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Purpose: We developed a novel augmented fluoroscopy-guided intrathoracic stamping technique for localizing small pulmonary nodules in the hybrid operating room. We conducted an observational study to investigate the feasibility of this technique and retrospectively compared two augmented fluoroscopy-guided approaches: intrathoracic and transbronchial., Methods: From August 2020 to March 2023, consecutive patients underwent single-stage augmented fluoroscopy-guided localization under general anaesthesia. This included intrathoracic stamping and bronchoscopic lung marking, followed by thoracoscopic resection in a hybrid operating room. Comparative analyses were performed between the two groups., Results: The data of 50 patients in the intrathoracic stamping and 67 patients in the bronchoscopic lung marking groups were analysed. No significant difference was noted in demographic data between the groups, except a larger lesion depth in the bronchoscopic lung marking group (14.7 ± 11.7 vs 11.0 ± 5.8 mm, p = 0.029). Dye localization was successfully performed in 49 intrathoracic stamping group patients (98.0%) and 67 bronchoscopic lung marking group patients (100%). No major procedure-related complications occurred in either group; however, the time flow (total anaesthesia time/global operating room time) was longer, and the radiation exposure (fluoroscopy duration/total dose area product) was larger in the bronchoscopic lung marking group., Conclusions: Augmented fluoroscopic stamping localization under intubated general anaesthesia is feasible and safe, providing an alternative with less global operating room time and lower radiation exposure for image-guided thoracoscopic surgery in the hybrid operating room., (© 2024. CARS.)

Objectives: The experience of thermal ablation of lung lesions is limited, especially performing the procedure under localisation by cone-beam CT in the hybrid operation room (HOR). Here, we present the experience of microwave ablation (MWA) of lung nodules in the HOR., Methods: We reviewed patients who underwent image-guide percutaneous MWA for lung nodules in the HOR under general anaesthesia between July 2020 and July 2022. The workflow in the HOR including the pre-procedure preparation, anaesthesia consideration, operation methods, and postoperative care was clearly described., Results: Forty lesions in 33 patients who underwent MWA under general anaesthesia (GA) in the HOR were analysed. Twenty-seven patients had a single pulmonary nodule, and the remaining six patients had multiple nodules. The median procedure time was 41.0 min, and the median ablation time per lesion was 6.75 min. The median global operation room time was 115.0 min. The median total dose area product was 14881 μGym 2 . The median ablation volume was 111.6 cm 3 . All patients were discharged from the hospital with a median postoperative stay of 1 day. Four patients had pneumothorax, two patients had pleural effusion during the first month of outpatient follow-up, and one patient reported intercostal neuralgia during the 3-month follow-up., Conclusions: Thermal ablation of pulmonary nodules under GA in the HOR can be performed safely and efficiently if we follow the workflow provided. The procedure provides an alternative to managing pulmonary nodules in patients., Clinical Relevance Statement: Thermal ablation of pulmonary nodules under GA in the HOR can be performed safely and efficiently if the provided workflow is followed., Key Points: • We tested the feasibility of microwave ablation of lung lesions performed in a hybrid operating room. • To this end, we provide a description of microwave ablation of the lung under cone-beam CT localisation. • We describe a workflow by which ablation of the pulmonary nodule can be performed safely under general anaesthesia., (© 2023. The Author(s), under exclusive licence to European Society of Radiology.)

The field of RNA therapeutics has been emerging as the third milestone in pharmaceutical drug development. RNA nanoparticles have displayed motile and deformable properties to allow for high tumor accumulation with undetectable healthy organ accumulation. Therefore, RNA nanoparticles have the potential to serve as potent drug delivery vehicles with strong anti-cancer responses. Herein, we report the physicochemical basis for the rational design of a branched RNA four-way junction (4WJ) nanoparticle that results in advantageous high-thermostability and -drug payload for cancer therapy, including metastatic tumors in the lung. The 4WJ nanostructure displayed versatility through functionalization with an anti-cancer chemical drug, SN38, for the treatment of two different cancer models including colorectal cancer xenograft and orthotopic lung metastases of colon cancer. The resulting 4WJ RNA drug complex spontaneously targeted cancers effectively for cancer inhibition with and without ligands. The 4WJ displayed fast renal excretion, rapid body clearance, and little organ accumulation with undetectable toxicity and immunogenicity. The safety parameters were documented by organ histology, blood biochemistry, and pathological analysis. The highly efficient cancer inhibition, undetectable drug toxicity, and favorable Chemical, Manufacturing, and Control (CMC) production of RNA nanoparticles document a candidate with high potential for translation in cancer therapy., Competing Interests: Declaration of competing interest P.G. has patents P2024-136-8471 and P2022-263-8315 pending to The Ohio State University. P.G. is the consultant, licensor, and grantee of Oxford Nanopore Technologies; as well as the cofounder and consultant of ExonanoRNA, LLC. Other authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023. Published by Elsevier Ltd.)

Background: Cancer metastasis is a major cause of cancer-related deaths, emphasizing the urgent need for effective therapies. Although it has been shown that GMI, a fungal protein from Ganoderma microsporum, could suppress primary tumor growth in a wide spectrum of cancer types, it is still unclear whether GMI exhibits anti-metastasis properties, particularly in lung cancers. Further investigation is needed., Aims and Objectives: The objective of this study is to investigate the potential inhibitory effects of GMI on lung cancer metastasis in vivo. Utilizing systematic and comprehensive approaches, our research aims to elucidate the underlying molecular mechanisms responsible for the anti-metastatic effects., Materials and Methods: In vitro migration and cell adhesion assays addressed the epithelial-to-mesenchymal transition (EMT)-related phenotype. Proteomic and bioinformatic analyses identified the GMI-regulated proteins and cellular responses. GMI-treated LLC1-bearing mice were analyzed using IVIS Spectrum to assess the anti-metastatic effect., Key Findings: GMI inhibits EMT as well as cell migration. GMI disrupts cell adhesion and downregulates integrin, resulting in inhibition of phosphorylated FAK. GMI induces macropinocytosis and lysosome-mediated degradation of integrin αv, α5, α6 and β1. GMI downregulates Slug via inhibition of FAK activity, which in turn enhances expressions of epithelial-related markers and decreases cell mobility. Mechanistically, GMI-induced FAK inhibition engenders MDM2 expression and enhances MDM2/p21/Slug complex formation, leading to Slug degradation. GMI treatment reduces the metastatic pulmonary lesion and prolongs the survival of LLC1-bearing mice., Significance: Our findings highlight GMI as a promising therapeutic candidate for metastatic lung cancers, offering potential avenues for further research and drug development., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Epidermal growth factor receptor (EGFR) abnormalities relevant to tumor progression. A newly developed strategy for cancer therapy is induction of EGFR degradation. GMI, an immunomodulatory protein from the medicinal mushroom Ganoderma microsporum, exhibits anticancer activity. However, its role in the intracellular trafficking and degradation of EGFR remains unclear. In this study, we discovered that GMI inhibits the phosphorylation of multiple tyrosine kinases. Specifically, GMI was discovered to suppress lung cancer cells harboring both wild-type and mutant EGFR by inhibiting EGFR dimerization and eliminating EGFR-mediated signaling. Functional studies revealed that GMI binds to the extracellular segment of EGFR. GMI interacts with EGFR to induce phosphorylation of EGFR at tyrosine1045, which triggers clathrin-dependent endocytosis and degradation of EGFR. Furthermore, in the mouse models, GMI was discovered to suppress tumor growth. Knockdown of EGFR in lung cancer cells abolishes GMI's anticancer activity in vivo and in vitro. Our results reveal the interaction mechanisms through which GMI induces EGFR degradation and abolishes EGFR-mediated intracellular pathway. Our study indicates that GMI is an EGFR degrader for inhibiting EGFR-expressing tumor growth., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) have become a standard care in non-small-cell lung cancer (NSCLC). However, its application to epidermal growth factor receptor (EGFR)-mutant NSCLC patients is confronted with drug resistance. This study aimed to clarify the potential role of Yes1-associated transcriptional regulator (YAP1) in ICIs treatment for EGFR-mutant NSCLC population., Methods: All the clinical data of NSCLC were downloaded from Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) for GSE11969 and GSE72094. Based on YAP1 expression, all the NSCLC patients including the EGFR-mutant and EGFR-wildtype (WT) patients were divided into two groups, YAP1_High and YAP1_Low. Using cBioPortal, genetic alterations were analyzed for identification of immunogenicity in EGFR-mutant NSCLC. MR analysis was used to analyze the hub gene of EGFR. The infiltration of immune cells and the expression of the identified tumor-associated antigens were identified with TIMER. By graph learning-based dimensionality reduction analysis, the immune landscape was visualized. Moreover, survival analysis was performed to verify the predictive value of YAP1 in ICIs treatment for EGFR-mutant NSCLC population using Ren's research data (NCT03513666)., Results: YAP1 was a poor prognostic factor of EGFR-mutant NSCLC population rather than lung adenocarcinoma (LUAD) patients. MR analysis revealed that the EGFR gene regulated YAP1 expression. YAP1 was identified as a hub gene closely associated with immunosuppressive microenvironment and poor prognosis in EGFR-mutant NSCLC population in TCGA LUAD. Tumors with YAP1_High showed an immune-"cold" and immunosuppressive phenotype, whereas those with YAP1_Low demonstrated an immune-"hot" and immunoactive phenotype. More importantly, it was verified that YAP1_High subpopulation had a significantly shorter progression-free survival (PFS) and overall survival (OS) after ICIs treatment in EGFR-mutant NSCLC patients in the clinical trial., Conclusions: YAP1 mediates immunosuppressive microenvironment and poor prognosis in EGFR-mutant NSCLC population. YAP1 is a novel negative biomarker of ICIs treatment in EGFR-mutant NSCLC population. Clinical Trials . This trial is registered with NCT03513666., Competing Interests: The authors declare that they have no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (Copyright © 2023 Ling-Chen Li et al.)

