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Deep-ultraviolet (UV) light-emitting diodes (LEDs) based on AlGaN crystals have low light-emission efficiency; therefore, there is a need to improve this light-emission efficiency for a wide range of applications such as water and air sterilizations. UV-light-transparent device structures are considered one of the many solutions toward increasing light output power. To this end, the present study focused on developing a transparent AlGaN-based tunnel junction (TJ) as the anode of a deep-UV LED. Deep-UV LEDs composed of n+/p+-type AlGaN TJs were fabricated under the growth condition that reduced the carrier compensation in the n+-type AlGaN layers. The operating voltage was 10.8 V under the direct current (DC) operation of 63 A/cm2. In addition, magnesium zinc oxide (MgZnO)/Al reflective electrodes were fabricated to enhance the output power of the AlGaN homoepitaxial TJ LED. The output power was 57.3 mW under a DC operation of 63 A/cm2, and it was 1.7 times higher than that realized using the conventional Ti/Al electrodes. The combination of the AlGaN-based TJ and MgZnO/Al reflective contact allows further improvement of the light output power. This study confirms that the AlGaN TJ is a promising UV-transmittance structure that can obtain a high light-extraction efficiency.

Concurrent chemoradiation therapy (CRT) is the standard of care for patients with unresectable stage II/III lung cancer. However, systemic chemotherapy is required for patients who are ineligible for radical radiation therapy. There is little evidence to date for the safety and efficacy of CRT administered after treatment with immune checkpoint inhibitors (ICIs). The cases reported here had inoperable stage III lung cancer (non‐small cell lung cancer and small cell lung cancer) and were ineligible for radical radiation therapy. They were administered ICIs plus chemotherapy and subsequently underwent late concurrent CRT. Because of the remarkable tumor shrinkage achieved by the ICIs plus chemotherapy, adverse events of CRT were tolerable. They were alive without tumor progression as of this report, over 1 year after CRT was terminated. CRT is administered with curative intent, while the intent of immunochemotherapy is palliative. Late concurrent CRT after immunochemotherapy is probably effective and tolerable. After treatment with systemic chemotherapy in patients judged ineligible for radical radiation therapy, radiation therapy should be reconsidered because of its importance once tumor shrinkage has been achieved., Late concurrent chemoradiation therapy following systemic therapy (immunotherapy or immunochemotherapy) should be considered as an important treatment option for patients initially judged ineligible for definitive chemoradiation therapy.

Epithelial-mesenchymal transition plays a crucial role in cancer progression and is a significant prognosticator for postoperative survival in patients with lung cancer. Predicting epithelial-mesenchymal transition preoperatively using computed tomography may help to determine the optimal surgical strategy.We performed an immunohistochemical analysis of E-cadherin and vimentin expressions using tumor specimens from resected primary lung adenocarcinoma and classified the results into 3 subgroups according to the expressions: epithelial, intermediate, and mesenchymal. The intermediate and mesenchymal groups were classified as the epithelial-mesenchymal transition conversion group. We analyzed the association between epithelial-mesenchymal transition and radiologic characteristics, especially computed tomographic features.The epithelial-mesenchymal transition conversion group comprised 162 patients (49.1%). Computed tomography revealed that tumors with epithelial-mesenchymal transition conversion showed a high consolidation/tumor ratio compared with those without conversion. Univariate analysis demonstrated that tumors with epithelial-mesenchymal transition were significantly associated with bronchial and/or vascular convergence (P .001) and notching (P = .028). When the cutoff value for the consolidation/tumor ratio was set by the receiver operating characteristic curve, independent predictive factors for epithelial-mesenchymal transition by multivariate analysis were high ratio (0.7946; P .001) and the presence of convergence (P = .05). Tumors with a high consolidation/tumor ratio and convergence had a 4-fold higher odds ratio for epithelial-mesenchymal transition, and patients had significantly poorer survival.Convergence and a high consolidation/tumor ratio were independently associated with epithelial-mesenchymal transition conversion. These preoperative radiologic results will help to predict epithelial-mesenchymal transition conversion in lung adenocarcinoma.

Background Video-assisted surgery helps surgeons learn surgical skills efficiently. The aim of this study was to evaluate the effect of mutual evaluation of trainees’ surgical techniques using tabulated common evaluation criteria. Methods We created a check sheet in which a standard pulmonary lobectomy procedure was divided into six parts and the checkpoints to note listed. Both the trainees and trainers used tabulated common evaluation criteria to evaluate lobectomies performed by the trainees. Results From September 2019 to March 2020, 30 lobectomies were performed by three trainees. The trainee’s evaluations of their own procedures were relatively high at first, then decreased, then gradually increased; however, the trainers’ evaluations showed no such tendency. Conclusions Mutual evaluation of surgery using tabulated common evaluation criteria enables trainees to review their own surgery objectively and receive evaluations by trainers, thus helping them to avoid the Dunning–Kruger effect and efficiently acquire basic surgical skills.

