Search

Lung cancer is the second most common cancer and the primary cause of cancer-related death in both men and women worldwide. Due to diagnosis at an advanced stage, it is associated with high mortality in the majority of patients. At present, various treatment approaches are available, such as chemotherapy, surgery, and radiotherapy, but all these approaches usually cause serious side effects like degeneration of normal cells, bone marrow depression, alopecia, extensive vomiting, etc. To overcome the aforementioned problems, researchers have focused on the alternative therapeutic approach in which various natural compounds are reported, which possessed anti-lung cancer activity. Phytocompounds exhibit their anti lung cancer activity via targeting various cell-signaling pathways, apoptosis and cell cycle arrest, and by regulating antioxidant status and detoxification. Apart from the excellent anti-cancer activity, clinical administration of phytocompounds is confined because of their high lipophilicity and low bioavailability. Therefore, researchers show their concern in the development of a stable, safe and effective approach of treatment with minimal side effects by the development of nanoparticle-based delivery of these phytocompounds to the target site. Targeted delivery of phytocompound through nanoparticles overcomes the aforementioned problems. In this article, the molecular mechanism of phytocompounds, their emerging combination therapy, and their nanoparticles-based delivery systems in the treatment of lung cancer have been discussed.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (EGFR-TKIs) are standard of care in the first-line (1L) setting for patients with metastatic non-small cell lung cancer (mNSCLC) with activating EGFR mutations. EGFR-activating mutations are a predictive factor for response to EGFR-TKIs. Meta-analyses have shown that patients with exon 21_L858R mutations exhibit reduced sensitivity to EGFR-TKIs, resulting in inferior patient outcomes compared to those with exon 19 deletion mutations, with worse overall survival, progression-free survival, objective response, and disease control rates. Clinical activity observed with 1L therapy with first-generation (1G), second-generation (2G), and third-generation (3G) EGFR-TKIs is not permanent, and resistance inevitably develops in all cases, supporting the importance of overall treatment planning. The introduction of the 3G EGFR-TKI, osimertinib, provides an opportunity to overcome T790M-mediated resistance to 1G and 2G EGFR-TKIs. Additionally, with the use of osimertinib, fewer T790M mutations are being detected as T790M is not a reported resistance mechanism to 3G EGFR-TKIs. However, there are currently no approved targeted therapies after 3G EGFR-TKIs. In order to further improve patient outcomes, there is a need to explore additional options for the overall treatment strategy for patients, including 1L and beyond. Combination of vascular endothelial growth factor (VEGF) inhibitors and EGFR-TKIs or chemotherapy and EGFR-TKIs may be a potential therapeutic approach in the 1L setting. This review discusses current treatment options for mNSCLC with activating EGFR mutations based on tumor, patient, and treatment characteristics and how an overall treatment plan may be developed.

Multidisciplinary care is needed to decide the best therapeutic approach and to provide optimal care to patients with lung cancer (LC). Multidisciplinary teams (MDTs) are optimal strategies for the management of patients with LC and have been associated with better outcomes, such as an increase in quality of life and survival. The Spanish Lung Cancer Group has promoted this review about the current situation of the existing national LC-MDTs, which also offers a set of excellence requirements and quality indicators to achieve the best care in any patient with LC. Time and sufficient resources; leadership; administrative and institutional support; and recording of activity are key factors for the success of LC-MDTs. A set of excellence requirements in terms of staff, resources and organization of the LC-MDT have been proposed. At last, a list of quality indicators has been agreed to achieve and measure the performance of current LC-MDTs.

Purpose Immunotherapy is an evolving therapeutic approach for non-small cell lung cancer (NSCLC). This study explored factors involved in patients’ perceptions about reporting or not reporting treatment-related symptoms experienced while undergoing immunotherapy. Methods Patients receiving immunotherapy for NSCLC were recruited in the USA and Europe. Qualitative interviews were conducted to elicit treatment-related symptoms and explore patients’ reasons and motivations for either reporting or not reporting these to their medical teams. Interviews were audio-recorded, transcribed, and coded for qualitative analysis. Results Sixty-six patients were interviewed (mean age: 62 years; 55% male; 91% with stage IV NSCLC). The most frequent symptoms that patients experienced but did not report were gastrointestinal (23% of patients), respiratory (17%), and energy related (12%). The most common reasons for not reporting symptoms included a perception that they were not severe enough, being unsure whether the experiences were side effects, and deciding that the experiences were expected and could be managed without assistance. Fear of having treatment discontinued was also mentioned but was not a prominent reason. The most common reasons for reporting symptoms were to ascertain if these were normal and expected, and to let the medical team know. Patients emphasized the importance of survival over treatment burden when balancing symptoms with treatment benefits. Conclusion Patients have a range of reasons for not reporting their treatment-related symptoms when undergoing immunotherapy for NSCLC. Reasons are more strongly related to determination of the severity versus manageability of patients’ experiences of symptoms than they are to the fear of having treatment discontinued.

Brain metastases (BMs) are the most common intracranial tumors and non-small cell lung cancer (NSCLC) are responsible for BM more than any other solid tumor. Its frequency is increasing due to of the availability of new imaging techniques, earlier diagnosis and improvement in treatment techniques and survival rates. NSCLC patients with BM represent heterogeneous prognostic group. The possibility of better prognostic stratification associated with more systemic therapy options and imaging and radiation technology advances have led to an increment of evaluation and indication of local ablative radiotherapy. The definite increment in quality of life and the potential overall survival (OS) benefit of its indication must be balanced with eventual higher risk of brain disseminated disease when whole brain irradiation is postponed. Therefore, a multidisciplinary evaluation is recommended to refine and personalize the therapeutic approach. The development of clinical nomograms or evaluation of circulating tumor cells/tumoral DNA that predict the survival free of new lesions may be the tools that will warranty further optimization of the treatment of NSCLC patients with BM. In this review, we report the main aspects of diagnosis, prognosis and therapeutic options and dilemmas evolving local ablative radiotherapy essentially based on seminal, updated prospective studies and ongoing trials.

