Modified Glasgow Prognostic Score predicts survival among advanced non-small cell lung carcinoma patients treated with anti-PD1 agents.

Immune checkpoint inhibitors were approved for advanced nonsmall cell lung cancer (NSCLC) treatment. Despite improved survival, not all patients benefit from these agents. Here, the prognostic impact of pretreatment modified Glasgow Prognostic Score (mGPS) and neutrophil-to-lymphocyte ratio (NLR) was assessed. From 77 patients included, 83.2% received at least one prior systemic therapy. Immune-related adverse events (irAE) occurred in 20 patients. A lower mGPS was associated with higher median overall survival (OS), and a lower Eastern Cooperative Oncology Group (ECOG), irAE and fewer metastatic sites with better survival. A trend towards greater OS and progression-free survival (PFS) was stated among patients with NLR <5. mGPS 0 was associated with better survival; ≥3 metastatic sites with worse PFS and OS; ECOG >2 with worse OS and irAE with better survival. Pretreatment mGPS seems to be useful for predicting survival among advanced NSCLC patients treated with anti-programmed cell death 1 drugs, with ECOG performance status, irAE occurrence, and number of metastatic sites acting as survival predictors.

Impact of Azathioprine use in chronic hypersensitivity pneumonitis patients.

INTRODUCTION: Systemic corticosteroids are widely used in chronic hypersensitivity pneumonitis (CHP); however, there is not much evidence to support their use, besides being associated with significant side effects. Azathioprine (AZA) use is common in CHP, although not prospectively tested in randomized controlled trials. Our objective was to evaluate the lung function trajectory of CHP patients after AZA initiation, as well as to assess the safety profile of this drug. METHODS: Retrospective analysis of patients initiated on AZA following a multidisciplinary team diagnosis of CHP. The longitudinal trajectory of lung function in the first 2 years of treatment was assessed. RESULTS: Thirty-five out of 62 patients (56.5%) remained on treatment after 2 years. AZA treatment was associated with a significant improvement in forced vital capacity (FVC) at 12 and 24 months (p = 0.015 and p < 0.001, respectively). A slight increase in total lung capacity (TLC) and 6-min walking test (6MWT) were also reported, although it did not reach statistical differences at the end of 2 years. No changes in diffusion capacity for carbon monoxide (DLCO) were observed. CONCLUSIONS: This is the first study identifying an improvement in lung function (FVC) of CHP patients on AZA treatment for 2 years. Prospective studies are needed to confirm these results and to more adequately select CHP patients who may benefit from AZA.

Diagnostic Yield of Computed Tomography-Guided Transthoracic Lung Biopsy in Diffuse Lung Diseases.

BACKGROUND: Accurate diagnosis is essential for successful management of diffuse lung disease (DLD). Histopathology may sometimes be necessary. Surgical lung biopsy, the gold standard, carries a risk of morbidity and mortality. Computed tomography (CT) guided transthoracic lung biopsy (CT-TLB) is a minimally invasive method for obtaining lung tissue. However, its diagnostic yield is unknown in DLD. OBJECTIVE: To assess the diagnostic yield of CT-TLB in DLD according to the predominant high-resolution CT (HRCT) patterns. METHODS: Between January 2009 and December 2016, we enrolled all consecutive adult patients with suspicion of DLD who underwent CT-guided transthoracic lung biopsy during the diagnostic work-up. All biopsies were performed by a senior interventional radiologist using CT fluoroscopy. RESULTS: The study included 169 patients (50.3% men) with a mean (±SD) age of 58.3 ± 14 years. Consolidation was the predominant HRCT pattern. A definitive or probable diagnosis was made in 66.3%. The most frequent diagnosis was organizing pneumonia (36.2%). Diagnostic yield was higher when the predominant HRCT pattern was consolidation or nodular. The most common complication was pneumothorax (17.8%); other complications included mild hemoptysis (7.7%), hemothorax (1.2%), and death (0.59%). No acute exacerbation of the underlying condition was observed. CONCLUSIONS: CT-TLB proved to be accurate and safe for the diagnosis of DLD. The overall diagnostic yield of the procedure was 66.3%. Given its low complication rates, CT-TLB can be an option in patients whose respiratory function is seriously impaired and in those with substantial comorbidities, where more invasive procedures cannot be performed for reasons of safety.