Immune checkpoint inhibitors (ICIs) have become the standard of care for the treatment of non‐small cell lung cancer (NSCLC). With the increasing use of ICIs, clinicians should be familiar with their immune‐related adverse events, including sarcoid‐like reactions, which have been associated with the use of ICIs in patients with cancer. Sarcoid‐like reactions are caused by uncontrolled T helper 1‐mediated immune responses resulting from ICIs, but their pathophysiology is not fully understood. Sarcoid‐like reactions are often clinically important because they mimic metastases from treated cancer. According to previous reports, sarcoid‐like reactions are typically observed in intrathoracic locations (lung and/or mediastinal lymph nodes) and the skin. In this study, we report an extremely rare case of extrathoracic sarcoid‐like reaction in the right external iliac lymph node following two cycles of pembrolizumab therapy in a patient with lung adenocarcinoma. The laboratory data and computed tomography images suggested that infectious and autoimmune diseases were not considered to be the causative agents. Residual bone metastasis might have caused T helper 1‐mediated immune responses by pembrolizumab, and contributed to sarcoid‐like reactions in the right external iliac lymph node. Sarcoid‐like reactions should be considered in the differential diagnosis of patients with lung cancer treated with ICIs who exhibit worsening extrathoracic lymph node swelling. Clinicians should be cautious not to mistake extrathoracic sarcoid‐like reactions of the lymph nodes for progression of the treated disease., Sarcoid‐like reactions are sometimes caused by immune checkpoint inhibitor through uncontrolled T helper 1‐mediated immune responses. Here, we report an extremely rare case of extrathoracic sarcoid‐like reaction in the right external iliac lymph node following two cycles of pembrolizumab therapy in a patient with lung adenocarcinoma. Clinicians should be cautious not to mistake extrathoracic sarcoid‐like reactions of the lymph nodes for progression of the treated disease.

Taichi Matsubara, Takashi Seto, Shinkichi Takamori, Takatoshi Fujishita, Ryo Toyozawa, Kensaku Ito, Masafumi Yamaguchi, Tatsuro Okamoto Department of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, Fukuoka, JapanCorrespondence: Taichi MatsubaraDepartment of Thoracic Oncology, National Hospital Organization Kyushu Cancer Center, 3-1-1, Notame, Minami-Ku, Fukuoka, 811-1395, JapanTel +81-92-541-3231Fax +81-92-551-4585Email t_matsu@med.kyushu-u.ac.jpPurpose: Anti-programmed death 1 (PD-1) antibodies have emerged as frontline treatments for patients with advanced non-small cell lung cancer (NSCLC) on the basis of global Phase III trials. However, current data regarding responses to anti–PD-1 therapy in older patients with NSCLC or those with poor performance status (PS) are limited. Therefore, we examined the therapeutic effect of anti PD-1 antibody in these patients.Patients: We retrospectively examined consecutive patients treated with anti–PD-1 monotherapy (pembrolizumab or nivolumab) from January 2016 to September 2018.Results: We enrolled 125 patients (median age, 60 years), 80.8% of whom were men. Patients aged ≥ 75 years were considered older patients (n = 15), and those with PS 2– 3 were regarded as having poor PS (n = 11). The objective response and disease control rates were 15.4% and 46.2%, respectively, in older patients and 9.1% and 27.3%, respectively, in those with poor PS. Progression-free survival (PFS) and overall survival (OS) did not significantly differ between older and younger patients. However, poor PS was significantly associated with poor survival. High programmed death ligand 1 (PD-L1) expression in tumor specimens (≥ 50%) was associated with favorable survival in the entire cohort as well as patients with poor PS. Safety analyses demonstrated no significant difference in the occurrence of any adverse event, including grade ≥ 3 adverse events, between patients with poor PS or older age and the remaining patients.Conclusion: Anti–PD-1 therapy had similar efficacy in older and younger patients with NSCLC, whereas survival was significantly worse in patients with poor PS. However, immune checkpoint inhibitors may be considered for patients with poor PS harboring positive PD-L1 expression.Keywords: immunotherapy, non-small cell lung cancer, lung cancer, prognosis

Pneumonitis can be triggered by anti-cancer therapies: cytotoxic chemotherapy, tyrosine kinase inhibitors, and immune checkpoint inhibitors. There are few treatment options for patients who develop such pneumonitis and their treatment including chemotherapy is generally difficult thus would limit patient’s prognosis. In this study, we investigated the clinical course of patients with lung cancer who developed anti-cancer therapy-related pneumonitis. We retrospectively examined data of patients who had developed pneumonitis triggered by anti-cancer agents and required hospitalization from January 2014 to March 2019 and analyzed their subsequent clinical course and prognosis. The median age of the 58 study patients was 68 years and 82.8% were men. The median interval between first receiving the responsible agent and drug-induced pneumonitis was 7.4 weeks. Approximately 38% of patients were subsequently able to receive some anti-cancer therapy. The median post-pneumonitis overall survival (OS) from commencement of anti-cancer treatment was 13.2 months. No significant differences were found in survival time between treatment agents. However, patients who received some anticancer therapy after pneumonitis had significantly longer survival times than those did not (HR = 4.11, p = 0.0003) and patients who took longer to develop pneumonitis had a longer survival (HR = 2.28, p = 0.0148). Multivariate analysis revealed that short interval to onset and no post-pneumonitis anticancer therapy were independent predictors of short survival. Although patients who developed pneumonitis had relatively short survival times, the interval between initial therapy and pneumonitis had survival impact. Survival can be prolonged by administering further cancer treatment after resolution of pneumonitis.

