Afatinib treatment in a large real-world cohort of nonsmall cell lung cancer patients with common and uncommon epidermal growth factor receptor mutation.

The epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) afatinib improves survival in nonsmall cell lung cancer (NSCLC) patients with EGFR mutation. We analysed the outcome between EGFR mutation subtypes in a large afatinib-treated cohort in which 516 EGFR-mutated NSCLC patients receiving afatinib as front-line treatment. EGFR uncommon mutations include exon 20 insertion, de novo T790M of high or low allele frequency (dT790MHAF /dT790MLAF ), non-T790M compound mutation and others, where EGFR exon 20 insertion and dT790MHAF were defined as type-I and the rest as type-II uncommon mutation. Four hundred and sixty-one (89.3%) and 55 (10.7%) patients were common and uncommon mutation, respectively. Exon 20 insertion and dT790MHAF patients demonstrated a significantly shortened progression-free survival (PFS) (2.6 and 4.1 months) compared to EGFR common mutation, dT790MLAF and other uncommon mutation patients (15.1, 27.0 and 18.4 months; P = 3 × 10-8 ). Type-I uncommon mutation was an independent predictor of PFS (HR 4.46 [95% CI, 2.60-7.64]; P < .001) and OS (HR 2.56 [95% CI, 1.37-4.75]; P = .003). EGFR L858R patients demonstrated a significantly higher CNS progression (cause-specific HR, 3.16; 95% CI 1.24-8.08; P = .016), and type-I uncommon mutation patients exhibited a significantly higher systemic progression (cause-specific HR, 4.95; 95% CI 2.30-10.60; P = 4.3 × 10-5 ). Tendencies of higher CNS and lower systemic progression were observed in type-II uncommon mutation patients. A PFS ≥ 12 months (OR 2.38 [95% CI, 1.18-4.89]; P = .016) and uncommon EGFR mutation (OR 0.08 [95% CI, 0.01-0.48]; P = .021) were independent predictors of secondary T790M. Afatinib-treated NSCLC patients presented an EGFR genotype-specific pattern of disease progression and outcome.

A Single-Institute Experience with C-ros Oncogene 1 Translocation in Non-Small Cell Lung Cancers in Taiwan.

(1) Background: The C-ros oncogene 1 (ROS1) gene translocation is an important biomarker for selecting patients for crizotinib-targeted therapy. The aim of this study was to understand the incidence, diagnostic algorithm, clinical course and objective response to crizotinib in ROS1 translocated lung non-small cell lung cancers (NSCLCs) in Taiwan. (2) Methods: First, we retrospectively studied the ROS1 status in 100 NSCLC samples using break-apart fluorescent in situ hybridization (FISH) and immunohistochemical (IHC) staining to establish a diagnostic algorithm. Then, we performed routine ROS1 IHC tests in 479 NSCLCs, as crizotinib was available from 2018 in Taiwan. We analyzed the objective response rate and the survival impact of crizotinib. (3) Results: Four ROS1 translocations were clustered in epidermal growth factor receptor (EGFR) wild-type adenocarcinomas but not in cases with EGFR mutations. Strong ROS1 expression was positively correlated with ROS1 translocation (p < 0.001). NSCLCs with ROS1 translocation had a poor prognosis compared to those without ROS1 translocation (p = 0.004) in the pre-crizotinib stage. Twenty NSCLCs were detected with ROS1 translocation in 479 wild-type EGFR specimens from 2018. Therefore, the incidence of ROS1 translocation is approximately 4.18% in EGFR wild-type NSCLCs. In these 20 ROS1 translocation cases, 19 patients received crizotinib treatment, with an objective response rate (ORR) of 78.95% (confidence interval = 69.34% to 88.56%), including 1 complete response, 14 partial responses, 3 stable cases and 1 progressive case. Overall survival and progression-free survival were better in the 19 ROS1-translocated NSCLCs of the prospective group with crizotinib treatment than the four ROS1-translocated NSCLCs of the retrospective group without crizotinib treatment. (4) Conclusions: ROS1-translocated NSCLCs had a poor prognosis and could have a beneficial outcome with crizotinib.

A retrospective study of alectinib versus ceritinib in patients with advanced non-small-cell lung cancer of anaplastic lymphoma kinase fusion in whom crizotinib treatment failed.

