Diagnostic Yield of 16S Ribosomal Ribonucleic Acid Gene-Based Targeted Metagenomic Sequencing for Evaluation of Pleural Space Infection: A Prospective Study.

Objective: To better understand the microbial profile of complicated parapneumonic effusions and empyema, and to evaluate whether antimicrobial selection would differ if guided by targeted metagenomic sequencing (tMGS) vs conventional cultures (CCs) alone. Patients and Methods: We analyzed the pleural fluid of a cohort of 47 patients undergoing thoracentesis from January 1, 2017 to August 31, 2019, to characterize their microbial profile. All samples underwent 16S ribosomal ribonucleic acid gene polymerase chain reaction, followed by tMGS. Results: Pleural space infection was deemed clinically present in 20 of the 47 (43%) participants. Of those, n=7 (35%) had positive pleural fluid cultures and n=14 (70%) had positive tMGS results. The organisms identified by tMGS were concordant with CCs; however, tMGS detected additional bacterial species over CCs alone. Streptococcus and Staphylococcus species were the most common organisms identified, with Streptococcus intermedius/constellatus identified in 5 patients. Polymicrobial infections were found in 6 of the 20 patients, with anaerobes being the most common organisms identified in these cases. Conclusion: Streptococci and staphylococci were the most common organisms identified in infected pleural fluid. Anaerobes were common in polymicrobial infections. When compared with CCs, tMGS had higher sensitivity than CCs. Targeted metagenomic sequencing identified additional organisms, not identified by CCs, with associated potential management implications.

Respiratory mucosal immunity against SARS-CoV-2 after mRNA vaccination.

SARS-CoV-2 mRNA vaccination induces robust humoral and cellular immunity in the circulation; however, it is currently unknown whether it elicits effective immune responses in the respiratory tract, particularly against variants of concern (VOCs), including Omicron. We compared the SARS-CoV-2 S-specific total and neutralizing antibody responses, and B and T cell immunity, in the bronchoalveolar lavage fluid (BAL) and blood of COVID-19-vaccinated individuals and hospitalized patients. Vaccinated individuals had significantly lower levels of neutralizing antibody against D614G, Delta (B.1.617.2), and Omicron BA.1.1 in the BAL compared with COVID-19 convalescents despite robust S-specific antibody responses in the blood. Furthermore, mRNA vaccination induced circulating S-specific B and T cell immunity, but in contrast to COVID-19 convalescents, these responses were absent in the BAL of vaccinated individuals. Using a mouse immunization model, we demonstrated that systemic mRNA vaccination alone induced weak respiratory mucosal neutralizing antibody responses, especially against SARS-CoV-2 Omicron BA.1.1 in mice; however, a combination of systemic mRNA vaccination plus mucosal adenovirus-S immunization induced strong neutralizing antibody responses not only against the ancestral virus but also the Omicron BA.1.1 variant. Together, our study supports the contention that the current COVID-19 vaccines are highly effective against severe disease development, likely through recruiting circulating B and T cell responses during reinfection, but offer limited protection against breakthrough infection, especially by the Omicron sublineage. Hence, mucosal booster vaccination is needed to establish robust sterilizing immunity in the respiratory tract against SARS-CoV-2, including infection by the Omicron sublineage and future VOCs.

NCCN Guidelines® Insights: Lung Cancer Screening, Version 1.2022.

The NCCN Guidelines for Lung Cancer Screening recommend criteria for selecting individuals for screening and provide recommendations for evaluation and follow-up of lung nodules found during initial and subsequent screening. These NCCN Guidelines Insights focus on recent updates to the NCCN Guidelines for Lung Cancer Screening.

Characterizing phenotypic abnormalities associated with high-risk individuals developing lung cancer using electronic health records from the All of Us researcher workbench.

