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.

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.

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.

Application of the International System for Reporting Serous Fluid Cytopathology (TIS): A retrospective institutional study.

BACKGROUND: Cytology of serous effusions is an important diagnostic tool for the diagnosis of cancer, staging, and prognosis of the patient. Herein, we retrospectively applied the International System for Reporting Serous Fluid Cytopathology (TIS) and provided the corresponding risks of malignancy (ROMs). METHODS: Pleural, pericardial, and peritoneal effusion samples were retrieved from the archives of our department and reclassified according to the TIS. The ROM for each category was calculated based on available surgical follow-up. RESULTS: A total of 3790 effusions were studied. Pleural samples (1292) were reclassified as follows: 27 (2.1%) as non-diagnostic (ND), 1014 (78.5%) as negative for malignancy (NFM), 86 (6.6%) as atypia of undetermined significance (AUS), 29 (2.3%) as suspicious of malignancy (SFM), and 136 (10.5%) as malignant (M). Pericardial samples (241) were reclassified as follows: 4 (1.6%) as ND, 173 (71.8%) as NFM, 10 (4.1%) as AUS, 7 (3%) as SFM, and 47 (19.5%), as M. Peritoneal cases (2257) were re-categorised as follows: 31 (1.4%) as ND, 1897 (84%) as NFM, 39 (1.7%) as AUS, 53 (2.4%) as SFM, and 237 (10.5%) as M. The respective ROM values for each category were 18.5%, 15%, 45.3%, 93%, and 100% in pleural effusions; 25%, 13.2%, 35%, 100%, and 100% in pericardial effusions; and 19.3%, 10.4%, 43.5%, 100%, and 100% in peritoneal effusions. CONCLUSIONS: Pleural, pericardial, and peritoneal cytology show high specificity and moderate sensitivity in the evaluation of serous effusions. The ROMs reported in our study were mostly concordant with those published according to the TIS.

The value of cytology in distinguishing malignant mesothelioma: An institutional experience of 210 cases reclassified according to the International System for Reporting Serous Fluid Cytopathology (ISRSFC).

OBJECTIVE: Malignant mesothelioma (MM) is usually diagnosed by histological examination of tissue samples; however, effusion cytology offers an opportunity to identify a strong possibility for mesothelioma diagnosis at an early stage. We conducted a retrospective analysis of cytological specimens from a large series of histologically proven MM diagnosed over 19 years. The cases were reviewed and reclassified according to the International System for Reporting Serous Fluid Cytopathology (ISRSFC). METHODS: A total of 450 cases were identified. Cytological analysis was present in 210 patients (164 pleural and 46 peritoneal effusions). All cases were reviewed and reclassified according to the proposed ISRSFC scheme. A comparison among the cytomorphological features was made throughout the different diagnostic categories. RESULTS: The 210 cases were histologically diagnosed as follows: 192 (91.4%) cases had an epithelioid type and 18 (8.6%) had a sarcomatoid subtype of MM. The cytological cases were reclassified as follows: 2 (0.9%) as non-diagnostic (ND), 81 (38.6%) as negative for malignancy (NFM), 4 (1.9%) as atypia of undetermined significance (AUS), 11 (5.2%) as suspicious for malignancy (SFM), 112 (53.4%) as malignant (MAL). Sarcomatoid cells in the MAL category were characterised cytomorphologically by more pronounced discohesion. In comparison with the epithelioid subtype, the tumour cells appeared solitary with moderate or marked nuclear pleomorphism, and irregular chromatin. CONCLUSIONS: It is important to recognise the cytological characteristics of this aggressive entity to suggest an early and precise possible diagnosis. Morphological features, coupled with clinico-radiological data may help the clinicians in adequately managing the patients.

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.

Educational interventions alone and combined with port protector reduce the rate of central venous catheter infection and colonization in respiratory semi-intensive care unit.

