Alectinib in Resected ALK-Positive Non-Small-Cell Lung Cancer.

BACKGROUND: Platinum-based chemotherapy is the recommended adjuvant treatment for patients with resectable, ALK-positive non-small-cell lung cancer (NSCLC). Data on the efficacy and safety of adjuvant alectinib as compared with chemotherapy in patients with resected ALK-positive NSCLC are lacking. METHODS: We conducted a global, phase 3, open-label, randomized trial in which patients with completely resected, ALK-positive NSCLC of stage IB (tumors ≥4 cm), II, or IIIA (as classified according to the seventh edition of the Cancer Staging Manual of the American Joint Committee on Cancer and Union for International Cancer Control) were randomly assigned in a 1:1 ratio to receive oral alectinib (600 mg twice daily) for 24 months or intravenous platinum-based chemotherapy in four 21-day cycles. The primary end point was disease-free survival, tested hierarchically among patients with stage II or IIIA disease and then in the intention-to-treat population. Other end points included central nervous system (CNS) disease-free survival, overall survival, and safety. RESULTS: In total, 257 patients were randomly assigned to receive alectinib (130 patients) or chemotherapy (127 patients). The percentage of patients alive and disease-free at 2 years was 93.8% in the alectinib group and 63.0% in the chemotherapy group among patients with stage II or IIIA disease (hazard ratio for disease recurrence or death, 0.24; 95% confidence interval [CI], 0.13 to 0.45; P<0.001) and 93.6% and 63.7%, respectively, in the intention-to-treat population (hazard ratio, 0.24; 95% CI, 0.13 to 0.43; P<0.001). Alectinib was associated with a clinically meaningful benefit with respect to CNS disease-free survival as compared with chemotherapy (hazard ratio for CNS disease recurrence or death, 0.22; 95% CI, 0.08 to 0.58). Data for overall survival were immature. No unexpected safety findings were observed. CONCLUSIONS: Among patients with resected ALK-positive NSCLC of stage IB, II, or IIIA, adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (Funded by F. Hoffmann-La Roche; ALINA ClinicalTrials.gov number, NCT03456076.).

A novel image deep learning-based sub-centimeter pulmonary nodule management algorithm to expedite resection of the malignant and avoid over-diagnosis of the benign.

OBJECTIVES: With the popularization of chest computed tomography (CT) screening, there are more sub-centimeter (≤ 1 cm) pulmonary nodules (SCPNs) requiring further diagnostic workup. This area represents an important opportunity to optimize the SCPN management algorithm avoiding "one-size fits all" approach. One critical problem is how to learn the discriminative multi-view characteristics and the unique context of each SCPN. METHODS: Here, we propose a multi-view coupled self-attention module (MVCS) to capture the global spatial context of the CT image through modeling the association order of space and dimension. Compared with existing self-attention methods, MVCS uses less memory consumption and computational complexity, unearths dimension correlations that previous methods have not found, and is easy to integrate with other frameworks. RESULTS: In total, a public dataset LUNA16 from LIDC-IDRI, 1319 SCPNs from 1069 patients presenting to a major referral center, and 160 SCPNs from 137 patients from three other major centers were analyzed to pre-train, train, and validate the model. Experimental results showed that performance outperforms the state-of-the-art models in terms of accuracy and stability and is comparable to that of human experts in classifying precancerous lesions and invasive adenocarcinoma. We also provide a fusion MVCS network (MVCSN) by combining the CT image with the clinical characteristics and radiographic features of patients. CONCLUSION: This tool may ultimately aid in expediting resection of the malignant SCPNs and avoid over-diagnosis of the benign ones, resulting in improved management outcomes. CLINICAL RELEVANCE STATEMENT: In the diagnosis of sub-centimeter lung adenocarcinoma, fusion MVCSN can help doctors improve work efficiency and guide their treatment decisions to a certain extent. KEY POINTS: • Advances in computed tomography (CT) not only increase the number of nodules detected, but also the nodules that are identified are smaller, such as sub-centimeter pulmonary nodules (SCPNs). • We propose a multi-view coupled self-attention module (MVCS), which could model spatial and dimensional correlations sequentially for learning global spatial contexts, which is better than other attention mechanisms. • MVCS uses fewer huge memory consumption and computational complexity than the existing self-attention methods when dealing with 3D medical image data. Additionally, it reaches promising accuracy for SCPNs' malignancy evaluation and has lower training cost than other models.