BACKGROUND: Crizotinib is the approved treatment for advanced non-small cell lung cancers (NSCLCs) of anaplastic lymphoma kinase (ALK) fusion. Failure of crizotinib treatment frequently involves drug intolerance or resistance. Comparison of using second-generation ALK inhibitors in this setting remains lacking. METHODS: Sixty-five ALK-positive advanced NSCLC patients receiving second-generation ALK inhibitors following treatment failure of crizotinib were retrospectively analyzed for the therapeutic efficacy. RESULTS: Forty-three (66.2%) and 22 (33.8%) patients received alectinib and ceritinib, respectively. Comparing alectinib to ceritinib treatment: the 12-month progression-free survival (PFS) rate (61.0% [95% confidence interval, 47.1 to 78.9%] vs. 54.5% [95% CI, 37.3 to 79.9%]); the hazard ratio (HR) for disease progression or death, 0.61 (95% CI, 0.31-1.17; p = 0.135). Multivariate Cox regression showed ECOG PS (0-1 vs. 2-3 HR 0.09 [95% CI, 0.02-0.33]; p < 0.001) and cause of crizotinib treatment failure (resistance vs. intolerance HR 2.75 [95% CI, 1.26-5.99]; p = 0.011) were the independent predictors for the PFS of second-generation ALK inhibitors. Treatment of alectinib, compared to ceritinib, was associated with a lower incidence of CNS progression (cause-specific HR, 0.10; 95% CI 0.01-0.78; p = 0.029) and a higher efficacy in patients whose cause of crizotinib treatment failure was intolerance (HR 0.29 [95% CI, 0.08-1.06]; p = 0.050). The most commonly noted adverse events were elevated AST/ALT in 10 (23.3%) patients treated with alectinib and diarrhea in 8 (36.4%) patients treated with ceritinib. CONCLUSION: Second-generation ALK inhibitors in crizotinib-treated patients showed a satifactory efficacy. Alectinib treatment demonstrated a CNS protection activity and a higher PFS in selected patients failing crizotinib treatment.

Trajectory of smoking behaviour during the first 6 months after diagnosis of lung cancer: A study from Taiwan.

AIMS: To identify different classes of change pattern/ trajectory of tobacco smoking behaviour after diagnosis of lung cancer using multi-wave data and to explore factors associated with the class membership. DESIGN: This is a multi-wave observational study. METHODS: Smoking behaviour data were collected at diagnosis and then every month for 6 months from 133 newly diagnosed people with lung cancer who had recently quit smoking or continued to smoke at diagnosis. These patients were recruited from three medical centres and data were collected from May 2014 to January 2017. Smoking behaviour was assessed based on patients' self-reports on whether they smoked during the last month (yes/no) for a total of seven times. Mixture latent Markov model and logistic regression were used to analyse data. RESULTS: Two latent classes of smoking trajectory were identified among recent quitters or current smokers of people with lung cancer, namely "perseverance for abstinence" and "indecisive for abstinence." Patients who were younger age (OR = 0.95, p = 0.026), exposure to second-hand smoke (OR = 3.35, p = 0.012) and lower self-efficacy for not smoking (OR = 0.96, p = 0.011) were more likely to belong to the class of "indecisive for abstinence." CONCLUSIONS: Heterogeneous classes of smoking trajectory existed in newly diagnosed people with lung cancer. The risk factors associated with a less favourable smoking trajectory can be incorporated into tailored smoking-cessation programs for patients newly diagnosed with lung cancer. IMPACT: The dynamic trajectory of smoking behaviour had not been adequately explored among newly diagnosed people with lung cancer. Two classes of smoking trajectory and the predictors associated with the class membership were identified. These findings suggest that the diagnosis of cancer is a teachable moment for smoking cessation. Patients with younger age, lower self-efficacy of not smoking and exposure to second-hand smoke at home need special attention.

Prognostic impact of combining whole-body PET/CT and brain PET/MR in patients with lung adenocarcinoma and brain metastases.