We previously validated in European patients with NSCLC treated with programmed death-1 (PD-1) checkpoint inhibitors the cumulative detrimental effect of concomitant medications.We evaluated the prognostic ability of a "drug score" computed on the basis of baseline corticosteroids, proton pump inhibitors, and antibiotics, in an independent cohort of Japanese patients with advanced NSCLC treated with PD-1 monotherapy. Subsequently, we assessed the impact of baseline probiotics on the score's diagnostic ability and their interaction with antibiotics in influencing survival.Among the 293 eligible patients, good (19.5 months), intermediate (13.4 months), and poor (3.7 months) risk groups displayed a significantly different overall survival (OS) (log-rank test for trend: p = 0.016), but with a limited diagnostic ability (C-index: 0.57, 95%CI: 0.53-0.61), while no significant impact on progression-free survival (PFS) was reported (log-rank test for trend: p = 0.080; C-index: 0.55, 95%CI: 0.52-0.58). Considering the impact of the probiotics∗antibiotics interaction (p-value 0.0510) on OS, we implemented the drug score by assigning 0 points to concomitant antibiotics and probiotics. With the adapted drug score good, intermediate, and poor risk patients achieved a median OS of 19.6 months, 13.1 months, and 3.7 months, respectively, with a similar diagnostic ability (log-rank test for trend: p = 0.006; C-index: 0.58, 95%CI: 0.54-0.61). However, the diagnostic ability for PFS of the adapted score was improved (log-rank test for trend: p = 0.034; C-index: 0.62, 95%CI: 0.54-0.69).Although we failed to validate the drug score in this independent Japanese cohort, we showed that probiotics may have an antibiotic-dependent impact on its prognostic value. Further investigation looking at the effect of concomitant medications and probiotics across cohorts of different ethnicities is warranted.

Three immune-nutritional parameters exist for malignant tumors using serum C-reactive protein (CRP) and albumin: the Glasgow prognostic score (GPS), the modified GPS (mGPS), and the CRP-albumin ratio (CAR). However, it remains unclear which of the three parameters is the most predictive of prognosis. Therefore, this study compared the clinical and prognostic significance of these parameters for non-small cell carcinoma (NSCLC). The study retrospectively enrolled 596 NSCLC patients who underwent surgical resection at the authors’ institution from January 2010 to December 2015 and investigated the clinicopathologic significance of GPS, mGPS, and CAR. The optimal cutoff value for CAR was determined by a receiver operating curve (ROC). The median age of the patients was 69 years. Lymph node metastases were identified in 99 patients, and 455 patients had a diagnosis of stage 1 disease. The positivity for GPS was 7.6%, and that of mGPS (score, 1 or 2) was 12.2%. Of the 596 patients, 480 patients (80.5%) were classified in the high CAR group. In univariate survival analyses, all three parameters were associated significantly with postoperative survival. The multivariate analyses showed CAR to be an independent prognostic factor. Additionally, survival analyses of the stage 1 subgroup were performed because CAR was higher for patients with an advanced stage of disease or lymph node metastases. In these subgroup analyses, CAR also was an independent prognostic factor. As the most prognostic index, CAR may be useful among the immunonutritional parameters using CRP and albumin for resected NSCLC.

Immunotherapy targeting programmed death‐1 or programmed death‐ligand 1 has become the standard of care for advanced non‐small cell lung cancer (NSCLC). Several recent clinical trials have investigated the efficacy of immune checkpoint inhibitors (ICIs) as neoadjuvant treatment for early NSCLC. However, the safety and feasibility of pulmonary resection after ICIs remain unclear. We herein report a patient in whom cohesion between the left main pulmonary artery and left upper bronchus was found during left upper lobectomy following neoadjuvant ICI combined with chemotherapy. After both central and peripheral sides of the left main pulmonary artery were clamped with the aim of controlling hemorrhage in case of vascular injury, the left main pulmonary artery and left upper bronchus were divided and individually cut with staplers. The thoracoscopic procedure was otherwise uneventful. The patient was discharged from our hospital with no postoperative complications. Thoracic surgeons should anticipate the possible need for management of cohesion between a pulmonary artery and bronchus in patients who have received immune checkpoint inhibitors preoperatively., We herein report a patient in whom cohesion between the left main pulmonary artery and left upper bronchus was found during left upper lobectomy following neoadjuvant immune checkpoint inhibitor combined with chemotherapy. The left main pulmonary artery and left upper bronchus were successfully divided and individually cut with staplers. Thoracic surgeons should anticipate the possible need for management of cohesion between a pulmonary artery and bronchus in patients who have received immune checkpoint inhibitors preoperatively.

Immunotherapy targeting programmed cell death-1 (PD-1) has become a standard pharmacological therapy. Although tumor mutation burden level was reported to depend on the tumor location in nonsmall cell lung cancer (NSCLC), predictive impact of the tumor location on the response to anti-PD-1 therapy is unknown. Two hundred and seventeen advanced or recurrent NSCLC patients treated with anti-PD-1 therapy at Kyushu University Hospital and National Hospital Organization Kyushu Cancer Center were analyzed. To minimize the bias arising from the patients' background, adjusted Kaplan-Meier survival curves and Cox proportional hazards regression analyses using inverse probability of treatment weights (IPTW) were performed. Of the 217 patients, 132, 27, and 58 had primary NSCLC in upper, middle, and lower lobes, respectively. Patients with NSCLC in upper lobe were significantly associated with younger age (P = .0070) and smoker (P = .0003). The epidermal growth factor receptor-wild type and tumor location in upper lobe were independent predictors of disease control (P = .0175 and P = .0425, respectively). The IPTW-adjusted Kaplan-Meier curves showed that patients with NSCLC in the upper lobes had significantly longer progression-free survival (PFS) and overall survival (OS) than those in middle/lower lobes (P = .0026 and P = .0015, respectively). On IPTW adjusted Cox analysis, NSCLC in the upper lobe was an independent predictor of PFS and OS (P = .0078 and P = .0034, respectively). Patients with primary NSCLC in the upper lobes may be good candidates for anti-PD-1 therapy. These findings should be validated prospectively.

