Abstract: Simple Summary Glioblastoma multiforme (GBM) is one of the most aggressive malignancies, accounting for 14.5% of all central nervous system tumors and 48.6% of malignant central nervous system tumors. The median overall survival (OS) of GBM patients is only 15 months. The aim of this review was to provide an overview of the epidemiology of GBM and factors that may have a significant impact on the risk of GBM. Abstract Glioblastoma multiforme (GBM) is one of the most aggressive malignancies, with a median overall survival of approximately 15 months. In this review, we analyze the pathogenesis of GBM, as well as epidemiological data, by age, gender, and tumor location. The data indicate that GBM is the higher-grade primary brain tumor and is significantly more common in men. The risk of being diagnosed with glioma increases with age, and median survival remains low, despite medical advances. In addition, it is difficult to determine clearly how GBM is influenced by stimulants, certain medications (e.g., NSAIDs), cell phone use, and exposure to heavy metals.

Abstract: Simple Summary Breast cancer is the most-commonly diagnosed malignant tumor in women in the world, as well as the first cause of death from malignant tumors. The incidence of breast cancer is constantly increasing in all regions of the world. For this reason, despite the progress in its detection and treatment, which translates into improved mortality rates, it seems necessary to look for new therapeutic methods, predictive and prognostic factors. The article presents a review of the literature on breast carcinoma - a disease affecting women in the world. Abstract Breast cancer is the most-commonly diagnosed malignant tumor in women in the world, as well as the first cause of death from malignant tumors. The incidence of breast cancer is constantly increasing in all regions of the world. For this reason, despite the progress in its detection and treatment, which translates into improved mortality rates, it seems necessary to look for new therapeutic methods, and predictive and prognostic factors. Treatment strategies vary depending on the molecular subtype. Breast cancer treatment is multidisciplinary; it includes approaches to locoregional therapy (surgery and radiation therapy) and systemic therapy. Systemic therapies include hormone therapy for hormone-positive disease, chemotherapy, anti-HER2 therapy for HER2-positive disease, and quite recently, immunotherapy. Triple negative breast cancer is responsible for more than 15–20% of all breast cancers. It is of particular research interest as it presents a therapeutic challenge, mainly due to its low response to treatment and its highly invasive nature. Future therapeutic concepts for breast cancer aim to individualize therapy and de-escalate and escalate treatment based on cancer biology and early response to therapy. The article presents a review of the literature on breast carcinoma—a disease affecting women in the world.

Abstract: Simple Summary The number of children and adults with cancer that are completely cured is still increasing thanks to effective anti-cancer therapy, but they may be confronted with the negative lasting effects of the treatment later in life. In this review, we provide an overview of major clinical symptoms and toxic side-effects observed in cancer survivors. We describe which types of anti-cancer treatments—primarily DNA-damaging chemotherapeutics—might cause these toxicities and what the (potential) underlying mechanisms are. These treatments not only damage cancer cells in their attempt at tumor killing but also harm healthy cells and tissues. Observations of side-effects in cancer patients and survivors strengthen the hypothesis that the primary induced DNA damage can lead to varying toxicities while also accelerating features of aging, depending on type and dose of chemotherapeutic, clearing method, and affected organ. Abstract Recent advances have increased survival rates of children and adults suffering from cancer thanks to effective anti-cancer therapy, such as chemotherapy. However, during treatment and later in life they are frequently confronted with the severe negative side-effects of their life-saving treatment. The occurrence of numerous features of accelerated aging, seriously affecting quality of life, has now become one of the most pressing problems associated with (pediatric) cancer treatment. Chemotherapies frequently target and damage the DNA, causing mutations or genome instability, a major hallmark of both cancer and aging. However, there are numerous types of chemotherapeutic drugs that are genotoxic and interfere with DNA metabolism in different ways, each with their own biodistribution, kinetics, and biological fate. Depending on the type of DNA lesion produced (e.g., interference with DNA replication or RNA transcription), the organ or cell type inflicted (e.g., cell cycle or differentiation status, metabolic state, activity of clearance and detoxification mechanisms, the cellular condition or micro-environment), and the degree of exposure, outcomes of cancer treatment can largely differ. These considerations provide a conceptual framework in which different classes of chemotherapeutics contribute to the development of toxicities and accelerated aging of different organ systems. Here, we summarize frequently observed side-effects in (pediatric) ex-cancer patients and discuss which types of DNA damage might be responsible.