Objective: The combination of stereotactic body radiation therapy (SBRT) and immune checkpoint inhibitors (ICIs) is actively being explored in advanced non-small-cell lung cancer (NSCLC) patients. However, little is known about the optimal fractionation and radiotherapy target lesions in this scenario. This study investigated the effect of SBRT on diverse organ lesions and radiotherapy dose fractionation regimens on the prognosis of advanced NSCLC patients receiving ICIs., Methods: The medical records of advanced NSCLC patients consecutively treated with ICIs and SBRT were retrospectively reviewed at our institution from Dec. 2015 to Sep. 2021. Patients were grouped according to radiation sites. Progression-free survival (PFS) and overall survival (OS) were recorded using the Kaplan-Meier method and compared between different treatment groups using the log-rank (Mantel-Cox) test., Results: A total of 124 advanced NSCLC patients receiving ICIs combined with SBRT were identified in this study. Radiation sites included lung lesions (lung group, n=43), bone metastases (bone group, n=24), and brain metastases (brain group, n=57). Compared with the brain group, the mean PFS (mPFS) in the lung group was significantly prolonged by 13.3 months (8.5 months vs. 21.8 months, HR=0.51, 95%CI: 0.28-0.92, P=0.0195), and that in the bone group prolonged by 9.5 months with a 43% reduction in the risk of disease progression (8.5 months vs. 18.0 months, HR=0.57, 95%CI: 0.29-1.13, P=0.1095). The mPFS in the lung group was prolonged by 3.8 months as compared with that in the bone group. The mean OS (mOS) in the lung and bone groups was longer than that of the brain group, and the risk of death decreased by up to 60% in the lung and bone groups as compared with that of the brain group. When SBRT was concurrently given with ICIs, the mPFS in the lung and brain groups were significantly longer than that of the bone group (29.6 months vs. 16.5 months vs. 12.1 months). When SBRT with 8-12 Gy per fraction was combined with ICIs, the mPFS in the lung group was significantly prolonged as compared with that of the bone and brain groups (25.4 months vs. 15.2 months vs. 12.0 months). Among patients receiving SBRT on lung lesions and brain metastases, the mPFS in the concurrent group was longer than that of the SBRT→ICIs group (29.6 months vs. 11.4 months, P=0.0003 and 12.1 months vs. 8.9 months, P=0.2559). Among patients receiving SBRT with <8 Gy and 8-12 Gy per fraction, the mPFS in the concurrent group was also longer than that of the SBRT→ICIs group (20.1 months vs. 5.3 months, P=0.0033 and 24.0 months vs. 13.4 months, P=0.1311). The disease control rates of the lung, bone, and brain groups were 90.7%, 83.3%, and 70.1%, respectively., Conclusion: The study demonstrated that the addition of SBRT on lung lesions versus bone and brain metastases to ICIs improved the prognosis in advanced NSCLC patients. This improvement was related to the sequence of radiotherapy combined with ICIs and the radiotherapy fractionation regimens. Dose fractionation regimens of 8-12 Gy per fraction and lung lesions as radiotherapy targets might be the appropriate choice for advanced NSCLC patients receiving ICIs combined with SBRT., (© 2023. Huazhong University of Science and Technology.)

Objectives: Hybrid operating rooms (HOR) have been increasingly used for image-guided lung surgery, and most surgical teams have used percutaneous localization for small pulmonary nodules. We evaluated the feasibility and safety of augmented fluoroscopic bronchoscopy localization under endotracheal tube intubation general anaesthesia followed by thoracoscopic surgery as a single-stage procedure in ab HOR., Methods: We retrospectively reviewed clinical records of patients who underwent single-stage augmented fluoroscopic bronchoscopy localization under general anaesthesia followed by thoracoscopic surgery in an HOR between August 2020 and March 2022., Results: Single-stage localization and resection were performed for 85 nodules in 74 patients. The median nodule size was 8 mm [interquartile range (IQR), 6-9 mm], and the median distance from the pleural space was 10.9 mm (IQR, 8-20 mm). All nodules were identifiable on cone-beam computed tomography images and marked transbronchially with indigo carmine dye (median markers per lesion: 3); microcoils were placed for deep margins in 16 patients. The median localization time was 30 min (IQR 23-42 min), and the median fluoroscopy duration was 3.3 min (IQR 2.2-5.3 min). The median radiation exposure (expressed as the dose area product) was 4303.6 μGym2 (IQR 2879.5-6268.7 μGym2). All nodules were successfully marked and resected, and the median global operating room time was 178.5 min (IQR 153.5-204 min). There were no localization-related complications, and the median length of postoperative stay was 1 day (IQR, 1-2 days)., Conclusions: Single-stage augmented fluoroscopic bronchoscopy localization under general anaesthesia followed by thoracoscopic surgery was feasible and safe., (© The Author(s) 2022. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Objectives: Esophageal squamous cell carcinoma with pulmonary metastasis has a poor prognosis, and the only treatment modality is systemic therapy such as chemotherapy. Previous studies showed that pulmonary metastasectomy may provide benefits and has been suggested in selected patients with colorectal cancer, renal cancer, and sarcoma. However, there were few literatures evaluating the impact and treatment outcome of pulmonary metastasectomy in esophageal squamous cell carcinoma patients with isolated lung metastases. Therefore, we conducted this study., Methods: We retrospectively reviewed our patients with esophageal squamous cell carcinoma with pulmonary metastasis. Patients with extrapulmonary metastasis were excluded. We categorized them into two groups - the pulmonary resection group and the systemic treatment only group. We compared the overall survival and progression-free survival between groups, and also analyzed the surgical modality, which includes single or multiple port surgery., Results: The analysis included 44 esophageal squamous cell carcinoma patients with lung metastasis. Among these 44 patients, 14 patients have received pulmonary metastasectomy, and 30 patients received systemic treatment only. Patients who received pulmonary metastasectomy had significantly better overall survival (p < 0.0001) and progression-free survival (p = 0.038) than those who received only systemic treatment. The one-year overall survival and progression-free survival were 100% and 48% in patients receiving pulmonary metastatectomy, and 49% and 33% in patients receiving only systemic treatment. Among 14 patients receiving pulmonary metastatectomy, 10 patients underwent single port surgery. There were no postoperative complications in these 14 patients., Conclusion: Esophageal squamous cell carcinoma patients with lung metastasis who can receive pulmonary metastasectomy have better prognosis, and some patients can achieve long-term survival. Our findings suggest that aggressive pulmonary metastasectomy is suggested in esophageal squamous cell carcinoma patients with if no contraindication. Key question: How about the role of pulmonary metastasectomy in esophageal squamous cell carcinoma patients with isolated lung metastasis?, Key Findings: Patients who received pulmonary metastasectomy had better overall survival and progression-free survival than those who received only systemic treatment., Take Home Message: Esophageal cancer with isolated pulmonary metastasis can be treated aggressively with pulmonary metastasectomy if no contraindication., (© 2022. The Author(s).)