Lymphangioleiomyomatosis With Atypical Presentation Following Pneumothorax: A Case Report.

Lymphangioleiomyomatosis (LAM) is a rare systemic disease that typically presents like cystic lung disease. High-resolution computed tomography (CT) is the recommended imaging technique, with cysts being the hallmark: typically multiple, well-circumscribed, thin-walled, with a variable diameter (usually <2 cm) and widespread in distribution. The gold standard for diagnosis is a biopsy. LAM should be considered in the differential diagnosis of cystic lung diseases. The authors report a case of LAM presenting with a pneumothorax, which due to its atypical imaging characteristics, mimicked another uncommon cystic disease. A multidisciplinary approach is crucial when dealing with presentations of rare diseases.

Lung and Pleural Immunoglobulin G4-Related Disease: Two Contrasting Case Reports.

Immunoglobulin G4-related disease (IgG4-RD) is an immunomediated disease that can virtually affect any organ. Despite the pancreas being known as the most frequently involved organ, pulmonary and pleural IgG4-RD is being increasingly reported. The authors present two cases of IgG4-RD diagnosed in the same year, with different presentations and outcomes, in which the lung and pleural involvement were essential for the diagnosis. Recognizing IgG4-RD as a possible cause of chronic pleural effusion and/or thickening and lung abnormalities is important for an early diagnosis and prognosis improvement.

Pleuroparenchymal fibroelastosis as a complication of chemotherapy: A case report.

Pleuroparenchymal fibroelastosis (PPFE) is a rare and recently described distinct pattern of lung apical fibrosis involving the upper lobe parenchyma and pleural dome. PPFE has definable and reproducible clinical, radiological and histopathological criteria, which allowed its classification as an independent interstitial lung disease. Several factors have been associated with PPFE, such as chemotherapy, especially with alkylating agents. The authors present a case of a 34-year-old female with previous history of Hodgkin lymphoma treated with first line chemotherapy (doxorubicin, bleomycin, vinblastine and dacarbazine). The patient had no other known comorbidities or relevant exposure to lung irritants. A total of 2 years after completing cancer treatment, the patient developed clinical and radiological features of PPFE. Given their previous history of malignancy, a biopsy of the lesion was obtained, which confirmed the diagnosis of PPFE. The authors present this case to raise awareness of this disease and to demonstrate that PPFE can develop months to years following chemotherapy treatment. Moreover, to date, none of these chemotherapy agents have been associated with the development of PPFE.

Mortality risk prediction with ILD-GAP index in a fibrotic hypersensitivity pneumonitis cohort.

BACKGROUND: Fibrotic hypersensitivity pneumonitis (fHP) is associated with significant morbidity and mortality. Interstitial lung disease-gender-age-physiology (ILD-GAP) performance in fHP outside the initial cohort was never performed. AIM: To assess the ILD-GAP index's ability to predict mortality in a Portuguese cohort of patients with fHP and analyse whether other clinical variables add value. METHODS: Retrospective analysis of fHP cohort in two Portuguese ILD centres. The baseline ILD-GAP index was calculated. Survival was analysed in months; mortality was the primary outcome. Univariate and multivariate analyses to identify mortality risk factors were performed. RESULTS: A total of 141 patients were included. Fifty-three patients (37.6%) died during the follow-up. The usual interstitial pneumonia (UIP) pattern was found in 49.6%, and their survival was inferior to non-UIP [32 months (interquartile range, IQR = 19, 60) versus 52 months (IQR = 28, 98), p = 0.048]. Patients with an ILD-GAP index higher than three double their risk of mortality [hazard ratio (HR) = 6.48, 95% confidence interval (CI) = (3.03-13.96)] when compared with the patients with an index between 2 and 3 [HR = 3.04, 95% CI = (1.62-5.71)] adjusting for acute exacerbation history. Even though UIP patients had worse survival, it did not reach statistical significance when UIP pattern was added to this model. Acute exacerbation history was an independent risk factor for mortality; however, ILD-GAP still predicted mortality after adjusting for this factor. PaO2 and 6-minute walk test desaturation were not significant risk factors. CONCLUSION: ILD-GAP index is a good predictor for mortality in fHP, even after adjusting for other mortality risk factors.