PURPOSE: The role of brain FDG-PET in patients with lung cancer and brain metastases remains unclear. Here, we sought to determine the prognostic significance of whole-body PET/CT plus brain PET/MR in predicting the time to neurological progression (nTTP) and overall survival (OS) in this patient group. METHODS: Of 802 patients with non-small cell lung cancer who underwent primary staging by a single-day protocol of whole-body PET/CT plus brain PET/MR, 72 cases with adenocarcinoma and brain metastases were enrolled for a prognostic analysis of OS. On the basis of the available follow-up brain status, only 52 patients were eligible for prognostic analysis of nTTP. Metastatic brain tumors were identified on post-contrast MR imaging, and the tumor-to-brain ratio (TBR) was measured on PET images. RESULTS: Multivariate analysis revealed that FDG-PET findings and eligibility for initial treatment with targeted therapy were significant independent predictors of nTTP and OS. A new index, termed the molecular imaging prognostic (MIP) score, was proposed to define three disease classes. MIP scores were significant predictors of both nTTP and OS (P < 0.001). Pre-existing prognostic indices such as Lung-molGPA scores were significant predictors of OS but did not predict nTTP. CONCLUSIONS: When staging is performed with whole-body PET/CT plus brain PET/MR, our new prognostic index may be helpful to stratify the outcomes of patients with lung adenocarcinoma and brain metastases. The superior prognostic power of this index for nTTP might be used to select appropriate patients for intracranial control and thereby achieve better quality of life.

NF-κB-driven suppression of FOXO3a contributes to EGFR mutation-independent gefitinib resistance.

Therapy with epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs, such as gefitinib or erlotinib) significantly prolongs survival time for patients with tumors harboring an activated mutation on EGFR; however, up to 40% of lung cancer patients exhibit acquired resistance to EGFR-TKIs with an unknown mechanism. FOXO3a, a transcription factor of the forkhead family, triggers apoptosis, but the mechanistic details involved in EGFR-TKI resistance and cancer stemness remain largely unclear. Here, we observed that a high level of FOXO3a was correlated with EGFR mutation-independent EGFR-TKI sensitivity, the suppression of cancer stemness, and better progression-free survival in lung cancer patients. The suppression of FOXO3a obviously increased gefitinib resistance and enhanced the stem-like properties of lung cancer cells; consistent overexpression of FOXO3a in gefitinib-resistant lung cancer cells reduced these effects. Moreover, we identified that miR-155 targeted the 3'UTR of FOXO3a and was transcriptionally regulated by NF-κB, leading to repressed FOXO3a expression and increased gefitinib resistance, as well as enhanced cancer stemness of lung cancer in vitro and in vivo. Our findings indicate that FOXO3a is a significant factor in EGFR mutation-independent gefitinib resistance and the stemness of lung cancer, and suggest that targeting the NF-κB/miR-155/FOXO3a pathway has potential therapeutic value in lung cancer with the acquisition of resistance to EGFR-TKIs.

Subxiphoid video-assisted thoracoscopic surgery versus standard video-assisted thoracoscopic surgery for anatomic pulmonary lobectomy.

BACKGROUND: A subxiphoid surgical approach to thoracic cavity operations has potential advantages such as preventing injuries to intercostal nerves and vessels due to the bypass of the intercostal space during thoracic surgery. The aim of this study was to compare the feasibility and efficacy of the subxiphoid and standard transthoracic approaches for anatomic pulmonary lobectomy in a canine model. METHODS: Nineteen dogs were assigned for pulmonary lobectomy using either the subxiphoid (n = 10) or standard transthoracic approaches (n = 9). Each group underwent thoracic exploration and anatomic pulmonary lobectomy. Subxiphoid thoracoscopy was performed with a flexible bronchoscope via a 3-cm incision over the xiphoid process. In the conventional thoracoscopy group, approach to the thoracic cavity was obtained through a 3-cm incision over the seventh intercostal space. Physiological parameters (respiratory rate and body temperature) and blood samples (white blood cell counts and arterial blood gases) were collected during the preoperative and postoperative periods. Surgical outcomes data (operating time, operative complications, and body weight gain) were also collected and compared between the groups. The animals were sacrificed 14 d after surgery for necropsy evaluations. RESULTS: Anatomic pulmonary lobectomy was successfully performed without intraoperative and postoperative complications in all animals. There were no significant differences in the mean operating times or weight gain after surgery between the subxiphoid and the standard transthoracic approach groups. In terms of physiological and pulmonary parameters, there were no observed differences between the two surgical groups for respiratory rate, body temperature, white blood cell counts, and arterial blood gases at any time during the study. Necropsy confirmed the success of lobectomy without complication in all studied animals. CONCLUSIONS: This study demonstrated that the subxiphoid approach was comparable with the standard transthoracic approach for anatomic pulmonary lobectomy, in terms of feasibility and effectiveness.

Transumbilical Thoracoscopy Versus Conventional Thoracoscopy for Lung Wedge Resection: Safety and Efficacy in a Live Canine Model.