Background: Several immune checkpoint inhibitors have been implemented for cancer treatment which have shown some degree of antitumor effcacy, while immune-related adverse events (irAEs) that affect multiple organ functions ensue which obviously should not be neglected. Though less common than other kinds of irAEs, Immune checkpoint inhibitors (ICIs) related Isolated ACTH deficiency (IAD) may cause long-term damage to pituitary-adrenal axis. Several case reports are available about IAD during anti-PD-1 therapy. We report the first case of immune checkpoint inhibitor-induced IAD following 3 month of sintilimab therapy., Case Presentation: A 66-year-old Chinese man was diagnosed with stage IIIB lung adenocarcinoma with involving ipsilateral intrapulmonary and hilar lymph node metastasis. After 3 months of combination therapy of nedaplatin, pemetrexed and sintilimab, the patient presented with general fatigue, nausea and vomiting. Laboratory investigation at admission revealed hyponatremia and hypokalemia. Further investigation revealed adrenocorticotropic hormone and cortisol levels were far below than normal limits. His other pituitary hormone levels were normal, except for mild elevation of follicle stimulating hormone and estradiol. Cranic magnetic resonance imaging showed a normal pituitary gland. Isolated adrenocorticotropic hormone deficiency was diagnosed, and corticosteroid replacement therapy was administered, leading to a significant improvement of his symptoms while ACTH level maintaining low level., Conclusions: Our patient developed isolated ACTH deficiency during combination cancer treatment with chemotherapy and sintilimab. Although isolated ACTH deficiency due to anti-PD-1 including sintilimab therapy is rare occurrence, it can often cause severe clinical symptoms. Its diagnosis basically relies on clinical symptoms and endocrinological examination. Unlike traditional hypophysitis diagnosed by cranial MRI, pituitary MRI of IAD due to anti-PD-1 often indicates normal pituitary gland implying that over-reliance on imaging findings is not recommended. Even if clinical symptoms have relieved after corticosteroid replacement therapy was commenced, low levels of ACTH or cortisol could maintain for a long period which highlights the need for long term corticosteroid therapy. The purpose of the current report was to provide increased awareness of early detection and therapy of IAD., (© 2022. The Author(s).)

Introduction: Green space and air pollution have been recognized as vital health determinants. There is a paucity of studies examining the interplay between green space, fine particulate matter (PM 2.5 ), and the incidence of specific cancers., Objective: We aimed to explore the contributions of green space and ambient PM 2.5 to the risk of specific cancers in terms of the most common cancers based on incidence or mortality rate in Taiwan and to ascertain the interaction between green space and PM 2.5 and their role in cancer risk., Materials and Methods: This retrospective longitudinal cohort study included 407,415 participants. Data were obtained from the 2000-2015 Mei Jau Health Examination Database linked to the Taiwan Cancer Registry and Causes of Death datasets. All participants were aged ≥20 years and had no history of cancer. The environmental exposure were the normalized difference vegetation index (NDVI) and the 2-year average PM 2.5 at baseline. Multivariate adjusted hazard ratios (HRs) were calculated using Cox proportional hazards models. We adjusted for covariates including demographics, anthropometrics, comorbidities, health behaviors, biochemical data, and environmental factors., Results: During a median follow-up of 10.37 years, 11,576 cancer cases were reported. PM 2.5 exposure increased the risk of all cancers (HR: 1.11, [95% CI: 1.06-1.15]), stomach cancer (HR: 1.27, [1.02-1.58]), endocrine gland cancer (HR: 2.13, [1.39-3.26]), breast cancer (HR: 1.12, [1.03-1.22]), and lung cancer (HR: 1.12, [1.01-1.24]). An increase in NDVI reduced the risk of prostate cancer (HR: 0.93, [0.88-0.99]) and lung cancer (HR: 0.95, [0.91-0.99]). NDVI influenced the incidence of prostate and all cancers by reducing PM 2.5 concentrations., Conclusion: Long-term PM 2.5 exposure is associated with an increased risk of some types of cancers. In contrast, an increase in environmental green space exposure is associated with lowering of the risk of prostate and lung cancer., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Previous studies in medical imaging have shown disparate abilities of artificial intelligence (AI) to detect a person's race, yet there is no known correlation for race on medical imaging that would be obvious to human experts when interpreting the images. We aimed to conduct a comprehensive evaluation of the ability of AI to recognise a patient's racial identity from medical images., Methods: Using private (Emory CXR, Emory Chest CT, Emory Cervical Spine, and Emory Mammogram) and public (MIMIC-CXR, CheXpert, National Lung Cancer Screening Trial, RSNA Pulmonary Embolism CT, and Digital Hand Atlas) datasets, we evaluated, first, performance quantification of deep learning models in detecting race from medical images, including the ability of these models to generalise to external environments and across multiple imaging modalities. Second, we assessed possible confounding of anatomic and phenotypic population features by assessing the ability of these hypothesised confounders to detect race in isolation using regression models, and by re-evaluating the deep learning models by testing them on datasets stratified by these hypothesised confounding variables. Last, by exploring the effect of image corruptions on model performance, we investigated the underlying mechanism by which AI models can recognise race., Findings: In our study, we show that standard AI deep learning models can be trained to predict race from medical images with high performance across multiple imaging modalities, which was sustained under external validation conditions (x-ray imaging [area under the receiver operating characteristics curve (AUC) range 0·91-0·99], CT chest imaging [0·87-0·96], and mammography [0·81]). We also showed that this detection is not due to proxies or imaging-related surrogate covariates for race (eg, performance of possible confounders: body-mass index [AUC 0·55], disease distribution [0·61], and breast density [0·61]). Finally, we provide evidence to show that the ability of AI deep learning models persisted over all anatomical regions and frequency spectrums of the images, suggesting the efforts to control this behaviour when it is undesirable will be challenging and demand further study., Interpretation: The results from our study emphasise that the ability of AI deep learning models to predict self-reported race is itself not the issue of importance. However, our finding that AI can accurately predict self-reported race, even from corrupted, cropped, and noised medical images, often when clinical experts cannot, creates an enormous risk for all model deployments in medical imaging., Funding: National Institute of Biomedical Imaging and Bioengineering, MIDRC grant of National Institutes of Health, US National Science Foundation, National Library of Medicine of the National Institutes of Health, and Taiwan Ministry of Science and Technology., Competing Interests: Declaration of interests MG has received speaker fees for a Harvard Medical School executive education class. HT has received consulting fees from Sirona medical, Arterys, and Biodata consortium. HT also owns lightbox AI, which provides expert annotation of medical images for radiology AI. MPL has received consulting fees from Bayer, Microsoft, Phillips, and Nines. MPL also owns stocks in Nines, SegMed, and Centaur. LAC has received support to attend meetings from MISTI Global Seed Funds. ATP has received payment for expert testimony from NCMIC insurance company. ATP also has a pending institutional patent for comorbidity prediction from radiology images. All other authors declare no competing interests., (Copyright © 2022 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Competing Interests: Disclosure: There is no conflict of interest or other disclosures.

Cancer genotyping has identified a large number of putative tumor suppressor genes. Carcinogenesis is a multistep process, but the importance and specific roles of many of these genes during tumor initiation, growth, and progression remain unknown. Here we use a multiplexed mouse model of oncogenic KRAS-driven lung cancer to quantify the impact of 48 known and putative tumor suppressor genes on diverse aspects of carcinogenesis at an unprecedented scale and resolution. We uncover many previously understudied functional tumor suppressors that constrain cancer in vivo . Inactivation of some genes substantially increased growth, whereas the inactivation of others increases tumor initiation and/or the emergence of exceptionally large tumors. These functional in vivo analyses revealed an unexpectedly complex landscape of tumor suppression that has implications for understanding cancer evolution, interpreting clinical cancer genome sequencing data, and directing approaches to limit tumor initiation and progression. SIGNIFICANCE: Our high-throughput and high-resolution analysis of tumor suppression uncovered novel genetic determinants of oncogenic KRAS-driven lung cancer initiation, overall growth, and exceptional growth. This taxonomy is consistent with changing constraints during the life history of cancer and highlights the value of quantitative in vivo genetic analyses in autochthonous cancer models. This article is highlighted in the In This Issue feature, p. 1601 ., (©2021 American Association for Cancer Research.)

