Lung cancer in patients with idiopathic pulmonary fibrosis: A retrospective multicentre study in Europe.

BACKGROUND AND OBJECTIVE: There remains a paucity of large databases for patients with idiopathic pulmonary fibrosis (IPF) and lung cancer. We aimed to create a European registry. METHODS: This was a multicentre, retrospective study across seven European countries between 1 January 2010 and 18 May 2021. RESULTS: We identified 324 patients with lung cancer among 3178 patients with IPF (prevalence = 10.2%). By the end of the 10 year-period following IPF diagnosis, 26.6% of alive patients with IPF had been diagnosed with lung cancer. Patients with IPF and lung cancer experienced increased risk of all-cause mortality than IPF patients without lung cancer (HR: 1.51, [95% CI: 1.22-1.86], p < 0.0001). All-cause mortality was significantly lower for patients with IPF and lung cancer with a monocyte count of either <0.60 or 0.60-<0.95 K/µl than patients with monocyte count ≥0.95 K/µl (HR [<0.60 vs. ≥0.95 K/µl]: 0.35, [95% CI: 0.17-0.72], HR [0.60-<0.95 vs. ≥0.95 K/µl]: 0.42, [95% CI: 0.21-0.82], p = 0.003). Patients with IPF and lung cancer that received antifibrotics presented with decreased all cause-mortality compared to those who did not receive antifibrotics (HR: 0.61, [95% CI: 0.42-0.87], p = 0.006). In the adjusted model, a significantly lower proportion of surgically treated patients with IPF and otherwise technically operable lung cancer experienced all-cause mortality compared to non-surgically treated patients (HR: 0.30 [95% CI: 0.11-0.86], p = 0.02). CONCLUSION: Lung cancer exerts a dramatic impact on patients with IPF. A consensus statement for the management of patients with IPF and lung cancer is sorely needed.

Radio-Histological Correlation of Lung Features in Severe COVID-19 Through CT-Scan and Lung Ultrasound Evaluation.

Background: Patients with coronavirus disease 2019 (COVID-19) can develop severe bilateral pneumonia leading to respiratory failure. Lung histological samples were scarce due to the high risk of contamination during autopsies. We aimed to correlate histological COVID-19 features with radiological findings through lung ultrasound (LU)-guided postmortem core needle biopsies (CNBs) and computerized tomography (CT) scans. Methodology: We performed an observational prospective study, including 30 consecutive patients with severe COVID-19. The thorax was divided into 12 explorations regions to correlate LU and CT-scan features. Histological findings were also related to radiological features through CNBs. Results: Mean age was 62.56 ± 13.27 years old, with 96.7% male patients. Postmortem LU-guided CNBs were performed in 13 patients. Thirty patients were evaluated with both thoracic LU and chest CT scan, representing a total of 279 thoracic regions explored. The most frequent LU finding was B2-lines (49.1%). The most CT-scan finding was ground-glass opacity (GGO, 29%). Pathological CT-scan findings were commonly observed when B2-lines or C-lines were identified through LU (positive predictive value, PPV, 87.1%). Twenty-five postmortem echo-guided histological samples were obtained from 12 patients. Histological samples showed diffuse alveolar damage (DAD) (75%) and chronic interstitial inflammation (25%). The observed DAD was heterogeneous, showing multiple evolving patterns of damage, including exudative (33.3%), fibrotic (33.3%), and organizing (8.3%) phases. In those patients with acute or exudative pattern, two lesions were distinguished: classic hyaline membrane; fibrin "plug" in alveolar space (acute fibrinous organizing pneumonia, AFOP). C-profile was described in 33.3% and presented histological signs of DAD and lung fibrosis. The predominant findings were collagen deposition (50%) and AFOP (50%). B2-lines were identified in 66.7%; the presence of hyaline membrane was the predominant finding (37.5%), then organizing pneumonia (12.5%) and fibrosis (37.5%). No A-lines or B1-lines were observed in these patients. Conclusion: LU B2-lines and C-profile are predominantly identified in patients with severe COVID-19 with respiratory worsening, which correspond to different CT patterns and histological findings of DAD and lung fibrosis.

