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The impact of corticosteroids for the treatment of immune-related adverse events (irAEs) on the antitumor effect of programmed cell death-1 (PD-1) inhibitor is unclear.A total of 172 patients with non-small cell lung cancer (NSCLC) treated with PD-1 inhibitors were retrospectively reviewed. Patients were divided into four groups: those who did not develop irAEs [1] and those who developed irAE and were either not treated with corticosteroids [2] or treated with low [3] or high doses [4], and overall survival (OS) was analyzed by the time of corticosteroid treatment. Landmark analysis was performed using Cox proportional hazard model with time-dependent covariates.A high-dose steroid treatment within 60 days correlated with a significantly worse OS than that of the group with irAEs without steroids (p=0.004). Moreover, there was no significant difference in OS between the irAE without steroid and low-dose steroid groups.Early severe irAEs and high-dose corticosteroid treatment were poor prognostic factors in patients with NSCLC treated with PD-1 inhibitors.

Sup. Table 2. Top 3 functional pathways from ingenuity pathways analysis (IPA) in DTC.

Purpose: EGFR inhibitors (EGFRi) are effective against EGFR-mutant lung cancers. The efficacy of these drugs, however, is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, T790M. We recently demonstrated that T790M can arise de novo during treatment; it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells [referred to as drug-tolerant cells (DTC)] prior to acquiring secondary mutations like T790M.Experimental Design: We have developed DTCs to EGFRi in EGFR-mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhibitors to eliminate DTCs and shrink EGFR-mutant lung cancer tumors in vivo.Results: We demonstrate surviving EGFR-mutant lung cancer cells upregulate the antiapoptotic protein MCL-1 in response to short-term EGFRi treatment. Mechanistically, DTCs undergo a protein biosynthesis enrichment resulting in increased mTORC1-mediated mRNA translation of MCL-1, revealing a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors. Moreover, MCL-1 is a key molecule governing the emergence of early EGFR-mutant DTCs to EGFRi, and we demonstrate it can be effectively cotargeted with clinically emerging MCL-1 inhibitors both in vitro and in vivo.Conclusions: Altogether, these data reveal that this novel therapeutic combination may delay the acquisition of secondary mutations, therefore prolonging therapy efficacy. Clin Cancer Res; 24(22); 5658–72. ©2018 AACR.

Figure S1. DTCs upregulate TORC1-mediated MCL-1 translation. Figure S2. High-content cell imaging assay. Figure S3. Genetic inhibition of MCL-1 is sufficient to induce apoptosis following EGFR inhibitor treatment. Figure S4. EGFR mutant tumors (PC9) respond to EGFR inhibitor/MCL-1 inhibitor (S63845) combination therapy in vivo. Figure S5. EGFR mutant tumors (HCC827) respond to EGFR inhibitor/MCL-1 inhibitor (S63845) combination therapy in vivo. Figure S6. Upregulation of MCL-1 in EGFR mutant cell lines occurs with other insults.

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Osimertinib is the standard of care in the initial treatment for advanced epidermal growth factor receptor (EGFR) mutation-positive lung cancer. However, clinical data and reliable prognostic biomarkers are insufficient.We performed a retrospective multicentre cohort study for 538 EGFR mutation-positive patients, who received osimertinib as the initial treatment between August 2018 and December 2019. The main outcome was progression-free survival (PFS).The median observation period was 14.7 months (interquartile range 11.4-20.0). The median PFS was 20.5 months (95% confidence interval [CI] 18.6-not reached). Multivariate analysis showed that sex (male) (hazard ratio [HR] 1.99, 95% CI 1.35-2.93, P = 0.001), malignant effusions (HR 1.51, 95% CI 1.11-2.04, P = 0.008), liver metastasis (HR 1.55, 95% CI 1.03-2.33, P = 0.037), advanced unresectable cases (HR 1.71, 95% CI, 1.04-2.82, P = 0.036), mutation type and programmed cell death-ligand 1 (PD-L1) expression were associated with PFS. The L858R (HR 1.55, 95% CI 1.01-2.38, P = 0.043) and uncommon mutations (HR 3.15, 95% CI 1.70-5.83, P 0.001) were associated with PFS. PD-L1 expression of 1-49% (HR 1.66, 95% CI 1.05-2.63, P = 0.029), ≥50% (HR 2.24, 95% CI 1.17-4.30, P = 0.015) and unknown (HR 1.53, 95% CI 1.05-2.22, P = 0.026) was associated with PFS. The main reasons for treatment discontinuation among 219 patients were disease progression (44.3%), pneumonitis (25.5%) and other adverse events (16.0%).During initial treatment with osimertinib, PD-L1 expression is significantly related to PFS. Adverse events are a noteworthy reason for discontinuation.