Background: The efficacy of next-generation epidermal growth factor receptor-tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer who have failed first-generation epidermal growth factor receptor-tyrosine kinase inhibitors still remains under investigation., Objective: The aim of this meta-analysis was to systematically assess the efficacy and safety profiles of next-generation epidermal growth factor receptor-tyrosine kinase inhibitors in patients with advanced non-small cell lung cancer who failed first-generation epidermal growth factor receptor-tyrosine kinase inhibitors., Methods: We performed a comprehensive search of several electronic databases up to September 2018 to identify clinical trials. The primary end point was overall survival, progression-free survival, disease controlled rate, objective response rate, and adverse events. Epidermal growth factor receptor-tyrosine kinase inhibitor emergent severe adverse events (grade ≥ 3) were analyzed. Odds ratio along with 95% confidence interval were utilized for main outcome analysis., Results: In total, we had 3 randomized controlled trials in this analysis. The group of next-generation epidermal growth factor receptor-tyrosine kinase inhibitors had significantly improved progression-free survival (odds ratio = 0.34, 95% confidence interval = 0.29-0.40, P < .00001), as well as objective response rate (odds ratio = 10.48, 95% confidence interval = 3.87-28.34, P < .00001) and disease controlled rate (odds ratio = 6.03, 95% confidence interval = 4.41-8.25, P < .00001). However, there was no significant difference in overall survival with next-generation epidermal growth factor receptor-tyrosine kinase inhibitors (odds ratio = 1.05, 95% confidence interval = 0.85-1.31, P = .66). Meanwhile, the odds ratio for treatment-emergent severe adverse events (diarrhea, rash/acne, nausea, vomiting, anemia) between patients who received next-generation epidermal growth factor receptor-tyrosine kinase inhibitors and those who received first-generation epidermal growth factor receptor-tyrosine kinase inhibitors did not show safety benefit ( P > .05)., Conclusions: Next-generation epidermal growth factor receptor-tyrosine kinase inhibitors were shown to be the better agent to achieve higher response rate and longer progression-free survival in patients with non-small cell lung cancer as the later-line therapy for previously treated patients with first-generation epidermal growth factor receptor-tyrosine kinase inhibitors. Meanwhile, they did not achieve benefit in overall survival and safety compared with the chemotherapy group. Further research is needed to develop a database of all EGFR mutations and their individual impacts on the various treatments.

Electronic-cigarettes (E-cigs) are marketed as a safe alternative to tobacco to deliver the stimulant nicotine, and their use is gaining in popularity, particularly among the younger population. We recently showed that mice exposed to short-term (12 wk) E-cig smoke (ECS) sustained extensive DNA damage in lungs, heart, and bladder mucosa and diminished DNA repair in lungs. Nicotine and its nitrosation product, nicotine-derived nitrosamine ketone, cause the same deleterious effects in human lung epithelial and bladder urothelial cells. These findings raise the possibility that ECS is a lung and bladder carcinogen in addition to nicotine. Given the fact that E-cig use has become popular in the past decade, epidemiological data on the relationship between ECS and human cancer may not be known for a decade to come. In this study, the carcinogenicity of ECS was tested in mice. We found that mice exposed to ECS for 54 wk developed lung adenocarcinomas (9 of 40 mice, 22.5%) and bladder urothelial hyperplasia (23 of 40 mice, 57.5%). These lesions were extremely rare in mice exposed to vehicle control or filtered air. Current observations that ECS induces lung adenocarcinomas and bladder urothelial hyperplasia, combined with our previous findings that ECS induces DNA damage in the lungs and bladder and inhibits DNA repair in lung tissues, implicate ECS as a lung and potential bladder carcinogen in mice. While it is well established that tobacco smoke poses a huge threat to human health, whether ECS poses any threat to humans is not yet known and warrants careful investigation., Competing Interests: The authors declare no competing interest., (Copyright © 2019 the Author(s). Published by PNAS.)

Hypoxic tumor niches are chief causes of treatment resistance and tumor recurrence. Sickle erythrocytes' (SSRBCs') intrinsic oxygen-sensing functionality empowers them to access such hypoxic niches wherein they form microaggregates that induce focal vessel closure. In search of measures to augment the scale of SSRBC-mediated tumor vaso-occlusion, we turned to the vascular disrupting agent, combretastatin A-4 (CA-4). CA-4 induces selective tumor endothelial injury, blood stasis, and hypoxia but fails to eliminate peripheral tumor foci. In this article, we show that introducing deoxygenated SSRBCs into tumor microvessels treated with CA-4 and sublethal radiation (SR) produces a massive surge of tumor vaso-occlusion and broadly propagated tumor infarctions that engulfs treatment-resistant hypoxic niches and eradicates established lung tumors. Tumor regression was histologically corroborated by significant treatment effect. Treated tumors displayed disseminated microvessels occluded by tightly packed SSRBCs along with widely distributed pimidazole-positive hypoxic tumor cells. Humanized HbS-knockin mice (SSKI) but not HbA-knockin mice (AAKI) showed a similar treatment response underscoring SSRBCs as the paramount tumoricidal effectors. Thus, CA-4-SR-remodeled tumor vessels license SSRBCs to produce an unprecedented surge of tumor vaso-occlusion and infarction that envelops treatment-resistant tumor niches resulting in complete tumor regression. Strategically deployed, these innovative tools constitute a major conceptual advance with compelling translational potential.

Indoor air pollution from bituminous coal combustion has been linked to the extremely high lung cancer rates of nonsmoking women in Xuan Wei County, Yunnan Province, China. Venting the smoke outdoors by installing chimneys was found to be effective at reducing the lung cancer risk in a cohort study of 21,232 farmers in central Xuan Wei. However, the lung cancer mortality rates in all 1.2 million residents of Xuan Wei have been increasing dramatically over the last four decades. It was higher than that in Yunnan Province and China overall, with significant heterogeneities in the geographic patterns of Xuan Wei. Intervention measures targeting certain types of coal or certain carcinogenic components in coal smoke need to be explored. To inform targeted intervention policies, it is essential to pinpoint the specific substance (particulate matter, organic extract, PAHs, free radicals, crystalline silica, and inorganic matter) that might account for the carcinogenicity of bituminous coal smoke. Exploring the underlying carcinogenesis mechanisms would also contribute to the intervention and control of the lung cancer epidemic in Xuan Wei, China. Here we review the suspected carcinogens and carcinogenesis mechanisms and discuss future research directions towards a better understanding of the etiology of lung cancer in Xuan Wei, China.

Background: In Xuan Wei, China, the lung cancer mortality rate is rising significantly more than that of the nation overall. However, it remains unclear 1) if improved diagnosis can just partially explain this observation and how other local risk factors may be correlated with the lung cancer mortality rate and 2) how the lung cancer mortality rates differ within Xuan Wei and how these spatiotemporal patterns are linked with local risk factors. To increase etiological knowledge, this study evaluated the spatial and temporal distributions of the health effects (the lung cancer mortality rates) from 2011 to 2015., Methods: Four steps of spatial analysis were applied, as follows: 1) hotspot analysis to determine the geographical patterns of lung cancer mortality, 2) spatially-weighted sum to identify areas with higher health risks, 3) bivariate statistical analysis to assess the overall correlation between coal mines and lung cancer mortality, and 4) geographically-weighted regression to test for correlations among different towns within Xuan Wei., Results: Women had higher lung cancer mortality rates than those in men, with an increasing trend in both sexes over time. The incidence rates in Laibin Town were the highest in Xuan Wei every year. Over the 5-year study period, the lung cancer mortality was increasingly concentrated in Laibin, Shuanglong, and Longchang, where the smoky coal mines are most concentrated. The population-level health risks from the coal mine in Xuan Wei were mapped and divided into five types of risk areas (Type I - Type IV). Correlation analysis revealed that there was no significant correlation between lung cancer mortality as a whole and coal mine distribution during the 5-year study period. However, the geographically-weighted regression revealed a stronger correlation in medium (Type III) and second-lowest (Type IV) health risks., Conclusions: Xuan Wei lung cancer mortality has increased continuously since the third national retrospective surveys on the causes of death by the Ministry of Health of the People's Republic of China (2004-2005), especially for local women and residents over 35 years of age. Geographically, lung cancer in Xuan Wei showed unique spatiotemporal clustering. The local lung cancer mortality was significantly correlated with the smoky coal mine geographically. Some specific towns (Laibin, Shuanglong, and Longchang) within Xuan Wei manifested high correlations between lung cancer mortality and coal mines. The effects of coal mines on lung cancer mortality rates also spread geographically outward from these areas. Public health concern regarding lung cancer in Xuan Wei should prioritize higher-risk towns surrounded by smoking coal mines. Intervention strategies for particular toxic coal types require further studies on their chemical characteristics and mechanisms of carcinogenesis. Additional studies are also warranted to systematically examine the local environmental health risks related to coal industries and combustion air pollution and eventually to conduct early screening of lung cancer for local people who are more exposed to smoky coal in high-risk areas.