Molecular Nodal Restaging Based on CEACAM5, FGFR2b and PTPN11 Expression Adds No Relevant Clinical Information in Resected Non-Small Cell Lung Cancer.

BACKGROUND: The relapse rate in non-small cell lung cancer (NSCLC) is high, even in localized disease, suggesting that the current approach to pathological staging is insufficiently sensitive to detect occult micrometastases present in resected lymph nodes. Therefore, we aimed to determine the prognostic value of the expression of embryonic molecular markers in histologically-negative lymph nodes of completely-resected NSCLC. METHODS: 76 completely-resected NSCLC patients were included: 60 pN0 and 16 pN1. Primary tumors and 347 lymph node were studied. CEACAM5, FGFR2b, and PTPN11 expression levels were evaluated through mRNA analysis using real-time RT-qPCR assay. Statistical analyses included the Kruskal-Wallis test, Kaplan Meier curves, and log-rank tests. RESULTS: CEACAM5 expression levels were scored as high in of 90 lymph nodes (26%). The molecular-positive lymph nodes lead to the restaging of 37 (62%) pN0 patients as molecular N1 or N2 and 5 (31%) pN1 cases were reclassified as molecular-positive N2. Surprisingly, molecular-positive patients associated with a better OS (overall survival, p = 0,04). FGFR2b overexpression was observed in 41 (12%) lymph nodes leading to the restaging of 17 patients (22%). Again a trend was observed toward a better DFS (disease-free survival) in the restaged patients (p = 0,09). Accordingly, high expression levels of CEACAM5 or FGFR2b in the primary were related to better DFS (p = 0,06; p < 0,02, respectively). CONCLUSION: Molecular nodal restaging based on expression levels of CEACAM5 and/or FGFR2b, does not add relevant clinical information to pathological staging of NSCLC likely related to the better prognosis of their overexpression in primary tumors.

Efficacy of CDK4/6 inhibitors in preclinical models of malignant pleural mesothelioma.

BACKGROUND: There is no effective therapy for patients with malignant pleural mesothelioma (MPM) who progressed to platinum-based chemotherapy and immunotherapy. METHODS: We aimed to investigate the antitumor activity of CDK4/6 inhibitors using in vitro and in vivo preclinical models of MPM. RESULTS: Based on publicly available transcriptomic data of MPM, patients with CDK4 or CDK6 overexpression had shorter overall survival. Treatment with abemaciclib or palbociclib at 100 nM significantly decreased cell proliferation in all cell models evaluated. Both CDK4/6 inhibitors significantly induced G1 cell cycle arrest, thereby increasing cell senescence and increased the expression of interferon signalling pathway and tumour antigen presentation process in culture models of MPM. In vivo preclinical studies showed that palbociclib significantly reduced tumour growth and prolonged overall survival using distinct xenograft models of MPM implanted in athymic mice. CONCLUSIONS: Treatment of MPM with CDK4/6 inhibitors decreased cell proliferation, mainly by promoting cell cycle arrest at G1 and by induction of cell senescence. Our preclinical studies provide evidence for evaluating CDK4/6 inhibitors in the clinic for the treatment of MPM.

Lung Ultrasound Score to Predict Outcomes in COVID-19.

BACKGROUND: Patients with coronavirus disease 2019 (COVID-19) can develop severe bilateral pneumonia leading to respiratory failure. We aimed to study the potential role of lung ultrasound score (LUS) in subjects with COVID-19. METHODS: We conducted an observational, prospective pilot study, including consecutive subjects admitted to an intermediate care unit due to COVID-19 pneumonia. LUS is a 12-zone examination method for lung parenchyma assessment. LUS was performed with a portable convex transducer, scores from 0 to 36 points. Clinical and demographic data were collected at LUS evaluation. Survival analysis was performed using a composite outcome including ICU admission or death. Subjects were followed for 30 d from LUS assessment. RESULTS: Of 36 subjects included, 69.4% were male, and mean age was 60.19 ± 12.75 y. A cutoff LUS ≥ 24 points showed 100% sensitivity, 69.2% specificity, and an area under the receiver operating characteristic curve of 0.85 for predicting worse prognosis. The composite outcome was present in 10 subjects (55.6%) with LUS ≥ 24 points, but not in the group with lower LUS scores (P < .001). Subjects with LUS ≥ 24 points had a higher risk of ICU admission or death (hazard ratio 9.97 [95% CI 2.75-36.14], P < .001). Significant correlations were observed between LUS and [Formula: see text], serum D-dimer, C-reactive protein, lactate dehydrogenase, and lymphocyte count. CONCLUSIONS: LUS ≥ 24 points can help identify patients with COVID-19 who are likely to require ICU admission or to die during follow-up. LUS also correlates significantly with clinical and laboratory markers of COVID-19 severity.