OBJECTIVE: The study sought to test the feasibility of conducting a phenome-wide association study to characterize phenotypic abnormalities associated with individuals at high risk for lung cancer using electronic health records. MATERIALS AND METHODS: We used the beta release of the All of Us Researcher Workbench with clinical and survey data from a population of 225 000 subjects. We identified 3 cohorts of individuals at high risk to develop lung cancer based on (1) the 2013 U.S. Preventive Services Task Force criteria, (2) the long-term quitters of cigarette smoking criteria, and (3) the younger age of onset criteria. We applied the logistic regression analysis to identify the significant associations between individuals' phenotypes and their risk categories. We validated our findings against a lung cancer cohort from the same population and conducted an expert review to understand whether these associations are known or potentially novel. RESULTS: We found a total of 214 statistically significant associations (P < .05 with a Bonferroni correction and odds ratio > 1.5) enriched in the high-risk individuals from 3 cohorts, and 15 enriched in the low-risk individuals. Forty significant associations enriched in the high-risk individuals and 13 enriched in the low-risk individuals were validated in the cancer cohort. Expert review identified 15 potentially new associations enriched in the high-risk individuals. CONCLUSIONS: It is feasible to conduct a phenome-wide association study to characterize phenotypic abnormalities associated in high-risk individuals developing lung cancer using electronic health records. The All of Us Research Workbench is a promising resource for the research studies to evaluate and optimize lung cancer screening criteria.

Utility of Transbronchial Biopsy in the Immunocompromised Host With New Pulmonary Radiographic Abnormalities.

OBJECTIVE: To assess how often transbronchial biopsy (TBBx) added unique positive findings apart from other synchronous bronchoscopic sampling techniques including the bronchoalveolar lavage-immunocompromised host (BAL-ICH) panel that justified changes in management in an array of immunocompromised patients with new pulmonary radiographic abnormalities. METHODS: We retrospectively reviewed all bronchoscopies performed at Mayo Clinic Rochester between January 2012 and December 2017; on the basis of the physician's selection of a BAL-ICH panel, we identified 192 immunocompromised patients who underwent bronchoscopy with both a BAL-ICH panel and TBBx. The results of the BAL-ICH panel and TBBx were compared and subsequent management decisions analyzed from clinical notes. We identified changes in immunosuppressive agents, antibiotics, chemotherapy, goals of care, and decisions on further evaluation and procedures. We assessed whether the TBBx findings added information not identified on the BAL-ICH panel and other bronchoscopic sampling methods performed during the same procedure that justified subsequent management changes. RESULTS: Of 192 bronchoscopic procedures performed on immunocompromised patients with acute and subacute pulmonary radiographic abnormalities, management changes justified by the unique positive results of the TBBx occurred 28% (51/192) of the time. Those immunocompromised by solid malignant neoplasms and receiving active immunosuppressive therapy had management changes justified 62.1% (18/29) of the time by the TBBx results. No additional fungal organisms were identified on TBBx that were accounted for on the BAL-ICH panel. CONCLUSION: Transbronchial biopsy may add information to other bronchoscopic findings in immunocompromised patients, especially those with solid malignant neoplasms receiving active immunosuppressive treatment. These potential benefits must be weighed against the risks inherent to the procedure.

Bronchoscopic Cryobiopsy and Forceps Biopsy for the Diagnostic Evaluation of Diffuse Parenchymal Lung Disease in Clinical Practice.

OBJECTIVE: To assess the contribution and safety of bronchoscopic cryobiopsy vs traditional forceps biopsy used in clinical practice for diagnosing diffuse parenchymal lung disease (DPLD). PATIENTS AND METHODS: We identified 271 patients who underwent bronchoscopic biopsy for DPLD at Mayo Clinic, MN (June 1, 2013, through September 30, 2017). Medical records were reviewed including prebiopsy clinical and radiographic impressions. Diagnostic yield was assessed in terms of a specific histologic pattern resulting in a diagnosis when combined with the clinical-radiologic context. Clinical utility was defined as a biopsy result deemed useful in patient management. RESULTS: The cohort included 120 cryobiopsy and 151 forceps biopsy cases with mean age 61±14 years and 143 (53%) men. Diagnostic yield (55% vs 41%; odds ratio [OR], 1.73; 95% CI, 1.07 to 2.83; P=.026) and clinical utility (60% vs 40%; OR, 2.21; 95% CI, 1.36 to 3.63; P=.001) were higher for the cryobiopsy group, and the association remained after control for prebiopsy clinical impressions (OR, 2.21; 95% CI, 1.22 to 4.08; P=.010 and OR, 3.23; 95% CI, 1.76 to 6.10; P<.001, respectively). However, pneumothorax (5.4% vs 0.7%; P=.022) and serious bleeding (7.1% vs 0%; P=.001) rates were higher for the cryobiopsy group. Thirty-day mortality was 1.6% in the cryobiopsy group vs 0% for the forceps biopsy group (P=.20). CONCLUSION: Bronchoscopic cryobiopsy revealed higher diagnostic yield and clinical utility than did forceps biopsy. However, procedure-related complications were higher in the cryobiopsy group. The choice of bronchoscopic biopsy procedure for patients with DPLD depends on the clinicalradiologic context.