Background/aim: Cetuximab has exhibited high EGFR-targeting specificity and clinical promise in previous studies. In this study, we formulated unit dose kits for preparation of high specific activity 188 Re-cetuximab for imaging and treatment of EGFR-positive cancer., Materials and Methods: 188 Re-cetuximab was prepared by adding 0.37-0.74 GBq/0.5 ml of 188 Re-perrhenate for 4 h at 37°C. Cell surface expression of EGFR, cell binding and cytotoxic effects were evaluated in vitro using both EGFR-positive (NCI-H292, A431) and EGFR-negative (BT483) tumors. A nanoSPECT/CT imaging study was performed in mice bearing EGFR-expressing NCI-H292 tumors., Results: 188 Re-cetuximab bound specifically to EGFR-expressing cells and labeling of radionuclides to cetuximab preserved the binding ability of the antibody. Besides, the cytotoxic effect of 188 Re-cetuximab was increased dose-dependently. NanoSPECT/CT imaging revealed that 188 Re-cetuximab could continually target the tumor region for at least 48 h., Conclusion: The highly specific targeted property of 188 Re-cetuximab suggested that it is suitable as a diagnostic tool and maybe a potent radioimmunotherapy agent in EGFR-positive cancers., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Tobacco smoke (TS) contains numerous cancer-causing agents, with polycyclic aromatic hydrocarbons (PAHs) and nitrosamines being most frequently cited as the major TS human cancer agents. Many lines of evidence seriously question this conclusion. To resolve this issue, we determined DNA adducts induced by the three major TS carcinogens: benzo( a )pyrene (BP), 4-(methylnitrosamine)-1-(3-pyridyl)-1-butanoe (NNK), and aldehydes in humans and mice. In mice, TS induces abundant aldehyde-induced γ-hydroxy-propano-deoxyguanosine (γ-OH-PdG) and α-methyl-γ-OH-PdG adducts in the lung and bladder, but not in the heart and liver. TS does not induce the BP- and NNK-DNA adducts in lung, heart, liver, and bladder. TS also reduces DNA repair activity and the abundance of repair proteins, XPC and OGG1/2, in lung tissues. These TS effects were greatly reduced by diet with polyphenols. We found that γ-OH-PdG and α-methyl-γ-OH-PdG are the major adducts formed in tobacco smokers' buccal cells as well as the normal lung tissues of tobacco-smoking lung cancer patients, but not in lung tissues of nonsmokers. However, the levels of BP- and NNK-DNA adducts are the same in lung tissues of smokers and nonsmokers. We found that while BP and NNK can induce BPDE-dG and O 6 -methyl-dG adducts in human lung and bladder epithelial cells, these inductions can be inhibited by acrolein. Acrolein also can reduce DNA repair activity and repair proteins. We propose a TS carcinogenesis paradigm. Aldehydes are major TS carcinogens exerting dominant effect: Aldehydes induce mutagenic PdG adducts, impair DNA repair functions, and inhibit many procarcinogens in TS from becoming DNA-damaging agents., Competing Interests: The authors declare no conflict of interest., (Copyright © 2018 the Author(s). Published by PNAS.)

Objective: Pulmonary radiotherapy has been reported to increase a risk of pneumonopathy, including pneumonitis and secondary pneumonia, however evidence from population-based studies is lacking. The present study intended to explore whether postoperative irradiation increases occurrence of severe pneumonopathy in lung cancer patients., Design, Setting and Participants: The nationwide population-based study analysed the Taiwan National Health Insurance Research Database (covered >99% of Taiwanese) in a real-world setting. From 2000 to 2010, 4335 newly diagnosed lung cancer patients were allocated into two groups: surgery-RT (n=867) and surgery-alone (n=3468). With a ratio of 1:4, propensity score was used to match 11 baseline factors to balance groups., Interventions/exposures: Irradiation was delivered to bronchial stump and mediastinum according to peer-audited guidelines., Outcomes/measures: Hospitalised pneumonia/pneumonitis-free survival was the primary end point. Risk factors and hazard effects were secondary measures., Results: Multivariable analysis identified five independent risk factors for hospitalised pneumonopathy: elderly (>65 years), male, irradiation, chronic obstructive pulmonary disease (COPD) and chronic kidney disease (CKD). Compared with surgery-alone, a higher risk of hospitalised pneumonopathy was found in surgery-RT patients (HR, 2.20; 95% CI, 1.93-2.51; 2-year hospitalised pneumonia/pneumonitis-free survival, 85.2% vs 69.0%; both p<0.0001), especially in elderly males with COPD and CKD (HR, 13.74; 95% CI, 6.61-28.53; p<0.0001). Unexpectedly, we observed a higher risk of hospitalised pneumonopathy in younger irradiated-CKD patients (HR, 13.07; 95% CI, 5.71-29.94; p<0.0001) than that of elderly irradiated-CKD patients (HR, 4.82; 95% CI, 2.88-8.08; p<0.0001)., Conclusions: A high risk of hospitalised pneumonopathy is observed in irradiated patients, especially in elderly males with COPD and CKD. For these patients, close clinical surveillance and aggressive pneumonia/pneumonitis prevention should be considered. Further investigations are required to define underlying biological mechanisms, especially for younger CKD patients., Competing Interests: Competing interests: None declared., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Aims: Clinical trials have reported conflicting results about whether celecoxib plus chemotherapy improves outcomes over chemotherapy alone in patients with advanced non-small cell lung cancer., Methods: We performed a meta-analysis comparing the primary and secondary endpoints of treatment with celecoxib plus chemotherapy vs. chemotherapy alone in patients with advanced non-small cell lung cancer., Results: Six eligible trials (1181 patients) were selected from the 206 studies that were identified initially. A significant difference, favouring celecoxib plus chemotherapy over chemotherapy alone, was observed in the overall response rate [odds ratio (OR) 1.34; 95% confidence interval (CI) 1.08, 1.67; P = 0.009). However, there was no difference in the 1-year survival rate (OR 1.08; 95% CI 0.86, 1.35; P = 0.512), clinical benefit (OR 1.05; 95% CI 1.88, 1.25; P = 0.613), complete response (OR 0.77; 95% CI 0.39, 1.51; P = 0.446) or partial response (OR 1.22; 95% CI 0.92, 1.63; P = 0.163). Toxicity did not differ significantly with the exception of the occurrence of leucopenia and thrombocytopenia., Conclusions: Celecoxib plus chemotherapy appeared to improve the overall response rate compared with chemotherapy alone in the treatment of patients with advanced non-small cell lung cancer. Further prospective randomized controlled trials are now needed., (© 2015 The British Pharmacological Society.)

Second-hand smoke (SHS) is associated with 20-30% of cigarette-smoke related diseases, including cancer. Majority of SHS (>80%) originates from side-stream smoke (SSS). Compared to mainstream smoke, SSS contains more tumorigenic polycyclic aromatic hydrocarbons and acrolein (Acr). We assessed SSS-induced benzo(a)pyrene diol epoxide (BPDE)- and cyclic propano-deoxyguanosine (PdG) adducts in bronchoalveolar lavage (BAL), lung, heart, liver, and bladder-mucosa from mice exposed to SSS for 16 weeks. In SSS exposed mice, Acr-dG adducts were the major type of PdG adducts formed in BAL (p < 0.001), lung (p < 0.05), and bladder mucosa (p < 0.001), with no significant accumulation of Acr-dG adducts in heart or liver. SSS exposure did not enhance BPDE-DNA adduct formation in any of these tissues. SSS exposure reduced nucleotide excision repair (p < 0.01) and base excision repair (p < 0.001) in lung tissue. The levels of DNA repair proteins, XPC and hOGG1, in lung tissues of exposed mice were significantly (p < 0.001 and p < 0.05) lower than the levels in lung tissues of control mice. We found that Acr can transform human bronchial epithelial and urothelial cells in vitro. We propose that induction of mutagenic Acr-DNA adducts, inhibition of DNA repair, and induction of cell transformation are three mechanisms by which SHS induces lung and bladder cancers.