Severity of radiation pneumonitis, from clinical, dosimetric and biological features: a pilot study.

BACKGROUND AND OBJECTIVE: Radiation pneumonitis (RP) could be a lethal complication of lung cancer treatment. No reliable predictors of RP severity have been recognized. This prospective pilot study was performed to identify early predictors of high grade lung toxicity and to evaluate clinical, biological or dosimetric features associated with different grades of toxicity. METHOD: Sixteen patients with non-small cell lung cancer with indication of concurrent chemoradiotherapy using 60 Gy/2 Gy/fraction starting at cycle one of platinum based chemotherapy were included. Bronchoalveolar lavage (BAL), pulmonary function testing (PFT), and 18F-2-fluoro-2-deoxy-D-glucose positron-emission tomography was performed before radiotherapy (RT), after three weeks of treatment, and two months post-RT. For analysis, patients were grouped by grade (low [G1-G2] vs. high [G3-G5]). The two groups were compared to identify predictors of RP. Protein expression BAL and lung tissue metabolism was evaluated in two patients (RP-G1 vs. RP-G3). Categorical variables such as comorbidities, stages and locations were summarized as percentages. Radiation doses, pulmonary function values and time to RP were summarized by medians with ranges or as means with standard deviation. Longitudinal analysis PFT was performed by a T-test. RESULTS: All 16 patients developed RP, as follows: G1 (5 pts; 31.3%); G2 (5 pts; 31.3%); G3 (5 pts; 31.3%); and G5 (1 pts; 6.1%). Patients with high grade RP presented significant decrease (p = 0.02) in diffusing lung capacity for carbon monoxide (DLCO) after three weeks of RT. No correlation between dosimetric values and RP grades was observed. BAL analysis of the selected patients showed that CXCL-1, CD154, IL-1ra, IL-23, MIF, PAI-1 and IFN-γ were overexpressed in the lungs of the RP-G3 patient, even before treatment. The pre-RT SUVmax value in the RP-G3 patient was non-significantly higher than in the patient with RP-G1. CONCLUSIONS: RT induces some degree of RP. Our data suggest that decrease in DLCO% is the most sensitive parameter for the early detection of RP. Moreover, we detect biological differences between the two grades of pneumonitis, highlighting the potential value of some cytokines as a prognostic marker for developing high grade lung toxicity. Further multicenter studies with larger sample size are essential to validate these findings.

Fasting plasma glucose is an independent predictor of survival in patients with locally advanced non-small cell lung cancer treated with concurrent chemoradiotherapy.

BACKGROUND: Diabetes is related with increased cancer mortality across multiple cancer types. Its role in lung cancer mortality is still unclear. We aim to determine the prognostic value of fasting plasma glucose (FPG) and diabetes mellitus in patients with locally advanced non-small cell lung cancer (NSCLC) treated with concurrent chemoradiotherapy. METHODS: One-hundred seventy patients with stage III NSCLC received definitive concurrent chemoradiotherapy from 2010 to 2014. Clinico-pathological data and clinical outcome was retrospectively registered. Fifty-six patients (33%), met criteria for type 2 diabetes mellitus (T2DM) at baseline. The prognostic value of FPG and other clinical variables was assessed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method and Cox proportional models and log-rank test were used. RESULTS: With a median follow-up of 36 months, median PFS was 8.0 months and median OS was 15.0 months in patients with FPG ≥7 mmol/L compared to 20 months (HR 1.13; 95% CI 1.07-1.19, p < 0.001) and 31 months (HR 1.09; 95% CI 1.04-1.15; p < 0.001) respectively, for patients with FPG < 7 mmol/L. In the multivariate analysis of the entire cohort adjusted by platinum compound and comorbidities, high levels of FPG as a continuous variable (HR 1.14; 95% CI 1.07-1.21; p < 0.001), the presence of comorbidity (HR 1.72; 95% CI 1.12-2.63; p = 0.012), and treatment with carboplatin (HR 1.95; 95% CI 1.26-2.99; p = 0.002) were independent predictors for shorter OS. In additional multivariate models considering non-diabetic patients as a reference group, diabetic patients with poor metabolic control (HbA1c > 8.5%) (HR 4.53; 95% CI 2.21-9.30; p < 0.001) and those receiving insulin (HR 3.22; 95% CI 1.90-5.46 p < 0.001) had significantly independent worse OS. CONCLUSION: Baseline FPG level is an independent predictor of survival in our cohort of patients with locally advanced NSCLC treated with concurrent chemoradiotherapy. Studies in larger cohorts of patients are warranted to confirm this relevant association.