Clinical Application of Next-Generation Sequencing of Plasma Cell-Free DNA for Genotyping Untreated Advanced Non-Small Cell Lung Cancer.

BACKGROUND: Analysis of circulating tumor DNA (ctDNA) has remarkable potential as a non-invasive lung cancer molecular diagnostic method. This prospective study addressed the clinical value of a targeted-gene amplicon-based plasma next-generation sequencing (NGS) assay to detect actionable mutations in ctDNA in patients with newly diagnosed advanced lung adenocarcinoma. METHODS: ctDNA test performance and concordance with tissue NGS were determined, and the correlation between ctDNA findings, clinical features, and clinical outcomes was evaluated in 115 patients with paired plasma and tissue samples. RESULTS: Targeted-gene NGS-based ctDNA and NGS-based tissue analysis detected 54 and 63 genomic alterations, respectively; 11 patients presented co-mutations, totalizing 66 hotspot mutations detected, 51 on both tissue and plasma, 12 exclusively on tissue, and 3 exclusively on plasma. NGS-based ctDNA revealed a diagnostic performance with 81.0% sensitivity, 95.3% specificity, 94.4% PPV, 83.6% NPV, test accuracy of 88.2%, and Cohen's Kappa 0.764. PFS and OS assessed by both assays did not significantly differ. Detection of ctDNA alterations was statistically associated with metastatic disease (p = 0.013), extra-thoracic metastasis (p = 0.004) and the number of organs involved (p = 0.010). CONCLUSIONS: This study highlights the potential use of ctDNA for mutation detection in newly diagnosed NSCLC patients due to its high accuracy and correlation with clinical outcomes.

Liquid Biopsy for Disease Monitoring in Non-Small Cell Lung Cancer: The Link between Biology and the Clinic.

INTRODUCTION: Cell-free DNA (cfDNA) analysis offers a non-invasive method to identify sensitising and resistance mutations in advanced Non-Small Cell Lung Cancer (NSCLC) patients. Next-generation sequencing (NGS) of circulating free DNA (cfDNA) is a valuable tool for mutations detection and disease's clonal monitoring. MATERIAL AND METHODS: An amplicon-based targeted gene NGS panel was used to analyse 101 plasma samples of advanced non-small cell lung cancer (NSCLC) patients with known oncogenic mutations, mostly EGFR mutations, serially collected at different clinically relevant time points of the disease. RESULTS: The variant allelic frequency (VAF) monitoring in consecutive plasma samples demonstrated different molecular response and progression patterns. The decrease in or the clearance of the mutant alleles was associated with response and the increase in or the emergence of novel alterations with progression. At the best response, the median VAF was 0% (0.0% to 3.62%), lower than that at baseline, with a median of 0.53% (0.0% to 9.9%) (p = 0.004). At progression, the VAF was significantly higher (median 4.67; range: 0.0-36.9%) than that observed at the best response (p = 0.001) and baseline (p = 0.006). These variations anticipated radiographic changes in most cases, with a median time of 0.86 months. Overall, the VAF evolution of different oncogenic mutations predicts clinical outcomes. CONCLUSION: The targeted NGS of circulating tumour DNA (ctDNA) has clinical utility to monitor treatment response in patients with advanced lung adenocarcinoma.

Transbronchial lung cryobiopsy in smoking-related interstitial lung diseases.

BACKGROUND: Transbronchial lung cryobiopsy (TBLC) is an emerging technique in the diagnostic approach to diffuse parenchymal lung diseases. However, the role of TBLC in smoking-related Interstitial Lung Diseases (ILDs) is still under discussion. OBJECTIVES: The aim of the present study was to describe our experience with TBLC in diagnostic work-up of patients with smoking-related ILDs. METHOD: We retrospectively reviewed data of patients evaluated in a tertiary hospital ILDs outpatient clinic, who underwent TBLC, from September 2014 to December 2019. TBLC was performed in accordance with the 2018 expert statement from the Cryobiopsy Working Group. RESULTS: Forty-five patients (25 men [55.6%]) with a mean age of 53.9 years [SD, 9.1] were included. The most frequent radiological pattern was ground glass opacity (42 patients). TBLC was performed in different segments of the same lobe in 38 patients and in two lobes in 7 patients. The mean maximal diameter of the samples was 5.2 mm (range, 3-16 mm [SD 2.0]). Pneumothorax occurred in seven patients (15%) and moderate bleeding occurred in one patient. A specific pathological diagnosis was achieved in 43 of 45 patients. The most frequent histopathologic pattern found was desquamative interstitial pneumonia (33 patients), followed by smoking-related interstitial fibrosis (7 patients), respiratory bronchiolitis - ILD (1 patient) and pulmonary Langerhans cell histiocytosis (1 patient). Two patients had alternative diagnosis (Pneumoconiosis and Interstitial Pneumonia with unspecific features) and one patient had normal lung parenchyma. A definitive multidisciplinary team (MDT) diagnosis was reached in 95.5% (43 of 45 cases). Two patients were submitted to additional diagnostic techniques. CONCLUSIONS: The results from this series support TBLC as a safe procedure with a meaningful diagnostic value in the context of a MDT approach of smoking-related ILDs. (Sarcoidosis Vasc Diffuse Lung Dis 2020; 37 (4): e2020013).