Diagnostic Yield and Bleeding Complications Associated With Bronchoscopic Biopsy of Endobronchial Carcinoid Tumors.

BACKGROUND: Bronchial carcinoid often appears hypervascular on bronchoscopic visualization and may be associated with hemoptysis. The diagnostic yield and bleeding complications associated with bronchoscopic biopsy of bronchial carcinoid tumors remain unclear. MATERIALS AND METHODS: Patients with bronchial carcinoid tumors that were bronchoscopically visualized and biopsied at our tertiary referral medical center, over an 8-year period from 2010 to 2017, were retrospectively identified and reviewed to assess diagnostic yield and bleeding complications. Correlations with patient characteristics and carcinoid tumor features were analyzed. RESULTS: Forty-nine patients were included (57% female). Tumors were predominantly (71%) located in proximal airways (mainstem and lobar bronchi). Bronchoscopic biopsy was diagnostic in 45 patients (92%). Thirteen patients (27%) experienced moderate (n=12, 25%) or severe (n=1, 2%) bleeding. Among these, 6 tumors (46%) had a vascular appearance and 4 patients (31%) had experienced recent hemoptysis. However, neither vascularity nor hemoptysis was associated with bleeding at biopsy (P=0.68 and 0.73, respectively). Carcinoid tumors were classified as typical in 79% and atypical in 21% with no difference in diagnostic yield or bleeding risk (P=0.28 and 0.92, respectively). Tumor size was also not associated with increased diagnostic yield or bleeding risk (P=0.54 and 0.39, respectively). CONCLUSION: Bronchoscopic biopsy of endobronchial carcinoid is associated with a high diagnostic yield and severe bleeding is rarely encountered. Diagnostic yield and bleeding seemed independent of vascular tumor appearance or history of recent hemoptysis.

5-year overall survival in patients with lung cancer eligible or ineligible for screening according to US Preventive Services Task Force criteria: a prospective, observational cohort study.

BACKGROUND: The US Preventive Services Task Force (USPSTF) recommends lung cancer screening among individuals aged 55-80 years with a 30 pack-year cigarette smoking history and, if they are former smokers, those who quit within the past 15 years. Our previous report found that two-thirds of newly diagnosed patients with lung cancer do not meet these criteria; they are reported to be either long-term quitters (≥15 years since quitting) or from a younger age group (age 50-54 years). We aimed to assess survival outcomes in these two subgroups. METHODS: For this prospective, observational cohort study we identified and followed up patients aged 50-80 years with lung cancer, with a smoking history of 30 pack-years or more, and included both current smokers and former smokers who quit within the past 30 years. We identified patients from two cohorts in the USA: a hospital cohort (Mayo Clinic, Rochester, MN) and a community cohort (Olmsted County, MN). Patients were divided into those meeting USPSTF criteria (USPSTF group) versus those not meeting USPSTF criteria (long-term quitters or the younger age group). The main outcome was overall survival at 5 years after diagnosis. 5-year overall survival was analysed with and without matching age and pack-years smoked for long-term quitters. The USPSTF group was subdivided into two age subgroups (55-69 years and 70-80 years) for multivariable regression analysis. FINDINGS: Between Jan 1, 1997, and Dec 31, 2017, 8739 patients with lung cancer were identified and followed up. Median follow-up was 6·5 (IQR 3·8-10·0) years, and median overall survival was 16·9 months (95% CI 16·2-17·5). 5-year overall survival was 27% (95% CI 25-30) in long-term quitters, 22% (19-25) in the younger age group, and 23% (22-24) in the USPSTF group. In both cohorts, 5-year overall survival did not differ significantly between long-term quitters and the USPSTF group (hospital cohort: hazard ratio [HR] 1·02 [95% CI 0·94-1·10]; p=0·72; community cohort: 0·97 [0·75-1·26]; p=0·82); matched analysis showed similar results in both cohorts. 5-year overall survival also did not differ significantly between the younger age group and the USPSTF group in both cohorts (hospital cohort: HR 1·16 [95% CI 0·98-1·38], p=0·08; community cohort: 1·16 [0·74-1·82]; p=0·52); multivariable regression analyses stratified by age group yielded similar findings. INTERPRETATION: Patients with lung cancer who quit 15 or more years before diagnosis and those who are up to 5 years younger than the age cutoff recommended for screening, but otherwise meet USPSTF criteria, have a similar risk of death to those individuals who meet all USPSTF criteria. Individuals in both subgroups could benefit from screening, as expansion of USPSTF screening criteria to include these subgroups could enable earlier detection of lung cancer and improved survival outcomes. FUNDING: National Institutes of Health and the Mayo Clinic Foundation.