PURPOSE: Transumbilical single-port surgery has been associated with less postoperative pain and offers better cosmetic outcomes than conventional 3-port laparoscopic surgery. This study compares the safety and efficacy of transumbilical thoracoscopy and conventional thoracoscopy for lung wedge resection. METHODS: The animals (n = 16) were randomly assigned to the transumbilical thoracoscopic approach group (n = 8) or conventional thoracoscopic approach group (n = 8). Transumbilical lung resection was performed via an umbilical incision and a diaphragmatic incision. In the conventional thoracoscopic group, lung resection was completed through a thoracic incision. For both procedures, we compared the surgical outcomes, for example, operating time and operative complications; physiologic parameters, for example, respiratory rate and body temperature; inflammatory parameters, for example, white blood cell count; and pulmonary parameters, for example, arterial blood gas levels. The animals were euthanized 2 weeks after the surgery for gross and histologic evaluations. RESULTS: The lung wedge resection was successfully performed in all animals. There was no significant difference in the mean operating times or complications between the transumbilical and the conventional thoracoscopic approach groups. With regard to the physiologic impact of the surgeries, the transumbilical approach was associated with significant elevations in body temperature on postoperative day 1, when compared with the standard thoracoscopic approach. CONCLUSIONS: This study suggests that both approaches for performing lung wedge resection were comparable in efficacy and postoperative complications.

Feasibility of transumbilical anatomic pulmonary lobectomy in a canine model.

PURPOSE: Transthoracic thoracoscopic lobectomy is the preferred method of surgical treatment for early lung cancer. Current methods require a transthoracic approach and are associated with chronic postoperative pain in up to 25% of patients. Single-port transumbilical uniport surgery may offer advantages over multiport surgery with less postoperative pain and better cosmetic results. The aim of this study was to evaluate the feasibility of a transumbilical anatomic lobectomy of the lung (TUAL) in a canine model. METHODS: TUAL was performed in 12 beagle dogs using a 3-cm umbilical incision combined with a 2.5-cm diaphragmatic incision. Variables evaluated for surgical outcomes were operating time, operative complications, body rectal temperature, respiratory rate, white blood cell count, and arterial blood gases. RESULTS: TUAL was successfully completed in ten animals. There were six bleeding complications related to surgery. In four animals, an avulsion of pulmonary vessel causes intraoperative bleeding, requiring simultaneous pulmonary artery and bronchus resections. In one animal, slipping of endoclip after vessel clipping caused perioperative bleeding. The other animal encountered bleeding complication during dissection of inferior pulmonary vein. Both animals required conventional thoracotomy to complete the surgery. CONCLUSIONS: TUAL in the canine model is feasible but associated with significant morbidity. With further development and refinement of instruments, comparative studies between the novel transumbilical lobectomy and the current video-assisted transthoracic lobectomy will clarify the role of transumbilical lobectomy in thoracic surgery.

Overall response to first-line tyrosine kinase inhibitor and second-line chemotherapy is predictive of survival outcome in epidermal growth factor receptor-mutated adenocarcinoma.

BACKGROUND: First-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are effective for the treatment of lung adenocarcinoma with an EGFR-sensitizing mutation, but resistance is inevitable. Chemotherapy is widely used in the second-line setting. The outcome following this treatment scheme has not been thoroughly evaluated. METHODS: From 2007 to 2011, consecutive patients with mutated EGFR receiving first-line TKI and second-line chemotherapy were retrospectively reviewed. The overall response was categorized into double responder, single responder and double nonresponder. RESULTS: Following this treatment scheme, baseline Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (HR 0.60; 95% CI 0.37-0.98; p = 0.041) and double responder (HR 0.24; 95% CI 0.07-0.78; p = 0.018) were independent predictors of overall survival. Absence of pleural metastasis independently predicted the response to first-line TKI (OR 2.60; 95% CI 1.13-5.99; p = 0.025). In TKI responders, ECOG performance status 0-1 before chemotherapy (OR 4.95; 95% CI 1.15-21.28; p = 0.006), an exon 19 deletion (OR 4.74; 95% CI 1.30-17.21; p = 0.018) and progression-free survival (PFS) on first-line TKI (OR 1.02; 95% CI 1.01-1.09; p = 0.049) independently predicted the response to second-line chemotherapy. A moderate linear relationship (Pearson's r = 0.441; p = 0.001) existed between the PFS of this treatment scheme in TKI responders. CONCLUSION: The status of double responder to first-line TKI and second-line chemotherapy was predictive of improved survival in EGFR-mutated adenocarcinoma.