Ultrathin Bronchoscopy with and without Virtual Bronchoscopic Navigation: Influence of Segmentation on Diagnostic Yield.

BACKGROUND: Bronchoscopy is a safe technique for diagnosing peripheral pulmonary lesions (PPLs), and virtual bronchoscopic navigation (VBN) helps guide the bronchoscope to PPLs. OBJECTIVES: We aimed to compare the diagnostic yield of VBN-guided and unguided ultrathin bronchoscopy (UTB) and explore clinical and technical factors associated with better results. We developed a diagnostic algorithm for deciding whether to use VBN to reach PPLs or choose an alternative diagnostic approach. METHODS: We compared diagnostic yield between VBN-UTB (prospective cases) and unguided UTB (historical controls) and analyzed the VBN-UTB subgroup to identify clinical and technical variables that could predict the success of VBN-UTB. RESULTS: Fifty-five cases and 110 controls were included. The overall diagnostic yield did not differ between the VBN-guided and unguided arms (47 and 40%, respectively; p = 0.354). Although the yield was slightly higher for PPLs ≤20 mm in the VBN-UTB arm, the difference was not significant (p = 0.069). No other clinical characteristics were associated with a higher yield in a subgroup analysis, but an 85% diagnostic yield was observed when segmentation was optimal and the PPL was endobronchial (vs. 30% when segmentation was suboptimal and 20% when segmentation was optimal but the PPL was extrabronchial). CONCLUSIONS: VBN-guided UTB is not superior to unguided UTB. A greater impact of VBN-guided over unguided UTB is highly dependent on both segmentation quality and an endobronchial location of the PPL. Segmentation quality should be considered before starting a procedure, when an alternative technique that may improve yield can be chosen, saving time and resources.

Preoperative nutritional status assessment predicts postoperative outcomes in patients with surgically resected non-small cell lung cancer.

BACKGROUND: As nutritional status plays an important role in outcomes after surgery, this study evaluated the association between preoperative nutritional status (NS) and postoperative outcomes after major resection for lung cancer. METHODS: We identified 219 patients with a diagnosis of cancer who underwent pulmonary resection from 2010 to 2012. Preoperative NS was assessed by anthropometric and biological parameters, body mass index (BMI), and the Nutritional Risk Index (NRI). We stratified this population into 4 BMI groups: underweight, normal weight, overweight and obese and 4 NRI groups: well-nourished; mildly malnourished; moderately malnourished and severely malnourished. The outcomes measured were postoperative complications; 30-day postoperative mortality; hospital length of stay (LOS), overall survival (OS) and disease-free survival (DFS). We performed both unadjusted analysis and adjusted multivariable analysis, controlling for statistically significant variables. RESULTS: Mean BMI and NRI were, respectively, 26.5 ± 4.3 and 112.4 ± 3.3. There were no significant differences between BMI categories and resection type, pathological stage, or overall postoperative complications. By contrast, significant differences (p < 0.05) in postoperative complications were observed among the NRI groups. LOS was longer in underweight and/or malnourished patients. In terms of OS, we found no significant differences according to NRI and BMI; however, patients with underweight had significantly shorter DFS compared with patients with overweight and obesity (log-rank p-value = 0.001). CONCLUSION: NS as measured by the NRI is an independent predictor of the risk of postsurgical complications, regardless of clinicopathologic characteristics. NRI might therefore be an useful tool for identifying early-stage lung cancer patients at risk for postoperative complications.