Immune checkpoint inhibitors (ICIs), a type of immunotherapy, have become one of the most important therapeutic options for first- and second-line treatment of advanced non-small cell lung cancer (NSCLC). Recent clinical studies have shown that immunotherapy can offer substantial survival benefits to patients with early-stage or resectable advanced NSCLC. However, considering the importance of timing when using ICIs and their associated adverse events (AEs), the advantages and disadvantages of using these agents need to be weighed carefully when deciding the use of a combined treatment. In addition, the inconsistency between imaging assessment and pathological results poses further challenges to the evaluation of efficacy of neoadjuvant immunotherapy. It is also important to develop new methodologies and discover suitable biomarkers that can be used to evaluate survival outcomes of immunotherapy and identify patients who would benefit the most from this treatment. In this review, we aimed to summarize previous results of ongoing clinical trials on neoadjuvant immunotherapy for lung cancer and discuss the challenges and future perspectives of this therapeutic approach in the treatment of resectable NSCLC.

During the last several years, multiple gene rearrangements with oncogenic potential have been described in NSCLC, identifying specific clinic-pathological subgroups of patients that benefit from a targeted therapeutic approach, including anaplastic lymphoma kinase (ALK), c-ros protooncogene 1 (ROS1) and, more recently, REarranged during Transfection (RET) and neurotrophic tyrosine receptor kinases (NTRK) genes. Despite initial impressive antitumor activity, the use of targeted therapies in oncogene-addicted NSCLC subgroups is invariably associated with the development of acquired resistance through multiple mechanisms that can include both on-target and off-target mechanisms. However, the process of acquired resistance is a rapidly evolving clinical scenario that constantly evolves under the selective pressure of tyrosine kinase inhibitors. The development of increasingly higher selective and potent inhibitors, traditionally used to overcome resistance to first generation inhibitors, is associated with the development of novel mechanisms of resistance that encompass complex resistance mutations, highly recalcitrant to available TKIs, and bypass track mechanisms. Herein, we provide a comprehensive overview on the therapeutic strategies for overcoming acquired resistance to tyrosine kinase inhibitors (TKIs) targeting the most well-established oncogenic gene fusions in advanced NSCLC, including ALK, ROS1, RET, and NTRK rearrangements.

Introduction Metastatic non-small cell lung cancer (NSCLC) is nowadays treated with a multimodal therapeutic approach including immunotherapy, targeted therapy and radiotherapy. Radiation therapy, in addition to immune checkpoint inhibitors, gives rise to a particular radiobiological effect known as “bystander effect” consisting of the radiation-induced damage in nearby unirradiated cells. Case report We report a case of a 79-year-old female patient with stage IV NSCLC treated with concomitant immuno-radiotherapy who showed a bystander effect on bone. Management and outcome: Primary tumour biopsy revealed an adenocarcinoma with a PDL1 expression >50%, while staging exams showed a right pulmonary lesion with a partial involvement of the contiguous rib and a single brain metastasis. The patient refused chemotherapy, so that Pembrolizumab 2 mg/Kg was administered every 3 weeks. After two administrations, the single brain metastasis was treated using stereotactic radiosurgery while the site of primitive lung cancer received an 8 Gy-single fraction 3 D-conformal radiotherapy. Three months after irradiation a chest CT showed a radiological remission of about 10% of the GTV and a partial eburnation of the vertebra located nearby the target volume. The CT images of a PET/CT at six months showed a complete vertebral eburnation. At the last follow-up, the patient was free of disease (brain MRI, spinal MRI and PET/CT). Discussion The present case alerts for unusual side effects provoked by bystander phenomenon in patients treated with a combination of immunotherapy and irradiation. Immune activation exacerbates the bystander effect causing normal tissues toxicities beyond what immunotherapies are causing by themselves.

Despite many advances in the latest period, lung cancer remains the cancer with the highest mortality. The latest developments concerning lung cancer treatment have changed the clinical practice by prolonging patient survival; however, unfortunately, there remains a high mortality rate firstly due to disease aggressivity and secondly through lack of early diagnosis and screening programs. Currently, researchers and clinicians are talking about personalized cancer treatment, and a complete diagnostic evaluation should consider, in addition to staging and histology, molecular aberrations, and genetics of the tumor tissue. The development of tyrosine kinase inhibitors (TKIs) has led to an improvement in survival for patients with EGFR mutations, this being the most studied driver mutation in adenocarcinoma; and at the same time an important predictive factor for patient outcome following the treatment with TKIs. Reseach must investigate the different TKI combination strategies in order to overcome resistance and to increase patient survival. Currently, there are ongoing clinical trials that will probably change the therapeutic approach for EGFR-mutated advanced or metastatic NSCLC patients.

A clear cell tumor is a histological entity that rarely originates outside of the kidney. We describe a rare case of a clear cell tumor of the lung, also known as "sugar cancer," that occurred in a 74 year-old male patient, and perform a brief literature review. This report highlights the importance of an adequate disease management team, including surgeons, oncologists, and pathologists, to identify the best therapeutic approach to improve survival rates and the quality of life of patients affected by this rare disease.

Tumor vasculature proliferates rapidly, generally lacks pericyte coverage, and is uniquely frag-ile making it an attractive therapeutic target. A subset of small-molecule tubulin binding agents cause disaggregation of the endothelial cytoskeleton leading to enhanced vascular permeability generating increased interstitial pressure. The resulting vascular collapse and ischemia cause downstream hypoxia, ultimately leading to cell death and necrosis. Thus, local damage gener-ates massive amplification and tumor destruction. The tumor vasculature is readily accessed and potentially a common target irrespective of disease site in the body. Development of a therapeutic approach and particularly next generation agents benefits from effective non-invasive assays. Imaging technologies offer varying degrees of sophistication and ease of implementation. This review considers technological strengths and weaknesses with examples from our own laboratory. Methods reveal vascular extent and patency, as well as insights into tissue viability, proliferation and necrosis. Spatiotemporal resolution ranges from cellular mi-croscopy to single slice tomography and full three-dimensional views of whole tumors and measurements can be sufficiently rapid to reveal acute changes or long-term outcomes. Since imaging is non-invasive, each tumor may serve as its own control making investigations par-ticularly efficient and rigorous. The concept of tumor vascular disruption was proposed over 30 years ago and it remains an active area of research.