Pulmonary Sarcoidosis: Prognostic Factors at Diagnosis in Patients from North of Portugal.

BACKGROUND: Sarcoidosis is a multisystemic granulomatous disease that affects the lungs in more than 90% of the patients. It is associated with a variable clinical course and considering all the different forms of disease presentation, there are an absence of reliable clinical prognostic markers that can predict the outcome at diagnosis. OBJECTIVE: The aim of our study was to investigate prognostic factors at diagnosis in a population of sarcoidosis patients from Northern Portugal. METHODS: A group of 110 patients with chronic evolution was compared with 129 patients with disease resolution regarding their clinical, radiologic and laboratorial features. RESULTS: We found a positive association between the chronic forms and lung function impairment, radiologic stage II, lower lymphocyte CD4/CD8 and extrapulmonary disease. Löfgren syndrome and asthenia instead had a protective significant association to chronicity. Our final logistic regression model found a significant independent association between age (adjusted OR=1.06), extrapulmonary involvement (adjusted OR=2.68), Löfgren's syndrome (adjusted OR=0.15) with outcome toward chronicity. CONCLUSIONS: In this first study searching for prognostic factors at diagnosis in a Northern Portuguese population, we found clinical prognosis factors that have been described in other populations that should be considered whenever sarcoidosis is identified.

Acute exacerbation of idiopathic pulmonary fibrosis.

Some patients with Idiopathic Pulmonary Fibrosis (IPF) have disease accelerated deterioration without identifiable cause referred as "acute exacerbation" or "accelerated stage". It is characterized by severe worsening of dyspnea, hypoxemia and new or progressive opacities on imaging studies. The typical histological findings are diffuse alveolar damage in addition to the features of usual interstitial pneumonia pattern. Mortality in this clinical entity is very high and no efficacious therapeutic have been described. The authors describe the clinical, functional and radiological features, treatment and evolution of five patients with IPF acute exacerbation. A discussion will be carry out concerning the IPF acute exacerbation usual features comparing with the alterations noticed in those patients.

Diagnostic yield and safety of transbronchial cryobiopsy in sarcoidosis.

INTRODUCTION: Transbronchial lung cryobiopsy (TBLC) is an endoscopic technique proven to be useful in diagnostic approach to interstitial lung disease (ILD), but its role in sarcoidosis is not fully established. The aim of the present study was to assess the diagnostic yield of TBLC in sarcoidosis and its safety profile. METHODS: Retrospective analysis of patients, evaluated in a tertiary hospital ILD outpatient clinic, who underwent TBLC in the diagnostic work-up. TBLC was performed in accordance with the 2018 expert statement from the Cryobiopsy Working Group. RESULTS: 32 patients were included (mean±sd age 47.7±12.6 years, 59.4% male) and divided into three groups: highly likely sarcoidosis (n=21), possible sarcoidosis (n=6) and unlikely sarcoidosis (n=5). A mean of 2.8±0.8 TBLCs were performed. The definitive diagnosis was established by TBLC in 20 out of 27 patients with suspected sarcoidosis. Two patients were diagnosed with sarcoidosis by other methods performed afterwards. TBLC leaded to other diagnosis as well, such as fungal infection (n=1), hypersensitivity pneumonitis (n=1) and silicosis (n=3), making the diagnostic yield for suspected sarcoidosis of TBLC of 92.6%. TBLC was also able to show compatible histological features in five patients whom sarcoidosis was not previously considered. The complications reported overall were pneumothorax in five (15.6%) patients and moderate bleeding in one (3.1%) case. CONCLUSION: In this cohort, TBLC was a safe, reliable and useful procedure in sarcoidosis diagnosis. These results suggest that TBLC can be used successfully in those cases where a definitive diagnosis could not be reached with the usual and less-invasive diagnostic tools.

