A prospective cohort evaluation of the sensitivity and specificity of the chest X-ray for the detection of lung cancer in symptomatic adults.

BACKGROUND: The accuracy of the chest x-ray (CXR) in the identification of lung cancer amongst symptomatic individuals is uncertain. PURPOSE: To determine the diagnostic accuracy of the CXR for the detection of non-small cell carcinomas (NSCLC) and all primary intrathoracic malignancies. METHODS: A prospective cohort study of consecutive CXR reports obtained within a primary care open access initiative. Eligibility criteria were symptoms specified by National Institute for Clinical Excellence as indicative of possible lung cancer and age over 50-yrs. A positive test was a CXR which led directly or indirectly to investigation with CT. The reference standards were malignancies observed within a one- or two-year post-test period. RESULTS: 8,948 CXR outcomes were evaluated. 496 positive studies led to a diagnosis of 101 patients with primary intrathoracic malignancy including 80 with NSCLC. Within two-years, a cumulative total of 168 patients with primary intrathoracic malignancies including 133 NSCLC were observed. The sensitivity and specificity for NSCLC were 76% (95 %CI 68-84) and 95% (95 %CI 95-96) within 1-year and 60% (95 %CI 52-69) and 95% (95 %CI 95-96) within 2-years. The 2-yr positive and negative likelihood ratios were 12.8 and 0.4. The results did not differ for NSCLC compared to all primary malignancies. Within this symptomatic population a negative test reduced the 2-year risk of lung cancer to 0.8%. CONCLUSIONS: A positive test strongly increases the probability of malignancy whereas a negative test does not conclusively exclude the disease. The findings allow the risk of malignancy following a negative test to be estimated.

Chest X-ray sensitivity and lung cancer outcomes: a retrospective observational study.

BACKGROUND: Chest X-ray (CXR) is the first-line investigation for lung cancer in many healthcare systems. An understanding of the consequences of false-negative CXRs on time to diagnosis, stage, and survival is limited. AIM: To determine the sensitivity of CXR for lung cancer and to compare stage at diagnosis, time to diagnosis, and survival between those with CXR that detected, or did not detect, lung cancer. DESIGN AND SETTING: Retrospective observational study using routinely collected healthcare data. METHOD: All patients diagnosed with lung cancer in Leeds Teaching Hospitals NHS Trust during 2008-2015 who had a GP-requested CXR in the year before diagnosis were categorised based on the result of the earliest CXR performed in that period. The sensitivity of CXR was calculated and analyses were performed with respect to time to diagnosis, survival, and stage at diagnosis. RESULTS: CXR was negative for 17.7% of patients (n = 376/2129). Median time from initial CXR to diagnosis was 43 days for those with a positive CXR and 204 days for those with a negative CXR. Of those with a positive CXR, 29.8% (95% confidence interval [CI] = 27.9% to 31.8%) were diagnosed at stage I or II, compared with 33.5% (95% CI = 28.8% to 38.6%) with a negative CXR. CONCLUSION: GPs should consider lung cancer in patients with persistent symptoms even when CXR is negative. Despite longer duration to diagnosis for those with false-negative CXRs, there was no evidence of an adverse impact on stage at diagnosis or survival; however, this comparison is likely to be affected by confounding variables.

Can dosimetry affect local control and survival in patients with early-stage lung cancer treated with Stereotactic Ablative Radiotherapy (SABR)? An analysis of the UK's largest cohort of lung SABR patients.

PURPOSE/OBJECTIVES: A recent study has shown that tight conformity of lung Stereotactic Ablative Radiotherapy (SABR) plans might worsen loco-regional control and can predict distant metastases. The study aims to report overall survival (OS), progression-free survival (PFS), local recurrence free survival (LRFS), and dosimetry of early-stage lung cancer patients treated with SABR and to try to explore any dosimetric predictor of outcomes. MATERIAL AND METHODS: Patients treated in our institute (May 2009-August 2018) were included. Electronic medical records were reviewed for baseline characteristics, treatment details, and outcomes. Dosimetric data were extracted from Xio and Monaco software. Patients were treated according to the United Kingdom (UK) SABR consortium guidelines. Kaplan-Meier's analysis with log-rank test was used for survival analysis. The univariate and multivariable Cox regression model was used for correlating dosimetric variables and outcomes. RESULTS: We treated 1266 patients with median age of 75 years and 47.4% were male. Median follow up was 56 months. Median OS was 36 months with 1, 2, and 5 years OS of 84.2%, 64.5%, and 31.5%, respectively. Median for PFS and LRFS was not reached. One, 2, and 5 years PFS were 87.4%, 78.4%, and 72.5%, respectively. One, 2, and 5 years LRFS were 98.2%, 95.1%, and 92.5%, respectively. Planning target volume (PTV), dose to 99% volume of PTV (D99), and R50 (volume receiving the 50% dose/volume (PTV)) were significantly associated with OS. PTV, mean lung dose (MLD), V20 (volume of lung minus gross tumour volume (GTV) receiving 20 Gy), V12.5 (volume of lung minus GTV receiving 12.5 Gy), and dose fractionation were significantly associated with PFS. Nothing was associated with LRFS on univariate analysis. R100 of >1.1 was associated with better OS, PFS, and LRFS compared to R100 ≤ 1.1. CONCLUSION: SABR achieves good clinical outcomes in patients with early-stage lung cancer; even in elderly patients with multiple comorbidities. In the largest UK early lung cancer cohort treated with SABR, we found that dosimetry correlates with clinical outcomes. Further validation of these results is needed to guide future optimisation of SABR delivery.