Identification of TCR rearrangements specific for genetic alterations in EGFR-mutated non-small cell lung cancer: results from the ADJUVANT-CTONG1104 trial.

Tumor response T cells, which have specific T cell receptor (TCR) rearrangements in tumor-infiltrating lymphocytes, determine their ability to interact with the mutation-derived neoantigens presented by antigen-presenting cells. Little is known about the genetic alterations related to specific TCR clones in non-small cell lung cancer (NSCLC) patients who have an epidermal growth factor receptor (EGFR) mutation. In this study, tumor tissues were collected from 101 patients with stage II/III resectable NSCLC with an EGFR mutation (57 patients were treated with gefitinib and 44 were treated with chemotherapy) in the ADJUVANT-CTONG1104 trial for high-throughput TCRß V region and exome sequencing. Ten clonal TCRs were associated with EGFR exon 19 deletion (del), EGFR exon 21 mutation (L858R), RB1 alteration, TP53 exon 4/5 missense mutation, TP53 nonsense mutation, or copy number gains in NKX2-1 and CDK4. Among the TCRs, there was frequent use of Vß20-1Jß2-3 specifically for EGFR exon 19 del or Vß9Jß2-1 specifically for EGFR exon 21 mutation (L858R), and these were significantly associated with favorable overall survival (OS) for NSCLC patients harboring EGFR exon 19 del or exon 21 L858R, particularly in the adjuvant gefitinib setting. Moreover, in comparison with the chemotherapy-preferable (CP) group, higher frequencies of Vß20-1Jß2-3 and Vß9Jß2-1 were found in the highly TKI-preferable (HTP) or TKI-preferable (TP) groups. Altogether, we identified ten TCR rearrangements specific for genetic alterations in NSCLC. Importantly, high abundance Vß20-1Jß2-3 or Vß9Jß2-1 may be an immune biomarker for guiding adjuvant gefitinib decisions for NSCLC patients harboring EGFR exon 19 del or EGFR exon 21 L858R.

Expression Changes in Programmed Death Ligand 1 from Precancerous Lesions to Invasive Adenocarcinoma in Subcentimeter Pulmonary Nodules: A Large Study of 2022 Cases in China.

PURPOSE: This large-scale, multicenter, retrospective observational study aimed to evaluate the clinicopathological and molecular profiles associated with programmed death-ligand 1 (PD-L1) expression in precancerous lesions and invasive adenocarcinoma in subcentimeter pulmonary nodules. PATIENTS AND METHODS: Patients with histologically confirmed atypical adenomatous hyperplasia (AAH), adenocarcinoma in situ (AIS), minimally invasive adenocarcinoma (MIA), and invasive adenocarcinoma (ADC) were included. PD-L1 expression was evaluated at each center using a PD-L1 immunohistochemistry 22C3 pharmDx kit (Agilent, Santa Clara, CA, USA). The tumor proportion score (TPS) cutoff values were set at ≥ 1% and ≥ 50%. RESULTS: A total of 2022 nodules from 1844 patients were analyzed. Of these, 9 (0.45%) nodules had PD-L1 TPS ≥ 50%, 187 (9.25%) had PD-L1 TPS 1-49%, and 1826 (90.30%) had PD-L1 TPS < 1%. A total of 378 (18.69%), 1016 (50.25%), and 628 (31.06%) nodules were diagnosed as AAH/AIS, MIA, and ADC, respectively, by pathology. A total of 1377 (68.10%), 591 (25.67%), and 54 (2.67%) nodules were diagnosed as pure ground-glass opacity (GGO), mixed GGO, and solid nodules, respectively, by computed tomography. There was a significant difference between PD-L1 expression and anaplastic lymphoma kinase (ALK) mutation status (P < 0.001). PD-L1 expression levels were significantly different from those determined using the International Association for the Study of Lung Cancer (IASLC) grading system (P < 0.001). CONCLUSIONS: PD-L1 expression was significantly associated with radiological and pathological invasiveness and driver mutation status in subcentimeter pulmonary nodules. The significance of PD-L1 expression in the evolution of early-stage lung adenocarcinoma requires further investigation.

ITHscore: comprehensive quantification of intra-tumor heterogeneity in NSCLC by multi-scale radiomic features.

