Different dissecting orders of the pulmonary bronchus and vessels during right upper lobectomy are associated with surgical feasibility and postoperative recovery for lung cancer patients.

BACKGROUND: Right upper lobectomy (RUL) for lung cancer with different dissecting orders involves the most variable anatomical structures, but no studies have analyzed its effects on postoperative recovery. This study compared the conventional surgical approach, VAB (dissecting pulmonary vessels first, followed by the bronchus), and the alternative surgical approach, aBVA (dissecting the posterior ascending arterial branch first, followed by the bronchus and vessels) on improving surgical feasibility and postoperative recovery for lung cancer patients. METHODS: According to the surgical approach, consecutive lung cancer patients undergoing RUL were grouped into aBVA and VAB cohorts. Their clinical, pathologic, and perioperative characteristics were collected to compare perioperative outcomes. RESULTS: Three hundred one patients were selected (109 in the aBVA cohort and 192 in the VAB cohort). The mean operation time was shorter in the aBVA cohort than in the VAB cohort (164 vs. 221 min, P < 0.001), and less blood loss occurred in the aBVA cohort (92 vs. 141 mL, P < 0.001). The rate of conversion to thoracotomy was lower in the aBVA cohort than in the VAB cohort (0% vs. 11.5%, P < 0.001). The mean duration of postoperative chest drainage was shorter in the aBVA cohort than in the VAB cohort (3.6 vs. 4.5 days, P = 0.001). The rates of postoperative complications were comparable (P = 0.629). The median overall survival was not arrived in both cohorts (P > 0.05). The median disease-free survival was comparable for all patients in the two cohorts (not arrived vs. 41.97 months) and for patients with disease recurrences (13.25 vs. 9.44 months) (both P > 0.05). The recurrence models in two cohorts were also comparable for patients with local recurrences (6.4% vs. 7.8%), distant metastases (10.1% vs. 8.3%), and both (1.8% vs. 1.6%) (all P > 0.05). CONCLUSIONS: Dissecting the right upper bronchus before turning over the lobe repeatedly and dissecting veins via the aBVA approach during RUL would promote surgical feasibility and achieve comparable postoperative recovery for lung cancer 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.

Potential Predictive Value of TP53 and KRAS Mutation Status for Response to PD-1 Blockade Immunotherapy in Lung Adenocarcinoma.

Purpose: Although clinical studies have shown promise for targeting programmed cell death protein-1 (PD-1) and ligand (PD-L1) signaling in non-small cell lung cancer (NSCLC), the factors that predict which subtype patients will be responsive to checkpoint blockade are not fully understood.Experimental Design: We performed an integrated analysis on the multiple-dimensional data types including genomic, transcriptomic, proteomic, and clinical data from cohorts of lung adenocarcinoma public (discovery set) and internal (validation set) database and immunotherapeutic patients. Gene set enrichment analysis (GSEA) was used to determine potentially relevant gene expression signatures between specific subgroups.Results: We observed that TP53 mutation significantly increased expression of immune checkpoints and activated T-effector and interferon-γ signature. More importantly, the TP53/KRAS comutated subgroup manifested exclusive increased expression of PD-L1 and a highest proportion of PD-L1+/CD8A+ Meanwhile, TP53- or KRAS-mutated tumors showed prominently increased mutation burden and specifically enriched in the transversion-high (TH) cohort. Further analysis focused on the potential molecular mechanism revealed that TP53 or KRAS mutation altered a group of genes involved in cell-cycle regulating, DNA replication and damage repair. Finally, immunotherapeutic analysis from public clinical trial and prospective observation in our center were further confirmed that TP53 or KRAS mutation patients, especially those with co-occurring TP53/KRAS mutations, showed remarkable clinical benefit to PD-1 inhibitors.Conclusions: This work provides evidence that TP53 and KRAS mutation in lung adenocarcinoma may be served as a pair of potential predictive factors in guiding anti-PD-1/PD-L1 immunotherapy. Clin Cancer Res; 23(12); 3012-24. ©2016 AACR.

Intraoperative frozen sections of the regional lymph nodes contribute to surgical decision-making in non-small cell lung cancer patients.

BACKGROUND: Individualization of pulmonary parenchymal resection and lymphadenectomy in lung cancer patients will likely become more important as surgical innovation. This study explored the utility of intraoperative pathological frozen sections of regional lymph nodes in non-small cell lung cancer (NSCLC) patients. METHODS: Patients with NSCLC underwent intraoperative sampling of N1 station lymph nodes depending on the location of the tumor, any other suspicious lymph nodes were also biopsied. The contribution of frozen-section analysis to surgical decision-making was evaluated. RESULTS: Of 74 lung cancer patients who underwent intraoperative frozen section analysis of lymph nodes, the positive rate was 18/74 (24.3%). The extents of agreement between preoperative N staging (cN) and intraoperative N staging (sN), cN staging and postoperative N staging (pN), and sN staging and pN staging were 62.2% (46/74), 63.5% (47/74), and 71.6% (53/74), respectively. When frozen section was combined with evaluation of pulmonary function and intrathoracic adhesions, surgical strategies were modified during operations in 18 cases (5 sN-positive, 13 sN-negative). Of these patients, five underwent extensive pulmonary parenchymal resection, and four had conservative lung parenchymal resection. In nine patients, the extent of lymph node dissection (LND) was changed. CONCLUSIONS: Intraoperative frozen section of regional lymph nodes led to 24.3% operative strategies modification in lung cancer. Frozen section analysis may make an important contribution to surgical decision-making in terms of pulmonary parenchymal resection and LND.