The rapid development of high-volume horizontal hydraulic fracturing for mining natural gas from shale has posed potential impacts on human health and biodiversity. The produced flow back waters after hydraulic stimulation are known to carry high levels of saline and total dissolved solids. To understand the toxicity and potential carcinogenic effects of these wastewaters, flow back waters from five Marcellus hydraulic fracturing oil and gas wells were analyzed. The physicochemical nature of these samples was analyzed by inductively coupled plasma mass spectrometry and scanning electron microscopy/energy dispersive X-ray spectroscopy. A cytotoxicity study using colony formation as the endpoint was carried out to define the LC50 values of test samples using human bronchial epithelial cells (BEAS-2B). The BEAS-2B cell transformation assay was employed to assess the carcinogenic potential of the samples. Barium and strontium were among the most abundant metals in these samples and the same metals were found to be elevated in BEAS-2B cells after long-term treatment. BEAS-2B cells treated for 6weeks with flow back waters produced colony formation in soft agar that was concentration dependent. In addition, flow back water-transformed BEAS-2B cells show better migration capability when compared to control cells. This study provides information needed to assess the potential health impact of post-hydraulic fracturing flow back waters from Marcellus Shale natural gas mining., (Copyright © 2015 Elsevier Inc. All rights reserved.)

To evaluate effectiveness of 23-valent pneumococcal polysaccharide vaccine (PPSV23) inoculated during defined "vaccination period," first 6 months post cancer diagnosis (ie, an anti-cancer treatment period), in elderly lung cancer patients on community-acquired pneumonia (CAP) hospitalization incidence.This was a nationwide population-based cohort study of 157 newly diagnosed elderly lung cancer patients receiving PPSV23 during "vaccination period", and 628 age and sex one-to-one matched controls enrolled in the National Health Insurance Research Database (NHIRD) of Taiwan between 2007 and 2010. All patients were ≥75 years old and still survival post "vaccination period." Incidence density (ID) of all-cause inpatient CAP and cumulative survival risk were analyzed by multivariate Poisson regression and Kaplan-Meier method, respectively.After a 4-year follow-up, IDs of all-cause inpatient CAP for vaccination and control cohorts were 297 and 444 per 1000 PYs, respectively. Less vaccinated patients had CAP incidence density >1 time per PY (12.7% vs 21.2%) than non-vaccinated patients. After adjusting for potential confounding variables, like influenza vaccination, comorbidities, cancer treatment modalities, and socioeconomic status, adjusted inpatient CAP incidence rate in PPSV23 vaccination cohort was 0.74 times lower than control cohort (incidence rate ratio [IRR] = 0.740, P = 0.0339). Two-year cumulative CAP hospitalization rates and overall survival rates were 37.1% vs. 55.4%, and 46.6% vs. 26.2%, respectively, for lung cancer patients with and without PPSV23 (both P < 0.001). Subgroup analysis showed that for elderly lung cancer patients not ever receiving influenza vaccine, PPSV23 still had trend to reduce all-cause inpatient CAP.For elderly lung cancer patients aged ≥75 years, PPSV23 inoculated during anti-cancer treatment period could reduce CAP hospitalizations and improve survival.

Aims: Luteolin is a natural flavonoid that possesses a variety of pharmacological activities, such as anti-inflammatory and anti-cancer abilities. Whether luteolin regulates the transformation ability of lung cancer cells remains unclear. The current study aims to uncover the effects and underlying mechanisms of luteolin in regulation of and epithelial-mesenchymal transition of lung cancer cells., Main Methods: The lung adenocarcinoma A549 cells were used in this experiment; the cells were pretreated with luteolin followed by administration with TGF-β1. The expression levels of various cadherin and related upstream regulatory modules were examined., Key Findings: Pretreatment of luteolin prevented the morphological change and downregulation of E-cadherin of A549 cells induced by TGF-β1. In addition, the activation of PI3K-Akt-IκBa-NF-κB-Snail pathway which leads to the decline of E-cadherin induced by TGF-β1 was also attenuated under the pretreatment of luteolin., Significance: We provide the mechanisms about how luteolin attenuated the epithelial-mesenchymal transition of A549 lung cancer cells induced by TGF-β1. This finding will strengthen the anti-cancer effects of flavonoid compounds via the regulation of migration/invasion and EMT ability of various cancer cells., (© 2013.)

Purpose: Ganetespib is a novel inhibitor of the heat shock protein 90 (Hsp90), a chaperone protein critical to tumor growth and proliferation. In this phase II study, we evaluated the activity and tolerability of ganetespib in previously treated patients with non-small cell lung cancer (NSCLC)., Experimental Design: Patients were enrolled into cohort A (mutant EGFR), B (mutant KRAS), or C (no EGFR or KRAS mutations). Patients were treated with 200 mg/m(2) ganetespib by intravenous infusion once weekly for 3 weeks followed by 1 week of rest, until disease progression. The primary endpoint was progression-free survival (PFS) at 16 weeks. Secondary endpoints included objective response (ORR), duration of treatment, tolerability, median PFS, overall survival (OS), and correlative studies., Results: Ninety-nine patients with a median of 2 prior systemic therapies were enrolled; 98 were assigned to cohort A (n = 15), B (n = 17), or C (n = 66), with PFS rates at 16 weeks of 13.3%, 5.9%, and 19.7%, respectively. Four patients (4%) achieved partial response (PR); all had disease that harbored anaplastic lymphoma kinase (ALK) gene rearrangement, retrospectively detected by FISH (n = 1) or PCR-based assays (n = 3), in crizotinib-naïve patients enrolled to cohort C. Eight patients (8.1%) experienced treatment-related serious adverse events (AE); 2 of these (cardiac arrest and renal failure) resulted in death. The most common AEs were diarrhea, fatigue, nausea, and anorexia., Conclusions: Ganetespib monotherapy showed a manageable side effect profile as well as clinical activity in heavily pretreated patients with advanced NSCLCs, particularly in patients with tumors harboring ALK gene rearrangement., (©2013 AACR)

Background: The aim of this sub-study is to explore the incidence of skin rash among advanced breast cancer(ABC) patients in a phase II trial treated with weekly nab-paclitaxel and cisplatin combination., Methods: Nab-paclitaxel(125 mg/m2) was administered on days 1, 8, 15, followed by cisplatin(75 mg/m2) on day 1 every 28 day cycle until disease progression, intolerable toxicities or the maximum of 6 cycles. Patients who received at least one injection of the study drug were included in this analysis of the incidence of skin rash among Chinese patients. Toxicity was graded using the CTCAE4.0 criteria. Statistical analysis was carried out by using SPSS 16.0 (SPSS Inc, Chicago, IL)., Results: Seventy three patients were enrolled and eligible for analysis. A total of 384 cycles were administered at the time of this analysis. Rash was presented in 27 patients (37.0%). The most common sites involved were face (14/27), neck (14/27), limbs (18/27) and frictional parts of the trunk (10/27). Macular and papular rash with pruritus commonly occurred 2 (95% CI: 1-7) days after the first day of chemotherapy. Only one patient developed Grade 3 skin toxicity with generalized erythroderma and disfigurement of the face requiring dose reduction. The rash gradually regressed 2 (95% CI: 1-10) days after antihistamines used, but pigmentation remained in 13/27 cases. The incidence rate of skin rash was significantly higher than what has been described for western patients (approximate 4%, P < 0.0001)., Conclusion: A higher rate of maculo-papular rash occurred in Chinese breast cancer patients treated with weekly nab-paclitaxel compared to western patients. The albumin component of nab-paclitaxel might be the cause of the skin disorder., Trial Registration: NCT01149798.