OBJECTIVES: To quantify intra-tumor heterogeneity (ITH) in non-small cell lung cancer (NSCLC) from computed tomography (CT) images. METHODS: We developed a quantitative ITH measurement-ITHscore-by integrating local radiomic features and global pixel distribution patterns. The associations of ITHscore with tumor phenotypes, genotypes, and patient's prognosis were examined on six patient cohorts (n = 1399) to validate its effectiveness in characterizing ITH. RESULTS: For stage I NSCLC, ITHscore was consistent with tumor progression from stage IA1 to IA3 (p < 0.001) and captured key pathological change in terms of malignancy (p < 0.001). ITHscore distinguished the presence of lymphovascular invasion (p = 0.003) and pleural invasion (p = 0.001) in tumors. ITHscore also separated patient groups with different overall survival (p = 0.004) and disease-free survival conditions (p = 0.005). Radiogenomic analysis showed that the level of ITHscore in stage I and stage II NSCLC is correlated with heterogeneity-related pathways. In addition, ITHscore was proved to be a stable measurement and can be applied to ITH quantification in head-and-neck cancer (HNC). CONCLUSIONS: ITH in NSCLC can be quantified from CT images by ITHscore, which is an indicator for tumor phenotypes and patient's prognosis. KEY POINTS: • ITHscore provides a radiomic quantification of intra-tumor heterogeneity in NSCLC. • ITHscore is an indicator for tumor phenotypes and patient's prognosis. • ITHscore has the potential to be generalized to other cancer types such as HNC.

Clinicopathological features and resistance mechanisms in HIP1-ALK-rearranged lung cancer: A multicenter study.

Anaplastic lymphoma kinase (ALK)-rearranged non-small cell lung cancer (NSCLC) respond well to ALK tyrosine kinase inhibitors (TKIs), and echinoderm microtubule-associated protein-like 4 (EML4)-ALK-rearranged NSCLC accounts for the majority of those patients. However, few studies have evaluated ALK-TKIs treatment for patients with huntingtin-interacting protein 1 (HIP1)-ALK fusions. This retrospective study evaluated the clinicopathological characteristics, genomic features, response to ALK-TKIs, and resistance mechanisms in 11 cases with HIP1-ALK fusions from five Chinese centers. Patients who received crizotinib at the Chinese centers had an objective response rate of 90% [9/10 cases, 95% confident index (CI): 54.1%-99.5%], median progression-free survival of 17.9 months (95% CI: 5.8-NA months), and median overall survival of 58.8 months (95% CI: 24.7-NA months). One patient who received first-line lorlatinib treatment achieved partial response for > 26.5 months. Despite the small sample size, HIP1-ALK (H21:A20) variant was the most common variant (four of 11 cases, 36.4%) and associated with better outcomes. Among the 11 cases, there were eight patients having available specimens for genetic testing before ALK-TKIs treatment and four patients undergoing biopsy after ALK-TKIs failure. The most common coexisting gene was TP53 among 11 patients and two of four patients after crizotinib failure harbored acquired ALK mutations (e.g., L1152V/Q1146K and L1196M). Brigatinib treatment appeared to be effective for a patient who failed crizotinib treatment because of the L1152V/Q1146K mutations, which might be related to increased binding affinity to these mutants. Although HIP1-ALK-rearranged NSCLC appears to initially respond well to ALK-TKIs, crizotinib resistance may be correlated with the AKAP9-BRAF fusion, ALK compound mutations (L1152V/Q1146K), and the ALK L1196M mutation. Larger studies are needed to evaluate the significance of HIP1-ALK-rearranged NSCLC.

Development and validation of a computed tomography-based immune ecosystem diversity index as an imaging biomarker in non-small cell lung cancer.

OBJECTIVES: To date, there are no data on the noninvasive surrogate of intratumoural immune status that could be prognostic of survival outcomes in non-small cell lung cancer (NSCLC). We aimed to develop and validate the immune ecosystem diversity index (iEDI), an imaging biomarker, to indicate the intratumoural immune status in NSCLC. We further investigated the clinical relevance of the biomarker for survival prediction. METHODS: In this retrospective study, two independent NSCLC cohorts (Resec1, n = 149; Resec2, n = 97) were included to develop and validate the iEDI to classify the intratumoural immune status. Paraffin-embedded resected specimens in Resec1 and Resec2 were stained by immunohistochemistry, and the density percentiles of CD3+, CD4+, and CD8+ T cells to all cells were quantified to estimate intratumoural immune status. Then, EDI features were extracted using preoperative computed tomography to develop an imaging biomarker, called iEDI, to determine the immune status. The prognostic value of iEDI was investigated on NSCLC patients receiving surgical resection (Resec1; Resec2; internal cohort Resec3, n = 419; external cohort Resec4, n = 96; and TCIA cohort Resec5, n = 55). RESULTS: iEDI successfully classified immune status in Resec1 (AUC 0.771, 95% confidence interval [CI] 0.759-0.783; and 0.770 through internal validation) and Resec2 (0.669, 0.647-0.691). Patients with higher iEDI-score had longer overall survival (OS) in Resec3 (unadjusted hazard ratio 0.335, 95%CI 0.206-0.546, p < 0.001), Resec4 (0.199, 0.040-1.000, p < 0.001), and TCIA (0.303, 0.098-0.944, p = 0.001). CONCLUSIONS: iEDI is a non-invasive surrogate of intratumoural immune status and prognostic of OS for NSCLC patients receiving surgical resection. KEY POINTS: • Decoding tumour immune microenvironment enables advanced biomarkers identification. • Immune ecosystem diversity index characterises intratumoural immune status noninvasively. • Immune ecosystem diversity index is prognostic for NSCLC patients.

