A Systemic Immune Inflammation Index and PD-L1 (SP142) Expression as a Potential Combined Biomarker of the Clinical Benefit of Chemo-Immunotherapy in Extensive-Stage Small-Cell Lung Cancer.

Background: No studies have identified combined biomarkers that may be more reasonable for the assessment of current chemo-immunotherapy in patients with extensive stage small-cell lung cancer (ES-SCLC). Methods: This study was conducted to investigate a combined biomarker with prognostic or predictive value in ES-SCLC. We determined the best independent prognostic biomarker among the four complete blood-count-derived inflammatory biomarkers (CBC-IBs). Subsequently, we analyzed the prognostic or predictive value of combining this independent CBC-IB with PD-L1 (SP142) expression. We prospectively assessed the SP142 analyses in tumor samples at diagnosis. Results: All in all, 55 patients with ES-SCLC were classified into four groups according to the systemic immune inflammation index (SII) (low/high) and SP142 (positive/negative). The best survival was observed in the low-SII/ SP142-positive group, whereas the worst survival was observed in the high-SII/SP142-negative group (p = 0.002). The combined SII-SP142 biomarker was better for predicting both survival and disease progression in patients with ES-SCLC. Conclusions: The combined SII-SP142 biomarker can be readily and universally obtained at a low cost in clinical practice, without requiring advanced genomics technology or specialized expertise. Although further studies are needed to confirm that the combined SII-SP142 biomarker is widely applicable, it should help clinicians to identify the best patients for combined chemotherapy with atezolizumab in ES-SCLC.

A Novel Score Using Lymphocyte-to-Monocyte Ratio in Blood and Malignant Body Fluid for Predicting Prognosis of Patients with Advanced Ovarian Cancer.

(1) Background: The lymphocyte-to-monocyte ratio (LMR), one of the systemic inflammatory markers, has been shown to be associated with prognosis of various solid tumors. However, no study has reported clinical utility of the LMR of malignant body fluid (mLMR) (2) Methods: We retrospectively analyzed clinical data of the final 92 patients of a total of 197 patients with advanced ovarian cancer newly diagnosed from November 2015 and December 2021 using our institute big data. (3) Results: Patients were divided into three groups according to their combined bLMR and mLMR scores (bmLMR score): 2, both bLMR and mLMR were elevated; 1, bLMR or mLMR was elevated; and 0, neither bLMR nor mLMR was elevated. A multivariable analysis confirmed that the histologic grade (p = 0.001), status of residual disease (p < 0.001), and bmLMR score (p < 0.001) were independent predictors of disease progression. A low combined value of bLMR and mLMR was strongly associated with a poor prognosis in patients with ovarian cancer. (4) Conclusions: Although further studies are required to apply our results clinically, this is the first study to validate the clinical value of mLMR for predicting prognosis of patients with advanced ovarian cancer.

Two cases of large tracheobronchial schwannomas completely resected by rigid bronchoscopy with multiple instruments.

Primary tracheobronchial schwannomas are extremely rare. Surgical treatment has been the first choice for these benign tumours due to the substantial residual rates and recurrences after bronchoscopic resection. In addition, there has been limited information on bronchoscopic removal of endobronchial schwannomas. We describe two cases of large tracheal and bronchial schwannomas that were completely and successfully resected by snare electrocautery, insulation-tipped knife, and argon plasma coagulation under rigid bronchoscopy. These cases highlight that rigid bronchoscopic treatment with these multiple instruments can be a good treatment option for endotracheal or endobronchial schwannomas.

Trends and an Online Survey on the Use of Rigid Bronchoscopy in Korea.