Algorithmic approach by endobronchial ultrasound-guided transbronchial needle aspiration for isolated intrathoracic lymphadenopathy: a study in a tuberculosis-endemic country.

BACKGROUND/PURPOSE: Isolated intrathoracic lymphadenopathy (IT-LAP) is clinically challenging because of the difficult anatomic location and wide range of associated diseases, including tuberculosis (TB). Although sampling via endobronchial ultrasound-guided transbronchial needle aspiration (EBUS-TBNA) for histopathology is a major development, there is still room for improvement. This study aimed to investigate an algorithmic approach driven by EBUS-TBNA and conventional bronchoscopy to streamline the management of IT-LAP. METHODS: Eighty-three prospectively enrolled patients with IT-LAP were subjected to an EBUS-TBNA diagnostic panel test (histopathology, cytology, and microbiology) and underwent conventional bronchoscopy for bronchoalveolar lavage. The results were structured into an algorithmic approach to direct patient treatment, workup, or follow-up. RESULTS: The diagnostic yields of EBUS-TBNA based on histopathology were similar for each disease entity: 77.8% for malignancy, 70.0% for TB, 75.0% for sarcoidosis, 80.0% for anthracosis, and 70.0% for lymphoid hyperplasia (p = 0.96). The incidence of malignancy was 10.8% for total IT-LAP patients, and 12.0% and 33.7% for patients with TB and sarcoidosis, respectively. Thirty-five (42.2%) patients were symptomatic. The leading diagnosis was sarcoidosis (60%), followed by TB (20%), malignancy (11.4%), lymphoid hyperplasia (5.7%), and anthracosis (2.9%). By logistic regression analysis, granulomatous disease (odds ratio: 13.45; 95% confidence interval: 4.45-40.67, p < 0.001) was an independent predictor of symptoms. Seven (8.4%) and three (3.6%) IT-LAP patients diagnosed active TB and suggestive of TB with household contact history, respectively, were all placed on anti-TB treatment. CONCLUSION: The algorithmic approach streamlines patient management. It enables early detection of malignancy, correctly places nonmalignant patients on an appropriate treatment regimen, and particularly identifies candidates at high risk of TB reactivation for anti-TB chemoprophylaxis.

Chronic obstructive pulmonary disease in stage I non-small cell lung cancer that underwent anatomic resection: the role of a recurrence promoter.

BACKGROUND: Despite the use of anatomic resection, the post-surgical recurrence rate remains high in early-stage non-small cell lung cancer (NSCLC). Chronic inflammation plays a role in the mechanism that promotes tumor initiation. This study aimed to investigate the association between recurrence outcome and chronic inflammation-related co-morbidities in early-stage resected NSCLC. METHODS: A review of medical records for recurrence outcome and co-morbidities, in terms of chronic obstructive pulmonary disease (COPD), DM, asthma and cardiovascular diseases, was performed with 181 patients with stage I NSCLC that underwent anatomic resection. RESULTS: Subjects with T descriptors as T2a disease (49.5 vs. 28.0%, p < 0.05) and the presence of COPD (42.4 vs. 20.7%, p < 0.01) had a higher risk of tumor recurrence. Univariate analysis for recurrence-free survival showed T descriptor as T2a (21.5 months vs. NR, p < 0.05) and the presence of COPD (20.5 months vs. NR, p < 0.01) as significant factors predicting reduced survival. The presence of COPD (HR: 1.98; 95% CI, 1.29-.02, p < 0.01) and T descriptor as T2a (HR: 2.01; 95% CI, 1.04-3.91, p < 0.05) remain independent predictors of reduced recurrence-free survival in the Cox regression model. Patients with COPD were at higher risk of brain recurrence (OR: 7.88; 95% CI, 1.50-41.3, p < 0.01). In contrast, patients without COPD showed a tendency toward recurrence in bone and liver (OR: 4.13; 95% CI, 1.08-15.8, p = 0.05). CONCLUSION: Subjects with COPD and T2a disease had a higher risk of recurrence. The role of COPD as a recurrence promoter merits further prospective investigation.

Feasibility and safety of endoscopic transumbilical thoracic surgical lung biopsy: a survival study in a canine model.