Targeted Therapy in Early Stage Non-small Cell Lung Cancer.

OPINION STATEMENT: Tyrosine kinase inhibitors (TKIs) have dramatically improved tumor response rates and survival benefits in advanced oncogenic non-small-cell lung cancer (NSCLC). Given the impressive success, a renewed interest has been raised in the study of these agents in the perioperative setting. Preliminary data have shown dramatic effectiveness compared to conventional chemotherapy. Given the explicit need to induce durable responses and raise cure rates, we summarize the current progression, identify key challenges, and raise potential opportunities for perioperative targeted therapy that range from precise biomarkers to optimal adjuvant regimens for individual patients. As perioperative treatment indeed provides researchers with a unique platform to address the challenges mentioned above, investigators could obtain a comprehensive analysis of genomic profiling and trace resistance mechanisms. Multidisciplinary collaboration and adaptive clinical trial designs are warranted to integrate translational research into personalized perioperative TKI treatment paradigms.

Identification and evaluation of circulating small extracellular vesicle microRNAs as diagnostic biomarkers for patients with indeterminate pulmonary nodules.

BACKGROUND: The identification of indeterminate pulmonary nodules (IPNs) following a low-dose computed tomography (LDCT) is a major challenge for early diagnosis of lung cancer. The inadequate assessment of IPNs' malignancy risk results in a large number of unnecessary surgeries or an increased risk of cancer metastases. However, limited studies on non-invasive diagnosis of IPNs have been reported. METHODS: In this study, we identified and evaluated the diagnostic value of circulating small extracellular vesicle (sEV) microRNAs (miRNAs) in patients with IPNs that had been newly detected using LDCT scanning and were scheduled for surgery. Out of 459 recruited patients, 109 eligible patients with IPNs were enrolled in the training cohort (n = 47) and the test cohort (n = 62). An external cohort (n = 99) was used for validation. MiRNAs were extracted from plasma sEVs, and assessed using Small RNA sequencing. 490 lung adenocarcinoma samples and follow-up data were used to investigate the role of miRNAs in overall survival. RESULTS: A circulating sEV miRNA (CirsEV-miR) model was constructed from five differentially expressed miRNAs (DEMs), showing 0.920 AUC in the training cohort (n = 47), and further identified in the test cohort (n = 62) and in an external validation cohort (n = 99). Among five DEMs of the CirsEV-miR model, miR-101-3p and miR-150-5p were significantly associated with better overall survival (p = 0.0001 and p = 0.0069). The CirsEV-miR scores were calculated, which significantly correlated with IPNs diameters (p < 0.05), and were able to discriminate between benign and malignant PNs (diameter ≤ 1 cm). The expression patterns of sEV miRNAs in the benign, adenocarcinoma in situ/minimally invasive adenocarcinoma, and invasive adenocarcinoma subgroups were found to gradually change with the increase in aggressiveness for the first time. Among all DEMs of the three subgroups, five miRNAs (miR-30c-5p, miR-30e-5p, miR-500a-3p, miR-125a-5p, and miR-99a-5p) were also significantly associated with overall survival of lung adenocarcinoma patients. CONCLUSIONS: Our results indicate that the CirsEV-miR model could help distinguish between benign and malignant PNs, providing insights into the feasibility of circulating sEV miRNAs in diagnostic biomarker development. TRIAL REGISTRATION: Chinese Clinical Trials: ChiCTR1800019877. Registered 05 December 2018, https://www.chictr.org.cn/showproj.aspx?proj=31346 .