Background and purpose Intensity-modulated radiation therapy (IMRT) is increasingly applied in concurrent chemoradiotherapy (CCRT) for locally-advanced non-small cell lung cancer (NSCLC), with improvement of target coverage and better sparing of normal tissue. IMRT tends to have a larger low-dose irradiation volume than 3D conformal radiotherapy, but the incidence of and risk factors for pneumonitis remain unclear, especially following the approval of durvalumab. Materials and methods We retrospectively reviewed the records of NSCLC patients treated by CCRT using IMRT at seven Japanese institutions. Primary outcomes were incidence of symptomatic pneumonitis and progression-free survival (PFS). Multivariate logistic regression analysis was used to identify risk factors for ≥grade 2 pneumonitis. Results Median follow-up from the start of CCRT was 14.3 months (n = 107 patients; median age 70 years, 29% female). Median lung V5 and V20 was 49.2% and 19.5%, respectively. Durvalumab was administered to 87 patients (81%). Pneumonitis developed in 95 (89%) patients of which 53% had grade 1, 28% grade 2, 6.5% grade 3, and 0.9% grade 4. Durvalumab had been discontinued in 16 patients (18.4%) due to pneumonitis. By multivariate analysis, age ≥70 years, male sex, and V5 ≥58.9% were identified as significantly associated with ≥grade 2 pneumonitis (p = 0.0065, 0.036 and 0.0013 respectively). The median PFS from the start of CCRT was not reached (95% CI, 14.2 months to not reached) in patients receiving durvalumab. Conclusion CCRT using IMRT followed by durvalumab was generally effective and tolerable; V5

Fenbendazole is a benzimidazole anthelmintic agent, with a broad antiparasitic range in animals such as dogs and pigs. The agent is also reported to exert antitumor effects and inhibit microtubule-associated tubulin polymerization, but its safety and tolerability profile in humans remains unclear. An 80-year-old female patient with advanced nonsmall cell lung cancer (NSCLC) was started on pembrolizumab monotherapy. The patient experienced severe liver injury 9 months later. An interview with her and her family revealed that she had been taking fenbendazole for a month, solely based on social media reports suggesting its effectiveness against cancer. After discontinuation of the self-administration of fenbendazole, the patient’s liver dysfunction spontaneously resolved. The antitumor inhibitory effects of fenbendazole have been reported; however, she did not experience tumor shrinkage. This is the first case report of a patient with advanced NSCLC who self-administered the anthelmintic, fenbendazole. Twitter and Facebook are online social media platforms which have been constructively used to exchange information among cancer patients. However, sources of medical information on these platforms are often unproven, and it is difficult for nonmedical professionals to accurately select and filter complex medical information. Physicians should enquire patients about self-administration of orally ingested products, including dietary supplements, herbs, or bioactive compounds, in cases of unexpected adverse reactions.

Background This study was performed to evaluate the clinical outcomes of hybrid treatment involving surgical resection and percutaneous radiofrequency ablation for patients with multiple lung metastases. Methods Seventeen patients (6 men, 11 women; median age, 52 years; range, 16–78 years) underwent hybrid treatment involving surgery and radiofrequency ablation to treat multiple lung metastases (median number, 4; range, 2–26) between May 2014 and February 2020. The primary lesions were colorectal carcinoma (n = 9), uterine endometrial carcinoma (n = 3), osteosarcoma (n = 2), renal cell carcinoma (n = 1), glottic carcinoma (n = 1), and fibrolamellar hepatocellular carcinoma (n = 1). Twenty‐four sessions each of surgery and radiofrequency ablation were performed. Safety, disease‐free survival, and overall survival were evaluated. Safety was assessed according to the Clavien‐Dindo Classification. Results A grade IVa adverse event of empyema developed in one patient (4%, 1/24) after surgery. A grade IIIa adverse event of pneumothorax and a grade II adverse event of lung abscess occurred in four (17%, 4/24) and one session (4%, 1/24) after radiofrequency ablation, respectively. During the median follow up of 34 months (range, 8–67 months), 10 patients (59%, 10/17) developed new metastases. The 5‐year disease‐free survival rate was 32%. Four or fewer lung metastases (p = 0.008) and metastases from colorectal carcinoma (p = 0.02) were factors significantly associated with longer disease‐free survival. One patient (6%, 1/17) died of tumor progression 29 months after initial treatment. The 5‐year overall survival rate was 88%. Conclusions The strategy of hybrid treatment involving surgery and radiofrequency ablation may offer good outcomes for patients with multiple lung metastases., Hybrid therapy involving surgical resection and percutaneous radiofrequency ablation for multiple lung metastases was effective, with 5‐year disease‐free and overall survival rates of 32% and 88%, respectively. Patients with four or fewer lung metastases and metastases from colorectal carcinoma appear to be good candidates for hybrid therapy.