Background Preoperative nutritional status is an important host-related prognostic factor for non-small cell lung carcinoma (NSCLC); however, the significance of postoperative changes in nutritional status remains unclear. This study aimed to elucidate the significance of postoperative decreases in serum albumin (ΔAlb) on the outcomes of early-stage NSCLC. Methods We analyzed 443 training cohort (TC) and 642 validation cohort (VC) patients with pStage IA NSCLC who underwent surgery and did not recur within 1 year. We measured preoperative serum albumin levels (preAlb) and postoperative levels 1 year after surgery (postAlb), and calculated ΔAlb as (preAlb − postAlb)/preAlb × 100%. A cutoff value of 11% for ΔAlb was defined on the basis of the receiver operating characteristic curve for the TC. Results Patients were divided into ΔAlb-Decreased and ΔAlb-Stable groups, including 100 (22.6%) and 343 (77.4%) in the TC, and 58 (9.0%) and 584 (90.1%) in the VC. ΔAlb-Decreased was associated with male sex (p = 0.0490), smoking (p = 0.0156), and non-adenocarcinoma (pp = 0.0169) and non-adenocarcinoma (p = 0.0251) in the VC. Multivariable analysis identified ΔAlb as an independent prognostic factor for disease-free survival (DFS) and overall survival (OS) in both cohorts (VC: DFS, HR = 1.9, 95%CI: 1.10–3.15, p = 0.0197; OS, HR = 2.0, 95%CI: 1.13–3.45, p = 0.0173). Moreover, subgroup analysis demonstrated that the prognostic value of ΔAlb was consistent for age, sex, smoking history, surgical procedure, and histological type. Conclusion We demonstrated a negative impact of postoperative decrease of the serum albumin on the prognosis of patients with early-stage NSCLC. Postoperative changes in nutritional status might be important in NSCLC outcomes.

Mesenchymal‐epithelial transition (MET) pathway activation is associated with the mechanisms that influence properties affecting cancer cell survival and invasiveness. The MET exon 14 skipping mutation (METex14del) is found in 2%–3% of patients with non‐small cell lung cancer (NSCLC). Previous studies reported that NSCLC patients harboring a METex14del responded well to MET‐tyrosine kinase inhibitors (TKIs), including tepotinib. Tepotinib is a highly selective, once‐daily oral MET inhibitor that has shown promising clinical activity in patients with NSCLC with METex14del. The Food and Drug Administration accepted a new drug application for tepotinib as a treatment for patients with metastatic NSCLC harboring METex14del in February 2021 [Correction added on 5 March 2021, after first online publication: the FDA approval date for tepotinib has been corrected from ‘September 2019’ to ‘February 2021’.]. However, in the previous clinical trials involving MET‐TKIs, only patients with stable central nervous system metastases were eligible, and those with untreated symptomatic brain metastases (BMs) were excluded. Therefore, the efficacy and safety of MET‐TKIs in that population remains unknown. We herein report a case of dramatic intracranial response to tepotinib in a patient with symptomatic BMs from lung adenocarcinoma harboring METex14del. In the current report, the symptoms derived from multiple BMs (headache and loss of appetite) rapidly disappeared, and brain magnetic resonance imaging (MRI) examination showed that all the lesions were too small to measure only 23 days after the commencement of tepotinib. For NSCLC patients with multiple BMs, whole‐brain irradiation is a standard‐of‐care therapy, but its adverse effects on neurocognition are concerning. Tepotinib might therefore be a therapeutic option for NSCLC patients with symptomatic multiple BMs harboring METex14del., In the previous clinical trials, patients with symptomatic brain metastases (BMs) from lung cancer harboring METex14del were excluded. We report a case of dramatic intracranial response to tepotinib in a patient with symptomatic BMs from lung adenocarcinoma harboring METex14del. Tepotinib might be a therapeutic option for lung cancer patients with symptomatic multiple BMs harboring METex14del.

Background/aim Adjuvant platinum-based chemotherapy (APC) has been the standard of care for patients with non-small-cell lung cancer (NSCLC) who have undergone complete pulmonary resection. This study analyzed the clinical and prognostic significance of immunonutritional indices in NSCLC patients receiving APC. Patients and methods We retrospectively reviewed 110 patients from 2008 to 2016. Three immunonutritional indices were calculated: neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), and prognostic nutritional index (PNI). Results The median age was 64 years, and 66 patients were males. Each index showed a significant correlation with primary tumor length. NLR and PLR were significantly correlated with vascular invasion. Prognostic analyses revealed that each index was significantly correlated with postoperative recurrence-free survival (RFS) and overall survival (OS). On multivariate analyses, PNI was an independent predictor of RFS and OS. Conclusion Host immunonutritional status may have a significant effect on the postoperative prognosis of NSCLC in patients receiving APC.

In patients with non‐small cell lung cancer (NSCLC), stereotactic radiotherapy (SRT) is one of the standard therapies for those suffering with intracranial metastatic NSCLC. Radiation‐induced necrosis (RIN) sometimes occurs as the result of the delayed effects of SRT. The magnetic resonance imaging (MRI) of RIN typically shows hypointense and hyperintense lesions on T1‐ and T2‐weighted images, respectively. We herein report a patient with a growing brain cystic lesion mimicking RIN adjacent to a post‐radiation brain metastasis from NSCLC harboring anaplastic lymphoma kinase rearrangement. The patient underwent surgical resection of the brain tumor because of the symptoms. The pathological diagnosis was cavernous hemangioma, and the pathological findings were an encapsulated nodular mass composed of dilated, cavernous vascular spaces with no residual tumor or recurrence. Clinicians should be aware of the possibility for the development of a brain cavernous hemangioma following SRT in NSCLC patients.