Successful treatment with brigatinib in a patient with ALK-rearranged lung adenocarcinoma who developed crizotinib-induced interstitial lung disease.

We present a 45-year-old patient diagnosed with anaplastic lymphoma kinase (ALK)-rearranged metastatic lung cancer who developed grade 4 interstitial lung disease (ILD) while on crizotinib treatment and was lately treated with brigatinib with no reappearance of ILD. To our knowledge, this is the first case report of successful treatment with brigatinib after crizotinib-induced ILD. Even though ILD secondary to brigatinib has been reported in clinical trials, no pulmonary toxicity has been seen in our patient, suggesting no crosslink lung toxicity between crizotinib and brigatinib.

Geriatric assessment may help decision-making in elderly patients with inoperable, locally advanced non-small-cell lung cancer.

BACKGROUND: Although concurrent chemoradiotherapy (cCRT) increases survival in patients with inoperable, locally advanced non-small-cell lung cancer (NSCLC), there is no consensus on the treatment of elderly patients. The aim of this study was to determine the prognostic value of the comprehensive geriatric assessment (CGA) and its ability to predict toxicity in this setting. METHODS: We enrolled 85 consecutive elderly (⩾75 years) participants, who underwent CGA and the Vulnerable Elders Survey (VES-13). Those classified as fit and medium-fit by CGA were deemed candidates for cCRT (platinum-based chemotherapy concurrent with thoracic radiation therapy), while unfit patients received best supportive care. RESULTS: Fit (37%) and medium-fit (48%) patients had significantly longer median overall survival (mOS) (23.9 and 16.9 months, respectively) than unfit patients (15%) (9.3 months, log-rank P=0.01). In multivariate analysis, CGA groups and VES-13 were independent prognostic factors. Fit and medium-fit patients receiving cCRT (n=54) had mOS of 21.1 months (95% confidence interval: 16.2, 26.0). In those patients, higher VES-13 (⩾3) was associated with shorter mOS (16.33 vs 24.3 months, P=0.027) and higher risk of G3-4 toxicity (65 vs 32%, P=0.028). CONCLUSIONS: Comprehensive geriatric assessment and VES-13 showed independent prognostic value. Comprehensive geriatric assessment may help to identify elderly patients fit enough to be treated with cCRT.

Phase II Trial of SBRT for Stage I NSCLC: Survival, Local Control, and Lung Function at 36 Months.

OBJECTIVES: The long-term impact of stereotactic body radiotherapy (SBRT) on respiratory function in patients with inoperable non-small cell lung cancer (NSCLC) has not been well studied. The aim of this phase II trial was to assess local control, survival, and lung function at 36 months after treatment. METHODS: From July 2008 to February 2012, 42 patients in whom inoperable NSCLC with peripheral lesions was diagnosed were consecutively enrolled. Lung function testing included measurement of forced expiratory vital capacity, forced expiratory volume in 1 second, and diffusing capacity for carbon monoxide. All lung function parameters were registered at baseline and evaluated prospectively after SBRT every 6 months for 2 years and annually thereafter. RESULTS: Of the 42 initial patients, four were excluded. At 36 months after SBRT, 22 patients were still evaluable (12 deaths and four patients lost to follow-up). At 36 months, the rate of local control was 94%. At 1, 2, and 3 years, respectively, overall survival rates were 92%, 75%, and 66%. Median overall survival was 57 months. Grade (G) 3 acute toxicity was observed in four patients (10%). Chronic G1 toxicity was observed in all 38 cases (100%), with the most common type being pneumonitis (26 patients [68%]). The mean lung function parameters at baseline and at 36 months after treatment were as follows: forced expiratory vital capacity 83% versus 79%; forced expiratory volume in 1 second 62% versus 57%; and diffusing capacity for carbon monoxide 54% versus 54%. These changes were not significant. CONCLUSIONS: In this trial, local control and survival rates after SBRT were very good. Treatment with SBRT had no significant impact on lung function at 36 months. These findings provide further support for the use of SBRT as a radical treatment for NSCLC. Lung toxicity is minimal, even in patients with poor pulmonary function before treatment.