Estimating lung cancer risk from chest X-ray and symptoms: a prospective cohort study.

BACKGROUND: Chest X-ray (CXR) is the first-line investigation for lung cancer in many countries but previous research has suggested that the disease is not detected by CXR in approximately 20% of patients. The risk of lung cancer, with particular symptoms, following a negative CXR is not known. AIM: To establish the sensitivity and specificity of CXR requested by patients who are symptomatic; determine the positive predictive values (PPVs) of each presenting symptom of lung cancer following a negative CXR; and determine whether symptoms associated with lung cancer are different in those who had a positive CXR result compared with those who had a negative CXR result. DESIGN AND SETTING: A prospective cohort study was conducted in Leeds, UK, based on routinely collected data from a service that allowed patients with symptoms of lung cancer to request CXR. METHOD: Symptom data were combined with a diagnostic category (positive or negative) for each CXR, and the sensitivity and specificity of CXR for lung cancer were calculated. The PPV of lung cancer associated with each symptom or combination of symptoms was estimated for those patients with a negative CXR. RESULTS: In total, 114 (1.3%) of 8996 patients who requested a CXR were diagnosed with lung cancer within 1 year. Sensitivity was 75.4% and specificity was 90.2%. The PPV of all symptoms for a diagnosis of lung cancer within 1 year of CXR was <1% for all individual symptoms except for haemoptysis, which had a PPV of 2.9%. PPVs for a diagnosis of lung cancer within 2 years of CXR was <1.5% for all single symptoms except for haemoptysis, which had a PPV of 3.9%. CONCLUSION: CXR has limited sensitivity; however, in a population with a low prevalence of lung cancer, its high specificity and negative predictive value means that lung cancer is very unlikely to be present following a negative result. Findings also support guidance that unexplained haemoptysis warrants urgent referral, regardless of CXR result.

Clinical and dosimetric predictors of radiation pneumonitis in early-stage lung cancer treated with Stereotactic Ablative radiotherapy (SABR) - An analysis of UK's largest cohort of lung SABR patients.

BACKGROUND: Stereotactic Ablative Radiotherapy (SABR) is the standard treatment for early-stage medically inoperable lung cancer. Predictors of radiation pneumonitis (RP) in patients treated with SABR are poorly defined. In this study, we investigate clinical and dosimetric parameters, which can predict symptomatic RP in early-stage lung cancer patients treated with SABR. MATERIALS AND METHODS: Patients treated with lung SABR between May 2009 and August 2018, in a single United Kingdom (UK) radiotherapy center were included. The patient's baseline characteristics, treatment details, and toxicity were retrieved from the electronic medical record. Dosimetric data was extracted from Xio and Monaco treatment planning systems. Patients were treated according to the UK SABR consortium guidelines. RP was graded retrospectively using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0, based on available clinical and imaging information. Univariate and multivariate binary logistic regression was performed to determine predictive factors for grade ≥ 2 radiation pneumonitis, using Statistical Package for the Social Sciences (SPSS) statistics version 21 software. The goodness of fit was assessed using the Hosmer and Lemeshow test. The optimal diagnostic threshold was tested using the Receiver operating characteristics (ROC) curve. The chi-square test was carried out to test the different risk factors against the likelihood of developing grade ≥ 2 pneumonitis. RESULTS: A total of 1266 patients included in the analysis. The median age of patients was 75 years. Six hundred sixty-six patients (52.6%) were female. Median follow up was 56 months. Sixty-five percent of patients received 55 Gy in 5 fractions. Forty-three percent of patients had Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 2 and 16.2% had PS of 3. The Median Charlson comorbidity index was 6 (range 2-11). Median Standardized Uptake Value (SUV) max of the tumor was 6.5. Four hundred two patients (31.8%) had confirmed histological diagnosis; other patients were treated based on a radiological diagnosis. The median tumor size was 20 mm (range 4 mm-63 mm). Median Planning Target Volume (PTV) was 30.3 cc. Median values of R100, R50, and D2cm were 1.1, 5.6, 32.8 Gy. The median value of mean lung dose, V20, and V12.5 were 3.9 Gy, 5 %and 9.3% respectively. Eighty-five (6.7%) patients developed symptomatic RP (grade ≥ 2) with only 5(0.4%) developing grade 3 RP. Five percent of patients developed rib fractures but only 28% of these were symptomatic. On univariate analysis lower lobe tumor location, larger tumor size, PTV, mean lung dose, lung V20Gy, and V12.5 Gy were significantly associated with grade ≥ 2 RP. On multivariate analysis, only mean lung dose was associated with grade ≥ 2 pneumonitis. ROC curve analysis showed optimal diagnostic threshold for tumour size, PTV, mean lung dose, V20 and V12.5; are 22.5 mm ((Area Under Curve (AUC)-0.565)), 27.15 cc (AUC-0.58), 3.7 Gy (AUC-0.633), 4.6% (AUC-0.597), 9.5% (AUC-0.616). The incidence of ≥grade 2 RP was significantly high for values higher than the ROC threshold. CONCLUSION: SABR treatment resulted in a very low rate of grade 3 pneumonitis. Lower lobe tumor location, larger tumor size, PTV, mean lung dose, V20, and V12.5 were found to be significant predictors of symptomatic radiation pneumonitis.