BACKGROUND: Transumbilical laparoscopy allows the patient to undergo various surgical procedures associated with abdominal disease. The aim of this study was to evaluate the feasibility and safety of transumbilical thoracic exploration and surgical lung biopsy in a canine survival model. METHODS: We performed the procedure in 12 dogs weighting 7.1-9.1 kg. The thoracic cavity was accessed using a metal tube inserted via umbilical and diaphragmatic incisions. After transumbilical thoracoscopy, we resected the predetermined lung lobe with an electrocautery loop. We carried out daily clinical examinations, including determination of respiratory rate and rectal temperature. Laboratory parameters (white blood cell count) and inflammatory parameters, including serum interleukin-6 and C-reactive protein, were measured before surgery and at postoperative days 1, 3, 7, and 14. We performed necropsies 2 wk after surgery. RESULTS: We successfully performed corrected surgical lung biopsies for the predetermined lung lobe in all animals, with a median time of 43.5 min (range, 32-65 min). We observed two perioperative complications: One dog had minor postoperative air leakage and one had hemodynamic collapse because of inadequate ventilation. These animals recovered well without signs of perioperative infection. Necropsies at 2 wk after surgery showed no evidence of mediastinitis or peritonitis. CONCLUSIONS: Exposure of the thoracic cavity and surgical lung biopsy via a transumbilical incision is feasible in this canine model of survival. This procedure may have potential advantages over currently used transthoracic thoracoscopy techniques.

Transoral endoscopic surgery versus conventional thoracoscopic surgery for thoracic intervention: safety and efficacy in a canine survival model.

PURPOSE: Transoral endoscopic surgery has been shown to be feasible and safe in both humans and animal models. The purpose of this study was to evaluate the safety and efficacy of transoral and conventional thoracoscopy for thoracic exploration, surgical lung biopsy, and pericardial window creation. METHODS: The animals (n = 20) were randomly assigned to the transoral endoscopic approach group (n = 10) or conventional thoracoscopic approach group (n = 10). Transoral thoracoscopy was performed with a flexible bronchoscope via an incision over the vestibulum oris. In conventional thoracoscopy, access to the thoracic cavity was obtained through a thoracic incision. Surgical outcomes (body weight, operating time, operative complications, and time to resumption of normal diet), physiologic parameters (respiratory rate, body temperature), inflammatory parameters [white blood cell (WBC) counts and C-reactive protein (CRP)], and pulmonary parameters (arterial blood gases) were compared for both procedures. RESULTS: The surgical lung biopsy and pericardial window creation were successfully performed in all animals except one animal in the transoral group. There was no significant difference in operating times between the groups. The increase in WBC in the transoral thoracoscopy group was significantly smaller on postoperative day 1 than in the conventional thoracoscopy group (p = 0.0029). The transoral group had an earlier return to preoperative body temperature (p = 0.041) and respiratory rate (p = 0.045) on day 7. With respect to pulmonary parameters, there was no significant difference in blood pH, pCO2, or PaCO2 between the transoral and transthoracic groups. All animals survived without complications 14 days after surgery. CONCLUSIONS: This study demonstrated that the transoral approach was comparable to conventional thoracoscopic surgery for lung biopsy and pericardial window creation in terms of safety and efficacy.

Overall Survival Improvement in Patients with Epidermal Growth Factor Receptor-Mutated Non-Small Cell Lung Cancer and Bone Metastasis Treated with Denosumab.

The impact of an initial skeletal-related event (SRE) and denosumab adjuvant treatment on the survival outcome of epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC) patients with bone metastasis remains unclear. This retrospective study included 400 metastatic EGFR-mutated NSCLC patients. Among 190 bone metastasis patients, 61 had initial SREs and 73 received denosumab. We analyzed patient characteristics, SRE-free survival (SRE-FS), and overall survival (OS). In metastatic EGFR-mutated NSCLC, bone metastasis was associated with a poorer OS (21.7 vs. 33.0 months; p < 0.001). Bone metastasis patients with initial SREs at diagnosis had an even shorter OS, compared with those without initial SRE (15.4 vs. 23.6 months; p = 0.026). Denosumab reduced SRE incidence (hazard ratio (HR) 0.57 (95% confidence interval (CI) 0.34−0.94; p = 0.027) and was associated with improved OS (26.6 vs. 20.1 months; p = 0.015). A multivariate analysis demonstrated that denosumab treatment was correlated with a lower incidence of SRE (HR 0.61 (95% CI 0.37−0.98); p = 0.042) and better OS (HR 0.60 (95% CI 0.41−0.88); p = 0.008). In subgroup analyses, denosumab prolonged SRE-FS (HR 0.36 (95% CI 0.19−0.79); p = 0.009) in patients without initial SREs and was related to a better OS (25.3 vs. 12.9 months; p = 0.016) in patients with initial or pre-existing SREs. Osteonecrosis of the jaw was diagnosed in two patients (2.74%) receiving denosumab. Our study confirmed the association between initial SREs and a worse outcome and provided novel evidence of the survival benefit of denosumab for EGFR-mutated NSCLC patients with bone metastasis.