Extracellular matrix fistula plug for repair of bronchopleural fistula.

INTRODUCTION: Bronchopleural fistula (BPF) is a feared complication of pulmonary resection. Fistula plugs (FP) have been described as an adequate treatment in anorectal disease. We describe our early experience placing an FP in the treatment of BPF. MATERIALS AND METHODS: We retrospectively reviewed 5 patients for whom a FP was placed for BPF at our institution. Demographic data, initial perioperative information, method and technique of FP placement, and success is reported. RESULTS: Five patients (4 male, 1 female) with a median age of 63 years (range, 57-76 years) underwent 6 FP placements for BPF. Two patients were post-pneumonectomy and 3 patients post-lobectomy. The median time to presentation following surgery was 118 days (range 22-218). Upon bronchoscopic or operative re-evaluation, 3 patients had successful cessation of their air leak at 0, 1 and 4 days. Two of three patients subsequently underwent a thoracic muscle flap placement to augment healing. One patient had a persistent air leak despite 2 separate FP placements. The air leak stopped with endobronchial valves (EBV) which were deployed proximal to the FP, 9 days after placement of the FP. Another patient had a successful muscle flap placed 80 days after FP placement. There were no complications associated with the FP. Three of five patients were deemed successfully treated with FP placement alone. CONCLUSION: In patients with a postoperative BPF and pleural window, placement of a FP had a modest success rate and can be considered as a treatment modality option for BPF.

Comparison of Programmed Death Ligand-1 Immunohistochemical Staining Between Endobronchial Ultrasound Transbronchial Needle Aspiration and Resected Lung Cancer Specimens.

BACKGROUND: In advanced non-small cell lung cancer (NSCLC), small biopsy specimens from endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) are often the only available material from cancer tissue for the analysis of programmed death ligand-1 (PD-L1) expression. We aim to assess the sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of PD-L1 expression at ≥ 1% and ≥ 50% on EBUS-TBNA samples compared with their corresponding surgically resected tumor. METHODS: We retrospectively reviewed all patients who underwent EBUS-TBNA followed by surgical resection of NSCLC between July 2006 and September 2016. Demographic information and periprocedural/surgical data were collected. The archived specimens were retrieved and assessed for PD-L1. A positive PD-L1 stain was defined using two separate cutoff points: ≥ 1% and ≥ 50% of tumor cell positivity. EBUS-TBNA aspirates were compared with the surgically resected specimen to calculate the sensitivity, specificity, PPV, and NPV. RESULTS: Sixty-one patients were included. For PD-L1 ≥ 1%, the sensitivity, specificity, PPV, and NPV were 72%, 100%, 100%, and 80%, respectively. For PD-L1 ≥ 50%, the sensitivity, specificity, PPV, and NPV were 47%, 93%, 70%, and 84%, respectively. The concordance rates for PD-L1 ≥ 1% and ≥ 50% were 87% and 82%, respectively. CONCLUSIONS: A PD-L1 cutoff of ≥ 1% on EBUS-TBNA has a strong correlation with resected tumor specimen. For PD-L1 ≥ 50%, there is a significant decrease in the sensitivity and PPV of EBUS-TBNA specimen when compared with resected tumor. When analyzing for PD-L1 expression using a cutoff of ≥ 50%, EBUS-TBNA specimens may misclassify the status of PD-L1.

Paclitaxel-coated balloon dilation for central airway obstruction.