Epithelioid hemangioendothelioma - a rare pulmonary tumor.

The authors report a case of a rare pulmonary neoplasm - epithelioid hemangioendothelioma, in a 39 year-old woman, asymptomatic until December 2003, when she developed pleuritic and right-sided chest pain. The patient presented a previous chest radiograph, performed 13 years before, which showed multiple small bilateral pulmonary nodules attributed to tuberculous sequelae. The definitive histological diagnosis was made by lung biopsy through thoracotomy. The patient developed a clinical and imagiological worsening and then therapy with interferon alpha-2a was started. Even with imagiological stability of pulmonary lesions the patient remained symptomatic and died nine months after the diagnosis had been established. The authors emphasise the rarity of this type of pulmonary neoplasm and discuss its clinical presentation, histological features, treatment and prognosis.

Incidental finding of a breast carcinoma on Ga-68-DOTA-1-Nal3-octreotide positron emission tomography/computed tomography performed for the evaluation of a pancreatic neuroendocrine tumor: A case report.

RATIONALE: Functional imaging using radiolabeled somatostatin analogues plays an important role in the management of patients with neuroendocrine tumors, and it is a promising tool in the new era of theragnosis and personalized medicine. PATIENTS CONCERNS: The authors present the case of a 63-year-old woman referred for evaluation of a suspected pancreatic neuroendocrine tumor by Ga-68-DOTA-1-Nal3-octreotide positron emission tomography/computed tomography (Ga-68-DOTA-NOC PET/CT). DIAGNOSES: PET/CT confirmed increased uptake of Ga-68-DOTA-NOC in a pancreatic lesion compatible with hyperexpression of somatostatin receptors in a neuroendocrine tumor. Furthermore, PET/CT revealed increased uptake in a breast lesion and in lymphadenomegalies (less intense than in the pancreatic tumor), which conducted to the incidental diagnosis of a breast carcinoma with lymph node metastases. INTERVENTIONS: For the breast cancer, the patient underwentneoadjuvant chemotherapy and anti-HER2 monoclonal antibody, after which she was submitted to surgery. Regarding thepancreatic neuroendocrine tumor, it was decided to maintain itunder surveillance. OUTCOMES: Breast carcinomas are known to express somatostatin receptors and this is the first report of Ga-68-DOTA-NOC uptake in a breast tumor. LESSONS: Ga-68-DOTA-NOC PET/CT could be useful for the management of breast cancer patients in the new era of theragnosis and personalized medicine.

Overall Survival Analysis and Characterization of an EGFR Mutated Non-Small Cell Lung Cancer (NSCLC) Population.

BACKGROUND: Patients with activating somatic mutations in the Epidermal Growth Factor Receptor (EGFR) have better clinical outcomes when treated with Tyrosine Kinase Inhibitors (TKI) over chemotherapy. However, the impact of the use of TKIs on overall survival outside clinical trials is not well established. OBJECTIVE: To characterize and analyze the overall survival of a Caucasian population with NSCLC and EGFR mutations. METHODS: A retrospective cohort analysis of patients with NSCLC screened for EGFR mutations (exons 18-21) between October 2009 and July 2013 was conducted. Clinical and pathological characteristics, mutational EGFR status, treatment and overall survival were evaluated. RESULTS: From the 285 patients which performed screening for EGFR mutations, 54 (18.9%) had mutations, 25 (46.3%) of which in exon 19 and 20 of which (37.0%) in exon 21. The occurrence of mutations was associated with female sex and non-smoking habits (both, P<.001). The median survival of the global population was 12.0 months, with a better overall survival in mutated than non-mutated patients (20.0 vs 11.0 months, respectively; P=.007). CONCLUSION: These data contribute for a better knowledge of our lung cancer population concerning the mutational status and clinical outcomes, confirming a better overall survival for the patients with EGFR TKI sensible mutations.