BACKGROUND: Although almost all interventional pulmonologists agree that rigid bronchoscopy is irreplaceable in the field of interventional pulmonology, less is known about the types of diseases that the procedure is used for and what difficulties the operators face during the procedure. The purpose of this study is to evaluate what diseases rigid bronchoscopy is used for, whether it is widely used, and what challenges the operators face in Korea. METHODS: We enrolled 14 hospitals in this retrospective cohort of patients who underwent rigid bronchoscopy between 2003 and 2020. An online survey was conducted with 14 operators to investigate the difficulties associated with the procedure. RESULTS: While the number of new patients at Samsung Medical Center (SMC) increased from 189 in 2003-2005 to 468 in 2018-2020, that of other institutions increased from 0 to 238. The proportion of SMC patients in the total started at 100% and steadily decreased to 59.2%. The proportion of malignancy as the indication for the procedure steadily increased from 29.1% to 43.0%, whereas post-tuberculous stenosis (25.4% to 12.9%) and post-intubation stenosis (19.0% to 10.9%) steadily decreased (all P for trends < 0.001). In the online survey, half of the respondents stated that over the past year they performed less than one procedure per month. The fewer the procedures performed within the last year, the more likely collaboration with other departments was viewed as a recent obstacle (Spearman correlation coefficient, rs = -0.740, P = 0.003) and recent administrative difficulties were encountered (rs = -0.616, P = 0.019). CONCLUSION: This study demonstrated that the number of patients undergoing rigid bronchoscopy has been increasing, especially among cancer patients. For this procedure to be used more widely, it will be important for beginners to systematically learn about the procedure itself as well as to achieve multidisciplinary consultation.

Efficacy of crizotinib retreatment after crizotinib-related interstitial lung disease in a patient with ROS1-rearranged advanced lung adenocarcinoma: A case report and potential crizotinib retreatment strategy.

Crizotinib is an oral selective small-molecular tyrosine kinase inhibitor (TKI) that suppress the activity of anaplastic lymphoma kinase (ALK) and ROS1 kinases, as well as mesenchymal-epithelial transition. The cumulative clinical trials in patients with advanced ALK- or ROS1-rearrangement NSCLC indicate that crizotinib has significant antitumor activity and a tolerable safety profile, with mild or moderate adverse events of visual disorders, diarrhea, nausea, and vomiting. As with other TKIs, however, the occurrence of crizotinib-related interstitial lung disease (crizotinib-ILD) remains a major clinical dilemma that can lead to the permanent discontinuation of TKI during cancer treatment. When there is no suitable alternative therapy for patients who develop crizotinib-ILD, some clinicians have reported successful crizotinib retreatment in cases of ALK-rearrangement NSCLC. Unfortunately, there are no specific guidelines for the treatment or retreatment of TKI-related ILD. We herein report the first successful crizotinib retreatment after crizotinib-ILD in a patient with ROS1-rearranged NSCLC, and suggest a retreatment strategy after crizotinib-ILD based on a literature review.

Efficacy and safety of apatinib as second or later-line therapy in extensive-stage small cell lung cancer: a prospective, exploratory, single-arm, multi-center clinical trial.

Background: A paucity of strategies exist for extensive-stage small cell lung cancer (ES-SCLC) patients who fail the first-line chemotherapy. Apatinib is a tyrosine kinase inhibitor (TKI) that selectively inhibits vascular endothelial growth factor receptor-2 (VEGFR-2), which has been demonstrated to have active anti-tumor activity in ES-SCLC when used only or combined with PD-1 inhibitors or chemotherapy with good tolerance. However, the efficacy and safety of apatinib monotherapy is unclear in second-line or beyond treatment of ES-SCLC. Methods: In this prospective, exploratory, single-arm, multi-center study, eligible patients were aged 18 years or older with histologically confirmed ES-SCLC, and had progressed on, or were intolerant to previous systemic treatment. Patients received apatinib 500 mg (orally qd, every 4 weeks a cycle). The efficacy was assessed after 1 cycle and then every 2 cycles based on computed tomography imaging per the Response Evaluation Criteria in Solid Tumors (RECIST, version 1.1). The primary endpoint was progression-free survival (PFS). The adverse events (AEs) were assessed per the National Cancer Institute Common Terminology Criteria for Adverse Events 4.0 (NCI-CTCAE 4.0). This study is registered in the Chinese Clinical Trial Registry, number ChiCTR-OPC-17013964. Results: From 28 July 2017 to 21 June 2019, 62 patients were screened for eligibility, among whom 57 patients were available for efficacy and safety analysis. The objective response rate (ORR) was 14.3% and disease control rate (DCR) was 79.6%. The median PFS was 5.6 months [95% confidence interval (CI): 3.3-8.0 months] and the median overall survival (OS) was 11.2 months (95% CI: 7.5-24.0 months). Among the participants who received apatinib as second-line treatment, the median PFS and OS were 6.1 months (95% CI: 2.6-7.6 months) and 12.0 months (95% CI: 7.9 months to not reached), respectively. The most common AEs of all grades were anemia (36.8%), hypertension (33.3%), fatigue (31.6%), blood bilirubin increased (22.8%), elevated transaminase (19.3%), and hand-foot syndrome (17.54%). Grade 3 AEs included 2 (3.5%) cases of hypertension and 1 (1.8%) case of fatigue. No grade 4/5 AEs were observed. Conclusions: Apatinib showed encouraging anti-tumor activity in pretreated ES-SCLC patients with tolerable toxicities. Further larger scale studies are warranted to demonstrate the efficacy of apatinib.