The biodistribution, pharmacokinetics, dosimetry and comparative therapeutic efficacy of intravenously administrated (188)Re-N,N-bis(2-mercaptoethyl)-N',N'-diethylethylenediamine (BMEDA)-labeled pegylated liposome ((188)Re-liposome) and 5-FU were investigated in a CT26-luc lung-metastatic model. After intravenous administration of (188)Re-liposome, tumor accumulation from the radioactivity was observed. Levels of radioactivity in tumors were maintained at steady levels (from 5.40 to 5.67 %ID/g) after 4 to 24 h. In pharmacokinetics, the AUC((0→∞)), MRT((0→∞)) and Cl of (188)Re-liposome in blood via intravenous route were 998 h %ID/ml, 28.7 h and 0.1 ml/h, respectively. The total excreted fractions of feces and urine were 0.61 and 0.26, respectively. Absorbed doses for (188)Re-liposome in the liver and red marrow were 0.31 and 0.08 mSv/MBq, respectively. Tumor-absorbed doses for (188)Re-liposome ranged from 48.4 to 1.73 mGy/MBq at 10 to 300 g tumor spheres. In therapeutic efficacy, the survival times of mice after (188)Re-liposome [80% maximum tolerated dose (MTD); 29.6 MBq], 5-FU (80% MTD; 144 mg/kg), liposome or normal saline treatments were evaluated. Consequently, radiotherapeutics of (188)Re-liposome attained a longer lifespan (increase of 34.9%; P=.005) in mice than in the normal saline group. The increase in lifespan of the (188)Re-liposome group was 2.5-fold greater than that of the 5-FU group. Therefore, intravenous administration of (188)Re-liposome could provide a benefit and it is a promising strategy for delivery of passive nanotargeted radiotherapeutics in oncology applications., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Background: Apricoxib, a novel once-daily selective cyclooxygenase-2 inhibitor, was investigated in combination with erlotinib for recurrent stage IIIB/IV nonsmall cell lung cancer to determine the maximum tolerated dose, dose-limiting toxicity, and recommended phase II dose (RP2D) based on changes in urinary prostaglandin E₂ metabolite (PGE-M)., Methods: Patients received escalating doses of apricoxib (100, 200, and 400 mg/day) in combination with erlotinib 150 mg/day until disease progression or unacceptable toxicity. Urinary PGE-M was used to assess biologic activity and inform the optimal biologic dose., Results: Twenty patients were treated (3 at 100 mg; 3 at 200 mg; 14 at 400 mg apricoxib) with a median of 4 cycles (range, 2-14 cycles); 8 patients (40%) received prior EGFR-directed therapies. No dose-limiting toxicity was observed. Study drug-related adverse events (AEs) included diarrhea, rash, dry skin, anemia, fatigue, and increased serum creatinine; 4 patients had grade ≥ 3 drug-related AEs (diarrhea, perforated duodenal ulcer, hypophosphatemia, and deep vein thrombosis). The RP2D was 400 mg/day based on safety, biologic activity based on decreases in urinary PGE-M, and pharmacokinetics. One patient had a partial response, and 11 had stable disease. Stable disease was observed in patients who had received prior EGFR inhibitor therapy but was greater in patients not previously treated with an EGFR inhibitor. Seventeen patients had elevated urinary PGE-M at baseline, and 14 (70%) had a decrease from baseline, which was associated with disease control., Conclusions: Apricoxib plus erlotinib was well tolerated and yielded a 60% disease control rate. A phase II trial is currently investigating 400 mg/day apricoxib plus 150 mg/day erlotinib in patients selected based on change in urinary PGE-M., (Copyright © 2010 American Cancer Society.)

Lung cancer is a lethal disease, and early metastasis is the major cause of treatment failure and cancer-related death. Tyrosine phosphorylated (P-Tyr) proteins are involved in the invasive and metastatic behavior of lung cancer; however, only a limited number of targets were identified. We attempt to characterize P-Tyr proteins and events involved in the metastatic process. In a previous work, we have developed a strategy for identification of protein phosphorylation. Here, this strategy was used to characterize the tyrosine phosphoproteome of lung cancer cells that have different invasive abilities (CL1-0 vs. CL1-5). Using our analytical strategy, we report the identification of 335 P-Tyr sites from 276 phosphoproteins. Label-free quantitative analysis revealed that 36 P-Tyr peptides showed altered levels between CL1-0 and CL1-5 cells. From this list of sites, we extracted two novel consensus sequences and four known motifs for specific kinases and phosphatases including EGFR, Src, JAK2, and TC-PTP. Protein-protein interaction network analysis of the altered P-Tyr proteins illustrated that 11 proteins were linked to a network containing EGFR, c-Src, c-Myc, and STAT, which is known to be related to lung cancer metastasis. Among these 11 proteins, 7 P-Tyr proteins have not been previously reported to be associated with lung cancer metastasis and are of greatest interest for further study. The characterized tyrosine phosphoproteome and altered P-Tyr targets may provide a better comprehensive understanding of the mechanisms of lung cancer invasion/metastasis and discover potential therapies.

The development of rapid and sensitive methods for the detection of immunogenic tumor-associated antigen is important not only for understanding their roles in cancer immunology but also for the development of clinical diagnostics. Alpha-enolase (ENO1), a p48 molecule, is widely distributed in a variety of tissues, whereas gamma-enolase (ENO2) and beta-enolase (ENO3) are found exclusively in neuron/neuroendocrine and muscle tissues, respectively. Because ENO1 has been correlated with small cell lung cancer, nonsmall cell lung cancer, and head and neck cancer, it can be used as a potential diagnostic marker for lung cancer. In this study, we developed a simple, yet novel and sensitive, electrochemical sandwich immunosensor for the detection of ENO1; it operates through physisorption of anti-ENO1 monoclonal antibody on polyethylene glycol-modified disposable screen-printed electrode as the detection platform, with polyclonal secondary anti-ENO1-tagged, gold nanoparticle (AuNP) congregates as electrochemical signal probes. The immunorecognition of the sample ENO1 by the congregated AuNP@antibody occurred on the surface of the electrodes; the electrochemical signal from the bound AuNP congregates was obtained after oxidizing them in 0.1 M HCl at 1.2 V for 120 s, followed by the reduction of AuCl(4-) in square wave voltammetry (SWV) mode. The resulting sigmoidally shaped dose-response curves possessed a linear dynamic working range from 10(-8) to 10(-12) g/mL. This AuNP congregate-based assay provides an amplification approach for detecting ENO1 at trace levels, leading to a detection limit as low as 11.9 fg (equivalent to 5 microL of a 2.38 pg/mL solution).

Activating mutation of the K-ras gene was one of the earliest discoveries of genetic alterations in lung cancer. Moreover, K-ras somatic mutations might be suggested for predicting resistance to molecular antibodies targeting the epidermal growth factor receptor (EGFR). However, activated K-ras mutant detection methods are limited to traditional techniques. The techniques are complicated and are used only in tissue samples, which are limited for clinical applications. In a previous study, we established a low-cost, convenient, and easy technique for detecting activated K-ras in a small number of circulating tumor cells by the colorimetric membrane array method (CLMA). However, the sensitivity still needs further improvement. The aim of this study is to develop a new platform with chemiluminescence as reporter and weighted values of target genes on the chip in order to achieve a more sensitive, easier to read, and more accurate platform-weighted chemiluminecent membrane array (WCHMA). In advance, we collected 209 peripheral blood samples of non-small cell lung cancer (NSCLC) from patients to evaluate clinical K-ras activation detection using Activating KRAS Detection Chip both conducted by CLMA and WCHMA. Results show 71 specimens with K-ras mutation, of which 59 were identified as positive through CLMA and 66 were positive through WCHMA. After statistical analysis, the sensitivity of CLMA was found to be 83% and the specificity was 96%. On the other hand, the sensitivity of WCHMA increased to 93% and the specificity remained at 94%. Results of the detection limitation of peripheral blood on two platforms are: 3cancer cells/cm(3) blood using WCHMA, which is better than 5cancer cells/cm(3) blood using CLMA. Further analysis on the correlation between the test results and clinical pathological features shows that the mean score obtained using WCHMA is significantly correlated to TNM stage, tumor size, and metastasis., (Copyright (c) 2009 Elsevier Ireland Ltd. All rights reserved.)

Epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors (TKIs) have been established as a treatment option in patients with advanced non-small cell lung cancer (NSCLC). Clinically, PCR and RFLP are commonly used to evaluate the efficacy of TKIs, and these methods require cancer tissues to proceed. In the event a peripheral blood test is able to replace current evaluation methods, a greater clinical application advantage may be achieved. Therefore, in this study, we selected 30 EGFR pathway-related genes and constructed activated EGFR chips to identify overexpression of EGFR pathway-related genes from the peripheral blood of 72 NSCLC patients and 100 normal subjects. According to ROC curve analysis, the best chip interpretation cutoff value was 11 genes. Correlation analysis showed high significance among EGFR mutations, overexpression and the overexpression of EGFR pathway-related genes (p<0.0001). The potential application of this new technique may provide an accurate, instantaneous and convenient drug evaluation tool.