Introduction Despite the extensive use of the combination of cytotoxic chemotherapy and programmed cell death protein 1/programmed death-ligand 1 checkpoint inhibitors for cancer treatment, the incidence and characteristics of pneumonitis caused by this combination therapy have not been examined in clinical settings. Methods We conducted a 36-centre, retrospective cohort study in patients with chemo-naive advanced non-squamous non-small cell lung cancer who received a combination of platinum, pemetrexed and pembrolizumab between December 2018 and June 2019. Results The study comprised 299 patients. The most frequent grade ≥3 non-hematologic adverse event was pneumonitis. There were 37 patients (12.4%, 95% CI 8.9–16.7) with all-grade pneumonitis and 10 (3.3%, 95% CI 1.6–6.1) with grade ≥3 pneumonitis. Of these, 21 (7.0%, 95% CI 4.4–10.5) and 9 patients (3.0%, 95% CI 1.4–5.6) developed all-grade and grade ≥3 pneumonitis within 90 days after initiating the combination therapy, respectively. The median time to treatment failure and progression-free survival was 5.9 (95% CI 5.0–6.8) and 7.5 (95% CI 6.5–8.7) months, respectively. In the survival analysis after adjusting for immortal time bias, pneumonitis was independently associated with shorter progression-free survival (HR 1.99, 95% CI 1.07–3.69, P = 0.03) and overall survival (HR 3.03, 95% CI 1.12–8.20, P = 0.03). Conclusions Treatment-related pneumonitis occurred at a higher rate in the real-world population than that reported previously; it led to worse survival outcomes. Pneumonitis requires more attention. Additional studies are required to improve the safety of this combination therapy. Trial registration number UMIN000038084

Although osimertinib is a standard first-line treatment for patients with advanced-stage non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutations, the incidence rate of pneumonitis associated with osimertinib is high. However, there are few reports about the safety and efficacy of osimertinib rechallenge after the development of pneumonitis.We conducted a retrospective multicentre cohort study of consecutive patients who developed pneumonitis associated with osimertinib as a first-line and received osimertinib rechallenge. The primary outcome was the incidence rate of any grade pneumonitis after osimertinib rechallenge. The secondary outcome was treatment efficacy in patients after osimertinib rechallenge.In total, 33 patients who received osimertinib rechallenge were included. Of them, 26 patients had grade 1, 6 patients had grade 2, and 1 patient had grade 3 initial pneumonitis. The median follow-up period after the osimertinib rechallenge was 16.9 months (interquartile range, 11.1-21.3 months). After the start of osimertinib rechallenge, five patients (15%) experienced mild relapsed pneumonitis. Three of the five patients had similar imaging patterns for initial and relapsed pneumonitis. No significant differences in characteristics were observed between patients with and without relapsed pneumonitis. The median progression-free survival after osimertinib rechallenge was not achieved (95% confidence interval: 10.3 months - not reached).Osimertinib rechallenge was feasible and effective for patients who developed initial pneumonitis associated with first-line osimertinib therapy. Osimertinib might be considered a treatment option even after the development of mild initial pneumonitis.

Background The data of sequential therapy of anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) in clinical practice have been limited. Methods We reviewed the clinical data of patients with ALK-rearranged non-small cell lung cancer who received crizotinib (CRZ) or alectinib (ALEC) between May 2012 and December 2016. Patients were divided into two groups based on the first-administered ALK-TKI, the CRZ or ALEC group. The combined time-to-treatment failure (TTF) was defined as the sum of the ‘TTF of CRZ’ plus the ‘TTF of ALEC’ if patients were treated with CRZ followed by ALEC in the CRZ group. The primary end-point is the comparison between the combined TTF and the TTF of ALEC in the ALEC group. Results Of 864 patients enrolled from 61 institutions, 840 patients were analysed. There were 535 of 305 patients in the CRZ/ALEC groups. The combined TTF in the CRZ group was significantly longer than TTF in the ALEC group (median, 34.4 versus 27.2 months; hazard ratio [HR], 0.709; P = 0.0044). However, there was no significant difference in overall survival (OS) between the patients who received ALEC after CRZ in the CRZ group and the patients in the ALEC group (median, 88.4 months versus. not reached; HR, 1.048; P = 0.7770). In the whole population, the CRZ group had a significantly shorter OS than the ALEC group (median, 53.6 months versus not reached; HR, 1.821, P Conclusion The combined TTF in the CRZ group was significantly longer than the TTF in the ALEC group; however, OS benefit of sequential therapy against ALEC as the first ALK-TKI was not shown.