A Preliminary Study on the Prognostic Impact of Neutrophil to Lymphocyte Ratio of the Bronchoalveolar Lavage Fluid in Patients with Lung Cancer.

The cumulative results indicate that the neutrophil to lymphocyte ratio of peripheral blood (pbNLR) is a useful prognostic factor in patients with various cancers. In contrast to peripheral blood, the bronchoalveolar lavage (BAL) fluid is in direct contact with the lung lesion. However, no study has reported on the clinical utility of the NLR of BAL fluid (bNLR) for patients with lung cancer. To investigate the clinical utility of the bNLR as a prognostic factor in patients with lung cancer, we conducted a retrospective review of the prospectively collected data. A total of 45 patients were classified into high bNLR (n = 29) and low bNLR (n = 16) groups. A high pbNLR and high bNLR were associated with a shorter overall survival (p < 0.001 and p = 0.011, respectively). A multivariable analysis confirmed that ECOG PS (p = 0.023), M stage (p = 0.035), pbNLR (p = 0.008), and bNLR (p = 0.0160) were independent predictors of overall survival. Similar to the pbNLR, a high bNLR value was associated with a poor prognosis in patients with lung cancer. Although further studies are required to apply our results clinically, this is the first study to show the clinical value of the bNLR in patients with lung cancer.

The clinical impact of three validated PD-L1 immunohistochemistry assays as a prognostic factor in small cell lung cancer.

BACKGROUND: Evidence of the clinical impact of programmed death-ligand 1 (PD-L1) expression in small cell lung cancer (SCLC) is scarce and conflicting, even though atezolizumab became the first PD-L1 inhibitor approved by the US Food and Drug Administration (FDA) in recent years for the initial treatment of extensive-stage (ES)-SCLC. METHODS: We investigated PD-L1 expression in SCLC tumors using the three validated PD-L1 immunohistochemistry (IHC) assays (SP263, SP142, and 22C3) and assessed the correlation between PD-L1 expression and clinicopathological factors to determine the prognostic value of PD-L1 expression. The three PD-L1 IHC analyses were prospectively used to assess tumor samples of patients with SCLC at diagnosis. RESULTS: Of the total of 59 patients, 47 patients received the active treatment beyond platinum-based chemotherapy at our institution. PD-L1 expression was positive in 39.0% with SP263, 37.3% with SP142, and 22.0% with 22C3. In a univariate analysis, the positive result of at least one of the three PD-L1 assays and the positive result of the SP142 assay were associated with longer overall survival (OS). A multivariable analysis confirmed that performance status, stage, and the SP142 assay were independent predictors of OS. In subgroup analysis, these results revealed more significant prognostic factors in ES than in limited-stage (LS). In patients with SCLC, especially those with ES, the expression of the SP142 assay is a significant independent prognostic factor. CONCLUSIONS: Although these results need to be further validated in larger cohorts, this information will benefit clinicians and patients in determining the immunotherapy for patients with ES-SCLC.