BACKGROUND: Central Line-Associated BloodStream Infections (CLABSIs) are emerging challenge in Respiratory semi-Intensive Care Units (RICUs). We evaluated efficacy of educational interventions on rate of CLABSIs and effects of port protector as adjuvant tool. METHODS: Study lasted 18 months (9 months of observation and 9 of intervention). We enrolled patients with central venous catheter (CVC): 1) placed during hospitalization in RICU; 2) already placed without signs of systemic inflammatory response syndrome (SIRS) within 48 h after the admission; 3) already placed without evidence of microbiologic contamination of blood cultures. During interventional period we randomized patients into two groups: 1) educational intervention (Group 1) and 2) educational intervention plus port protector (Group 2). We focused on CVC-related sepsis as primary outcome. Secondary outcomes were the rate of CVC colonization and CVC contamination. RESULTS: Eighty seven CVCs were included during observational period. CLABSIs rate was 8.4/1000 [10 sepsis (9 CLABSIs)]. We observed 17 CVC colonizations and 6 contaminations. Forty six CVCs were included during interventional period. CLABSIs rate was 1.4/1000. 21/46 CVCs were included into Group 2, in which no CLABSIs or contaminations were reported, while 2 CVC colonizations were found. CONCLUSIONS: Our study clearly shows that both kinds of interventions significantly reduce the rate of CLABSIs. In particular, the use of port protector combined to educational interventions gave zero CLABSIs rate. TRIAL REGISTRATION: NCT03486093 [ ClinicalTrials.gov Identifier], retrospectively registered.

Molecular Testing in EBUS-TBNA Specimens of Lung Adenocarcinoma: A Study of Concordance Between Cell Block Method and Liquid-Based Cytology in Appraising Sample Cellularity and EGFR Mutations.

PURPOSE: Cytological endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) specimens of mediastinal lymph node metastasis are frequently used to perform concomitant diagnosis, staging and genetic testing in non-small-cell lung cancer (NSCLC). The purposes of this single-center retrospective study were to evaluate EBUS-TBNA samples' adequacy for molecular testing of epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK), and to analyze the concordance between the cell block method and liquid-based cytology (LBC) in appraising the sample cellularity and in detecting EGFR mutation. MATERIALS AND METHODS: We retrospectively examined 82 patients who underwent EBUS-TBNA from October 2012 to September 2015 and received a confirmed diagnosis of lymph node metastasis of lung adenocarcinoma. Each sample was processed using both cell block and LBC to carry out DNA analysis (adequacy criterion: tumor cell percentage > 25%) and EGFR mutation testing. RESULTS: Fifty-four patients were male, 66 were current or former-smokers, and the median age was 67 years. The median size of sampled lymph nodes was 14.8 mm. Seventy-one and 66 samples were adequate to perform cell block and LBC, respectively. The κ-statistic (0.78) showed an excellent concordance. EGFR mutation was detected in eight patients using cell block and in seven using LBC, with a simple percentage agreement of 87.5%. ALK translocation was found in two patients. CONCLUSIONS: This study demonstrates the feasibility of EGFR mutation analysis with both cell block and LBC, with an excellent concordance between the two methods. Considering that the majority of advanced NSCLCs are diagnosed on cytology specimens, LBC is feasible and needs to be implemented for ancillary tests (immunocytochemistry, molecular analysis).

Ultrasonography of the Mediastinum: Techniques, Current Practice, and Future Directions.

In the everyday practice of respiratory physicians, ultrasound techniques play a key role by enabling several diagnostic and interventional procedures. The application of ultrasound to endoscopic procedures allows both a visualization and a guided sampling of mediastinal and hilar lymph nodes. Endobronchial ultrasound can be combined with transbronchial needle aspiration, and, similarly, endoscopic ultrasound can be combined with fine-needle aspiration to sample virtually all mediastinal nodal stations from the airways and the esophagus. Endobronchial ultrasound-transbronchial needle aspiration and endoscopic ultrasound-fine needle aspiration showed a complementary diagnostic yield, and, recently, endoscopic ultrasound with bronchoscope was introduced in clinical practice to perform a transesophageal needle aspiration by using an ultrasound bronchoscope. This technique allows a single operator to perform both transbronchial and transesophageal needle sampling with the same instrument during a single bronchoscopic procedure. Mediastinal staging impacts the management of patients affected by lung cancer, and the most recent guidelines clearly state that endobronchial ultrasound and endoscopic ultrasound should be the initial tissue sampling procedure over surgical staging. In addition, endoscopic ultrasound techniques demonstrated an excellent yield in diagnosing lymphoma and benign diseases, for example, sarcoidosis. The aim of this review was to discuss the current role and future perspectives of endosonography techniques available for the evaluation of the mediastinum. Special emphasis was placed on equipment and technical aspects, the diagnostic role, and future directions of development.