Immune Reconstitution Inflammatory Syndrome: Opening Pandora's Box.

One of the purposes of antiretroviral therapy (ART) is to restore the immune system. However, it can sometimes lead to an aberrant inflammatory response and paradoxical clinical worsening known as the immune reconstitution inflammatory syndrome (IRIS). We describe a 23-year-old male, HIV1 infected with a rapid progression phenotype, who started ART with TCD4+ of 53 cells/mm3 (3,3%) and HIV RNA = 890000 copies/mL (6 log). Four weeks later he was admitted to the intensive care unit with severe sepsis. The diagnostic pathway identified progressive multifocal leukoencephalopathy, digestive Kaposi sarcoma, and P. aeruginosa bacteraemia. Five weeks after starting ART, TCD4+ cell count was 259 cells/mm3 (15%) and HIV RNA = 3500 copies/mL (4 log). He developed respiratory failure and progressed to septic shock and death. Those complications might justify the outcome but its autopsy opened Pandora's box: cerebral and cardiac toxoplasmosis was identified, as well as hemophagocytic syndrome, systemic candidiasis, and Mycobacterium avium complex infection. IRIS remains a concern and eventually a barrier to ART. Male gender, young age, low TCD4 cell count, and high viral load are risk factors. The high prevalence of subclinical opportunistic diseases highlights the need for new strategies to reduce IRIS incidence.

Acute fibrinous and organizing pneumonia: A report of 13 cases in a tertiary university hospital.

INTRODUCTION: Acute fibrinous and organizing pneumonia (AFOP) is a rare diffuse pulmonary disease, but it is not yet known whether it is a distinct form of interstitial pneumonia or simply a reflection of a tissue sampling issue. METHODS: Cross-sectional evaluation of clinical and radiological findings, treatments, and outcomes for patients with histologically confirmed AFOP at a tertiary university hospital between 2002 and 2015. RESULTS: Thirteen patients (7 women, 53.8%) with a mean ±â€ŠSD age of 53.5 ±â€Š16.1 years were included. The main symptoms were fever (69.2%), cough (46.2%), and chest pain (30.8%). All patients presented a radiological pattern of consolidation and 5 (38.5%) had simultaneous ground-glass areas. Histology was obtained by computed tomography-guided transthoracic biopsy in 61.5% of cases and by surgical lung biopsy in the remaining cases. Several potential etiologic factors were identified. Eight patients (61.5%) had hematologic disorders and 3 had undergone an autologous hematopoietic cell transplant. Two (15.4%) had microbiologic isolates, 5 (38.4%) had drug-induced lung toxicity, and 2 (15.4%) were classified as having idiopathic AFOP. In addition to antibiotics and diuretics used to treat the underlying disease, the main treatment was corticosteroids, combined in some cases with immunosuppressants. Median survival was 78 months and 6 patients (46.2%) were still alive at the time of analysis. CONCLUSION: Our findings for this series of patients confirm that AFOP is a nonspecific reaction to various agents with a heterogeneous clinical presentation and clinical course that seems to be influenced mainly by the severity of the underlying disorder.

PNET with neuroendocrine differentiation of the lung: Report of an unusual entity.

Ewing's sarcoma/primitive neuroectodermal tumor (PNET) has been the subject of recent reports describing morphologic variants (adamantinoma-like, large cell, spindle cell, sclerosing, clear cell, and vascular-like) of the most classic form, as well as cases displaying unusual morphologic differentiation and atypical immunohistochemical features. We report a case of an uncommon lung tumor in a 20-year-old female, morphologically and molecularly consistent with an Ewing's sarcoma/PNET tumor with foci of squamous differentiation, and peculiar expression of vimentin, high-molecular-weight keratins, p63, synaptophysin, and chromogranin. This case raises a challenging differential diagnostic problem with therapeutic implications: Should the patient be treated following the protocols for Ewing's sarcoma/PNET tumors or as for lung carcinoma with neuroendocrine features? The patient we report here was treated with neoadjuvant chemotherapy for Ewing's sarcoma/PNET according to Euro Ewing 99 study protocol followed by surgery and has no evidence of disease 15 months after the initial diagnosis. This highlights the importance of achieving the correct diagnosis of these atypical tumors using all clinical, morphological, and ancillary methods available to allow for their correct and timely treatment.