Abstract: Simple Summary Primary liver cancer, also known as Hepatocellular carcinoma (HCC), is considered to be a major global health challenge. Due to delays in diagnosis at early asymptomatic stages, HCC reaches a severe aggressive stage, thereby having a significant negative impact on patient survival. In addition, HCC shows marked resistance to conventional cancer treatments such as chemo- and radiotherapy. A variety of new and advanced therapies are continuously being evaluated to acquire a breakthrough in HCC treatment to enhance overall and recurrence-free survival. Appropriate identification and selection of target genes and utilization of safe and effective therapeutic approaches, such as gene therapy or immunotherapy, are key strategies for the effective treatment for HCC. This review paper intends to provide a perspective on emerging approaches as avenues towards more effective and safer therapies for HCC. Abstract Hepatocellular carcinoma (HCC) arises from hepatocytes and accounts for 90% of primary liver cancer. According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, globally HCC is the sixth most common cancer and the third most common cause of cancer-related deaths. Reasons for HCC prognosis remaining dismal are that HCC is asymptomatic in its early stages, leading to late diagnosis, and it is markedly resistant to conventional chemo- and radiotherapy. Liver transplantation is the treatment of choice in early stages, while surgical resection, radiofrequency ablation (RFA) and trans arterial chemoembolization (TACE) are Food and Drug Administration (FDA)-approved treatments for advanced HCC. Additional first line therapy for advanced HCC includes broad-spectrum tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, as well as a combination of immunotherapy and anti-angiogenesis therapy, namely atezolizumab and bevacizumab. However, these strategies provide nominal extension in the survival curve, cause broad spectrum toxic side effects, and patients eventually develop therapy resistance. Some common mutations in HCC, such as in telomerase reverse transcriptase (TERT), catenin beta 1 (CTNNB1) and tumor protein p53 (TP53) genes, are still considered to be undruggable. In this context, identification of appropriate gene targets and specific gene delivery approaches create the potential of gene- and immune-based therapies for the safe and effective treatment of HCC. This review elaborates on the current status of HCC treatment by focusing on potential gene targets and advanced techniques, such as oncolytic viral vectors, nanoparticles, chimeric antigen receptor (CAR)-T cells, immunotherapy, and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), and describes future prospects in HCC treatment.

Abstract: Simple Summary Diagnosing cancer at an early stage increases the chance of performing effective treatment in many tumour groups. Key approaches include screening patients who are at risk but have no symptoms, and rapidly and appropriately investigating those who do. Machine learning, whereby computers learn complex data patterns to make predictions, has the potential to revolutionise early cancer diagnosis. Here, we provide an overview of how such algorithms can assist doctors through analyses of routine health records, medical images, biopsy samples and blood tests to improve risk stratification and early diagnosis. Such tools will be increasingly utilised in the coming years. Abstract Improving the proportion of patients diagnosed with early-stage cancer is a key priority of the World Health Organisation. In many tumour groups, screening programmes have led to improvements in survival, but patient selection and risk stratification are key challenges. In addition, there are concerns about limited diagnostic workforces, particularly in light of the COVID-19 pandemic, placing a strain on pathology and radiology services. In this review, we discuss how artificial intelligence algorithms could assist clinicians in (1) screening asymptomatic patients at risk of cancer, (2) investigating and triaging symptomatic patients, and (3) more effectively diagnosing cancer recurrence. We provide an overview of the main artificial intelligence approaches, including historical models such as logistic regression, as well as deep learning and neural networks, and highlight their early diagnosis applications. Many data types are suitable for computational analysis, including electronic healthcare records, diagnostic images, pathology slides and peripheral blood, and we provide examples of how these data can be utilised to diagnose cancer. We also discuss the potential clinical implications for artificial intelligence algorithms, including an overview of models currently used in clinical practice. Finally, we discuss the potential limitations and pitfalls, including ethical concerns, resource demands, data security and reporting standards.