The technique of endoscopic airway tumor treatment.

More than half of primary lung cancers are not resectable at diagnosis and 40% of deaths may be secondary to loco-regional disease. Many of these patients suffer from symptoms related to airways obstruction. Indications for therapeutic endoscopic treatment are palliation of dyspnea and other obstructive symptoms in advanced cancerous lesions and cure of early lung cancer. Bronchoscopic management is also indicated for all those patients suffering from benign or minimally invasive neoplasm who are not suitable for surgery due to their clinical conditions. Clinicians should select cases, evaluating tumor features (size, location) and patient characteristics (age, lung function impairment) to choose the most appropriate endoscopic technique. Laser therapy, electrocautery, cryotherapy and stenting are well-described techniques for the palliation of symptoms due to airway involvement and local treatment of endobronchial lesions. Newer technologies, with an established role in clinical practice, are endobronchial ultrasound (EBUS), autofluorescence bronchoscopy (AFB), and narrow band imaging (NBI). Other techniques, such as endobronchial intra-tumoral chemotherapy (EITC), EBUS-guided-transbronchial needle injection or bronchoscopy-guided radiofrequency ablation (RFA), are in development for the use within the airways. These endobronchial interventions are important adjuncts in the multimodality management of lung cancer and should become standard considerations in the management of patients with advanced lung cancer, benign or otherwise not approachable central airway lesions. We aimed at revising several endobronchial treatment modalities that can augment standard antitumor therapies for advanced lung cancer, including rigid and flexible bronchoscopy, laser therapy, endobronchial prosthesis, and photodynamic therapy (PDT).

Influence of the Learning Effect on the Diagnostic Yield of Endobronchial Ultrasound-guided Transbronchial Needle Aspiration of Mediastinal and Hilar Lymph Nodes.

BACKGROUND: The diagnostic yield of conventional transbronchial needle aspiration (TBNA) is characterized by a learning effect. The aim of this retrospective study was to verify whether a learning curve similarly affected the yield of endobronchial ultrasound-guided (EBUS)-TBNA. To this end, we evaluated the sensitivity and diagnostic accuracy of EBUS-TBNA during the first 3 years of activity. METHODS: EBUS-TBNA was performed by 2 operators with no previous experience in this technique. Cytologic samples were obtained from mediastinal and hilar lymph nodes enlarged at a chest computed tomography scan and/or with increased fluorodeoxyglucose uptake at computed tomography/positron emission tomography scan in patients with suspected lung cancer. The cytologic diagnosis of EBUS-TBNA samples has been compared with the final diagnosis obtained from further diagnostic procedures, surgery, or clinical-radiologic follow-up. RESULTS: From October 2012 to October 2015, we collected 408 EBUS-TBNA cytologic samples from 313 patients: 223 samples were positive for metastatic involvement and 185 were nonmetastatic. The latter included 137 true-negative and 48 false-negative results. The final diagnosis comprised 271 metastatic and 137 nonmetastatic lymph nodes. The overall sensitivity for cancer was 82% and diagnostic accuracy was 88%. Sensitivity and accuracy per year were as follows: first year, 78% and 82% in 90 nodal samples; second year, 83% and 89% in 144 nodal samples; third year, 85% and 91% in 174 nodal samples. CONCLUSIONS: EBUS-TBNA can be considered as a reliable tool even if performed by operators without previous experience in this procedure, and the diagnostic yield continues to increase progressively over a long time.

Idiopathic Pulmonary Fibrosis: Molecular Endotypes of Fibrosis Stratifying Existing and Emerging Therapies.