Right upper lobectomy performed as dividing posterior ascending artery-bronchus-pulmonary vessels is alternative to primary indolent scar carcinomas.

We describe a case of pulmonary indolent malignancy requiring a strategic surgery and introduce an alternative technique of right upper lobectomy via video-assisted thoracic surgery (VATS) for primary lung cancer patients. A 42-year-old male non-smoker was referred to the hospital following the detection of an opacity with a cystic airspace in the right upper lobe during a routine physical examination. During a regular follow-up over 3.5 years, the solid component enlarged and the cystic wall thickened. Based on a suspicion of indolent scar carcinoma, a right upper lobectomy was performed using VATS. The preoperative diagnosis was clinical T1bN0M0, stage Ia primary lung cancer. Our surgical procedure, posterior single-direction aBVA, consists of dividing the posterior ascending artery branch and then the right upper bronchus, followed by the right upper pulmonary vessels. By efficiently reducing the operation time and blood loss, our method is potentially superior to conventional right upper lobectomy.

Rare discrepancies in a driver gene alteration within histologically heterogeneous primary lung cancers.

OBJECTIVES: Most lung adenocarcinomas consist of mixtures of histological subtypes harboring different frequencies of driver gene mutations. However, little is known about intratumoral heterogeneity(ITH) within histologically heterogeneous primary lung cancers. Investigating key driver genes in respective morphological pattern is crucial to personalized treatment. METHODS: Morphologically different areas within the same surgically resected adenocarcinomas were extracted from tissues to analyze gene status in each growth pattern. Driver genes, epidermal growth factor receptor (EGFR), KRAS and EML4-ALK, were assessed by assays with different sensitivities. RESULTS: Seventy-nine consecutive eligible patients harboring a driver gene (EGFR=65; KRAS=10; EML4-ALK=4) were enrolled. For EGFR mutations, ITH occurred in 13.3% (8/60) by direct sequencing (DS) and 1.7% (1/60) by amplification refractory mutation system (ARMS) (P=0.016) among adenocarcinomas, but consistent within five adeno-squamous cell carcinomas by both methods. ITH among KRAS mutations were detected in 20% (2/10) by DS, whereas consistent (10/10) by high resolution melting. No discrepancies in EML4-ALK rearrangements existed according to fluorescence in situ hybridization. CONCLUSION: Rare ITHs of EGFR/KRAS/EML4-ALK alterations within histologically heterogeneous primary lung adenocarcinomas existed by methods with higher sensitivity. Discrepancies might be due to abundance of mutant tumor cells and detection assays.

Clinical trials in lung cancer surgery and research cooperation.

BACKGROUND: With China having an increasingly huge burden of lung cancers, the number of Chinese studies was the second largest all over the world. METHODS: We used the advanced search option available on the ClinicalTrials.gov to review clinical trials regarding surgical issues. In the drop down menus, we chose "all studies" for recruitment status and "interventional" for study type and all trials reported until Aug, 2013 on the website were included. RESULTS: Clinical trials on lung cancer surgeries (658 records) mainly aim at surgical procedures and (neo)adjuvant clinical studies, among which phase III trials account for 15.5%. Only 34.9% (230 records) trials were completed, and 43 studies presented their results on ClinicalTrials.gov. The median time to completion (MTC) of phase III surgical procedure trials is 9.4 years. The MTCs of phase III neo-adjuvant and adjuvant trials have not been reached, but definitely are longer than 10 years. In comparison, the MTC of phase III trials in the first-line treatment are only 4.3 years. COMMENTS: We summarized the characteristics of these trials using real-world case examples. Our analyses reveal that it is critically needed for regulatory authorities, clinical trial sponsors, collaborative research groups, and academic institutions to work together to build up the infrastructure and research cooperation for clinical trials with a surgical component. In 2007, a national collaborative clinical research group, Chinese Thoracic Oncology Group (CTONG), was established. CTONG is a network of researchers, physicians and health-care professionals in public institutions throughout China and currently has a growing membership of 25 hospitals. A CTONG-sponsored trial (CTONG1104) is discussed to illustrate our experience in surgical clinical trials. In summary, it is imperative for investigators to collaborate in cooperative clinical trials in order to expedite applications of therapies from clinical researches to cancer treatment. Since cancer treatment is multidisciplinary, current surgical trials should have multiple treatment combinations while retaining a surgical focus, and be carried out systematically with the cooperation of extensive monitoring and coordinating systems.