Abstract: Simple Summary Ovarian cancer was the third most common gynecological cancer globally in 2020. Ovarian carcinoma is the most common type of ovarian cancer, comprising over 90% of all ovarian cancer cases. The risk of ovarian cancer increases in females with age, along with having a family history, having a family cancer syndrome, and breast cancer susceptibility gene (BRCA) mutations. Investigation of the latest disease burden, risk factors, and temporal trends of ovarian cancer is important for the reduction of its associated mortality globally. The global incidence and mortality rates of ovarian cancer for 185 countries in 2020 were retrieved from the Global Cancer Observatory (GLOBOCAN) database established by the International Agency for Research on Cancer (IARC, WHO, Lyon, France). The incidence of ovarian cancer has been increasing substantially among younger females, probably caused by the increasing prevalence of obesity, metabolic syndrome, estrogen exposure and nulliparity. Abstract This study aimed to investigate the most updated worldwide incidence and mortality, risk factors, and epidemiologic trend of ovarian cancer in different countries, regions, and age groups. The Global Cancer Observatory database was used for incidence and mortality rates of ovarian cancer in 2020. Data from Cancer Incidence in Five Continents and the WHO mortality database was accessed for trend analysis. Age-standardized rates (ASRs, per 100,000 persons) were calculated for incidence and mortality. The 10-year annual average percent change (AAPC) was estimated by Joinpoint regression analysis. There was an overall decreasing trend of ovarian cancer, yet its burden has been increasing in lower-income countries and among younger females in some countries. Intensive lifestyle modifications are warranted, especially for the populations at high risk for ovarian cancer, including smoking cessation, alcohol use reduction, physical activity, weight control, and treatment of metabolic diseases.

Abstract: The extracellular matrix (ECM) is highly dynamic as it is constantly deposited, remodeled and degraded to maintain tissue homeostasis. ECM is a major structural component of the tumor microenvironment, and cancer development and progression require its extensive reorganization. Cancerized ECM is biochemically different in its composition and is stiffer compared to normal ECM. The abnormal ECM affects cancer progression by directly promoting cell proliferation, survival, migration and differentiation. The restructured extracellular matrix and its degradation fragments (matrikines) also modulate the signaling cascades mediated by the interaction with cell-surface receptors, deregulate the stromal cell behavior and lead to emergence of an oncogenic microenvironment. Here, we summarize the current state of understanding how the composition and structure of ECM changes during cancer progression. We also describe the functional role of key proteins, especially tenascin C and fibronectin, and signaling molecules involved in the formation of the tumor microenvironment, as well as the signaling pathways that they activate in cancer cells.

Abstract: Having the capability to proteolyze diverse structural and signaling proteins, matrix metalloproteinase 9 (MMP9), one of the best-studied secretory endopeptidases, has been identified as a crucial mediator of processes closely associated with tumorigenesis, such as the extracellular matrix reorganization, epithelial to mesenchymal transition, cell migration, new blood vessel formation, and immune response. In this review, we present the current state of knowledge on MMP9 and its role in cancer growth in the context of cell adhesion/migration, cancer-related inflammation, and tumor microenvironment formation. We also summarize recent achievements in the development of selective MMP9 inhibitors and the limitations of using them as anticancer drugs.

Abstract: Simple Summary The relationship between the immune system and tumours is currently one of the most studied topics in the field of cancer. Previously, it was thought that a tumour could be malignant on its own; nonetheless, nowadays, we know that it needs the support of different cells and factors, namely, the tumour microenvironment (TME). Among the components that constitute the TME, we find immune cells responsible for supporting the tumour, which play a key role in this tumoural milieu. Although immune cells, under normal conditions, can identify and destroy nascent tumour cells in a process named cancer immunosurveillance, they can be influenced by different factors in the presence of the tumour in a process termed cancer immunoediting. The fact that immune cells can behave as guardians (anti-tumour immunity) or as bystanders or supporters of the tumour (pro-tumour immunity) makes them a “double-edged sword” in the TME. Abstract Our body is constantly exposed to pathogens or external threats, but with the immune response that our body can develop, we can fight off and defeat possible attacks or infections. Nevertheless, sometimes this threat comes from an internal factor. Situations such as the existence of a tumour also cause our immune system (IS) to be put on alert. Indeed, the link between immunology and cancer is evident these days, with IS being used as one of the important targets for treating cancer. Our IS is able to eliminate those abnormal or damaged cells found in our body, preventing the uncontrolled proliferation of tumour cells that can lead to cancer. However, in several cases, tumour cells can escape from the IS. It has been observed that immune cells, the extracellular matrix, blood vessels, fat cells and various molecules could support tumour growth and development. Thus, the developing tumour receives structural support, irrigation and energy, among other resources, making its survival and progression possible. All these components that accompany and help the tumour to survive and to grow are called the tumour microenvironment (TME). Given the importance of its presence in the tumour development process, this review will focus on one of the components of the TME: immune cells. Immune cells can support anti-tumour immune response protecting us against tumour cells; nevertheless, they can also behave as pro-tumoural cells, thus promoting tumour progression and survival. In this review, the anti-tumour and pro-tumour immunity of several immune cells will be discussed. In addition, the TME influence on this dual effect will be also analysed.

