Proteogenomic analysis of lung adenocarcinoma reveals tumor heterogeneity, survival determinants, and therapeutically relevant pathways.

We present a deep proteogenomic profiling study of 87 lung adenocarcinoma (LUAD) tumors from the United States, integrating whole-genome sequencing, transcriptome sequencing, proteomics and phosphoproteomics by mass spectrometry, and reverse-phase protein arrays. We identify three subtypes from somatic genome signature analysis, including a transition-high subtype enriched with never smokers, a transversion-high subtype enriched with current smokers, and a structurally altered subtype enriched with former smokers, TP53 alterations, and genome-wide structural alterations. We show that within-tumor correlations of RNA and protein expression associate with tumor purity and immune cell profiles. We detect and independently validate expression signatures of RNA and protein that predict patient survival. Additionally, among co-measured genes, we found that protein expression is more often associated with patient survival than RNA. Finally, integrative analysis characterizes three expression subtypes with divergent mutations, proteomic regulatory networks, and therapeutic vulnerabilities. This proteogenomic characterization provides a foundation for molecularly informed medicine in LUAD.

Endovascular steerable and endobronchial precurved guiding sheaths for transbronchial needle delivery under augmented fluoroscopy and cone beam CT image guidance.

BACKGROUND: Endobronchial navigation is performed in a variety of ways, none of which are meeting all the clinicians' needs required to reach diagnostic success in every patient. We sought to characterize precurved and steerable guiding sheaths (GS) in endobronchial targeting for lung biopsy using cone beam computed tomography (CBCT) based augmented fluoroscopy (AF) image guidance. METHODS: Four precurved GS (EdgeTM 45, 90, 180, 180EW, Medtronic) and two steerable GS [6.5 F Destino Twist (DT), Oscor; 6 F Morph, BioCardia] were evaluated alone and in combination with an electromagnetic tracking (EM) guide and biopsy needles in three experimental phases: (I) bench model to assess GS deflection and perform biopsy simulations; (II) ex vivo swine lung comparing 2 steerable and 2 precurved GS; and (III) in vivo male swine lung to deliver a needle (n=2 swine) or to deliver a fiducial marker (n=2 swine) using 2 steerable GS. Ex vivo and in vivo image guidance was performed with either commercial or prototype AF image guidance software (Philips) based on either prior CT or procedural CBCT. Primary outcomes were GS delivery angle (θGS) and needle delivery angle (θN) in bench evaluation and needle delivery error (mm) (mean ± se) for ex vivo and in vivo studies. RESULTS: The steerable DT had the largest range of GS delivery angles (θN: 0-114°) with either the 21 G or 19 G biopsy needle in the bench model. In ex vivo swine lung, needle delivery errors were 8.7±0.9 mm (precurved Edge 90), 5.4±1.9 mm (precurved Edge 180), 4.7±1.2 mm (steerable DT), and 5.6±2.4 mm (steerable Morph). In vivo, the needle delivery errors for the steerable GS were 6.0±1.0 mm (DT) and 15±7.0 mm (Morph). In vivo marker coil delivery was successful for both the steerable DT and morph GS. A case report demonstrated successful needle biopsy with the steerable DT. CONCLUSIONS: Endobronchial needle delivery with AF guidance is feasible without a bronchoscope with steerable GS providing comparable or improved accuracy compared to precurved GS.

Optimizing routine screening for cardiac sarcoidosis through use of commonly available studies.

BACKGROUND: Sarcoidosis is a multisystem granulomatous disorder with unclear etiology. Morbidity and mortality vary based on organ involvement, with cardiac sarcoidosis (CS) associated with higher mortality; despite this, CS remains underdiagnosed. The Heart Rhythm Society (HRS) expert consensus statement recommends screening sarcoidosis patients for CS utilizing a symptom screen, EKG, and echocardiogram (TTE), while the American Thoracic Society (ATS) guideline recommends only EKG and symptom screening. These recommendations, however, are based on limited data with recommendations for further studies. RESEARCH QUESTION: The purpose is to evaluate the prevalence of abnormal screening tests in patients with sarcoidosis and the correlation of these tests with the subsequent diagnosis of CS. A specific emphasis was placed on evaluating the sensitivity of the recommendations versus the sensitivity of a modified criteria. STUDY DESIGN: and Methods: This study retrospectively evaluated a database of prospectively enrolled patients from a tertiary military academic center. All patients who underwent imaging with cardiac MRI and/or FDG-PET were identified. These results were correlated with screening studies (symptom screen, EKG, TTE, and ambulatory rhythm monitoring (ARM)) and used to calculate sensitivity, specificity, and positive and negative predictive values for each test. Using a clinical diagnosis of CS as the reference standard, the sensitivity and specificity of the HRS criteria were calculated and compared to a modified screening rubric developed a priori, consisting of minor changes to the criteria and the addition of ARM. RESULTS: This study evaluated 114 patients with sarcoidosis with 132 advanced imaging events, leading to a diagnosis of CS in 36 patients. Utilizing HRS screening recommendations, the sensitivity for CS was 63.9%, while the modified criteria increased sensitivity to 94.4%. INTERPRETATION: This study suggests that the HRS guidelines lack sensitivity to effectively screen for CS and that a modified screening model which includes ARM may be more effective.