We previously reported useful methods that can be implemented to identify intersegmental boundary lines (IBLs) by using an intravenous indocyanine green (ICG) fluorescence imaging system (ICG-FS) during a thoracoscopic anatomical segmentectomy (TAS). The aim of this study was to evaluate the recently released third-generation ICG-FS that features an emphasizing xenon-light source for IBL identification.We prospectively studied cases involving 106 consecutive patients who underwent TAS. Intraoperatively, we used the third-generation ICG-FS, the conventional ICG methods (CIM) emphasizing xenon-light (CIM-X), and the spectra-A method (SAM) emphasizing xenon-light (SAM-X), for IBL identification. Furthermore, 16 of the 106 patients (15%) could be simultaneously evaluated using old-generation ICG-FSs, CIM, and SAM. All images were completely quantified for illuminance and for three colors, red, green, and blue.IBLs were successfully identified in all the patients (100%) with no adverse events. The SAM-X significantly increased the illuminance, especially in the resecting segments, compared to the CIM (39.0 versus 22.2, P 0.01) and SAM (39.0 versus 29.3, P 0.01), with enhanced red color compared to the CIM (33.1 versus 21.9, P 0.01) and SAM (33.1 versus 14.0, P 0.01). Furthermore, the SAM-X significantly increased the illuminance contrast compared to the CIM-X (34.1 versus 15.3, P 0.01).The present study suggests that the SAM-X potentially provided images with the highest visibility and colorfulness compared to the older generation ICG-FSs or CIM-X. Secure IBL identification can be more easily and safely performed using the SAM-X.

Background The aim of this study was to evaluate regional postoperative preserved pulmonary function (PPPF) and three‐dimensional (3D) volumetric changes according to the number of resected subsegments and investigate the factors that most affected pre‐/post PPPF. Methods Patients who underwent thoracoscopic lobectomy (n = 73), and segmentectomy (n = 87) were eligible for inclusion in the study. They were classified according to the number of resected subsegments which ranged from 1 to 10. The percentage of pre‐/postoperative forced expiratory volume in 1 s (FEV1) was used for comparison. Furthermore, lung volumetric changes were calculated using 3D computed tomography (CT) volumetry. Results The percentage of pre‐/postoperative EFV1 between 4 and 5–7 and between 5–7 and 10 were significant (p = 0.03 and p, Segmentectomy is feasible and useful for postoperative preserved pulmonary function. However, chronic inflammation has been statistically identified as a risk factor for postoperative preserved pulmonary function.

BACKGROUND: Various radiological tools have been introduced to determine the malignancy or prognosis of lung carcinomas. We retrospectively summarized the clinical outcomes to evaluate whether radiological tools such as consolidation-to-tumor ratio (CTR), tumor disappearance ratio (TDR), and mediastinal diameter (MD) are suitable for surgically resected non-small-cell lung cancer (NSCLC). METHODS: This retrospective study included 260 patients (128 men and 132 women; median age, 64 years) with cT1N0-staged NSCLC who underwent thoracotomy. Disease-free survival (DFS) and overall survival (OS) outcomes were analyzed using the Kaplan-Meier method and Cox proportional hazards model. RESULTS: When the adjusted hazard ratios (HRs) with reference to cT1a/1 mi were calculated, significant differences were observed in cT1b and cT1c for DFS (P=0.04 and P0.5) for DFS (P=0.01). For HRs with reference to TDR (≤25%), significant differences were observed in TDR (>75%) for DFS (P=0.02) and OS (P=0.02). For HRs with reference to MD (≤5 mm), significant differences were observed in 6–20 mm (P=0.04) and >20 mm (P=0.02) for DFS and in >20 mm (P=0.02) for OS. CONCLUSIONS: All radiological tools revealed significant correlations with prognosis in the patients with cT1N0-staged NSCLCs. We recommend the use of MD in a clinical context. However, further investigation of this issue is needed.