Abstract: Simple Summary Cancer-associated fibroblasts (CAFs) are found in the tumor microenvironment and exhibit several protumorigenic functions. Preclinical studies suggest that CAFs can be reduced, eliminated, or reprogrammed; however, clinical translation has not yet occurred. A better understanding of these cells and their functions will undoubtedly improve cancer treatments. In this review, we summarize current research, highlight major challenges, and discuss future opportunities for improving our knowledge of CAF biology and targeting. Abstract Cancer-associated fibroblasts (CAFs) are a heterogenous group of activated fibroblasts and a major component of the tumor stroma. CAFs may be derived from fibroblasts, epithelial cells, endothelial cells, cancer stem cells, adipocytes, pericytes, or stellate cells. These complex origins may underlie their functional diversity, which includes pro-tumorigenic roles in extracellular matrix remodeling, the suppression of anti-tumor immunity, and resistance to cancer therapy. Several methods for targeting CAFs to inhibit tumor progression and enhance anti-tumor immunity have recently been reported. While preclinical studies have shown promise, to date they have been unsuccessful in human clinical trials against melanoma, breast cancer, pancreas cancer, and colorectal cancers. This review summarizes recent and major advances in CAF-targeting therapies, including DNA-based vaccines, anti-CAF CAR-T cells, and modifying and reprogramming CAF functions. The challenges in developing effective anti-CAF treatment are highlighted, which include CAF heterogeneity and plasticity, the lack of specific target markers for CAFs, the limitations in animal models recapitulating the human cancer microenvironment, and the undesirable off-target and systemic side effects. Overcoming these challenges and expanding our understanding of the basic biology of CAFs is necessary for making progress towards safe and effective therapeutic strategies against cancers in human patients.

Abstract: Simple Summary Triple negative breast cancer (TNBC) represents 15 to 20% of all breast cancers in the United States. The main treatment option remains chemotherapy, despite limited efficacy. New biologic and targeted agents are increasingly emerging for the treatment of TNBC. Given the continuous advances in the field of TNBC, this review assesses the latest developments in basic characterization, subtyping, and treatment of TNBC, including novel drug developments with antibody-drug conjugates, immune checkpoint inhibitors, PARP inhibitors, and androgen receptor targeted agents. Abstract Breast cancer (BC) is the most common malignancy affecting women. It is a highly heterogeneous disease broadly defined by the differential expression of cell surface receptors. In the United States, triple negative breast cancer (TNBC) represents 15 to 20% of all BC. When compared with other subtypes of BC, TNBC tends to present in younger women, and has a higher mortality rate of 40% in advanced stages within the first 5 years after diagnosis. TNBC has historically had limited treatment options when compared to other types of BC. The mainstay of treatment for TNBC remains cytotoxic chemotherapy despite the emergence of new biologic and targeted agents. Defining the specific tumor molecular profile including PDL-1 and androgen receptor testing is expanding treatment options in the clinical setting. Identifying more targetable, novel biomarkers that may better define therapeutic targets or prognostic markers is currently underway. TNBC nomenclature is expected to be updated in favor of other nomenclature which would help direct therapy, and further redefine TNBC’s heterogeneity. Given the continuous advances in the field of TNBC, this review assesses the latest developments in basic characterization, subtyping, and treatment of TNBC, including novel drug developments with antibody-drug conjugates, immune checkpoint inhibitors, PARP inhibitors and androgen receptor targeted agents. Future trials are necessary in the face of these innovations to further support the use of new therapies in TNBC and the detection of the appropriate biomarkers.