Patient motivations for non-adherence to lung cancer screening in a military population.

BACKGROUND: Lung cancer remains the leading cause of cancer deaths in the United States, and lung cancer screening has been shown to decrease this mortality. Adherence to lung cancer screening is paramount to realize the mortality benefit, and reported adherence rates vary widely. Few reports address non-adherence to screening, and our study sought to understand the non-compliant patients in our military population. METHODS: This Institutional Review Board approved retrospective review of patients enrolled in our screening program from 2013-2019 identified patients who failed to obtain a subsequent Low Dose CT scan (LDCT) within 15 months of their prior scan. Attempts were made to contact these patients and elucidate motivations for non-adherence via telephone. RESULTS: Of the 242 patients enrolled, 183 (76%) patients were adherent to the protocol. Significant predictors of non-adherence versus adherence were younger age (P=0.008), female sex (P=0.005), and enlisted officer rank (P=0.03). There was no difference with regards to race, smoking status, pack-years, negative screens, lung-RADS level, or nodule size. 31 (52%) non-adherent patients were contacted, and 24 (77%) reported their reason for non-adherence was lack of follow-up for a LDCT. Twenty (64%) were interested in re-enrollment. Of the total screening cohort, 15 interventions were performed, with lung cancer identified in 5 (2%)-a 67% false positive rate. One stage IV lung cancer was found in a non-adherent patient who re-enrolled. CONCLUSIONS: Lack of perceived contact for follow-up was expressed as the primary reason for non-compliance in our screening program. Compliance is critical to the efficacy of any screening modality, and adherence rates to lung cancer screening may be increased through improved contact with patients via multiple avenues (i.e., phone, email, and letter). There is benefit in contacting non-adherent patients as high rates of re-enrollment are possible.

The role for medical thoracoscopy in pneumothorax.

Pneumothorax is a life threatening situation that requires fast treatment. There are two major classifications: Primary and Secondary. Staging of pneumothorax is also very important for treatment. Treatment of pneumont can be performed either from thoracic surgeons, or pulmonary physicians. In our current work we provide up-to-date information regarding pneumothorax classification, staging and treatment from the point of view of expert pulmonary physicians.

Unusual causes of pneumothorax.

Pneumothorax is divided to primary and secondary. It is a situation that requires immediate treatment, otherwise it could have severe health consequences. Pneumothorax can be treated either by thoracic surgeons, or pulmonary physicians. In our current work, we will focus on unusual cases of pneumothorax. We will provide the etiology and treatment for each case, also a discussion will be made for each situation.

Bronchoscopic interventions for severe COPD.

Chronic obstructive pulmonary disease (COPD) causes severe handicap among smokers. Most patients have to remain under continuous oxygen therapy at home. Moreover, respiratory infections are very common among these patients and vaccination is obligatory against influenza. Emphysema and bronchiectasis are observed with computed tomography (CT) and in several situations these parenchymal damages are responsible for pneumothorax in one case and pseudomonas aeroginosa infection. Novel mini-invasive techniques are used currently for emphysema treatments which are described extensively throughout our current work.

Approach of the treatment for pneumothorax.

Pneumothorax can occur in several situations such as; chronic obstructive pulmonary disease (COPD) where emphysema is observed or due to a biopsy for malignancy suspicion. In any case it is a dangerous situation that requires immediate attention and treatment. Pneumothorax can be divided in primary and secondary. Staging of pneumothorax is also very important. In our current editorial we summarize etiology and treatment of pneumothorax from a panel of pulmonary physicians, oncologists and thoracic surgeons.

Transbronchial lung biopsy and pneumothorax.

Mini-interventional procedures are used in the everyday clinical practice by pulmonary physicians and radiologists. Fine needle aspiration and biopsy forceps are the tools mostly used. During these procedures pneumothorax can occur and immediate treatment is necessary. In our current work, we will focus on minimal invasive techniques for biopsy and pneumothorax treatment.

Thoracoscopic detection of occult indeterminate pulmonary nodules using bronchoscopic pleural dye marking.