Background: GPR87 is a G protein receptor that is specifically expressed in tumor cells, such as lung cancer, and rarely expressed in normal cells. GPR87 is a promising target for cancer therapy, but its ligand is controversial. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer therapy in which a photosensitizer, IRDye700DX (IR700), binds to antibodies and specifically destroys target cells by irradiating them with near-infrared light. Here, we aimed to develop a NIR-PIT targeting GPR87. Methods: We evaluated the expression of GPR87 in resected specimens of lung cancer and malignant pleural mesothelioma (MPM) resected at Nagoya University Hospital using immunostaining. Humanized anti GPR87 antibody (huGPR87) was generated by introducing VH and VL genes into mouse anti GPR87 antibody which generated by standard hybridoma method. HuGPR87 was conjugated with IR700 and the therapeutic effect of NIR-PIT was evaluated in vitro and in vivo using lung cancer or MPM cell lines. Findings: Among the surgical specimens, 54% of lung cancer and 100% of MPM showed high expression of GPR87. It showed therapeutic effects on lung cancer and MPM cell lines in vitro, and showed therapeutic effects in multiple models in vivo. Interpretation: These results suggest that NIR-PIT targeting GPR87 is a promising therapeutic approach for the treatment of thoracic cancer. Funding: Funding: This research was supported by the Program for Developing Next-generation Researchers (Japan Science and Technology Agency), KAKEN (18K15923, JSPS), Souhatsu (JST). Declaration of Interest: None to declare Ethical Approval: All in vivo procedures were performed in accordance with the Nagoya University Animal Care and Use Committee's "Guide for the Management and Use of Laboratory Animal Resources" (approval numbers 2017-29438, #2018-30096, # 2019-31234, #2020-20104). The use of specimens from patients was approved by the Ethics Committee of the Nagoya University Clinical Research Committee (Approval No. 2018-0046).

Lung cancer is one of the worldwide leading causes of death and is one of the most diagnosed cancers. The choice of the treatment system for lung cancer depends on the progression stage of the cancer. Chemoradiotherapy ensuring systemic transmission of metastatic lesions is the only therapeutic approach available in patients with stage 4 lung cancer. Several factors both outside and inside may contribute to lung cancer development. The therapeutic windows and solubility of low water solubility cancer drugs have been enhanced by nanoscale technology. Nanoparticles not only improve the potential of chemotherapy-involved drugs but also minimize toxic effects that are not specific. The delivery strategies provide the opportunity, by creating “multifunctional” particles, to modify pharmacokinetic outlines, reducing toxicity, and increasing therapeutic markers. Inhalation of anticancer drugs due to its noninvasive characteristics and ability to deliver patient-led drug delivery becomes an attractive treatment strategy.

In present times cancer is among one of the deadliest diseases of the world. Mutations in DNA lead to uncontrolled cell growth and cell proliferation resulting in cancer. Lung cancer not only contributes to an estimated 1.2 million deaths per year but is also known to have the lowest 5-year survival rate. Genomic mutations severely affect the signaling pathways which lead to the formation of tumors and progression of disease. A deep study of these pathways would help in the development of specific drugs which would help in targeting dysregulated pathways. However, current ongoing chemotherapy and other treatments are accompanied by a lot of side effects. A number of phytochemicals have antitumor potential and also are nontoxic toward other body cells. Utilization of these beneficial properties could play a role in providing a cost-effective and environment friendly way of cancer treatment. However, many previous supplementation trials have also shown inconsistent results. This chapter evaluates the limitation of current anticancer drugs available and the potential of phytochemicals as novel therapeutic against lung cancer.

Tumor repopulation during cycles of radiotherapy limits the radio-response in ensuing cycles and causes failure of treatment. It is thus of vital importance to unveil the mechanisms underlying tumor repopulating cells. Increasing evidence suggests that a subpopulation of drug-tolerant persister cancer cells (DTPs) could survive the cytotoxic treatment and resume to propagate. Whether these persister cells contribute to development of radio-resistance remains elusive. Based on the genetic profiling of DTPs by integrating datasets from Gene Expression Omnibus database, this study aimed to provide novel insights into tumor-repopulation mediated radio-resistance and identify predictive biomarkers for radio-response in clinic. A prognostic risk index, grounded on four persister genes (LYNX1, SYNPO, GADD45B, and PDLIM1), was constructed in non-small-cell lung cancer patients from The Cancer Genome Atlas Program (TCGA) using stepwise Cox regression analysis. Weighted gene co-expression network analysis further confirmed the interaction among persister-gene based risk score, radio-response and overall survival time. In addition, the predictive role of risk index was validated in vitro and in other types of TCGA patients. Gene set enrichment analysis was performed to decipher the possible biological signaling, which indicated that two forces behind persister cells, stress response and survival adaptation, might fuel the tumor repopulation after radiation. Targeting these persister cells may represent a new prognostic and therapeutic approach to enhance radio-response and prevent radio-resistance induced by tumor repopulation.

A recent acute respiratory syndrome, also known as Coronavirus Disease 2019 (COVID-19) has spread worldwide and caused tremendous economic issue and public health concern. While the precise pathological pathway and transmission method remains unknown, current focus among the research has been shifted to developing an efficacious vaccine or treatment to the disease. One potential therapeutic target known currently is angiotensin converting enzyme 2 (ACE2). It has been shown in previous study that ACE2 could potentially help SARS-CoV-2 virus get into the lung cells and further help the virus thrive. However, though great effort has been put into the vaccine development towards the prevention of the interaction between ACE2 and SARS-CoV-2, the development has been facing a lot of problem, especially since the actual binding pattern of these two still remains unclear. Here, instead of investing the interaction between ACE2 and SARS-CoV-2, researching the most vulnerable cell type that susceptible for the COVID-19 infection can provide a faster and more precise method in fighting against the disease. Alveolar type 2 progenitor cells (AT2 cell), known as "stem-like" cells in the lung tissue helping decrease lung injury and control immune response in lung area, have long been regarded as critical cells for the development of adenocarcinoma. In lung cancer field, lipoplex has been developed to target AT2 cell specifically. Previous finding indicates that AT2 cells contain ACE2 and TMPRSS2, which are critical for SARS-CoV-2 virus infection. Therefore, AT 2 cells could be potential target for COVID19 treatment and drug specifically for AT2 could be considered as treatment candidate for SARS-CoV2.