Randomized controlled trial of an alternative drainage strategy vs routine chest tube insertion for postoperative pain after thoracoscopic wedge resection.

BACKGROUND: Thoracoscopic surgery has greatly alleviated the postoperative pain of patients, but postsurgical acute and chronic pain still exists and needs to be addressed. Indwelling drainage tubes are one of the leading causes of postoperative pain after thoracic surgery. Therefore, the aim of this study was to explore the effects of alternative drainage on acute and chronic pain after video-assisted thoracoscopic surgery (VATS). METHODS: Ninety-two patients undergoing lung wedge resection were selected and randomly assigned to the conventional chest tube (CT) group and the 7-Fr central venous catheter (VC) group. Next, the numeric rating scale (NRS) and pain DETECT questionnaire were applied to evaluate the level and characteristics of postoperative pain. RESULTS: NRS scores of the VC group during hospitalization were significantly lower than those of the CT group 6 h after surgery, at postoperative day 1, at postoperative day 2, and at the moment of drainage tube removal. Moreover, the number of postoperative salvage analgesics (such as nonsteroidal anti-inflammatory drugs [(NSAIDs]) and postoperative hospitalization days were notably reduced in the VC group compared with the CT group. However, no significant difference was observed in terms of NRS pain scores between the two groups of patients during the follow-up for chronic pain at 3 months and 6 months. CONCLUSION: In conclusion, a drainage strategy using a 7-Fr central VC can effectively relieve perioperative pain in selected patients undergoing VATS wedge resection, and this may promote the rapid recovery of such patients after surgery. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03230019. Registered July 23, 2017.

Wait-and-See Treatment Strategy Could be Considered for Lung Adenocarcinoma with Special Pleural Dissemination Lesions, and Low Genomic Instability Correlates with Better Survival.

BACKGROUND: This study aimed to evaluate the feasibility of a wait-and-see strategy for non-small cell lung cancer (NSCLC) patients with special pleural dissemination lesions (r-pM1a and s-pM1a). Furthermore, the study characterized genomic alternations about disease progression. METHODS: For this study, 131 NSCLC patients with a diagnosis of pM1a were retrospectively selected. Survival differences were evaluated among patients treated with three different initial postoperative treatments: chemotherapy, targeted therapy, and wait-and-see strategy. Whole-exome sequencing (WES) was performed on primary and metastatic tumors of 10 patients with dramatic progression and 13 patients with gradual progression. RESULTS: The wait-and-see group showed better progression-free survival (PFS) than the chemotherapy group (p < 0.001) but PFS similar to that of targeted group (p = 0.984). This pattern persisted in epidermal growth factor receptor (EGFR)-positive patients. For patients with EGFR-negative/unknown status, PFS was longer in the wait-and-see group than in the two treatment groups. Furthermore, better overall survival (OS) was observed for the patients who received chemotherapy or targeted therapy after the wait-and-see strategy than for those who received chemotherapy or targeted therapy immediately. Lymph node status was an independent prognostic factor for PFS and OS. Finally, WES analysis showed that a high genomic instability index (GIS) and chromosome 18q loss were more common in metastatic tumors, and low GIS was significantly associated with better PFS (p = 0.016). CONCLUSIONS: The wait-and-see strategy could be considered for special pM1a patients without lymph nodes metastasis, and patients with a low GIS may be suitable for this strategy.

Germline variation networks in the PI3K/AKT pathway corresponding to familial high-incidence lung cancer pedigrees.

BACKGROUND: There were scarcely germline variants of familial lung cancer (LC) identified. We conducted an study with whole-exome sequencing of pedigrees with familial lung cancer to analyze the potential genetic susceptibility. METHODS: Probands with the highest hereditary background were identified by our large-scale epidemiological study and five ones were enrolled as a learning set. The germline SNPs (single-nucleotide polymorphisms) of other five similar probands, four healthy individuals in the formerly pedigrees and three patients with sporadic LC were used as a validation set, controlled by three healthy individuals without family history of any cancer. The network of mutated genes was generated using STRING-DB and visualized using Cytoscape. RESULTS: Specific and shared somatic mutations and germline SNPs were not the shared cause of familial lung cancer. However, individual germline SNPs showed distinct protein-protein interaction network patterns in probands versus healthy individuals and patients with sporadic lung cancer. SNP-containing genes were enriched in the PI3K/AKT pathway. These results were validated in the validation set. Furthermore, patients with familial lung cancer were distinguished by many germline variations in the PI3K/AKT pathway by a simple SVM classification method. It is worth emphasizing that one person with many germline variations in the PI3K/AKT pathway developed lung cancer during follow-up. CONCLUSIONS: The phenomenon that the enrichments of germline SNPs in the PI3K/AKT pathway might be a major predictor of familial susceptibility to lung cancer.

