm). The primary end point was the rate of the successful accomplishment of the institution's clinical protocol for molecular profiling of nonsquamous non-small cell lung cancer (EGFR and KRAS testing, followed by ALK testing for tumors with EGFR and KRAS wild-type status). RESULTS: Complete genotyping was achieved in 108 of 126 patients (85.7%) (90.8% in the ROSE arm vs 80.3% in the EBUS arm, P = .09). The patients in the ROSE arm were less likely to have samples that could be used only for pathologic diagnosis because of minimal tumor burden (0 vs 6, P = .05), and were more likely to have the bronchoscopy terminated after a single biopsy site (58.9% vs 44.1%, P = .01). CONCLUSIONS: ROSE prevents the need for a repeat invasive diagnostic procedure aimed at molecular profiling in at least one out of 10 patients with advanced lung cancer and significantly reduces the risk of retrieving samples that can be used only for pathologic subtyping because of minimal tumor burden. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT01799382; URL: www.clinicaltrials.gov.