Background The epithelial–mesenchymal transition (EMT) describes the process through which cells lose epithelial characteristics and gain a mesenchymal phenotype. The EMT contributes to tumor invasion and cancer progression, and is associated with metastasis and poor survival of patients with non–small-cell lung cancer. However, little is known about the relationships between the EMT and the clinicopathologic characteristics of patients with stage IA lung adenocarcinoma. Patients and Methods We conducted immunohistochemical analysis of the expression of the EMT markers E-cadherin and vimentin of specimens acquired from 183 consecutive patients with stage IA lung adenocarcinoma. The clinicopathologic significance of the association of the EMT status with E-cadherin and vimentin expression was analyzed after propensity score matching. Results E-cadherin and vimentin were detected in 68.3% and 18.6% of stage IA lung adenocarcinomas, respectively. The presence of cells with EMT conversion was associated with older patient age. A propensity score–matched cohort (128 patients) was used for further analyses. Computed tomography revealed that tumors with EMT conversion showed solid-dominant nodules compared to those without conversion. Survival analysis after propensity score matching showed that the EMT correlated with poor disease-free survival (hazard ratio = 2.57, P = .0451) and overall survival (hazard ratio = 4.23, P = .0471). Multivariate analysis revealed that the EMT was an independent predictor of shorter disease-free survival. Conclusion The EMT was a significant predictor of poor prognosis of patients with stage IA lung adenocarcinoma. The EMT status may serve as an indicator for administering adjuvant therapy.

BACKGROUND: Controlling nutritional status (CONUT) and skeletal muscle area (SMA) are both useful prognostic factors in patients with non-small cell lung cancer (NSCLC). We hypothesized that low serum creatine kinase (CK) would be a surrogate of decreased SMA, and defined a novel prognostic factor, CONUT/CK score (CNKS). The aim of this study was to elucidate the clinical significance of CNKS in NSCLC patients. METHODS: One hundred and eighty-nine patients who underwent surgical resection of NSCLC and whose preoperative computed tomography images were available were enrolled. The CNKS was calculated by summing CONUT score and CK score, which was defined as 0 if the CK concentration is within normal range, and 2 if it is under lower limit. The optimal cut-off values of CNKS and CONUT score were 4 and 2, respectively. RESULTS: Low CK was significantly associated with decreased SMA (P=0.012). The high CNKS group was significantly associated with men and smoking history (P=0.006 and P=0.015, respectively). The high CNKS group had significantly shorter overall survival (OS) and disease-free survival (DFS) (P

Molecular drugs targeting mutated or rearranged oncogene drivers have become one of the standard recognized treatments in patients with advanced and recurrent non-small cell lung cancer. RET is located in the long arm of human chromosome 10 and encodes a receptor tyrosine kinase protein, and RET fusion-positive lung adenocarcinoma occurs in 1%–2% of cases. Clinical trials of multikinase inhibitors, including cabozantinib, vandetanib, sorafenib, and lenvatinib, that inhibit RET oncogene activity have shown their antitumor efficacy. Recently, RET inhibitors such as pralsetinib and selpercatinib that are specialized for RET kinase have also been developed, and their efficacy was investigated in previous clinical trials (BLU-667 and LOXO-292). In this review, we summarized the effects and adverse events of multikinase and selective RET inhibitors and the various diagnostic techniques for RET gene fusion. In the perspective part, we focused on the unsolved issues on treatment for RET fusion-positive lung cancer and future developments.

Genetic alterations underlying the development of lung cancer in individuals with idiopathic pulmonary fibrosis (IPF) have remained unclear. To explore whether genetic alterations in IPF tissue contribute to the development of IPF-associated lung cancer, we here evaluated tumor mutation burden (TMB) and somatic variants in 14 paired IPF and tumor samples from patients with IPF-associated lung adenocarcinoma. We also determined TMB for 22 samples of lung adenocarcinoma from patients without IPF. TMB for IPF-associated lung adenocarcinoma was significantly higher than that for matched IPF tissue (median of 2.94 vs. 1.26 mutations/Mb, P = 0.002). Three and 102 somatic variants were detected in IPF and matched lung adenocarcinoma samples, respectively, with only one pair of specimens sharing one somatic variant. TMB for IPF-associated lung adenocarcinoma was similar to that for lung adenocarcinoma samples with driver mutations (median of 2.94 vs. 2.51 mutations/Mb) and lower than that for lung adenocarcinoma samples without known driver mutations (median of 2.94 vs. 5.03 mutations/Mb, P = 0.130) from patients without IPF. Our findings suggest that not only the accumulation of somatic mutations but other factors such as inflammation and oxidative stress might contribute to the development and progression of lung cancer in patients with IPF.