Background Next generation sequencing (NGS) of tumor of patients with advanced non–small cell lung cancer (NSCLC) is now a standard of care that informs the clinician on the best therapeutic approach for their patients. The purpose of our study was to investigate the overall impact of NGS testing on survival as well as potential racial differences in utilization, therapeutic decision, and genomic alterations. Method Using a large institutional database, 928 patients with stage IV NSCLC were identified. NGS testing using Foundation One platform was used. Clinical and genomic characteristics were compared by race. We used a propensity-modeling technique to compare groups that were sequenced or not in terms of overall survival. Time to event data was analyzed using Kaplan-Meier method and Cox model. Results A total of 295 patients underwent NGS. Patients undergoing NGS testing had significantly longer survival of 25.3 months versus those who did not undergo sequencing with a median survival of 14.6 months (P = .002) irrespective if they received targeted therapy or not. There was no difference in terms of NGS utilization based on race (P = .32). African American individuals had significantly higher rates of ALK rearrangements and mutations in PBRM1, SETD2, TSC2, and FBXW7. Conclusion Our study demonstrates that within a large single institution there is no racial difference in NGS utilization and that NGS testing directly impacts survival. We identify a number of differences in genomic findings between African American and white individuals.

RAS (KRAS, NRAS and HRAS) is the most frequently mutated gene family in cancers, and, consequently, investigators have sought an effective RAS inhibitor for more than three decades. Even 10 years ago, RAS inhibitors were so elusive that RAS was termed ‘undruggable’. Now, with the success of allele-specific covalent inhibitors against the most frequently mutated version of RAS in non-small-cell lung cancer, KRASG12C, we have the opportunity to evaluate the best therapeutic strategies to treat RAS-driven cancers. Mutation-specific biochemical properties, as well as the tissue of origin, are likely to affect the effectiveness of such treatments. Currently, direct inhibition of mutant RAS through allele-specific inhibitors provides the best therapeutic approach. Therapies that target RAS-activating pathways or RAS effector pathways could be combined with these direct RAS inhibitors, immune checkpoint inhibitors or T cell-targeting approaches to treat RAS-mutant tumours. Here we review recent advances in therapies that target mutant RAS proteins and discuss the future challenges of these therapies, including combination strategies. RAS proteins, which are frequently altered in cancer, were once considered undruggable, but compounds targeting some mutant RAS proteins have recently demonstrated clinical efficacy. In this Review, Malek and colleagues explore how these and other drugs that target RAS or associated pathways might be used effectively, particularly in combinations, and discuss other RAS-targeted therapies in the pipeline.

Background The deeper knowledge of non–small-cell lung cancer (NSCLC) biology and the discovery of driver molecular alterations have opened the era of precision medicine in lung oncology, thus significantly revolutionizing the diagnostic and therapeutic approach to NSCLC. In Italy, however, molecular assessment remains heterogeneous across the country, and numbers of patients accessing personalized treatments remain relatively low. Nationwide programs have demonstrated that the creation of consortia represent a successful strategy to increase the number of patients with a molecular classification. Patients and Methods The Alliance Against Cancer (ACC), a network of 25 Italian Research Institutes, has developed a targeted sequencing panel for the detection of genomic alterations in 182 genes in patients with a diagnosis of NSCLC (ACC lung panel). One thousand metastatic NSCLC patients will be enrolled onto a prospective trial designed to measure the sensitivity and specificity of the ACC lung panel as a tool for molecular screening compared to standard methods. Results and Conclusion The ongoing trial is part of a nationwide strategy of ACC to develop infrastructures and improve competences to make the Italian research institutes independent for genomic profiling of cancer patients.

Over the last two decades, the identification of targetable oncogene drivers has revolutionized the therapeutic landscape of non-small cell lung cancer (NSCLC). The extraordinary progresses made in molecular biology prompted the identification of several rare molecularly defined subgroups. In this review, we will focus on the novel and emerging actionable oncogenic drivers in NSCLC. Recently, novel oncogene drivers emerged as promising therapeutic targets besides the well-established EGFR mutations, and ALK/ROS1 rearrangements, considerably expanding the list of potential exploitable genetic aberrations. However, the therapeutic algorithm in these patients is far less defined. The identification of uncommon oncogene drivers is reshaping the diagnostic and therapeutic approach to NSCLC. The introduction of novel highly selective inhibitors is expanding the use of targeted therapies to rare and ultra-rare subsets of patients, further increasing the therapeutic armamentarium of advanced NSCLC.

Approximately one-third of all non-small-cell lung cancer (NSCLC) are locally-advanced at diagnosis, and 15–17% of these tumors are unresectable at presentation. Definitive chemo-radiotherapy (CRT) represents the standard therapeutic approach. However, the literature has shown that only 15% of patients are alive at 5 years and this percentage has remained unchanged despite various attempts of improvement. The recent introduction of immunotherapy has not only strongly changed the clinical scenario but has also drawn attention to a stage of disease apparently forgotten for decades. Stage III NSCLC can represent an interesting setting for the combined use of chemo-radiation and immunotherapy, due to the potential synergistic effect between radiation and immune checkpoint inhibitors. We reviewed the available literature in order to report the state of art of stage III NSCLC, by focusing on trials that evaluate different combinations of CRT and new drugs of PD-1/PD-L1 axis, and anti-CTLA-4. The future goal in the management of unresectable stage III NSCLC will be the optimal patients’ selection combined with the use of individualized immuno/chemotherapies that could potentially improve clinical outcomes.

Major pulmonary resection by VATS (video-assisted thoracoscopic surgery) has become a standard therapeutic approach, not only for early stage lung tumors but also for patients with locally advanced disease. However, while in cases of clinical N2 disease surgical resection after neoadjuvant therapy is an established treatment protocol, more uncertainty exists on whether the intraoperative discovery of unexpected N2 disease should lead to following through with surgical resection or aborting it in favor of pre-operative treatment. A literature review using the PICO framework was conducted to compare the short and long-term oncological outcomes of the different therapeutic strategies. Although survival outcomes appear to be only moderately superior in patients treated by neoadjuvant therapy followed by surgery compared with those undergoing adjuvant therapy, an important issue is that slightly more than 50% of the operated patients eventually undergo post-operative chemotherapy. Surgical morbidity is certainly responsible for this reduced treatment completion rate; therefore, favoring VATS over thoracotomy may improve the feasibility of adjuvant treatment protocols. Furthermore, there is now evidence that the thoroughness of lymphadenectomy and the complete resection rates are as satisfactory by VATS as by thoracotomy, resulting in equal oncological outcomes. Therefore, in light of the earlier functional recovery of patients operated on by VATS and their greater ability to withstand postoperative adjuvant therapies, considering the effectiveness of this treatment protocol compared to the detrimental effects of an exploratory surgery, we recommend that, in case of unexpected N2 involvement, the surgeon should proceed with a complete resection and systematic mediastinal lymphadenectomy through the same VATS approach.