This study aims to assess the feasibility and impact on long-term pulmonary function of chest drain removal on the operation day following thoracoscopic right upper lobectomy for clinical stage I non-small cell lung cancer. We retrospectively evaluated the data of 116 patients between May 2013 and March 2019. We evaluated the correlations of clinical parameters of chest drain removal and medium- and long-term pulmonary function by comparing removal on operation day (R group) and retainment (D group). The R group comprised 64 patients, and the D group had 52 patients. Fifty patients (96.2%) in the D group had chest drain removed within 3 postoperative days. Since February 2016, chest drain removal on operation day was performed in 64 of 74 patients (86.5%) according to our chest drain removal protocol. Removal of chest drains on operation day was associated with shorter postoperative hospitalization (p

We aimed to analyze the feasibility and risk factors associated with early mobilization (EM) within 4 h after thoracoscopic lobectomy and segmentectomy. This study retrospectively evaluated 214 consecutive patients who underwent thoracoscopic anatomical pulmonary resection using our EM protocol between October 2017 and February 2019. We compared the correlations of the patients’ characteristics including the total number of drugs and perioperative parameters such as air leak, and orthostatic hypotension (OH) between the EM (E group) and failed EM (F group) groups. Second, we evaluated risk factors for OH, which often causes critical complications. A total of 198 patients (92.5%: E group) completed the EM protocol, whereas 16 patients did not (7.5%: F group). The primary causes of failure were severe pain, air leak, postoperative nausea and vomiting, and OH (n = 1, 3, 8, and 4). Upon univariate analysis, air leakage, OH, and non-hypertension were identified as risk factors for failed EM (all p

We constructed a data set of EGFR‐mutant non–small‐cell lung carcinoma (NSCLC) patients, and compared the overall survival of first‐generation (1G), and second‐generation (2G) EGFR‐tyrosine kinase inhibitors (TKIs) in clinical practice using a propensity score. We reviewed the clinical data of consecutive EGFR‐mutated NSCLC patients who received EGFR‐TKI therapy between January 2008 and August 2017 at 11 institutions in Japan. The primary endpoint was overall survival (OS). When comparing OS between 1G and 2G EGFR‐TKIs, propensity score analyses were performed using 2 methods: matching and inverse probability of treatment weighting (IPTW). (Clinical Trial information: UMIN000030121) In total, 1400 patients from 11 institutions were enrolled in this study, and the data from the 1366 patients who received only EGFR‐TKI therapy were analyzed (gefitinib [GEF], N = 732; erlotinib [ERL], N = 416; afatinib, N = 218). Median OS times (months [95%CI]) were 29.7 [27.5‐33.5] in the 1G group (gefitinib, 32.0 [28.1‐35.8]; erlotinib, 27.5 [23.9‐31.7]), and 38.6 [32.2‐NR] in the 2G group (afatinib), respectively. The trend of longer OS for afatinib against 1G EGFR‐TKIs remained, even after adjusted by propensity score. (unadjusted, hazard ratio [HR] 0.676, P = .0023; adjusted by IPTW, HR 0.685 P

The incidence of real-world pneumonitis and durvalumab rechallenge during chemoradiotherapy and durvalumab consolidation for non-small cell lung cancer is unknown.We retrospectively evaluated the medical records of 302 consecutive patients diagnosed with non-small cell lung cancer who started chemoradiotherapy between May 2018 and May 2019.Median age was 70 (range: 40-87) years. Volume of lung parenchyma that received 20 Gy (V20) exceeded 35% in 2% and mean lung dose exceeded 20 Gy in 1% of patients. Durvalumab consolidation was delivered to 225 patients (75%). Overall, 83% (n = 251), 34% (n = 103), 7% (n = 21), and 1% (n = 4) of the patients developed any grade of pneumonitis, symptomatic pneumonitis, ≥grade 3 pneumonitis, and fatal (grade 5) pneumonitis, respectively. Corticosteroids were administered to 25% of the patients to treat pneumonitis. Multivariate analysis identified the predictive factors for the development of symptomatic pneumonitis: V20 Gy or more ≥ 25% (odds ratio [OR]: 2.37, P = 0.008) and mean lung dose (MLD) ≥ 10 Gy (OR: 1.93, P 0.0047). Of the 52 patients who received corticosteroids for pneumonitis after durvalumab initiation, 21 were rechallenged with durvalumab. Overall, 81% of patients met the PACIFIC study's rechallenge criteria and did not experience a severe pneumonitis relapse.High V20 and MLD were independent risk factors of symptomatic pneumonitis. More than 80% of the patients who were rechallenged with durvalumab after pneumonitis met the PACIFIC study's rechallenge criteria. Consequently, severe relapse did not occur. Cooperation between radiation and medical oncologists is important for safe chemoradiotherapy and the safe completion of durvalumab consolidation therapy.