INTRODUCTION: Central airway obstruction (CAO) often requires repeated interventional procedures which offer variable efficacy, a time-limited effect, and have inherent limitations. Paclitaxel has been used to prevent restenosis in blood vessels. The literature describing the use of paclitaxel to prevent recurrent airway stenosis is limited. We sought to describe our experience using a paclitaxel-coated balloon (PCB) for CAO. MATERIAL AND METHODS: We performed a retrospective review of all patients who underwent PCB airway dilation. We collected: basic demographics, details of the CAO, details of the bronchoscopes used, PCB size, PCB dilation pressure, duration of PCB inflation, concurrent non-PCB interventions, estimated pre- and post-PCB CAO luminal diameter, follow up bronchoscopy date and luminal diameter, and spirometry results. RESULTS: PCB dilation was performed in 10 cases on 5 patients. Eight PCB dilations were performed for CAO related to distal airway stent stenosis. Concurrent non-PCB interventions were performed with 6 PCB dilations. Nine cases documented improvements and 1 was unchanged immediately post-PCB dilation. Median luminal diameter pre-PCB dilation was 2 mm. Immediately post-PCB dilation, the median change in luminal diameter was 2 mm. Follow up bronchoscopy information was available for 9 cases. For these 9 cases, luminal diameter was unchanged in 5 and worse in 4 when compared to immediate post-PCB dilation. CONCLUSION: PCB dilation in benign CAO produced a modest effect in this cohort of challenging airways. Larger prospective studies are needed to assess how a PCB would perform when compared to a non-drug coated balloon.

Lung Cancer Screening, Version 3.2018, NCCN Clinical Practice Guidelines in Oncology.

Lung cancer is the leading cause of cancer-related mortality in the United States and worldwide. Early detection of lung cancer is an important opportunity for decreasing mortality. Data support using low-dose computed tomography (LDCT) of the chest to screen select patients who are at high risk for lung cancer. Lung screening is covered under the Affordable Care Act for individuals with high-risk factors. The Centers for Medicare & Medicaid Services (CMS) covers annual screening LDCT for appropriate Medicare beneficiaries at high risk for lung cancer if they also receive counseling and participate in shared decision-making before screening. The complete version of the NCCN Guidelines for Lung Cancer Screening provides recommendations for initial and subsequent LDCT screening and provides more detail about LDCT screening. This manuscript focuses on identifying patients at high risk for lung cancer who are candidates for LDCT of the chest and on evaluating initial screening findings.

RNAseq analysis of bronchial epithelial cells to identify COPD-associated genes and SNPs.

BACKGROUND: There is a need for more powerful methods to identify low-effect SNPs that contribute to hereditary COPD pathogenesis. We hypothesized that SNPs contributing to COPD risk through cis-regulatory effects are enriched in genes comprised by bronchial epithelial cell (BEC) expression patterns associated with COPD. METHODS: To test this hypothesis, normal BEC specimens were obtained by bronchoscopy from 60 subjects: 30 subjects with COPD defined by spirometry (FEV1/FVC < 0.7, FEV1% < 80%), and 30 non-COPD controls. Targeted next generation sequencing was used to measure total and allele-specific expression of 35 genes in genome maintenance (GM) genes pathways linked to COPD pathogenesis, including seven TP53 and CEBP transcription factor family members. Shrinkage linear discriminant analysis (SLDA) was used to identify COPD-classification models. COPD GWAS were queried for putative cis-regulatory SNPs in the targeted genes. RESULTS: On a network basis, TP53 and CEBP transcription factor pathway gene pair network connections, including key DNA repair gene ERCC5, were significantly different in COPD subjects (e.g., Wilcoxon rank sum test for closeness, p-value = 5.0E-11). ERCC5 SNP rs4150275 association with chronic bronchitis was identified in a set of Lung Health Study (LHS) COPD GWAS SNPs restricted to those in putative regulatory regions within the targeted genes, and this association was validated in the COPDgene non-hispanic white (NHW) GWAS. ERCC5 SNP rs4150275 is linked (D' = 1) to ERCC5 SNP rs17655 which displayed differential allelic expression (DAE) in BEC and is an expression quantitative trait locus (eQTL) in lung tissue (p = 3.2E-7). SNPs in linkage (D' = 1) with rs17655 were predicted to alter miRNA binding (rs873601). A classifier model that comprised gene features CAT, CEBPG, GPX1, KEAP1, TP73, and XPA had pooled 10-fold cross-validation receiver operator characteristic area under the curve of 75.4% (95% CI: 66.3%-89.3%). The prevalence of DAE was higher than expected (p = 0.0023) in the classifier genes. CONCLUSIONS: GM genes comprised by COPD-associated BEC expression patterns were enriched for SNPs with cis-regulatory function, including a putative cis-rSNP in ERCC5 that was associated with COPD risk. These findings support additional total and allele-specific expression analysis of gene pathways with high prior likelihood for involvement in COPD pathogenesis.