Over the last decade, we have witnessed a paradigm shift in cancer treatment, with the advent of novel therapeutic approaches that target or manipulate the immune system, also known as immunotherapy. Blocking immune checkpoints has emerged as an effective strategy with unprecedented results in several solid tumors, including lung cancer. Since 2012 when PD(L)-1 inhibitors showed first clinical signals of activity in lung cancer, immune checkpoint blockade (ICB) has emerged as a novel effective therapeutic strategy in different settings, determining a dramatic change in the therapeutic landscape of both non-small cell lung cancer (NSCLC) and, more recently, small cell lung cancer (SCLC). Although the benefit from this novel therapeutic approach is undeniable, several open questions still remain unanswered. Herein, we summarize the major breakthroughs in the immunotherapy journey in lung cancer and how it is changing our clinical practice.

Lung cancer is one of the main causes of cancer-related mortality worldwide. Over the years, different therapeutic modalities have been adopted depending on tumor stage and patient characteristics, such as surgery, radiotherapy (RT), and chemotherapy. Recently, with the development of immune-checkpoint inhibitors (ICI), the treatment of metastatic and locally advanced non-small cell lung cancer (NSCLC) has experienced a revolution that has resulted in a significant improvement in overall survival with an enhanced toxicity profile. Despite this paradigm shift, most patients present some kind of resistance to ICI. In this setting, current research is shifting towards the integration of multiple therapies, with RT and ICI being one of the most promising based on the potential immunostimulatory synergy of this combination. This review gives an overview of the evolution and current state of the combination of RT and ICI and provides evidence-based data that can improve patient selection. The combination in lung cancer is a safe therapeutic approach that improves local control and progression-free survival, and it has the potential to unleash abscopal responses. Additionally, this treatment strategy seems to be able to re-sensitize select patients that have reached a state of resistance to ICI, further enabling the continuation of systemic therapy. Sin financiación 6.639 JCR (2020) Q1, 51/242 Oncology 1.818 SJR (2020) Q1, 63/354 Oncology No data IDR 2020 UEM

Somatic KRAS mutations are the most common oncogenic variants in lung cancer and are associated with poor prognosis. Using a Kras–induced lung cancer mouse model, CC-LR, we previously showed a role for inflammation in lung tumorigenesis through activation of the NF-κB pathway, along with induction of interleukin 6 (IL6) and an IL17-producing CD4(+) T-helper cell response. IL22 is an effector molecule secreted by CD4(+) and γδ T cells that we previously found to be expressed in CC-LR mice. IL22 mostly signals through the STAT3 pathway and is thought to act exclusively on non-hematopoietic cells with basal IL22 receptor (IL22R) expression on epithelial cells. Here, we found that higher expression of IL22R1 in patients with KRAS mutant lung adenocarcinoma was an independent indicator of poor recurrence-free survival. We then showed that genetic ablation of Il22 in CC-LR mice (CC-LR/IL22KO mice) caused a significant reduction in tumor number and size. This was accompanied by significantly lower tumor cell proliferation, angiogenesis, and STAT3 activation. Il22 ablation was also associated with significant reduction in lung-infiltrating inflammatory cells and expression of pro-tumor inflammatory cytokines. Conversely, this was accompanied with increased antitumor Th1 and cytotoxic CD8(+) T cell responses, while suppressing the pro-tumor immunosuppressive T regulatory cell response. In CC-LR/IL22KO mice, we found significantly reduced expression of core stemness genes and the number of prototypical SPC(+)CCSP(+) stem cells. Thus, we conclude that IL22 promotes Kras mutant lung tumorigenesis by driving a pro-tumor inflammatory microenvironment with proliferative, angiogenic, and stemness contextual cues in epithelial/tumor cells.

In the era of precision medicine, predictive biomarkers have revolutionized the therapeutic approach to advanced non-small cell lung cancer (NSCLC) (1). So far, sensitizing epidermal growth factor ( EGFR ) mutations (exon 19 deletion or exon 21 L858R) and anaplastic lymphoma kinase ( ALK ) rearrangements are among the best described targetable alterations, against which highly effective small molecules tyrosine-kinase inhibitors (TKIs) have been developed.

As the leading cause of death worldwide, lung cancer has proven itself incurable in the advanced stages. For early stages, endobronchial ultrasounds transbronchial needle aspiration (EBUS-TBNA) is now considered the standard to assess mediastinal lymph node, to define the multimodality therapeutic approach. In recent years, EBUS-TBNA has extended its use also in the metastatic and locally recurrent disease. New molecules, with specific mutations that give resistance to current target therapies, have made re-biopsy at disease progression an important assessment, with therapeutic and clinical implication. Here we present the oncologist’s point of view on EBUS-TBNA in the staging process, at recurrence and progression.

We report a rare case of advanced lung cancer with epidermal growth factor receptor and anaplastic lymphoma kinase co-alterations and brain metastasis, in which icotinib treatment was effective for both the primary lung tumor and the brain metastasis. The patient achieved important clinical remission with a progression-free survival for two years. Our treatment strategy appears to be a promising therapeutic approach for this subgroup of patients.

Lung cancers are common malignancies, which have a very poor prognosis. These are the leading cause of cancer deaths in France and worldwide. Behind this unfavourable prognosis hides many disparities according to age, sex, social level and exposure to risk factors. The detection of the genetic abnormalities, which drive carcinogenesis has totally changed the therapeutic approach. Tumours are now classified according to their molecular profile which is itself associated with new demographic data. We here review the most recent data on this topic.