Background/aim Pulmonary pleomorphic carcinoma (PPC) is rare, and few studies have reported its features. We assessed the clinicopathological features, surgical outcomes, oncogenic status and programmed death-ligand 1 (PD-L1) expression of PPC. Patients and methods We retrospectively reviewed data from 22 consecutive patients who underwent resection of PPC between 2007 and 2017. Results The predominant tissue type of the epithelial component was adenocarcinoma in 15 patients (68%) and the others in 7 patients (32%), and the 3-year disease-free survival rate tended to be better in patients with an adenocarcinoma component compared to patients with another component (40.0% vs. 17.1%, p=0.059). PD-L1 expression was observed in all eight tumors whose PD-L1 status could be examined and high PD-L1 expression (≥50%) was frequent (5/8, 63%). Conclusion A predominant adenocarcinoma epithelial component in PPC might be associated with better survival outcomes and high PD-L1 expression might be frequent in PPC.

8545 Background: This study assessed the clinicopathological background of early-stage KRAS-mutated non-small-cell lung cancer and analyzed the biological process of KRAS-mutated tumor using an RNA sequencing procedure. Methods: We used a cohort of consecutive series of 179 surgically resected early-stage non-small-cell lung cancers harboring KRASmutations and analyzed the clinicopathological features, including the KRAS genotypes, affecting the recurrence-free survival and prognosis. Consequently, we performed RNA sequencing to determine the gene expression profiles of nineteen KRAS-mutated non-small-cell cancers. Results: The most common KRAS genotype was p.G12C (57; 31.8%). A high p-stage (hazard ratio [HR], 4.181; P < 0.0001) and solid predominant adenocarcinoma histology (HR, 2.343; P = 0.0076) were significant independent prognostic factors for the recurrence-free survival. A high p-stage (HR, 3.793; P < 0.0001), solid predominant adenocarcinoma histology (HR, 2.373; P = 0.0147), and KRAS p.G12V genotype (HR, 1.975; P = 0.0407) were significant independent prognostic factors for the overall survival. A gene expression analysis of the two factors revealed the p.G12V genotype to be closer to those of stem cells, and the traits of e an enhanced fatty acid and amino acid metabolism as well as a solid predominant phenotype were shown to an acquired a trait that can withstand hypoxia and the effect of prostaglandin-endoperoxide synthase Conclusions: The KRAS p.G12V genotype and solid predominant adenocarcinoma phenotype may be independent predictive factors of a poor clinical course in resected early-stage non-small-cell lung cancers, possibly due to the differentiation tendency observed in stem cells, the trait of an enhanced fatty acid and amino acid metabolism, and the effect of prostaglandin-endoperoxide synthase.

8567 Background: Chemo-immunotherapy is the standard 1st-line therapy for patients with extensive-stage small cell lung cancer (ES-SCLC). Prospective data about underrepresented populations outside the clinical trial such as elderly or poor risk has not been revealed. Methods: We conducted a 32-hospitals prospective cohort study of consecutive patients with ES-SCLC who received carboplatin and etoposide with atezolizumab as 1st-line therapy between September 2019 and September 2020. The primary outcome was 6-months progression-free survival (PFS) probability of all patients. The secondary outcomes were overall survival (OS), PFS, time to treatment failure, objective response rate, safety, and differences in efficacy and safety depending on whether or not the key eligible study criteria of previous trials are met. Results: In total, 207 patients with ES-SCLC were analyzed. The median age was 72 years, and 64 patients (31%) were elderly (≥75 years). Most patients (89%) had a performance status (PS) of 0 or 1. As a result, 132 (64%) was categorized as eligible patients. The 6-months PFS probability of all patients was 38.8 % (95%CI:32.4-45.7%). Between eligible and ineligible patients, there was significant difference of patients who attained disease control (93% versus 77%, p = 0.002). Median PFS was significantly longer in eligible patients than ineligible patients (5.1 vs. 4.7 months; P =.03, HR 0.72 (95% CI 0.53–0.97)), and median OS was longer in eligible patients than ineligible patients, without any significant difference (15.8 vs. 13.1 months; P =.10, HR 0.73 (95% CI 0.51–1.07)). Survival analysis identified a PS score of 0-1 (HR: 0.60, 95% CI: 0.39-0.97, p = 0.03) as a significant predictor of better PFS, while PS score of 0-1 (HR: 0.51, 95% CI: 0.31-0.89, p = 0.01) and younger patients ( < 75 years) (HR: 0.66, 95% CI: 0.45-0.97, p = 0.03) as significant-good predictor of OS. The rate of severe AEs was higher in ineligible patients than in eligible (39% vs. 27%, respectively; p = 0.07), although the difference was not significant. Older age was significantly associated with severe AEs (p = 0.049). Conclusions: The real-world efficacy of chemo-immunotherapy for ES-SCLC was similar to that of pivotal clinical trials. However, trial-ineligible patients with ES-SCLC had poor treatment outcome and the higher rates of severe adverse events in this prospective cohort study. Our study suggests that positive results among the trial eligible patients may not translate to ineligible patients. Clinical trial information: UMIN000038064.