Association of smoking status with non-small cell lung cancer patients harboring uncommon epidermal growth factor receptor mutation.

Introduction: Uncommon epidermal growth factor receptor (EGFR) mutations include single and complex mutations. However, the association of the smoking status of patients with uncommon and complex EGFR mutations remains unclear. Methods: This retrospective study evaluates the spectrum of uncommon EGFR mutations and investigates the influence of smoking status on the frequency of various uncommon EGFR mutations using a multi-institutional medical database. Results: Between 2010 and 2019, 5,608 non-small cell lung cancer (NSCLC) patients were analyzed. EGFR mutations were detected in 3,155 (56.3%) patients. Among the 399 (12.6%) patients with uncommon mutations, 198 had single uncommon and 201 complex mutations, including 87 exon 20 insertions, 79 de novo T790M, 70 complex common, and 52 complex uncommon mutations. For comparison, we also included 402 patients with common EGFR mutations. The percentage of ever-smokers was significantly higher in patients with uncommon EGFR mutations than in patients with common EGFR mutations (25.8% vs. 17.4%, p = 0.005). Furthermore, the percentage of ever-smokers was higher in those with a complex mutation than in those with a single uncommon mutation (30.3% vs. 21.2%, p = 0.040). Among patients carrying uncommon EGFR mutations, ever-smokers had significantly more complex uncommon EGFR mutations than never-smokers (22.3% vs. 9.8%, p = 0.002). Among patients carrying G719X, L861Q, and S768I, ever-smokers tended to have complex EGFR mutations more frequently than never-smokers (64.7% vs. 28.7%, 50.0% vs. 18.7%, 88.9% vs. 81.2%, respectively). Conclusions: Our study demonstrates not only a comprehensive spectrum of uncommon EGFR mutations, but also a positive relationship between smoking status and uncommon EGFR mutation frequency, especially complex uncommon EGFR mutations. The results suggest that smoking contributes to the development of complex EGFR mutations.

Feasibility of the transtracheal approach for the thoracic cavity in a large animal model.

BACKGROUND: The aim of this study was to evaluate the performance of a novel transtracheal endoscopic technique for thoracic evaluation and intervention in a large animal model. METHODS: In 12 animals (6 pigs and 6 dogs) under general anesthesia, a tracheal incision was made on the right lateral wall of the lower trachea and used as an entrance for thoracic evaluation and intervention. Postoperative follow-up included endoscopy at 1 and 2 weeks after surgery and necropsy at 2 weeks after surgery. RESULTS: Transtracheal opening and thoracic exploration were achieved in all animals. Four animals (3 pigs and 1 dog) died as a result of complications from the procedure. At the follow-up endoscopy, healing at the tracheal opening region was noted in seven animals. CONCLUSIONS: The transtracheal approach to the thoracic cavity is technically feasible in both porcine and canine models (4/12 animals died). The canine model is perhaps more suitable than the porcine model for the study of the transtracheal approach to the thoracic cavity.

Single-dose antimicrobial prophylaxis in transoral surgical lung biopsy: a preliminary experience.

BACKGROUND: The feasibility of the transtracheal approach to the thoracic cavity has been demonstrated, but surgical lung biopsy via the tracheal approach still remains a challenge. This study aimed to evaluate the feasibility and outcome of transoral surgical lung biopsy under a single preoperative dose of parenteral antibiotics. METHODS: Transoral thoracoscopy and surgical lung biopsy were performed for 10 anesthetized dogs after a single intravenous injection of cefazoline (20 mg/kg). A 12-mm transoral incision was created on the vestibulum, and a homemade metallic tube was advanced into the thoracic cavity via the pretracheal and substernal space under endoscopic guidance. After thoracic exploration, surgical lung biopsy was performed using an electrosurgical snare with a flexible bronchoscope inserted through the metallic tube. The resection margin of the lung was secured with a homemade endoloop. The animals were killed by day 14 after the surgery for gross and histologic evaluations. RESULTS: The thoracic cavity was evaluated and lung biopsy was performed successfully (for 3 lobes in the right lung and 2 lobes in the left lung) in 9 of the 10 dogs. Neither mortality nor intraoperative complications were observed. The average time for the transoral thoracoscopy and surgical lung biopsy was 133.5 min. Postmortem examination showed complete healing, with fibrosis and moderate adhesion over the resection margin. No evidence of either mediastinitis or intrathoracic infection was observed. CONCLUSION: This study showed the feasibility of transoral thoracoscopy and surgical lung biospy in dogs. Moreover, single-dose prophylaxis with cefazoline in transoral surgical lung biopsy was found to be effective in preventing potential infection.