International audience; Lung cancer is the leading cause of cancer-related mortality and more than half of the cases are diagnosed at a metastatic stage. Major progress in terms of systemic treatments has been achieved in recent decades. Access to new anti-PD-(L) 1 immunotherapies and targeted therapies for non-small cell lung cancer (NSCLC) with oncogenic addiction such as EGFR mutation or ALK rearrangement have led to improved outcomes. Patients with limited progression of their disease during systemic treatment may be a particular subgroup. This oligoprogressive state is characterized by a limited number of sites in progression, implying that the other sites remain controlled and therefore sensitive to systemic treatments. The advent of non-invasive techniques such as stereotactic radiotherapy, radiofrequency, and mini-invasive surgery has led to a precise re-evaluation of local ablative treatments in this situation. Local treatment of the oligoprogressive lesion(s) may allow modification of the natural history of the disease, maintenance of effective systemic targeted treatment and, ultimately, to improved survival. Data validating an aggressive local therapeutic approach in oligoprogressive NSCLC patients are currently limited and essentially retrospective. Several international trials are underway that could confirm the clinical benefit of radical local treatment in oligoprogressive advanced NSCLC patients.

Les proliférations plasmocytaires malignes extra-médullaires isolées qu'on appelle plasmocytomes sont rares. Elles sont décrites habituellement au niveau de la tête et du cou (80% des cas) et exceptionnellement ailleurs. Nous rapportons l'observation d'un patient de 62 ans qui présente un plasmocytome solitaire pulmonaire mimant initialement un cancer bronchique primitif. Nous rapportons notre attitude thérapeutique et discutons à travers une revue de la littérature la rareté de ce cas clinique, les facteurs pronostiques ainsi que les modalités de prise charge de ces tumeurs.

Background: Small-cell lung cancer (SCLC) is an aggressive disease with still limited therapeutic options. Despite being both a chemo- and radiation-sensitive malignancy, SCLC recurrence occurs in most cases and negatively impacts patients’ prognosis. Over the last few years, a deeper understanding of SCLC molecular aberrations has led to the identification of Notch pathway deregulation as a crucial event in SCLC tumorigenesis, disease progression and chemoresistance. In particular, the delta-like protein 3 (DLL3), a Notch inhibitory ligand whose expression is directly related to the key neuroendocrine transcription factor ASCL1, was found to be expressed in ~85% of SCLCs, while it exhibits minimal to absent surface expression in normal lungs. DLL3 thus represents an appealing novel biomarker as well as a potential target in SCLC. Conclusions: The first DLL3-targeted antibody-drug conjugate rovalpituzumab tesirine (Rova-T, SC16LD6.5) has shown promising results in terms of efficacy and safety for the management of extensive SCLC, supporting further studies on this novel therapeutic approach that combines specific SCLC targeting with the cell-killing ability of a pyrrolobenzodiazepine dimer. In the present review, we discuss currently available evidence on the biological role of Notch signaling in SCLC from early preclinical findings to current and future clinical implications.

Lung cancer (LC) is the leading cause of cancer-related death worldwide, despite a decreasing incidence rate in recent years, especially in men. Most risk factors for LC could be linked to an individual's reproductive system and secondary sex characteristics ('sex-related') and/or to some physical, behavioral and personality traits ('gender-related') peculiar to males rather than females or vice versa. An imbalance of these etiologic factors could explain why some LC features may differ between sexes. For this review, an extended literature data collection was performed, using keywords to identify 'sex/gender' and 'LC'. Differences between genders in LC epidemiology, pathological and molecular characteristics, loco-regional and/or systemic treatments outcome and prognosis were systematically analyzed. The possible predictive role of physio-pathological factors in males and females paves the way for a personalized therapeutic approach, emphasizing the need to include gender as a stratification factor in future clinical trials design.

Immune checkpoint inhibition with monoclonal antibodies has emerged as a promising therapeutic approach but in most tumor types responses are unpredictable and observed in a minority of treated patients. Positive and negative predictive biomarkers for efficacy of these costly drugs are desperately needed. Immunohistochemistry (IHC) for programmed death ligand (PD-L1) expression in tumor and inflammatory infiltrate has emerged as one predictive biomarker of some value. However, multiple confounders including those inherent to any IHC and the unique complexities of the biology of the immune response have limited its utility. Tumor mutational burden (TMB) has emerged as a seemingly more promising predictive biomarker for immunotherapy with checkpoint inhibitors in several tumor types and is likely to be incorporated into future treatment algorithms for these agents. Given this, the need to define and standardize key parameters of the most promising biomarkers becomes essential to allow all stakeholders to make meaningful observations and inferences as to the efficacy of ostensibly similar agents and combinations in various settings. This review briefly summarizes approaches to measurement of TMB and ongoing efforts to achieve harmonization of this key biomarker.

The understanding of cancer biology and the identification of various molecular pathways and targeted oncogenic drivers have led to a paradigm shift in treatment of non-small cell lung cancer. In the last two decades, the therapeutic approach for non-small cell lung cancer (NSCLC) has gradually transitioned from empiric treatment with chemotherapeutic regimens to personalized medicine with precision targets. The major key players in these novel approaches involve targeted therapy, such as tyrosine kinase inhibitors (TKI) and immunotherapy, such as immune checkpoint inhibitors (ICI) blocking intrinsic down regulators of immunity, to achieve anti-cancer effects. These novel agents are generally better tolerated than chemotherapeutics and it is essential to be cognizant of the various drug related adverse effects. Regular follow up of patients with NSCLC by chest computed tomography (CT) surveillance to monitor for disease progression or recurrence is a prerequisite. It is becoming increasingly challenging to identify pulmonary complications related to the use of novel TKI and ICI. Our review focuses on various pulmonary complications of TKI and ICI in patients undergoing treatment for NSCLC, chest CT manifestations, management strategies, and treatment outcomes described in various case reports and case series.