BACKGROUND: Sarcopenia characterized by skeletal muscle loss may influence postoperative outcomes through physical decline and weakened immunity. We aimed to investigate clinical significance of sarcopenia in resected early-stage non-small cell lung cancer (NSCLC). METHODS: We retrospectively reviewed 315 consecutive patients with pathologic stage I NSCLC who had undergone lobectomy with systematic nodal dissection. Sarcopenia was defined as the lowest quartile of psoas muscle area on the 3rd vertebra on the high-resolution computed tomography (HRCT) image. Clinicopathological variables were used to investigate the correlation to postoperative complications as well as overall and recurrence-free survival. RESULTS: Upon multivariable analysis, male sex [odds ratio (OR) =5.780, 95% confidence interval (CI): 2.681–12.500, P

令和2年度

Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients' reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients.

Programmed death-ligand 1 (PD-L1) expression is a predictor of immune checkpoint inhibitor (ICI) treatment efficacy. The clinical efficacy of ICIs for non-small-cell lung cancer (NSCLC) patients harboring major mutations, such as EGFR or ALK mutations, is limited. We genotyped 190 patients with advanced lung adenocarcinomas who received nivolumab or pembrolizumab monotherapy, and examined the efficacy in NSCLC patients with or without major mutations. Among the patients enrolled in the genotyping study, 47 patients harbored EGFR mutations, 25 patients had KRAS mutations, 5 patients had a HER2 mutation, 6 patients had a BRAF mutation, and 7 patients had ALK rearrangement. The status of PD-L1 expression was evaluated in 151 patients, and the rate of high PD-L1 expression (&ge, 50%) was significantly higher in patients with ALK mutations. The progression-free survival was 0.6 (95% CI: 0.2&ndash, 2.1) months for ALK-positive patients and 1.8 (95% CI: 1.2&ndash, 2.1) months for EGFR-positive patients. All patients with ALK rearrangement showed disease progression within three months from the initiation of anti-PD-1 treatment. Our data suggested that ICI treatment was significantly less efficacious in patients with ALK rearrangement than in patients with EGFR mutations, and PD-L1 expression was not a critical biomarker for ICI treatment for patients with one of these mutations.

Purpose: EGFR inhibitors (EGFRi) are effective against EGFR-mutant lung cancers. The efficacy of these drugs, however, is mitigated by the outgrowth of resistant cells, most often driven by a secondary acquired mutation in EGFR, T790M. We recently demonstrated that T790M can arise de novo during treatment; it follows that one potential therapeutic strategy to thwart resistance would be identifying and eliminating these cells [referred to as drug-tolerant cells (DTC)] prior to acquiring secondary mutations like T790M. Experimental Design: We have developed DTCs to EGFRi in EGFR-mutant lung cancer cell lines. Subsequent analyses of DTCs included RNA-seq, high-content microscopy, and protein translational assays. Based on these results, we tested the ability of MCL-1 BH3 mimetics to combine with EGFR inhibitors to eliminate DTCs and shrink EGFR-mutant lung cancer tumors in vivo. Results: We demonstrate surviving EGFR-mutant lung cancer cells upregulate the antiapoptotic protein MCL-1 in response to short-term EGFRi treatment. Mechanistically, DTCs undergo a protein biosynthesis enrichment resulting in increased mTORC1-mediated mRNA translation of MCL-1, revealing a novel mechanism in which lung cancer cells adapt to short-term pressures of apoptosis-inducing kinase inhibitors. Moreover, MCL-1 is a key molecule governing the emergence of early EGFR-mutant DTCs to EGFRi, and we demonstrate it can be effectively cotargeted with clinically emerging MCL-1 inhibitors both in vitro and in vivo. Conclusions: Altogether, these data reveal that this novel therapeutic combination may delay the acquisition of secondary mutations, therefore prolonging therapy efficacy. Clin Cancer Res; 24(22); 5658–72. ©2018 AACR.