Impact of Chemotherapy-Induced Peripheral Neuropathy on Quality of Life in Patients with Advanced Lung Cancer Receiving Platinum-Based Chemotherapy.

Chemotherapy-induced peripheral neuropathy (CIPN) is a common adverse effect of neurotoxic anticancer drugs that may affect quality of life (QoL). Purpose: The purposes of this study were to: assess the levels of CIPN, anxiety, depression, CIPN-related QoL, and general QoL; and identify the factors related to CIPN-related QoL and general QoL in patients with advanced lung cancer (LC) receiving platinum-based chemotherapy. This cross-sectional study examined patients with advanced LC who received platinum-based chemotherapy from the thoracic oncology inpatient wards of a medical center in northern Taiwan. Structured questionnaires were used to measure patients' CIPN (European Organization for Research and Treatment of Cancer quality of life questionnaire-chemotherapy-induced peripheral neuropathy 20), anxiety (Hospital Anxiety and Depression Scale Depression Scale [HADS]), depression (HADS), CIPN-related QoL (Functional Assessment of Cancer Therapy /Gynecologic Oncology Group-Neurotoxicity subscale [FACT/GOG-Ntx]), and general QoL (Functional Assessment of Cancer Therapy-General Input [FACT-G]). Of 93 patients with advanced LC, 53.8% reported CIPN-sensory impairment and 47.3% reported CIPN-motor impairment. The most common CIPN symptoms were difficulty getting or maintaining an erection (only for men > 65 years) and difficulty in climbing stairs or getting up out of a chair. Poor CIPN-related QoL (FACT/GOG-Ntx) was associated with more CIPN-sensory and more CIPN-motor impairment. Poor general QoL (FACT-G) was associated with a higher level of depression, a higher level of anxiety, and receipt of more chemotherapy cycles. More than half of LC patients report impairment related to CIPN, calling for holistic treatment to improve QoL.

First- or second-generation epidermal growth factor receptor tyrosine kinase inhibitors in a large, real-world cohort of patients with non-small cell lung cancer.

BACKGROUND: There are limited comparisons of first- and second-generation EGFR tyrosine kinase inhibitors (TKIs) in large, real-world cohorts of non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutations. METHODS: Patients with advanced NSCLC (N = 612) with common EGFR mutations receiving first-line gefitinib/erlotinib and afatinib were grouped and propensity-score matched. Progression-free survival (PFS), overall survival (OS) and secondary T790M mutations were analyzed. RESULTS: The gefitinib/erlotinib and afatinib groups each contained 206 patients after matching. Compared with gefitinib/erlotinib, patients receiving afatinib achieved longer median PFS (16.3 versus 14.2 months; log-rank test p = 0.020) and had a lower risk of progression [hazard ratio (HR) 0.73 (95% confidence interval (CI), 0.57-0.94); p = 0.017]. Median OS (37.3 versus 34.2 months; log-rank test p = 0.500) and reduction in risk of death [HR 0.89 (95% CI, 0.65-1.23); p = 0.476] did not differ significantly between groups. T790M positivity was significantly higher in the gefitinib/erlotinib than afatinib group (70.9% versus 44.6%, p < 0.001). Multivariate analysis demonstrated that afatinib was independently associated with lower T790M positivity [odds ratio (OR) 0.27 (95% CI, 0.14-0.53); p < 0.001], whereas ⩾12 months PFS after EGFR-TKI treatment [OR 3.00 (95% CI, 1.56-5.98); p = 0.001] and brain metastasis [OR 2.12 (95% CI, 1.08-4.26); p = 0.030] were associated with higher T790M positivity. Sequential third-generation EGFR-TKI treatment was administered to 63 patients, in whom median OS after the second-third-generation and first-third-generation EGFR-TKI sequences were 38.8 and 29.1 months, respectively. CONCLUSION: Compared with gefitinib/erlotinib, afatinib had a higher treatment efficacy and a lower secondary T790M positivity in a large, real-world cohort of Asian patients with EGFR-mutated NSCLC.