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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.

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

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.

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.

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 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.

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.

Programmed cell death-1 (PD-1) and programmed cell death-ligand 1 (PD-L1) have been identified as novel targets of immunotherapy of lung cancer. In present study, we evaluated the metabolic characteristics of lung cancer by using 18 F-fluorodeoxyglucose positron emission tomography/computed tomography (18 F-FDG PET/CT) with regard to PD-L1 protein expression. PD-L1 protein expression was evaluated by immunohistochemistry with the antibody clone SP142 in 579 surgically resected primary lung cancer patients. Cases with less than 5% tumor membrane staining were considered negative. We examined the association between the frequency of PD-L1 protein expression and the maximum standardized uptake value (SUVmax) in preoperative 18 F-FDG PET/CT. The cut-off values for SUVmax were determined by receiver operating characteristic curve analyses. The SUVmax was significantly higher in nonsmall cell lung cancer (NSCLC) patients with PD-L1 protein expression compared with those without PD-L1 protein expression (P

A tracheal metastasis (TM) from non-pulmonary malignancy is extremely rare, and there are very few reports regarding TM. Here, we report a case of the successful tracheal resection of TM of colorectal cancer. A 36-year-old man underwent a surgical resection for the rectal cancer. Approximately 5 years after the surgical resection of the primary rectal cancer, an isolated TM was identified. The patient was successfully treated with a tracheal resection. In conclusion, the current case suggested that the best treatment of the isolated TM might be a surgical resection.

Background Perianal Paget’s disease (pPD) is uncommon, with only about 180 cases documented in the literature. Anorectal carcinoma with pagetoid spread is even rarer. Case presentation An 81-year-old woman underwent rectal cancer extirpation with a transanal approach 17 years prior. She has since undergone two reoperations for local rectal cancer recurrence. Then, warts frequently appeared on the vulva on several occasions. Warts appeared on the vulva 1 year ago, which were diagnosed as pPD by biopsy. She underwent perineal tumor resection, and the final histological diagnosis was rectal cancer recurrence with pagetoid spread. The resected stump was positive for cancer cells, and tumor progression was rapid. She underwent additional abdominoperineal resection (Miles’ operation) with lymph node dissection. However, disease progression was rapid and she died 7 months after the Miles’ operation. Conclusions There are some case reports describing anorectal carcinoma with pagetoid spread, however, almost of all those cases were synchronous primary anorectal cancer. Here, we report the first case of metachronous recurrence rectal cancer with pagetoid spread arising 17 years after surgery.

Background The usefulness of the controlling nutritional status (CONUT) score for preoperative nutritional assessment has been reported in resected colorectal and esophageal cancer, but not in lung cancer with obstructive lung disease. Patients and methods We retrospectively reviewed 109 patients with adenocarcinoma with obstructive pulmonary disease. We set 1 as the cut-off value for the CONUT score and classified patients into high (≥1) and low (0) CONUT groups. Results Among 109 patients, 35 (32.1%) had low CONUT scores, and 74 (67.8%) had high CONUT scores. The high-CONUT group was significantly associated with a lower body mass index (p=0.025) and wild-type epidermal growth factor receptor mutation status (p=0.011). A multivariate analysis showed that the CONUT score was independently associated with disease-free and overall survival. Conclusion The results of this study suggest that the CONUT score was an independent prognostic factor for disease-free and overall survival in patients with lung adenocarcinoma with obstructive lung disease.

BACKGROUND/AIM Enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase that is deeply involved in the pathogenesis of lung cancer. We evaluated the metabolic characteristics of non-small cell lung cancer (NSCLC) in patients with and without expression of EZH2 using 18F-fluorodeoxyglucose positron-emission tomography/ computed tomography (18F-FDG PET/CT). MATERIALS AND METHODS The EZH2 protein expression of 268 patients with resected NSCLC, whose preoperative 18F-FDG PET/CT information was available, was evaluated by immunohistochemistry with clone 6A10 antibody; cases with Allred score ≥3 were considered positive. RESULTS Maximized standard uptake values in cases of EZH2-positive NSCLC and adenocarcinoma were significantly higher in comparison to EZH2-negative cases (p

A 69-year-old man with locally advanced squamous cell lung cancer in the left hilum underwent left upper sleeve lobectomy following neoadjuvant chemoradiotherapy with an S-1/cisplatin regimen. On postoperative day (POD) 5, the chest X-ray findings deteriorated, and computed tomography (CT) images showed pulmonary congestion of the left residual lung. We then performed emergent left completion pneumonectomy. Although the Postoperative course after re-operation was uneventful, and the patient was scheduled to be discharged on POD 12 when the serum creatinine level and plasma D-dimer level increased to 1.34 mg/dL and 17.4 µg/mL respectively. CT images revealed a giant thrombus in the left superior pulmonary vein (LSPV) stump, and we immediately started anticoagulant therapy of apixaban at 10 mg/day. We confirmed that the thrombus was reduced in size on POD 30, and the patient was discharged without any further complications. The elevated plasma D-dimer level was a key finding in this case for diagnosing pulmonary vein stump thrombosis (PVT) after left lung surgery. The 23 reported cases of PVT were found incidentally through follow-up CT scan or after serious complications occurred. This is the first case reporting the utility of the plasma D-dimer test for diagnosing PVT after surgical resection of the left lung. Early detection of PVT by a plasma D-dimer test may therefore positively contribute to better outcomes in the postoperative course of surgical resection of the left lung.