Preoperative Neutrophil-to-Lymphocyte Ratio as a Prognostic Factor in Uterine Sarcoma.

BACKGROUND: Recent studies have demonstrated that the tumor microenvironment, known to be influenced by inflammatory cells, plays a crucial role in cancer progression and clinical outcome of patients. The objective of the present study was to investigate prognostic values of preoperative neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) for disease-free survival (DFS) and overall survival (OS) of uterine sarcoma patients. METHODS: Ninety-nine patients with uterine sarcoma treated in eight multicenter institutions over the last 20 years were retrospectively analyzed. Curves of DFS and OS were calculated using the Kaplan-Meier method, and univariate and multivariate analyses of various prognostic factors were performed using a Cox proportional hazard regression model. RESULTS: High NLR was significantly associated with worse DFS (p = 0.007) and OS (p = 0.039). Advanced stage (p = 0.017) and high mitotic index (p = 0.036) retained their prognostic significance for DFS. Other clinical variables, including PLR, CA125, and lactate dehydrogenase (LDH) failed to show significant impact. CONCLUSIONS: Our findings showed that an elevated preoperative NLR was associated with poor clinical outcome in uterine sarcoma patients. Our results suggest that high NLR in early-stage uterine sarcoma patients might indicate that such patients need more intensive treatments.

Diagnosis of pulmonary cement embolism using only the bone window setting on computed tomography: a case report.

Pulmonary cement embolism (PCE) is one of several complications of percutaneous vertebroplasty and kyphoplasty. Generally, PCE can be easily diagnosed based on typical chest radiograph findings such as single or multiple radiographically dense opacities with a tubular or branch shape in the lung field along with a recent history of percutaneous vertebroplasty or kyphoplasty. These findings can be alarming and may be encountered on routine chest radiographs, even in asymptomatic patients. One study showed that PCEs that were not visualized on chest radiograph were also not shown on chest computed tomography. However, we encountered a patient with dyspnea who had normal chest radiograph findings but was diagnosed with PCE through only the bone window setting on chest computed tomography. The present case will be beneficial to all physicians examining older patients with dyspnea.

A Rare Case of Fatal Endobronchial Mucormycosis Masquerading as Endobronchial Tuberculosis.

Pulmonary mucormycosis is a relatively rare but often fatal opportunistic fungal infection that occurs mostly in immunocompromised patients. Endobronchial mucormycosis, a distinct clinical form of pulmonary mucormycosis, is very rare, and only a few cases have been reported. The most common bronchoscopic findings in patients with endobronchial mucormycosis are stenosis, erythematous mucosa and airway obstruction. Here, we present a case of fatal endobronchial mucormycosis mimicking actively caseating endobronchial tuberculosis in a young diabetic patient living in a country with an intermediate tuberculosis burden.

The optimal sequence of bronchial brushing and washing for diagnosing peripheral lung cancer using non-guided flexible bronchoscopy.

The optimum sequence of bronchial brushing and washing for diagnosing peripheral lung cancer, defined as an invisible endobronchial tumour, is not clear and requires further study. We prospectively obtained washing samples after brushing in patients with peripheral lung tumours during non-guided flexible bronchoscopy (FB) to investigate the diagnostic yield of these samples and conducted a retrospective review of the prospectively collected data. The study included 166 patients who met the inclusion criteria. The overall diagnostic yield of bronchial brushing and washing for peripheral lung cancer was 52.4%. The diagnostic yields of brushing and washing were 37.3% and 46.4%, respectively, and that of washing was superior according to McNemar's test (p = 0.017, κ = 0.570). Furthermore, washing was diagnostic, whereas brushing was not, in 15.1% of all cases. Comparison of positive washing cytology (brushing) with the respective pathological diagnosis yielded a concordance rate of 88.3% (90.3%), with κ = 0.769 (0.801) (p < 0.001). Performing washing after brushing during non-guided FB is a very safe, cost-effective procedure that may help improve the diagnostic yield in patients with suspected peripheral lung cancer. Our information will also benefit clinicians performing diagnostic bronchoscopy in patients with suspected peripheral lung cancer when fluoroscopic guidance or advanced bronchoscopy techniques are not available.