BACKGROUND: The annual incidence of a small indeterminate pulmonary nodule (IPN) on computed tomography (CT) scan remains high. While traditional paradigms exist, the integration of new technologies into these diagnostic and treatment algorithms can result in alternative, potentially more efficient methods of managing these findings. METHODS: We report on an alternative diagnostic and therapeutic strategy for the management of an IPN. This approach combines electromagnetic navigational bronchoscopy (ENB) with an updated approach to placement of a pleural dye marker. This technique lends itself to a minimally invasive wedge resection via either video-assisted thoracoscopic surgery (VATS) or a robotic approach. RESULTS: Subsequent to alterations in the procedure, a cohort of 22 patients with an IPN was reviewed. Navigation was possible in 21 out of 22 patients with one patient excluded based on airway anatomy. The remaining 21 patients underwent ENB with pleural dye marking followed by minimally invasive wedge resection. The median size of the nodules was 13.4 mm (range: 7-29). There were no complications from the ENB procedure. Indigo carmine dye was used in ten patients. Methylene blue was used in the remaining 11 patients. In 81% of cases, the visceral pleural marker was visible at the time of surgery. In one patient, there was diffuse staining of the parietal pleura. In three additional patients, no dye was identified within the hemithorax. In all cases where dye marker was present on the visceral pleural surface, it was in proximity to the IPN and part of the excised specimen. CONCLUSIONS: ENB with pleural dye marking can provide a safe and effective method to localize an IPN and can allow for subsequent minimally invasive resection. Depending on the characteristics and location of the nodule, this method may allow more rapid identification intraoperatively.

Molecular Targeted Drugs and Biomarkers in NSCLC, the Evolving Role of Individualized Therapy.

Lung cancer first line treatment has been directed from the non-specific cytotoxic doublet chemotherapy to the molecular targeted. The major limitation of the targeted therapies still remains the small number of patients positive to gene mutations. Furthermore, the differentiation between second line and maintenance therapy has not been fully clarified and differs in the clinical practice between cancer centers. The authors present a segregation between maintenance treatment and second line and present a possible definition for the term "maintenance" treatment. In addition, cancer cell evolution induces mutations and therefore either targeted therapies or non-specific chemotherapy drugs in many patients become ineffective. In the present work pathways such as epidermal growth factor, anaplastic lymphoma kinase, met proto-oncogene and PI3K are extensively presented and correlated with current chemotherapy treatment. Future, perspectives for targeted treatment are presented based on the current publications and ongoing clinical trials.

Battlefield applications for handheld ultrasound.

Combat medical care provides unique challenges and opportunities for military medical teams. The austerity of the environment severely limits access to many diagnostic and therapeutic tools. Because of their compact size, handheld ultrasound (US) machines are increasingly being used in these constrained environments. A growing body of literature documents the diagnostic utility of handheld US for trauma encountered in the battlefield. Furthermore, US guidance may assist in the performance of some procedures performed in battlefield medical care. This review will provide an overview of the history, current status, limitations and potential future of US utility for the battlefield.

The distance-saturation product predicts mortality in idiopathic pulmonary fibrosis.

INTRODUCTION: The 6-min walk test (6MWT) has prognostic value in various pulmonary disorders including idiopathic pulmonary fibrosis (IPF). We determined the individual prognostic accuracy of distance walked and oxygen saturation during the 6MWT in patients with IPF. We defined a new composite index, the distance-saturation product (DSP), which is the product of distance walked and lowest oxygen saturation during the 6-min walk test. We compared the performance of the DSP to the individual 6MWT parameters in predicting mortality. METHODS: We evaluated pulmonary function tests, 6-min walk parameters and the DSP between survivors and non-survivors. The ability of each measure to discriminate outcomes was determined by receiver operator curves. RESULTS: 81 patients (48 survivors, 33 non-survivors) were included. Pulmonary function tests were similar and did not correlate with survival. Desaturation was greater (89.4% versus 83.7%, P<0.001) and distance walked was lower (406.9 versus 181.3m, P = 0.005) in non-survivors. The DSP was significantly lower among non-survivors (364.8 versus 153.5m%, P < 0.001) and predicted mortality more accurately than either individual 6MWT component (P = 0.035 versus desaturation, P=0.040 versus distance). A DSP <200 m% was associated with a seven-fold greater risk of 12-month mortality and an 18.0% shorter median survival compared with a DSP > 200 m% (P < 0.001). DISCUSSION: Each component of the 6-min walk independently predicted mortality in IPF with greater accuracy than spirometry. However, a composite of both parameters, the DSP, provides slightly greater accuracy and represents a novel measure for assessing survival in patients with IPF.