Background/aim Surgical resection can be applied in cases of early-stage small-cell lung cancer (SCLC). Predicting the histology of SCLC and discriminating SCLC from other histologies would be useful for determining the optimal treatment strategies for small pulmonary nodules that have not been preoperatively diagnosed. Materials and methods The study population included 17 patients with resected SCLC and 296 patients with adenocarcinoma (ADC) whose preoperative CT were available. The tumors of all patients were smaller than 3.0 cm. Results Univariate and multivariate analyses demonstrated that SCLC was significantly associated with the presence of notching and the absence of surrounding ground glass opacity, air bronchogram, pleural indentation, and spiculation in comparison to ADC. Conclusion The CT scans of patients with SCLC of less than 3.0 cm in size showed notching more frequently than those of patients with ADC, whereas surrounding GGO, air bronchogram, pleural indentation and spiculation were observed less frequently compared to ADC.

ObjectivesEpithelial-mesenchymal transition (EMT) and the histone methyltransferase Enhancer of Zeste Homologue 2 (EZH2) are important regulators of lung cancer progression and metastasis. Although recent studies support the correlation between EZH2 expression and EMT, no reports have investigated their association using immunohistochemistry or explored their prognostic impact on lung adenocarcinoma. The aim of this study was to elucidate the association between EZH2 and EMT, and their prognostic significance.MethodsEZH2 and the EMT markers E-cadherin and Vimentin were examined by IHC in lung adenocarcinoma specimens that were resected from 2003-2012. Associations between EZH2 and EMT markers and their correlations with survival were analyzed.ResultsWe enrolled 350 patients, approximately 70% of whom were diagnosed as pathological stage I. The rates of positive E-cadherin, Vimentin, and EZH2 expression were 60.3%, 21.4%, and 52.0%, respectively. There was a significant positive correlation between EZH2 and Vimentin expression (p = 0.008), and EZH2 scores were higher in the Mesenchymal group (p = 0.030). In multivariate analysis, EZH2 was an independent predictor of Vimentin expression, and vice versa. EMT and EZH2 overexpression were significantly correlated with poor disease-free and overall survival. Furthermore, the Epithelial group with high EZH2 expression had significantly worse disease-free and overall survival. Positive staining for EMT markers was unfavorable regarding disease-free survival among patients with low EZH2 expression.ConclusionsEMT and high EZH2 expression were associated with poor NSCLC prognoses. Vimentin is a key factor linking EMT and EZH2 in lung adenocarcinoma.

Inflammatory biomarkers have been associated with clinical outcomes in non-small cell lung cancer (NSCLC). However, the best prognostic marker(s) has not been identified, and the association between inflammatory markers and clinical characteristics is poorly understood. We selected 1,237 patients with resected NSCLC from Kyushu University (2003-2015) and Kyushu Cancer Center (2009-2015) in Japan. Pearson product-moment correlation coefficient among inflammatory markers and area under curve (AUC) of receiver operating characteristic (ROC) curve analyses for overall survival (OS) were calculated. We analyzed the associations between inflammatory markers and clinical factors using Student's t-test. Univariate and multivariate analyses with Cox proportional hazards regression analyses were performed to evaluate the relationship between survival and clinical factors. The cut-off values for neutrophil-lymphocyte ratio (NLR), lymphocyte-monocyte ratio (LMR), platelet-lymphocyte ratio, and derived NLR (dNLR) were determined by ROC curve analyses for OS. We found a strong positive correlation between NLR and dNLR (r = 0.9629). The AUC of LMR was the highest amongst the measured metrics, and the AUC of NLR was higher than dNLR. Levels of some inflammatory markers were associated with sex, smoking, squamous cell carcinoma, and pathological stage. LMR ≥ 5.11 and lactate dehydrogenase (LDH) concentration ≥ 222 (U/L) were independent predictors of both disease-free survival (DFS) and OS (LMR; P = 0.0009 and 0.0008, LDH; P = 0.0195 and 0.0187, respectively). Certain inflammatory markers, potentially linked to smoking, were associated with an advanced pathological stage in NSCLC. LMR and LDH were independent predictors of both DFS and OS.