To explore the clinicopathological and surgical characteristics and to determine the prognostic outcome of patients who underwent second pulmonary resection for secondary primary lung cancer(SPLC).We retrospectively examined 35 patients who underwent second pulmonary resection for secondary primary non-small cell lung cancer from 2009 to 2016.The median age was 67 years and 54% of patients were male. Twenty-one patients were resected for synchronous disease and 14 were resected for metachronous disease. The median interval between first and second surgery was 9.8 months. Six patients underwent lobectomy twice for both lung cancers. Sublober resection was significantly performed at second surgery, and tumor size of SPLC was significantly smaller than that of first cancer. There was no significant difference for pathological stage between first and second cancer:27 patients were diagnosed as stageⅠat first surgery, and 33 were diagnosed as stageⅠat second surgery. The five-year recurrence free survival (RFS) rate was 74.1%, and five-year overall survival (OS) rate was 85.7%. There were no significant survival differences between synchronous and metachronous secondary cancer groups for RFS and OS. Surgical pro cedures and secondary cancer profile (synchronous or metachronous) were not associated with postoperative survival by univariate and multivariate analyses.Surgical resection for SPLC may be tolerable if lobectomy is required for curative resection.

Immune checkpoint inhibitors (ICIs) targeting programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have markedly improved the prognosis of many patients with advanced non-small cell lung cancer (NSCLC). However, the relationship between the patient’s nutritional/immunologic status and the outcomes of ICI treatment remains unclear. In previous retrospective studies, we reported that the controlling nutritional status (CONUT) score, skeletal muscle area, and neutrophil-to-lymphocyte ratio were independent predictors of the response of NSCLC patients to anti-PD-1 drugs. The aim of this prospective multi-center study is to investigate the clinical impact of pre-treatment nutritional/immunologic indices and early post-treatment changes in the indices on treatment outcomes in advanced NSCLC. The main inclusion criteria are: (1) stage IV NSCLC, or stage III NSCLC not applicable for definitive chemoradiotherapy; (2) treatment with ICIs (monotherapy or combined with chemotherapy) as first-line therapy; and (3) available data on PD-L1 expression on tumor cells. A total of 300 patients will be enrolled prospectively. Enrollment will begin in 2020 and the final analyses will be completed by 2025.

In this study, we enhanced the emission power of AlGaN-based tunnel junction deep-ultraviolet LEDs (TJ LEDs) by using a MgZnO and aluminum stacked structure as UV reflective electrodes on the anode side. The emission wavelength of the fabricated TJ LED was 284 nm, and the emission power was 57.3 mW at 63 A cm−2. The polycrystalline MgZnO enabled both conductivity and UV transmittance to be achieved, approximately doubling with a reflectance of the fabricated TJ LED at 284 nm compared to conventional TJ LED with Ti/Al. These factors contributed to the increased emission power of TJ LEDs.

Immune checkpoint inhibitors (ICIs) have become one of the standard therapies in non-small-cell lung cancer (NSCLC). Although inflammatory indices, including Glasgow prognostic score (GPS), modified Glasgow prognostic score (mGPS), and C-reactive protein/albumin ratio (CAR) were reported to be reliable predictors for survival in cancer patients, their clinical utility in NSCLC patients treated with ICIs is unknown.Advanced or recurrent NSCLC patients (n = 304) treated with ICI monotherapy at the National Hospital Organization Kyushu Cancer Center and Kyushu University Hospital between January 2016 and December 2019 were analyzed. Information on patient demographics, GPS, mGPS, and CAR at diagnosis were collected. The time-dependent area under curves (AUCs) of receiver operating characteristic curves for the prediction of overall survival (OS) for each factor were compared.Of the three indices, GPS was the most significantly correlated with the degree of disease control rate (DCR) (DCR of GPS of 0, 1, and 2: 63.6 %, 49.4 %, and 41.4 %, respectively). The time-dependent AUC values of GPS for the prediction of OS were superior to those of mGPS and CAR (time-dependent AUC values of GPS, mGPS, and CAR for the prediction of 1-year OS: 0.7005, 0.6736, and 0.6565, respectively). GPS was significantly correlated with performance status (PS) (P 0.0001) and clinical stage (P = 0.0139). GPS in combination with PS effectively predicted survival at 1 year ranging from 83.5 % (GPS = 0, PS = 0) to 25.0 % (GPS = 2, PS = 2, 3). A multivariable analysis revealed that GPS was an independent predictor of PFS and OS (P = 0.0009 and P = 0.0100, respectively).We report for the first time that GPS represents a simple and useful prognostic factor in NSCLC patients treated with ICIs and should be validated prospectively.

Background Immunotherapy targeting programmed cell death-1 (PD-1) and programmed death-ligand 1 (PD-L1) has become the forefront strategy for systemic therapy in advanced non-small cell lung cancer (NSCLC) patients. PD-L1 expression on tumor cells has been reported as an eligible biomarker of response to such immunotherapies. However, useful biomarkers of response to atezolizumab, an anti PD-L1 antibody, are unestablished. Methods We retrospectively analyzed clinicopathological characteristics including PD-L1 expression in NSCLC patients treated with atezolizumab from January 2018 at our department. In addition, we investigated the prognostic effect of the following pretreatment immune-inflammation-nutritional parameters: prognostic nutritional index (PNI), neutrophil/lymphocyte ratio (NLR), platelet/lymphocyte ratio (PLR), and modified Glasgow prognostic score (mGPS). Results Twenty-four patients were enrolled in this study. The median age was 64.5 (range, 49-82) years, and 17 (70.8%) were men. Among this cohort, two patients showed high PD-L1 expression (≥50%), seven showed low (1-49%) expression, and the other 15 patients showed 0% or unknown expression. Survival analyses showed that low PNI was an independent predictor of short time to treatment failure (TTF) [hazard ratio (HR) =6.87, P=0.0052], and high NLR (HR =3.53, P=0.0375) and high mGPS (HR =23.2, P=0.0038) were independent prognostic factors for overall survival (OS) after atezolizumab. Furthermore, the NLR high/mGPS high group had far worse prognosis than the NLR low/mGPS low group. Conclusions The therapeutic and prognostic effect of atezolizumab may depend on the host immune-nutritional status. This study provided novel but retrospective evidence, and thus further prospective studies are needed.