Phosphatidic Acid Increases Epidermal Growth Factor Receptor Expression by Stabilizing mRNA Decay and by Inhibiting Lysosomal and Proteasomal Degradation of the Internalized Receptor.

Overexpression of epidermal growth factor receptor (EGFR) is one of the frequent mechanisms implicated in cancer progression, and so is the overexpression of the enzyme phospholipase D (PLD) and its reaction product, phosphatidic acid (PA). However, an understanding of how these signaling molecules interact at the level of gene expression is lacking. Catalytically active PLD enhanced expression of EGFR in human breast cancer cells. Overexpression of the PLD2 isoform increased EGFR mRNA and protein expression. It also negated an EGFR downregulation mediated by small interfering RNA targeting EGFR (siEGFR). Several mechanisms contributed to the alteration in EGFR expression. First was the stabilization of EGFR transcripts as PLD2 delayed mRNA decay, which prolonged their half-lives. Second, RNase enzymatic activity was inhibited by PA. Third, protein stabilization also occurred, as indicated by PLD resistance to cycloheximide-induced EGFR protein degradation. Fourth, PA inhibited lysosomal and proteasomal degradation of internalized EGFR. PLD2 and EGFR colocalized at the cell membrane, and JAK3 phosphorylation at Tyr980/Tyr981 followed receptor endocytosis. Further, the presence of PLD2 increased stabilization of intracellular EGFR in large recycling vesicles at ∼15 min of EGF stimulation. Thus, PLD2-mediated production of PA contributed to the control of EGFR exposure to ligand through a multipronged transcriptional and posttranscriptional program during the out-of-control accumulation of EGFR signaling in cancer cells.

A novel phospholipase D2-Grb2-WASp heterotrimer regulates leukocyte phagocytosis in a two-step mechanism.

Phagocytosis is a primary innate response of both macrophages and neutrophils involving the formation of filamentous actin (F-actin)-rich protrusions that are extended around opsonized pathogens to form a phagocytic cup, resulting in their subsequent internalization. The molecular mechanism for this is still not completely understood. We now show for the first time that phospholipase D2 (PLD2) binds to growth factor receptor-bound protein 2 (Grb2) and to the Wiskott-Aldrich syndrome protein (WASp) to form a heterotrimer complex, PLD2-Grb2-WASp, and present the mechanism of interaction. Grb2 binds to the Y169/Y179 residues of PLD2 using its only SH2 domain, and it interacts with the poly-proline region of WASp using its two SH3 domains. The PLD2-Grb2-WASp heterotrimer can be visualized in early phagocytic cups of macrophages ingesting opsonized red blood cells, where it associates with polymerized actin. Cup colocalization and phagocytosis are disrupted with mutants that alter binding at either of the two proteins or by silencing Grb2 with RNA interference (RNAi). WASp association to PLD2-K758R, a lipase-inactive mutant, still occurs, albeit at lower levels, indicating that PLD2 plays a second role in phagocytosis, which is the production of phosphatidic acid (PA) and activation of phosphatidylinositol 5-kinase (PI5K) with subsequent synthesis of phosphatidylinositol 4,5-bisphosphate (PIP(2)). The latter can be blocked with RNAi, which negates phagocytosis. Lastly, a constitutively "open" active form of WASp (WASp-L270P) brings phagocytosis to its maximum level, which can be mimicked with WASp-WT plus PLD2 or plus PA. Since neither a protein-protein disruption nor lack of PLD activity completely negates cup formation or phagocytosis, we posit a two-step mechanism: PLD2 anchors WASp at the phagocytic cup through Grb2 following protein-protein interactions and also activates it, making key lipids available locally. The heterotrimer PLD2-Grb2-WASp then enables actin nucleation at the phagocytic cup and phagocytosis, which are at the center of the innate immune system function.