An integrated digital/clinical approach to smoking cessation in lung cancer screening: study protocol for a randomized controlled trial.

BACKGROUND: Delivering effective tobacco dependence treatment that is feasible within lung cancer screening (LCS) programs is crucial for realizing the health benefits and cost savings of screening. Large-scale trials and systematic reviews have demonstrated that digital cessation interventions (i.e. web-based and text message) are effective, sustainable over the long-term, scalable, and cost-efficient. Use of digital technologies is commonplace among older adults, making this a feasible approach within LCS programs. Use of cessation treatment has been improved with models that proactively connect smokers to treatment rather than passive referrals. Proactive referral to cessation treatment has been advanced through healthcare systems changes such as modifying the electronic health record to automatically link smokers to treatment. METHODS: This study evaluates the impact of a proactive enrollment strategy that links LCS-eligible smokers with an evidence-based intervention comprised of a web-based (WEB) program and integrated text messaging (TXT) in a three-arm randomized trial with repeated measures at one, three, six, and 12 months post randomization. The primary outcome is biochemically confirmed abstinence at 12 months post randomization. We will randomize 1650 smokers who present for a clinical LCS to: (1) a usual care control condition (UC) which consists of Ask-Advise-Refer; (2) a digital (WEB + TXT) cessation intervention; or (3) a digital cessation intervention combined with tobacco treatment specialist (TTS) counseling (WEB + TXT + TTS). DISCUSSION: The scalability and sustainability of a digital intervention may represent the most cost-effective and feasible approach for LCS programs to proactively engage large numbers of smokers in effective cessation treatment. We will also evaluate the impact and cost-effectiveness of adding proven clinical intervention provided by a TTS. We expect that a combined digital/clinical intervention will yield higher quit rates than digital alone, but that it may not be as cost-effective or feasible for LCS programs to implement. This study is innovative in its use of interoperable, digital technologies to deliver a sustainable, scalable, high-impact cessation intervention and to facilitate its integration within clinical practice. It will add to the growing knowledge base about the overall effectiveness of digital interventions and their role in the healthcare delivery system. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03084835 . Registered on 9 March 2017.

The flip-flop fungus sign: an FDG PET/CT sign of benignity.

Benign granulomatous processes such as fungal infection may mimic metastatic lung cancer on FDG PET/CT. We found that these processes often have draining lymph node(s) with equal or greater FDG activity than associated lung nodule(s), a "flip-flop" of what is commonly seen in lung cancer. The aim of this study was to examine the utility of this "flip-flop fungus" (FFF) sign for diagnosing benign pulmonary disease. FDG PET/CT scans performed between 9/09-3/13 for the indications of pulmonary nodule or mass were reviewed. Scans with at least one hilar or mediastinal FDG avid draining node were included. Patients with a history of cancer, lack of pathologic confirmation, or without at least two years of imaging follow-up were excluded. A total of 209 FDG PET/CT exams were included and reviewed in a blinded fashion. A positive FFF sign had a sensitivity of 60.0% (95% CI: 47.6-71.5%) and specificity of 84.9% (95% CI: 77.8-90.4%) (P<0.0001) for benign disease. With additional strict imaging criteria applied, the FFF sign had a specificity of 98.6% (95% CI: 94.9-99.8%) (P<0.0001) and a positive predictive value of 90.0% (95% CI: 68.3-98.5%). A positive FFF sign was predominately due to granulomatous disease (91%), mostly histoplasmosis (73%). A positive FFF sign combined with positive fungal serology (n=16) had a specificity of 100% for benign disease. The FFF sign predicts benign disease in patients with a lung nodule(s) and an FDG avid draining lymph node(s) that would otherwise be considered worrisome for cancer.