Immune checkpoint inhibitors (ICIs) have become a standard therapy in non-small cell lung cancer (NSCLC). Although lung cancer adjoining emphysematous bullae (Ca-ADJ) were reported to express higher programmed cell death-ligand 1 (PD-L1), the predictive impact of Ca-ADJ on the response to ICIs is unknown. Two hundred and fifty-seven advanced or recurrent NSCLC patients treated with ICI monotherapy at Kyushu University Hospital and National Hospital Organization Kyushu Cancer Center were analyzed. To minimize the bias arising from the patients’ background, adjusted Kaplan–Meier survival curves and Cox proportional hazards regression analyses using inverse probability of treatment weights (IPTW) were performed. Of the 257 patients, 55 had Ca-ADJ. Patients with Ca-ADJ were significantly associated with younger age (P = 0.0343), male sex (P = 0.0070), and smoking (P = 0.0080). The objective response rate of cases with Ca-ADJ was significantly higher than that of those without Ca-ADJ (36.4% vs. 20.8%, respectively; P = 0.0167). The disease control rate of cases with Ca-ADJ was also significantly higher than tumors without Ca-ADJ (63.6% vs. 47.5%, respectively; P = 0.0341). The IPTW-adjusted Kaplan–Meier curves showed that patients with Ca-ADJ had significantly longer progression-free survival (PFS) and overall survival (OS) than those without Ca-ADJ (P = 0.0407 and P = 0.0126, respectively). On IPTW-adjusted Cox analysis, Ca-ADJ was an independent predictor of PFS and OS (P

The pack-year index, which is calculated by multiplying a smoking period by the number of cigarette packs smoked per day, is frequently used to investigate the risk of developing lung cancer. Notably, however, whether the smoking period or the number of packs per day is more predictive of postoperative prognosis remains unclear in non-small cell lung cancer (NSCLC) patients who receive curative lung resection. Initial screening included 2055 consecutive lung cancer patients who had underwent curative lung resection between 2000 and 2016 at a single center in Japan. Data from 1134 NSCLC patients with smoking history were ultimately analyzed. Time-dependent areas under the curve (AUCs) were used to compare diagnostic accuracy. On univariate analysis, the number of packs smoked per day was not a significant predictor of disease-free survival (DFS; p = 0.2387) or overall survival (OS; p = 0.1357). On multivariable analysis, smoking period was an independent predictor of DFS and OS (both p

The transformation of adenocarcinoma to small cell lung cancer has been reported as acquisition of resistance to epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitors. We here report a patient who presented histologically confirmed transformation of adenocarcinoma to small cell lung cancer after treatment with immune checkpoint inhibitor. A 65-year-old man was treated with pembrolizumab as first-line therapy and achieved temporarily a stable disease with progression after six cycles of this agent. At that stage, a transbronchial biopsy showed small cell lung cancer, and he was found to have high serum concentrations of neuron-specific enolase despite concentrations of numerous tumor markers, including neuron-specific enolase, having been within normal limits at the time of presentation. The patient thereafter was treated as a small cell carcinoma patient using cisplatin plus irinotecan and amrubicin.

Introduction During treatment with immune checkpoint inhibitors, immune-related adverse events sometimes occur, and their management is a critical concern associated with such treatment. Encephalitis and meningitis are some of the critical immune-related adverse events. Atezolizumab is an immune checkpoint inhibitor that inhibits the programmed cell death-ligand. Encephalitis and meningitis were reported in 0.8% of the patients in the atezolizumab versus docetaxel in patients with previously treated NSCLC. However, none of the reports have clarified the details concerning atezolizumab-induced encephalitis and meningitis, including their background, time of onset, treatment, and therapeutic course. We herein report about three patients who experienced atezolizumab-induced meningitis in our department. Methods Of the 29 patients who received atezolizumab in our department between October 2015 and September 2018, three developed aseptic meningitis. We retrospectively examined their clinical, radiologic, and cytologic features. Results In all three cases, a depressed level of consciousness followed fever in cycle 1, days 15 and 16 after administration of atezolizumab. Cerebrospinal fluid examination revealed that the number of cells was not increased despite the protein level being high. No definite malignant cells were identified in the cerebrospinal fluid in any of the three cases. Only one patient exhibited abnormal enhancement along the lines of the corpus callosum on magnetic resonance imaging. On the basis of these findings, the patients were diagnosed with atezolizumab-induced meningitis. After the administration of methylprednisolone (1000 mg for 3 d), they promptly became conscious and alert. Conclusion Atezolizumab-induced meningitis may have some specific features, such as a characteristic development period, findings in magnetic resonance imaging, and premonitory symptoms.