This report presents an unusual case of life-threatening massive bleeding in the pulmonary trunk adjacent to the right ventricular outflow tract during resection of a large primary mediastinal nonseminomatous germ cell tumor (PMNSGCT) in the absence of cardiovascular surgeons. The patient was a 21-year-old male whose large mediastinal tumor was diagnosed as an extragonadal PMNSGCT, which was a mixture of a yolk sac tumor and an immature teratoma. Generally, chemotherapy causes extensive peripheral tumor necrosis of PMNSGCTs, thus enabling their complete resection. In this case, surgeons considered the resection as possible by dissecting the peripheral necrotic tissue, and cardiovascular surgeons were thus not consulted. Enlarged modified left hemi-clamshell thoracotomy (HCST) was applied. While dissecting around the pulmonary trunk, the assistant-held forceps accidentally touched the tensed pulmonary trunk, which caused bleeding. We immediately contacted the collaborating cardiac surgery department at another hospital for assistance. Meanwhile, massive bleeding occurred, leading to hemorrhagic shock, and thus direct cardiac massage was required. Our team managed to establish a venoarterial (VA) extracorporeal membrane oxygenation (ECMO). After the arrival of cardiac surgeons, a suction circuit was added, and bleeding was stopped using sutures. Finally, complete resection of the tumor was achieved, and the patient awoke the following day without any brain dysfunction. After discussions with all the members involved in the surgery, we developed an in-hospital consensus on how to perform surgeries for large thoracic tumors safely at our cancer center without the cardiovascular surgery department. We herein present the case and consensus and discuss the relevant issues.

// Yuko Oya 1 , Tatsuya Yoshida 1 , Hiroaki Kuroda 2 , Masashi Mikubo 3 , Chiaki Kondo 1 , Junichi Shimizu 1 , Yoshitsugu Horio 1 , Yukinori Sakao 2 , Toyoaki Hida 1 and Yasushi Yatabe 3 1 Department of Thoracic Oncology, Aichi Cancer Center Hospital, Nagoya, Japan 2 Department of Thoracic Surgery, Aichi Cancer Center Hospital, Nagoya, Japan 3 Department of Pathology and Molecular Diagnostics, Aichi Cancer Center Hospital, Nagoya, Japan Correspondence to: Tatsuya Yoshida, email: t.yoshida@aichi-cc.jp Keywords: nivolumab, non-small cell lung cancer, programmed cell death-1(PD-1), programmed cell death-ligand 1 (PD-L1) Received: June 27, 2017 Accepted: September 21, 2017 Published: October 07, 2017 ABSTRACT Background: Nivolumab offers a superior survival benefit over docetaxel in patients with advanced, previously treated non-small-cell lung cancer (NSCLC). An association between programmed cell death ligand-1 (PD-L1) expression and the efficacy of nivolumab has been reported in many studies. However, the association between the clinical parameters and efficacy of nivolumab remains unclear in advanced NSCLC patients. Results: Among 124 patients, 108 (88%) were performance status (PS) 0 to 1. PD-L1 expression was assessed in 89 patients, with 51 (57%) patients having PD-L1 positive expression. In all patients, the objective response rate (ORR) in patients with elevated CRP levels (≥ 1 mg/dl) was significantly worse than those without elevated CRP levels (< 1 mg/dl) (8.3 vs 23.4%, p = 0.0180). The PS (≥ 2), smoking index (< 400), CRP levels (≥ 1 mg/dl) and LDH (≥ 245 IU/L) were significantly associated with a shorter PFS and OS in patients treated with nivolumab. Multivariate analyses showed that the PS (≥ 2), smoking index (< 400), CRP levels (≥ 1 mg/dl) and LDH (≥ 245 IU/L) and PD-L1 expression were significant factors associated with a longer PFS of nivolumab. Materials and Methods: We retrospectively analyzed 124 patients who received nivolumab as a subsequent treatment. The patient characteristics, laboratory data at baseline (C-reactive protein [CRP] and lactate dehydrogenase [LDH]), PD-L1 expression, nivolumab response, progression-free survival (PFS), and overall survival (OS) were evaluated. Conclusions: Clinical parameters, such as PS, serum CRP, serum LDH, and smoking status, were significantly associated with the response duration and survival in patients treated with nivolumab.