Electromagnetic navigational bronchoscopy-directed dye marking for locating pulmonary nodules.

BACKGROUND: Small peripheral pulmonary nodules, which are usually deep-seated with no visual markers on the pleural surface, are often difficult to locate during surgery. At present, CT-guided percutaneous techniques are used to locate pulmonary nodules, but this method has many limitations. Thus, we aimed to evaluate the accuracy and feasibility of electromagnetic navigational bronchoscopy (ENB) with pleural dye to locate small peripheral pulmonary nodules before video-associated thoracic surgery (VATS). METHODS: The ENB localisation procedure was performed under general anaesthesia in an operating room. Once the locatable guide wire, covered with a sheath, reached the ideal location, it was withdrawn and 0.2-1.0 mL of methylene blue/indocyanine green was injected through the guide sheath. Thereafter, 20-60 mL of air was instilled to disperse the dye to the pleura near the nodules. VATS was then performed immediately. RESULTS: Study subjects included 25 patients with 28 nodules. The mean largest diameter of the pulmonary nodules was 11.8 mm (range, 6.0-24.0 mm), and the mean distance from the nearest pleural surface was 13.4 mm (range, 2.5-34.9 mm). After the ENB-guided localisation procedure was completed, the dye was visualised in 23 nodules (82.1%) using VATS. The average duration of the ENB-guided pleural dye marking procedure was 12.6 min (range, 4-30 min). The resection margins were negative in all malignant nodules. Complications unrelated to the ENB-guided localisation procedure occurred in two patients, including one case of haemorrhage and one case of slow intraoperative heart rate. CONCLUSION: ENB can be used to safely and accurately locate small peripheral pulmonary nodules and guide surgical resection. TRIAL REGISTRATION NUMBER: ChiCTR1900021963.

Toward an Expert Level of Lung Cancer Detection and Classification Using a Deep Convolutional Neural Network.

BACKGROUND: Computed tomography (CT) is essential for pulmonary nodule detection in diagnosing lung cancer. As deep learning algorithms have recently been regarded as a promising technique in medical fields, we attempt to integrate a well-trained deep learning algorithm to detect and classify pulmonary nodules derived from clinical CT images. MATERIALS AND METHODS: Open-source data sets and multicenter data sets have been used in this study. A three-dimensional convolutional neural network (CNN) was designed to detect pulmonary nodules and classify them into malignant or benign diseases based on pathologically and laboratory proven results. RESULTS: The sensitivity and specificity of this well-trained model were found to be 84.4% (95% confidence interval [CI], 80.5%-88.3%) and 83.0% (95% CI, 79.5%-86.5%), respectively. Subgroup analysis of smaller nodules (<10 mm) have demonstrated remarkable sensitivity and specificity, similar to that of larger nodules (10-30 mm). Additional model validation was implemented by comparing manual assessments done by different ranks of doctors with those performed by three-dimensional CNN. The results show that the performance of the CNN model was superior to manual assessment. CONCLUSION: Under the companion diagnostics, the three-dimensional CNN with a deep learning algorithm may assist radiologists in the future by providing accurate and timely information for diagnosing pulmonary nodules in regular clinical practices. IMPLICATIONS FOR PRACTICE: The three-dimensional convolutional neural network described in this article demonstrated both high sensitivity and high specificity in classifying pulmonary nodules regardless of diameters as well as superiority compared with manual assessment. Although it still warrants further improvement and validation in larger screening cohorts, its clinical application could definitely facilitate and assist doctors in clinical practice.

Recursive partitioning analysis of patients with oligometastatic non-small cell lung cancer: a retrospective study.