Feasibility of Bronchial Washing Fluid-Based Approach to Early-Stage Lung Cancer Diagnosis.

A blood-based approach such as circulating tumor DNA remains challenging in diagnosis for early-stage disease. Bronchial washing (BW) is a minimally invasive procedure that yields fluids that may contain tumor DNA. Therefore, we prospectively enrolled 12 patients with early-stage non-small cell lung cancer without endoscopically visible tumors. Somatic mutations were analyzed using ultra-deep next-generation sequencing in 48 paired specimens (primary tumor tissue, normal tissue, BW supernatant, and BW precipitate). In primary tumors, 130 missense mutations/indels (5-16 per patient) and 20 driver mutations (0-3 per patient) were found. Concordance of driver mutations between BW fluids and primary tumors was 95.0%. The allele frequencies for missense mutations/indels in BW supernatants significantly correlated with those in primary tumors and were higher than those in BW precipitates. These findings suggest that BW supernatants are reflective of tumor-associated mutations and could be used for early-stage lung cancer diagnosis.

Small-cell Lung Cancer Presenting as Fatal Pulmonary Hemorrhage.

Small-cell lung cancer (SCLC) is a lung cancer histological subtype unusual in its favorable response to cytotoxic chemotherapy. Life-threatening manifestations at presentation are rarely reported and should be an important clinical concern. We report a case of a 63-year-old man presenting with rapid-onset refractory severe thrombocytopenia, development of massive hemoptysis, and death from respiratory failure. This case provides clinicians a reference for this unusual presentation and carries clinical implications for managing SCLC patients.

Dramatic response of acute disseminated intravascular coagulation to erlotinib in a patient with lung adenocarcinoma with activating EGFR mutation.

Disseminated intravascular coagulation (DIC) is a commonly encountered clinical situation characterized by thrombotic occlusion or bleeding in patients with lung cancer. DIC in patients with cancer is usually asymptomatic, taking a chronic form as a compensatory mechanism. Although acute DIC in patients with lung cancer is rarely reported, it can be fatal. We herein describe a patient with lung adenocarcinoma with an activating mutation of the epidermal growth factor receptor (EGFR) gene who developed acute DIC after minor surgical excision. The patient's condition dramatically improved immediately after administration of erlotinib. This report alerts physicians to the occurrence of acute DIC and serves as a reference in treating EGFR mutation-positive lung cancer in patients with DIC.

Lung Cancer Risk and Residential Exposure to Air Pollution: A Korean Population-Based Case-Control Study.

PURPOSE: To investigate the association between long-term exposure to ambient air pollution and lung cancer incidence in Koreans. MATERIALS AND METHODS: This was a population-based case-control study covering 908 lung cancer patients and 908 controls selected from a random sample of people within each Korean province and matched according to age, sex, and smoking status. We developed land-use regression models to estimate annual residential exposure to particulate matter (PM10) and nitrogen dioxide (NO2) over a 20-year exposure period. Logistic regression was used to estimate odds ratios (ORs) and their corresponding 95% confidence intervals (CI). RESULTS: Increases in lung cancer incidence (expressed as adjusted OR) were 1.09 (95% CI: 0.96-1.23) with a ten-unit increase in PM10 (µg/m³) and 1.10 (95% CI: 1.00-1.22) with a ten-unit increase in NO2 (ppb). Tendencies for stronger associations between air pollution and lung cancer incidence were noted among never smokers, among those with low fruit consumption, and among those with a higher education level. Air pollution was more strongly associated with squamous cell and small cell carcinomas than with adenocarcinoma of the lung. CONCLUSION: This study provides evidence that PM10 and NO2 contribute to lung cancer incidence in Korea.

A Panel of Novel Detection and Prognostic Methylated DNA Markers in Primary Non-Small Cell Lung Cancer and Serum DNA.