Objective: To guide the optimal selection among first-generation epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) in clinical practice. This review attempted to provide a thorough comparison among three first-generation EGFR-TKIs, namely icotinib, erlotinib, and gefitinib, with regard to their molecular structure, pharmacokinetic parameters, clinical data, adverse reactions, and contraindications. Data Sources: An electronic literature search of the PubMed database and Google Scholar for all the available articles regarding gefitinib, icotinib, and erlotinib in the English language from January 2005 to December 2014 was used. Study Selection: The search terms or keywords included but not limited to “lung cancer”, “nonsmall cell lung cancer (NSCLC)”, “epidemiology”, “EGFR”, “TKIs”, and “optimal selection “. Results: As suggested by this review, even though the three first-generation EGFR-TKIs share the quinazoline structure, erlotinib had the strongest apoptosis induction activity because of its use of a different side-chain. The pharmacokinetic parameters indicated that both erlotinib and icotinib are affected by food. The therapeutic window of erlotinib is narrow, and the recommended dosage is close to the maximum tolerable dosage. Icotinib enjoys a wider therapeutic window, and its concentration in the blood is within a safe dosage range even if it is administered with food. Based on multiple large-scale clinical trials, erlotinib is universally applied as the first-line treatment. In marked contrast, icotinib is available only in China as the second- or third-line therapeutic approach for treating advanced lung cancer. In addition, it exhibits a similar efficacy but better safety profile than gefitinib. Conclusions: Although there is a paucity of literature regarding whether icotinib is superior to erlotinib, its superior toxicity profile, noninferior efficacy, and lower cost indicate that it is a better alternative for Chinese patients living with advanced NSCLC.

Lung cancer in humans is majorly represented by non-small cell lung cancer cells, and there is a constant search for an efficient therapeutic approach. This study aims to find the anti-proliferative and apoptotic effects of matricin on H1299 cells via activation of MAPK pathway. Non-small cell H1299 cells were subjected to viability analysis with MTT assay and anti-proliferation analysis with different concentrations of matricin. Apoptosis was determined with annexin V/propidium iodide (PI) and flow cytometric analysis. Analysis of oxidative stress markers, reduced glutathione, lipid peroxidation (LPO), superoxide dismutase (SOD), and catalase (CAT) activities were done using standard assay kits. Apoptosis enzymes caspase-3, caspase-8, and caspase-9 levels were measured using colorimetric kit analysis. Western blot analysis on apoptotic proteins was performed to determine the involvement of MAPK pathway activation in apoptosis. Matricin significantly ( P

Worldwide, lung cancer remains the most common cause of cancer-related mortality, with non-small cell lung cancer (NSCLC) accounting for 85% of all diagnosed lung cancer cases. Chemotherapy is considered the standard of care for patients with advanced NSCLC; however, the tumors can develop mechanisms that inactivate these drugs. Comparative genomic analyses have revealed that disruptions in the kelch-like ECH-associated protein 1 (Keap1)-nuclear factor erythroid-2-related factor-2 (Nrf2) pathway are frequent in NSCLC, although Nrf2 mutations occur less frequently than Keap1 mutations. As the Keap1-Nrf2 pathway appears to be a primary regulator of key cellular processes that aid to resist the action of chemotherapy drugs, the clinical implementation of Nrf2 inhibitors in patients with advanced NSCLC may be a useful therapeutic approach for patients harboring KEAP1-NRF2 mutations. The aim of the present review was to highlight findings of how constitutive Nrf2 activation may be a specific biomarker for predicting patients most likely to benefit from classical chemotherapy drugs, overall improving patient survival rate.

Malignant pleural effusion (MPE) affects more than 1 million people globally. There is a dearth of evidence on the therapeutic approach to MPE, and not surprisingly a high degree of variability in the management thereof. We aimed to provide practicing clinicians with an overview of the current evidence on the management of MPE, preferentially focusing on studies that report patient-related outcomes rather than pleurodesis alone, and to provide guidance on how to approach individual cases. A pleural intervention for MPE will perforce be palliative in nature. A therapeutic thoracentesis provides immediate relief for most. It can be repeated, especially in patients with a slow rate of recurrence and a short anticipated survival. Definitive interventions, individualized according the patient’s wishes, performance status, prognosis and other considerations (including the ability of the lung to expand) should be offered to the remainder of patients. Chemical pleurodesis (achieved via intercostal drain or pleuroscopy) and indwelling pleural catheter (IPC) have equal impact on patient-based outcomes, although patients treated with IPC spend less time in hospital and have less need for repeat pleural drainage interventions. Talc slurry via IPC is an attractive recently validated option for patients who do not have a nonexpandable lung.

Immune oncology treatment with immune checkpoint inhibitors (ICIs) is revolutionizing therapeutic approach for advanced non-small cell lung cancer (NSCLC) patients, in terms of longer survival and improved quality of life. To date, the widely used and approved biomarker is programmed death ligand 1 (PD-L1) expression on tumour cells, but it is considered not accurate and it is more likely that many factors, related to both cancer and host, may better predict response to ICI. Among those factors, great attention is being dedicated to tumour mutation burden, defined as the number of somatic non-synonymous mutations in cancer cells assessed with next-generation sequencing technologies. Moreover, recent evidences have shown that not only the quantity of tumour mutations, but also their quality may influence response to treatment with ICI. In fact, it seems that clonal heterogeneity of cancer cells, and of predicted neo-antigens, may affect anticancer response in patients receiving ICI. Our aim would be to report and discuss the available evidences on this topic along with the techniques used to assess clonal heterogeneity as a biomarker that in future might help physicians to improve NSCLC patients’ selection for immune-oncology treatments.

Micro-abstract Brain metastases are a frequent finding in patients with advanced non-small cell lung cancer (NSCLC). The characteristics of 118 patients with synchronous brain metastases (BM) out of a cohort of 678 individuals with advanced NSCLC (17%) are reported, with synchronous BM having a negative impact on survival. Prognostic factors for survival of the patients with and without BM are presented. Background Brain metastases occur frequently in patients with newly diagnosed non-small cell lung cancer. We aim to describe the characteristics, treatment and course of disease in patients with synchronous BM in an advanced NSCLC cohort, and to comparatively analyze prognostic factors for patients with and without BM. Patients and methods Of 678 consecutive unselected patients with stage IV NSCLC, 118 presented with synchronous BM (17%; 95% confidence interval [CI]: 15–20%). The patient characteristics, prognostic factors, therapeutic approach and use of specific therapeutic measures including systemic treatment were analyzed. Results BM were found more frequently in younger patients, females, non-smokers and those with a lower thoracic stage. 29% of patients with BM exhibited neurologic symptoms. Patients with BM showed worse overall survival (median survival 8.0 vs 9.7 months; HR 1.24 [1.05–1.54]; p =0.045). In multivariable analysis poor performance status at diagnosis showed the strongest negative association with survival. Conclusion Synchronous BM are frequent among patients with NSCLC even in early thoracic stages and negatively impact survival. Based on the findings presented in this paper, a therapy algorithm for treating BM is proposed, with systemic therapy being one valuable option.