Background: GD2/GM2 synthase is a key enzyme in the synthesis of GD2 and GM2 gangliosides found on the surface of neuroblastoma and small cell lung carcinoma (SCLC) cells. In neuroblastoma, persistent levels of GD2/GM2 synthase RNA in bone marrow (BM) following therapy portend poorer progression-free and overall survival. We conducted this study to determine if GD2/GM2 synthase RNA could be detected in SCLC cell lines and human tissues, and whether mRNA transcript levels corresponded with disease status., Experimental Design: Initially, a pilot study enrolled patients with SCLC to determine the rate of GD2 expression at various points in the patients' disease course. Peripheral blood (PB), bone marrow and tumor tissues were used to measure GD2/GM2 synthase levels. In addition, SCLC cell lines were analyzed for GD2/GM2 synthase expression. Based on data from that initial analysis, a prospective trial was developed enrolling patients with newly diagnosed SCLC and following them serially. GD2/GM2 synthase transcript was determined by a sensitive quantitative reverse transcription-PCR (qRT-PCR) assay and normalized to glyceraldehyde-3-phosphate dehydrogenase (GAPDH)., Results: Six SCLC cell lines were assayed for expression of GD2/GM2 synthase, and high expression was detected in all. GD2/GM2 synthase transcript levels were obtained from tumor tissue, BM, or PB of 29 patients in the pilot study. 6/10 (60%) tumor tissues or BM samples were positive (median 332.7 units; range 13-2323 units); 8/19 (42%) untreated patients were GD2/GM2 synthase positive in their PB prior to beginning therapy (median 10.2; range 5.1-32.2); 3/4 (75%) patients who were first tested when they developed recurrent disease were positive in their PB (median 16.1; range 8.5-19.9). The fourth patient had an initial value of 2.0 (negative), which increased to 8.4 (positive) within 1 month without treatment. Seven of 12 patients with baseline positive GD2/GM2 synthase values had post-treatment levels measured, all of which were 50% decrease following successful treatment. Patients in the prospective trial demonstrated lower rates of positivity, with only 3/26 (12%) patients exhibiting detectable transcript levels in the peripheral blood prior to treatment. All 3 of these patients had their transcript levels fall below 5 after treatment. 11/26 patients had baseline levels of zero. Bone marrow was drawn at baseline on 7 patients in the prospective trial and 3 (43%) had transcript levels above 5 (range 0.65-27.43 units). There was no correlation between elevated levels in the BM and elevated levels in the PB., Conclusions: Although initial studies demonstrated that GD2/GM2 synthase transcripts were measurable in the peripheral blood of SCLC patients at diagnosis and declined with successful treatment, in a separate prospective study, these results could not be confirmed. Thus, GD2/GM2 is not a reliable biomarker in SCLC., (Copyright 2009 Elsevier Ireland Ltd. All rights reserved.)

Introduction: Lewis Y (Le(y)) is a blood group antigen with robust expression on the surface of epithelial tumors, including small cell lung cancer (SCLC), making it a potential target for antibody-based immunotherapy. 3S193, an immunoglobulin G3 monoclonal antibody, has demonstrated superior specificity, affinity, and cytotoxicity over other anti-Le(y) antibodies. A phase I trial of humanized 3S193 (hu3S193) with dosing up to 40 mg/m2 demonstrated tumor targeting without serious toxicities or the development of human anti-human antibodies., Methods: We tested the targeting and pharmacokinetics of hu3S193 in patients with SCLC. Eligibility required progressive SCLC treated with up to three previous chemotherapy regimens, measurable disease not previously irradiated, and tumor samples positive for 3S193 by immunohistochemistry. Patients received four weekly injections of hu3S193, five patients at 10 mg/m2 and five patients at 20 mg/m2. The first and fourth injections were radiolabeled with indium-111 for gamma camera imaging., Results: Of 40 patients screened, 25 of 34 (74%) assessable SCLC tumor samples were 3S193 positive by immunohistochemistry. Ten patients were treated with hu3S193; nine completed all four injections. All fluorodeoxyglucose (FDG)-avid lesions >2 cm were visualized on antibody single-photon emission computed tomography. Some lesions overlying vascular structures could not be visualized. No difference was noted in imaging or pharmacokinetics between the first and fourth injections. Toxicities included grade 2 urticaria (n = 1), grade 1 vomiting (n = 2), and grade 2 hypertension (n = 1) transiently after infusion at the higher dose., Conclusions: Given the strong tumor targeting, particularly at the higher dose, the favorable toxicity profile, and the potential for immunomodulatory effects, hu3S193 warrants further investigation in SCLC.

Pulmonary neuroendocrine tumors are a distinct subset of tumors composing approximately 20% of all lung cancers. The major categories of pulmonary neuroendocrine tumors include typical and atypical carcinoids, large cell neuroendocrine carcinoma, and the more common small cell lung cancer. They are classified into different categories in the 2004 World Health Organization system, but share structural and morphologic features. Despite these shared features, their clinical characteristics range from indolent to aggressive, and therefore the approach to treatment depends on the histologic subtype. This article discusses the current understanding of the epidemiology, pathologic characteristics, treatment, and prognosis of this spectrum of diseases.

Both geldanamycin (GA) and radicicol (RA) are HSP90 binding agents that possess antitumour activities. Although the in vitro data indicated that the inhibitory constant of RA is much bigger than that of GA, the in vivo data on drug efficacy might reveal different results. We have recently shown that treatment with GA induces a heat-shock response and that calcium mobilization may be involved in the process. By using induction of HSP70 as the endpoint assay, we found changes in upstream signaling mediators, including HSF1 and calcium mobilization, as well as possible involvement of protein kinase in human non-small cell lung cancer H460 cells treated with GA and RA. Our results demonstrated that calcium mobilization, a calcium dependent and H7-sensitive protein kinase, along with HSF1 activation by phosphorylation, are all involved in the HSP70 induction process triggered by the drugs. However, only GA, but not RA, can provoke a rapid calcium mobilization and thereby result in an instant induction of HSP70. Furthermore, the rapid calcium influx, followed by instant HSP induction, could be achieved in GA- or RA-treated cells placed in a medium containing excessive calcium while the response was completely abolished in cells depleted of calcium. Taken together, our findings suggest that differential calcium signaling may account for the differential induction of HSP and the action of GA and RA., ((c) 2005 Wiley-Liss, Inc.)

Background: Expression of neuroectodermal markers is a key feature of small cell lung carcinoma (SCLC). Although immune responses against a number of these proteins have been associated with paraneoplastic neuronal disease (PND), most patients with SCLC have anti-neuroectodermal antibodies in the absence of PND. Whether these immune responses affect the clinical outcome in SCLC is critical in understanding the potential value of these proteins as cancer vaccine targets as well as in the pathogenesis of PND., Methods: The authors investigated the frequency of immunoglobulin G autoantibodies against Sry-like high-mobility group box (SOX)1, 2, 3 and Zinc-finger gene of the cerebellum (ZIC)2 proteins in stored serum samples from 90 patients utilizing the lambda-phage plaque assay. Data obtained from patient records were utilized to measure clinical correlates of seroreactivity., Results: Antibodies to SOX1 were present in 28% of patients and another 28% had anti-ZIC2 antibodies, classifying these as some of the most frequent antibody responses observed in SCLC. None had autoimmune paraneoplastic disease. Antibody titers were frequently as high as > or = 1:10(6) and were stable for < or = 6 months after diagnosis. Seroreactivity against either SOX1 or ZIC2 correlated with younger age, lower lactate dehydrogenase levels, and better response to initial therapy., Conclusions: The frequent and stable presence of SOX Group B and/or ZIC2 antibodies in SCLC, but not in healthy individuals examined, indicates they are serological markers of SCLC. However, the correlation between known clinical parameters of less aggressive disease and seroreactivity suggests that these antibodies are indicators of better prognosis in SCLC and warrants further studies to clarify the nature of the underlying immune responses., (Copyright 2005 American Cancer Society.)

Background: These experiments were conducted to determine whether p185 can be therapeutically targeted in adenocarcinoma of the lung using an anti-p185-gelonin conjugate. c-erbB-2/p185 is overexpressed in up to one third of non-small cell lung cancers. CALU-3 is a human lung adenocarcinoma cell line that overexpresses p185. muMoAb-4D5 is a murine anti-p185 monoclonal immunoglobulin G1. Gelonin is a potent type 1 ribosomal inhibitory protein., Methods: 4D5 and gelonin were covalently modified and linked. Purification was confirmed by SDS-polyacrylamide gel electrophoresis. Dose-dependent cytotoxicity was quantified using 3H-thymidine uptake by CALU-3 cells after incubation with 4D5-gelonin conjugate or with control substances (4D5, gelonin, unconjugated 4D5 + gelonin, or control antibody MOPC-21)., Results: The 4D5-gelonin conjugate showed a 50% inhibitory concentration of 3.5 x 10(-10) mol/L, but 4D5 alone demonstrated no cytotoxic effect. Gelonin and the unconjugated 4D5-gelonin mixture had one tenth the cytotoxicity of the 4D5-gelonin conjugate (inhibitory concentration = 6.5 x 10(-9) mol/L and 8.5 x 10(-9) mol/L, respectively). The conjugate exhibited minimal toxicity against a p185-negative cell line (NIH3T3)., Conclusions: Selective and efficient killing of human lung adenocarcinoma cells can be achieved in vitro using c-erbB-2/p185-directed therapy.