Idiopathic pulmonary fibrosis (IPF) is a specific form of chronic, progressive fibrosing interstitial pneumonia of unknown causes. Current diagnostic criteria are based on radiological, clinical, and histopathological features but, unfortunately, still many patients remain undiagnosed. Two currently approved therapies, pirfenidone and nintedanib, slow down disease progression but failed to block or revert it. On the other hand, many of the therapeutic agents tested in several clinical trials have not given satisfactory answers, probably due to the pathological heterogeneity of the disease. A growing number of studies show that IPF phenotype is the common clinical outcome of a variety of different pathophysiological mechanisms that identify disease subgroups characterised by specific genetic and molecular biomarkers (endotypes). The precision medicine approach is identifying and analysing the complex system of genetic, molecular, environmental, and behavioural variables underlying the development of the disease and the response to therapy. These molecular pathways are potential targets for novel agents and useful diagnostic, prognostic, and theragnostic biomarkers. We outline the status of knowledge in this field by discussing the complex pathogenetic pathways underlying different disease subgroups and assessing a stratification approach to novel therapeutic agents based on these endotypes.

Usefulness of Conventional Transbronchial Needle Aspiration for Sampling of Mediastinal Lymph Nodes in Lung Cancer.

BACKGROUND: Transbronchial needle aspiration (TBNA) is recognized as a valuable tool for the sampling of mediastinal lymph nodes. In this study, we report data about the diagnostic yield of conventional TBNA in the diagnosis and staging of lung cancer. METHODS: All patients with suspected lung cancer who underwent bronchoscopy with conventional TBNA in the years 2008 to 2012 were evaluated. TBNA was performed on mediastinal lymph nodes enlarged at chest computed tomography scan and/or with increased fluorodeoxyglucose uptake on positron emission tomography/computed tomography scan. Cytologic results derived from TBNA have been compared, with the final diagnosis obtained with other more invasive procedures and/or with a clinical-radiologic follow-up of at least 12 months. RESULTS: TBNA was performed on 375 patients. However, 19 patients were lost to follow-up, and data from 356 patients with a total 459 TBNA specimens were analyzed. TBNA was positive for metastatic involvement of lymph nodes in 172 of 282 patients with cancer, with a sensitivity of 61%. Sensitivity achieved 65% when we considered the total of 459 TBNA specimens. The overall diagnostic accuracy of TBNA was 69%. The nodal stations more frequently examined were 7 (subcarinal: 190 TBNAs), 4R (right lower paratracheal: 147 TBNAs), and 10R (right hilar: 76 TBNAs), with a sensitivity of 66%, 66%, and 67%, respectively. CONCLUSION: Conventional TBNA remains a useful method for the diagnosis and staging of lung cancer, with a good diagnostic yield in several nodal stations.

Role of ultrasound-guided transbronchial biopsy in the diagnosis of peripheral pulmonary lesions.

INTRODUCTION: Endobronchial ultrasound (EBUS) can be used as an alternative to fluoroscopy to visualize a peripheral pulmonary lesion (PPL) and to provide an image guidance for transbronchial biopsy (TBB). The aim of this study was to verify the accuracy of EBUS-guided TBB in the diagnosis of PPLs. METHODS: All the patients with CT-scan evidence of PPL who underwent bronchoscopy with EBUS in the period between 2008 and 2011 were retrospectively evaluated. EBUS was performed using a radial-type miniature ultrasound probe. Once obtained an EBUS image of the PPL, we measured the distance of the PPL from the outer orifice of the working channel of the bronchoscope in order to perform TBB at PPL site. RESULTS: A total of 662 patients were examined. The mean diameter of lesions was 36 ± 20 mm. PPLs were visualized in 494 patients (75%) and the TBB was performed in 479 patients. Thirty-two patients were lost in follow-up and data from 447 patients were analyzed. TBB results were 255 cancers and 192 non-malignant lesions. The final diagnosis reported was 359 cases of cancer and 88 of benign lesion. EBUS-guided TBB had a sensitivity of 71% for the diagnosis of cancer, a negative predictive value of 46% and an overall diagnostic accuracy of 77%. CONCLUSIONS: These data obtained from a large series of patients and using an original method show that EBUS represents a valid support to bronchoscopy and that the EBUS-guided TBB has a high diagnostic yield in the diagnosis of PPLs.