We report a rare case of multiple primary lung tumors displaying heterogeneous EGFR and KRAS molecular profiles, in which the patient underwent surgical resection of the gefitinib-insensitive peripheral lesion and continued gefitinib treatment for the gefitinib-sensitive bilateral multiple ground-glass opacity (GGO) lesions. The patient achieved complete remission and has been free of disease for 1.5 years. To the best of our knowledge, this novel strategy has not been previously reported. We consider our strategy to be safe and effective, and it appears to be a promising therapeutic approach for synchronous multiple primary lung cancer (SMPLC).

Background Radiotherapy associated with chemotherapy is a well-established treatment modality for locally advanced non-small cell lung cancers. Radiation-induced second malignancies, particularly radiation-induced sarcomas, are rare. Some authors reported a recent increase in the incidence of this rare complication, especially because of the improved prognosis and survival of patients after radiotherapy. Pathogenic mechanisms of radiation-induced sarcomas are poorly understood. However, diagnosis criteria are well established. Treatment options must be discussed and adapted to the patient’s profile. Surgery in irradiated tissue is challenging, with limited treatment options with chemotherapy and radiotherapy. Case presentation We report the case of a 62-year-old Moroccan man diagnosed as having chondrosarcoma of his right scapula, who was irradiated 10 years ago for stage IIIB non-small cell lung cancer. This case was managed by a complete resection of the tumor with good functional and oncological outcomes. To the best of our knowledge, the scapular location of radiation-induced sarcoma after irradiation for lung cancer has never been described in the literature. Conclusion Radiation-induced sarcoma of the scapula represents a rare situation that must be actively researched to have access to an optimal therapeutic approach.

Introduction: Surgery remains the primary treatment option for the treatment of early stage lung cancer. However, relapses invariably occur in a significant number of patients, sometimes even early. Objectives: Characterization of patients with lung cancer who underwent surgery with curative intent. Evaluation of demographic, radiological and pathological data and determination of its relationship with recurrence and clinical outcome. Materials and Methods: Retrospective analysis of all patients that underwent surgery with curative intent for lung cancer treatment, from 2008 to 2014. Results: Included 191 patients with mean age of 64.1(±9.3) years and 73.3% were male. It was performed lobectomy in 87.4%, atypical resection in 5.8%, pneumonectomy in 4.7% and segmentectomy in 2.1%. Adenocarcinoma was the most common histological type (71.7%). Recurrence occurred in 39.3% (24.1% local; 15.2% at distance) and in 30.4% the recurrence was early (≤2years). The median survival of patients has not been reached; 68.1% are still alive after a maximum of 107months of follow-up. We found that the presence of pleural invasion (p=0.046), venous permeation (p=0.01), and TNM (p Conclusion: In this case series of patients, besides the TNM classification, certain pathological characteristics such as the presence of pleural invasion and venous permeation have shown to be associated with early recurrence. Thus, these features should be taken into account in the prognostic evaluation, and may justify a more aggressive therapeutic approach after surgery.

Immunotherapy aims to amplify the anticancer immune response through reactivation of the lymphocytic response raised against several tumor neo-antigens. To obtain an effective immune response, this therapeutic approach requires that a number of immunological checkpoints be passed, such as the activation of excitatory costimulatory signals or the avoidance of coinhibitory molecules. Among the immune checkpoints, the interaction of the membrane-bound ligand PD-1 and its receptor PD-L1 has received much attention because of remarkable efficacy in numerous clinical trials for various cancer types, including non-small cell lung cancer (NSCLC). However, several limitations exist with these therapeutic agents when used as monotherapy, with objective responses observed in only 30-40% of patients, with the majority of patients demonstrating innate resistance, and approximately 25% of responders later demonstrating disease progression. Recent developments in the understanding of cancer immunology have the potential to identify mechanisms of innate and acquired resistance to immune checkpoint inhibitors through translational research in human samples. This review focuses on the biological basic principles for immunological checkpoint blockade, and highlights the current status and the perspectives of this therapeutic approach in NSCLC patients.

The MET proto-oncogene plays crucial roles in cell growth and proliferation, survival and apoptosis, epithelial-mesenchymal transition (EMT) and invasion, potentially conditioning the development and progression of the carcinogenesis process. The MET-associated aberrant signaling could be triggered by a variety of mechanisms, such as mutations, gene amplification, increased gene copy number and Met/HGF protein expression. Among the various MET alterations, MET exon 14 splicing abnormalities, causing the loss of the Met juxtamembrane (JM) domain, recently emerged as a new potential oncogenic driver and have been identified and validated across different cancer and histology subtypes. Moreover, this aberration was found to be mutually exclusive with other recognized drivers, thus strongly nominating its potential oncogenic role. Recently, the clinical activity of anti-Met-targeted therapy was demonstrated particularly in patients harboring MET exon 14 skipping lung cancer, resulting in a renewed enthusiasm to further test MET precision therapy in prospective trials. In this review, the key preclinical and clinical data regarding MET exon 14 skipping splicing variants as an actionable genomic aberration in cancer are described, and the perspectives deriving from the validation of such alteration as a potential target, which may further allow driving the therapeutic approach in this molecularly selected patients' subgroup, are explored.

Some tumors evade immune responses by exploiting immune checkpoint pathways and other regulatory mechanisms. Recent advances in the understanding of immune evasion strategies has given rise to development of novel immunotherapies that can restore the patient's own immune system to respond to and eliminate cancer cells.Multiple agents targeting the programmed cell death protein 1 (PD-1) pathway, both anti-PD-1 and anti-programmed death ligand-1 (a key ligand for PD-1) compounds, are currently in active clinical development for lung cancer. Preliminary data of efficacy as monotherapy or in combination with chemotherapy are promising. In this review, we will summarize the immunomodulatory environment in NSCLC, we will focus on immune-checkpoint inhibitors, and the data currently available in lung cancer.The immune-mediated therapies represent an exciting new therapeutic approach, but evidences are still early in lung cancer, and more data from clinical studies are needed to optimize the clinical impact of these therapies.