BACKGROUND: Local consolidative treatment (LCT) is important for oligometastasis, defined as the restricted metastatic capacity of a tumor. This study aimed to determine the effects and prognostic heterogeneity of LCT in oligometastatic non-small cell lung cancer. METHODS: This retrospective study identified 436 eligible patients treated for oligometastatic disease at the Guangdong Provincial People's Hospital during 2009-2016. A Cox regression analysis was used to identify potential predictors of overall survival (OS). After splitting cases randomly into training and testing sets, risk stratification was performed using recursive partitioning analysis with a training dataset. The findings were confirmed using a validation dataset. The effects of LCT in different risk groups were evaluated using the Kaplan-Meier method. RESULTS: The T stage (p = 0.001), N stage (p = 0.008), number of metastatic sites (p = 0.031), and EGFR status (p = 0.043) were identified as significant predictors of OS. A recursive partitioning analysis was used to establish a prognostic risk model with the following four risk groups: Group I included never smokers with N0 disease (3-year OS: 55.6%, median survival time [MST]: 42.8 months), Group II included never smokers with N+ disease (3-year OS: 32.8%, MST: 26.5 months), Group III included smokers with T0-2 disease (3-year OS: 23.3%, MST: 19.4 months), and Group IV included smokers with T3/4 disease (3-year OS: 12.5%, MST: 11.1 months). Significant differences in OS according to LCT status were observed in all risk groups except Group IV (p = 0.45). CONCLUSIONS: Smokers with T3/4 oligometastatic non-small cell lung cancer may not benefit from LCT.

Gefitinib versus vinorelbine plus cisplatin as adjuvant treatment for stage II-IIIA (N1-N2) EGFR-mutant NSCLC (ADJUVANT/CTONG1104): a randomised, open-label, phase 3 study.

BACKGROUND: Cisplatin-based adjuvant chemotherapy is the standard of care for patients with resected stage II-IIIA non-small-cell lung cancer (NSCLC). RADIANT and SELECT trial data suggest patients with EGFR-mutant stage IB-IIIA resected NSCLC could benefit from adjuvant EGFR tyrosine kinase inhibitor treatment. We aimed to compare the efficacy of adjuvant gefitinib versus vinorelbine plus cisplatin in patients with completely resected EGFR-mutant stage II-IIIA (N1-N2) NSCLC. METHODS: We did a randomised, open-label, phase 3 trial at 27 centres in China. We enrolled patients aged 18-75 years with completely resected (R0), stage II-IIIA (N1-N2), EGFR-mutant (exon 19 deletion or exon 21 Leu858Arg) NSCLC. Patients were stratified by N stage and EGFR mutation status and randomised (1:1) by Pocock and Simon minimisation with a random element to either gefitinib (250 mg once daily) for 24 months or intravenous vinorelbine (25 mg/m2 on days 1 and 8) plus intravenous cisplatin (75 mg/m2 on day 1) every 3 weeks for four cycles. The primary endpoint was disease-free survival in the intention-to-treat population, which comprised all randomised patients; the safety population included all randomised patients who received at least one dose of study medication. Enrolment to the study is closed but survival follow-up is ongoing. The study is registered with ClinicalTrials.gov, number NCT01405079. FINDINGS: Between Sept 19, 2011, and April 24, 2014, 483 patients were screened and 222 patients were randomised, 111 to gefitinib and 111 to vinorelbine plus cisplatin. Median follow-up was 36·5 months (IQR 23·8-44·8). Median disease-free survival was significantly longer with gefitinib (28·7 months [95% CI 24·9-32·5]) than with vinorelbine plus cisplatin (18·0 months [13·6-22·3]; hazard ratio [HR] 0·60, 95% CI 0·42-0·87; p=0·0054). In the safety population, the most commonly reported grade 3 or worse adverse events in the gefitinib group (n=106) were raised alanine aminotransferase and asparate aminotransferase (two [2%] patients with each event vs none with vinorelbine plus cisplatin). In the vinorelbine plus cisplatin group (n=87), the most frequently reported grade 3 or worse adverse events were neutropenia (30 [34%] patients vs none with gefitinib), leucopenia (14 [16%] vs none), and vomiting (eight [9%] vs none). Serious adverse events were reported for seven (7%) patients who received gefitinib and 20 (23%) patients who received vinorelbine plus cisplatin. No interstitial lung disease was noted with gefitinib. No deaths were treatment related. INTERPRETATION: Adjuvant gefitinib led to significantly longer disease-free survival compared with that for vinorelbine plus cisplatin in patients with completely resected stage II-IIIA (N1-N2) EGFR-mutant NSCLC. Based on the superior disease-free survival, reduced toxicity, and improved quality of life, adjuvant gefitinib could be a potential treatment option compared with adjuvant chemotherapy in these patients. However, the duration of benefit with gefitinib after 24 months might be limited and overall survival data are not yet mature. FUNDING: Guangdong Provincial Key Laboratory of Lung Cancer Translational Medicine; National Health and Family Planning Commission of People's Republic of China; Guangzhou Science and Technology Bureau; AstraZeneca China.