AIM To investigate the radiological features on computed tomography (CT) of brain metastasis (BM) from epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). PATIENTS AND METHODS Thirty-four patients with NSCLC with BMs who underwent surgical resection of the BMs at the Department of Neurosurgery, Kyushu University from 2005 to 2016 were enrolled in the study. The EGFR statuses of the 34 BMs were investigated. Radiological features, including the number, size, and location of the tumor, were delineated by CT. RESULTS Patients with EGFR-mutated BMs had significantly higher frequencies of multiple metastases than those with the non-EGFR-mutated type (p=0.042). BMs harboring mutations in EGFR were more frequently observed in the central area of the brain compared to those without mutations in EGFR (p=0.037). CONCLUSION Careful follow-up of patients with EGFR-mutated NSCLC may be necessary given the high frequencies of multiple BMs and their location in the central area of the brain.

The aim of this study was to elucidate the relationship between family‐associated factors and the postoperative prognosis in patients with nonsmall cell lung cancer (NSCLC). Additionally, we investigated whether having children was associated with the postoperative maintenance of the nutritional status. We selected 438 NSCLC patients who had undergone curative lung resection between 2004 and 2011 at Kyushu University (Fukuoka, Japan), whose family‐associated factors were available. Nutritional indices, including the prognostic nutritional index (PNI), were used to estimate the change in the nutritional status for 1 year after surgery. A propensity score analysis was conducted after adjusting the following variables: sex, age, smoking history, performance status, pathological stage, and histological type. Three hundred patients (68.5%) had both children and partners. Forty‐nine patients (11.2%) only had children, and 56 (12.8%) patients only had a partner. Thirty‐three patients (7.5%) did not have a partner or children. The overall survival (OS) and disease‐free survival (DFS) of the partner‐present and partner‐absent patients did not differ to a statistically significant extent (P = .862 and P = .712, respectively). However, childless patients showed significantly shorter OS and DFS in comparison with patients with children (P = .005 and P = .002, respectively). The postoperative exacerbation of PNI was significantly greater in childless patients than in patients with children (P = .003). These results remained after propensity score matching. Childless patients had a significantly poorer postoperative prognosis than those with children. Surgeons caring for childless NSCLC patients should be aware of the poorer postoperative outcomes in this population.

Programmed death-1 (PD-1) and programmed death-ligand 1 (PD-L1) inhibitors have been approved as a standard therapy for metastatic non-small cell lung cancer (NSCLC). Although PD-L1 expression serves as a predictive biomarker for the efficacy of immunotherapy, there are no established biomarkers to predict the expression of PD-L1. The inflammatory markers C-reactive protein (CRP) and neutrophil-lymphocyte ratio (NLR) were recently shown to predict the efficacy of nivolumab for NSCLC patients. Therefore, here we investigated the potential association of PD-L1 expression with systemic inflammatory markers, including CRP, NLR, lymphocyte-monocyte ratio and platelet-lymphocyte ratio.We retrospectively examined tumor PD-L1 expression in 508 surgically resected primary NSCLC cases by immunohistochemical analysis (cut-off value: 1%). The association of PD-L1 expression with preoperative systemic inflammatory markers was assessed by univariate and multivariate analyses. We generated a PD-L1 association score (A-score) from serum CRP level (cut-off value: 0.3 mg/dl) and smoking status to predict PD-L1 expression.Among the total 508 patients, 188 (37.0%) patients were positive for PD-L1 expression at the 1% cut-off value and 90 (17.5%) had elevated serum CRP level. Multivariate logistic regression revealed that PD-L1 positivity was significantly associated with advanced stage, the presence of vascular invasion and high serum CRP level (P = .0336, .0106 and 0.0018, respectively). Though not significant, smoking history tended to be associated with PD-L1 protein expression (P = .0717). There was no correlation with other inflammatory markers. Smoking history with elevated CRP level (A-score: 2) was strongly associated with PD-L1 protein expression (odds ratio: 5.18, P .0001), while it was inversely associated with EGFR mutation (odds ratio: 0.11, P .0001).Our results indicate that among all systemic inflammatory markers examined, serum CRP seems to predict PD-L1 expression in patients with NSCLC however the clinical applicability is limited given the obtained area under the receiver operating characteristic curve values.

Background Little is known about the programmed death-ligand 1 (PD-L1) expression in multifocal lung cancer, such as the expression in multiple primary lung cancer and pulmonary metastasis. In this translational study, we investigated PD-L1 expression and its relationship with the epidermal growth factor receptor ( EGFR ) mutation status in resected multifocal lung cancer. Methods The PD-L1 expression in 152 samples of multifocal lung cancer from 59 patients was evaluated by an immunohistochemical analysis. Results Among the 152 lung cancer lesions of 59 patients, PD-L1 expression was observed in 29 lesions (19.1%) of 20 patients (33.9%). Among 43 patients with 112 multiple primary lung cancer lesions, 15 lesions (13.4%) of 13 patients (30.2%) were PD-L1 positive; and among 16 patients with 40 pulmonary metastatic lesions, 14 lesions (35.0%) of 7 patients (43.8%) were PD-L1-positive. Among 43 patients with multiple primary lung cancer, there was disagreement of PD-L1 expression in 12 patients (27.9%, κ = 0.104). On the contrary, among 16 patients with pulmonary metastasis, disagreement of PD-L1 expression was observed only in 1 patient (6.3%, κ = 0.871). In pulmonary metastatic lesions, the frequency of PD-L1 positivity among lesions with wild-type EGFR was significantly higher than among lesions with mutated EGFR (66.7% versus 0%: p Conclusions This study provides important evidence of higher levels of agreement of PD-L1 expression in pulmonary metastasis compared with in multiple primary lung cancer, and high positivity of PD-L1 expression in pulmonary metastatic lesions with wild-type EGFR in an Asian population.