Purpose: To establish a novel panel of cancer-specific methylated genes for cancer detection and prognostic stratification of early-stage non-small cell lung cancer (NSCLC).Experimental Design: Identification of differentially methylated regions (DMR) was performed with bumphunter on "The Cancer Genome Atlas (TCGA)" dataset, and clinical utility was assessed using quantitative methylation-specific PCR assay in multiple sets of primary NSCLC and body fluids that included serum, pleural effusion, and ascites samples.Results: A methylation panel of 6 genes (CDO1, HOXA9, AJAP1, PTGDR, UNCX, and MARCH11) was selected from TCGA dataset. Promoter methylation of the gene panel was detected in 92.2% (83/90) of the training cohort with a specificity of 72.0% (18/25) and in 93.0% (40/43) of an independent cohort of stage IA primary NSCLC. In serum samples from the later 43 stage IA subjects and population-matched 42 control subjects, the gene panel yielded a sensitivity of 72.1% (31/41) and specificity of 71.4% (30/42). Similar diagnostic accuracy was observed in pleural effusion and ascites samples. A prognostic risk category based on the methylation status of CDO1, HOXA9, PTGDR, and AJAP1 refined the risk stratification for outcomes as an independent prognostic factor for an early-stage disease. Moreover, the paralog group for HOXA9, predominantly overexpressed in subjects with HOXA9 methylation, showed poor outcomes.Conclusions: Promoter methylation of a panel of 6 genes has potential for use as a biomarker for early cancer detection and to predict prognosis at the time of diagnosis. Clin Cancer Res; 23(22); 7141-52. ©2017 AACR.

Prognostic impact of a new score using neutrophil-to-lymphocyte ratios in the serum and malignant pleural effusion in lung cancer patients.

BACKGROUNDS: Various studies have reported that the neutrophil-to-lymphocyte ratio in the serum (sNLR) may serve as a cost-effective and useful prognostic factor in patients with various cancer types. However, no study has reported the prognostic impact of the NLR in malignant pleural effusion (MPE). To address this gap, we investigated the clinical impact of NLR as a prognostic factor in MPE (mNLR) and a new scoring system that use NLRs in the serum and MPE (smNLR score) in lung cancer patients. METHODS: We retrospectively reviewed all of the patients who were diagnosed with lung cancer and who presented with pleural effusion. To maintain the quality of the study, only patients with malignant cells in the pleural fluid or tissue were included. The patients were classified into three smNLR score groups, and clinical variables were investigated for their correlation with survival. RESULTS: In all, 158 patients were classified into three smNLR score groups as follows: 84 (53.2%) had a score of 0, 58 (36.7%) had a score of 1, and 16 (10.1%) had a score of 2. In a univariate analysis, high sNLR, mNLR, and increments of the smNLR score were associated with shorter overall survival (p < 0.001, p = 0.004, and p < 0.001, respectively); moreover, age, Eastern Cooperative Oncology Group performance status (ECOG PS), histology, M stage, hemoglobin level, albumin level, and calcium level were significant prognostic factors. A multivariable analysis confirmed that ECOG PS (p < 0.001), histology (p = 0.001), and smNLR score (p < 0.012) were independent predictors of overall survival. CONCLUSIONS: The new smNLR score is a useful and cost-effective prognostic factor in lung cancer patients with MPE. Although further studies are required to generalize our results, this information will benefit clinicians and patients in determining the most appropriate therapy for patients with MPE.

Mitochondria in chronic obstructive pulmonary disease and lung cancer: where are we now?

Recent advances in mitochondrial biogenesis have provided the emerging recognition that mitochondria do much more than 'simply providing energy for cellular function'. Currently, a constantly improving understanding of the mitochondrial structure and function has been providing valuable insights into the contribution of defects in mitochondrial metabolism to various human diseases, including chronic obstructive pulmonary disease and lung cancer. The growing interest in mitochondria research led to development of new biomedical fields in the two main smoking-related lung diseases. However, there is considerable paucity in our understanding of mechanisms by which mitochondrial dynamics regulate lung diseases. In this review, we will discuss our current knowledge on the role of mitochondrial dysfunction in the pathogenesis of chronic obstructive pulmonary disease and non-small-cell lung cancer.