Crizotinib in advanced non-small-cell lung cancer with concomitant ALK rearrangement and c-Met overexpression.

OBJECTIVE: Crizotinib can target against mesenchymal-epithelial transition (MET) and anaplastic lymphoma kinase (ALK), which has been considered as a multi-targeted tyrosine kinase inhibitor (TKI). The objective of this study was to explore the efficacy of crizotinib in advanced non-small-cell lung cancer (NSCLC) with concomitant ALK rearrangement and c-Met overexpression. METHODS: Totally, 4622 advanced NSCLC patients from two institutes (3762 patients at the Guangdong Lung Cancer Institute from January 2011 to December 2016 and 860 cases at the Perking Cancer Hospital from January 2015 to December 2016) were screened for ALK rearrangement with any method of IHC, RACE-coupled PCR or FISH. C-Met expression was performed by IHC in ALK-rearranged patients, and more than 50% of cells with high staining were defined as c-Met overexpression. The efficacy of crizotinib was explored in the ALK-rearranged patients with or without c-Met overexpression. RESULTS: Sixteen patients were identified with c-Met overexpression in 160 ALK-rearranged cases, with the incidence of 10.0% (16/160). A total of 116 ALK-rearranged patients received the treatment of crizotinib. Objective response rate (ORR) was 86.7% (13/15) in ALK-rearranged patients with c-Met overexpression and 59.4% (60/101)in those without c-Met overexpression, P = 0.041. Median PFS showed a trend of superiority in c-Met overexpression group (15.2 versus 11.0 months, P = 0.263). Median overall survival (OS) showed a significant difference for ALK-rearranged patients with c-Met overexpression group of 33.5 months with the hazard ratio (HR) of 3.2. CONCLUSIONS: C-Met overexpression co-exists with ALK rearrangement in a small population of advanced NSCLC. There may be a trend of favorable efficacy of crizotinib in such co-altered patients.

Mixed Responses to Systemic Therapy Revealed Potential Genetic Heterogeneity and Poor Survival in Patients with Non-Small Cell Lung Cancer.

BACKGROUND: A subset of patients with non-small cell lung cancer (NSCLC) fosters mixed responses (MRs) to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors (TKIs) or chemotherapy. However, little is known about the clinical and molecular features or the prognostic significance and potential mechanisms. METHODS: The records of 246 consecutive patients with NSCLC receiving single-line chemotherapy or TKI treatment and who were assessed by baseline and interim positron emission tomography/computed tomography scans were collected retrospectively. The clinicopathological correlations of the MR were analyzed, and a multivariate analysis was performed to explore the prognostic significance of MR. RESULTS: The overall incidence of MR to systemic therapy was 21.5% (53/246) and predominated in patients with stage IIIB-IV, EGFR mutations and those who received TKI therapy (p < .05). Subgroup analyses based on MR classification (efficacious versus inefficacious) showed significant differences in subsequent treatment between the two groups (p < .001) and preferable progression-free survival (PFS) and overall survival (OS) in the efficacious MR group. Multivariate analyses demonstrated that the presence of MR was an independent unfavorable prognostic factor for PFS (hazard ratio [HR], 1.474; 95% confidence interval [CI], 1.018-2.134; p = .040) and OS (HR, 1.849; 95% CI, 1.190-2.871; p = .006) in patients with NSCLC. Induced by former systemic therapy, there were more T790M (18%), concomitant EGFR mutations (15%), and changes to EGFR wild type (19%) in the MR group among patients with EGFR mutations, which indicated higher incidence of genetic heterogeneity. CONCLUSION: MR was not a rare event in patients with NSCLC and tended to occur in those with advanced lung adenocarcinoma treated with a TKI. MR may result from genetic heterogeneity and is an unfavorable prognostic factor for survival. Further studies are imperative to explore subsequent treatment strategies. The Oncologist 2017;22:61-69Implications for Practice: Tumor heterogeneity tends to produce mixed responses (MR) to systemic therapy, including TKI and chemotherapy; however, the clinical significance and potential mechanisms are not fully understood, and the subsequent treatment after MR is also a clinical concern. The present study systemically assessed patients by PET/CT and differentiated MR and therapies. The study identified a relatively high incidence of MR in patients with advanced NSCLC, particularly those treated with targeted therapies. An MR may be an unfavorable prognostic factor and originate from genetic heterogeneity. Further studies are imperative to explore subsequent treatment strategies.