Abstract: Simple Summary The estimated survival time for glioblastoma patients is extremely low; only about 5% of patients survive five years post diagnosis. The standard of care for glioblastoma patients involves surgery, radiation therapy, and chemotherapy with temozolomide. However, due to the extremely invasive capability of glioblastoma cells, tumors develop very diffusely, integrating into the healthy brain tissue. Indeed, the separation of healthy brain tissue and the tumor boundaries, by standard surgical microscopy, is very challenging. Therefore, the maximum safe removal of the tumor mass is difficult, leaving some tumor cells behind. Therefore, understanding the molecular mechanisms of tumor cell infiltration and developing anti-invasive approaches are of the utmost priority. Here, we provide a review of the characteristics and molecular mechanisms of glioblastoma invasion, and include a perspective of clinical applications. Abstract Glioblastoma is the most common and malignant primary brain tumor, defined by its highly aggressive nature. Despite the advances in diagnostic and surgical techniques, and the development of novel therapies in the last decade, the prognosis for glioblastoma is still extremely poor. One major factor for the failure of existing therapeutic approaches is the highly invasive nature of glioblastomas. The extreme infiltrating capacity of tumor cells into the brain parenchyma makes complete surgical removal difficult; glioblastomas almost inevitably recur in a more therapy-resistant state, sometimes at distant sites in the brain. Therefore, there are major efforts to understand the molecular mechanisms underpinning glioblastoma invasion; however, there is no approved therapy directed against the invasive phenotype as of now. Here, we review the major molecular mechanisms of glioblastoma cell invasion, including the routes followed by glioblastoma cells, the interaction of tumor cells within the brain environment and the extracellular matrix components, and the roles of tumor cell adhesion and extracellular matrix remodeling. We also include a perspective of high-throughput approaches utilized to discover novel players for invasion and clinical targeting of invasive glioblastoma cells.

Abstract: Simple Summary Lung cancer is the leading cause of cancer-related death worldwide, with an average 5-year survival rate of approximately 15%. Among the multiple histological type of lung cancer, adenocarcinoma is the most common. Adenocarcinoma is characterized by a high degree of heterogeneity at many levels, including histological, cellular, and molecular. Understanding the cell of origin of adenocarcinoma, and the molecular changes during tumor progression, will allow better therapeutic strategies. Abstract Lung adenocarcinoma, the major form of lung cancer, is the deadliest cancer worldwide, due to its late diagnosis and its high heterogeneity. Indeed, lung adenocarcinoma exhibits pronounced inter- and intra-tumor heterogeneity cofounding precision medicine. Tumor heterogeneity is a clinical challenge driving tumor progression and drug resistance. Several key pieces of evidence demonstrated that lung adenocarcinoma results from the transformation of progenitor cells that accumulate genetic abnormalities. Thus, a better understanding of the cell of origin of lung adenocarcinoma represents an opportunity to unveil new therapeutic alternatives and stratify patient tumors. While the lung is remarkably quiescent during homeostasis, it presents an extensive ability to respond to injury and regenerate lost or damaged cells. As the lung is constantly exposed to potential insult, its regenerative potential is assured by several stem and progenitor cells. These can be induced to proliferate in response to injury as well as differentiate into multiple cell types. A better understanding of how genetic alterations and perturbed microenvironments impact progenitor-mediated tumorigenesis and treatment response is of the utmost importance to develop new therapeutic opportunities.

Abstract: Simple Summary Terpenoids are bioactive compounds with a variety of pharmacological activities, including anticancer activity. This review paper aimed to focus on the anticancer activities of certain terpenoids, including their molecular mechanism, signaling pathways and clinical trials. In addition, this review provides insight and future directions to the development of some terpenoids as potential anticancer agents. Abstract Cancer is a life-threatening disease and is considered to be among the leading causes of death worldwide. Chemoresistance, severe toxicity, relapse and metastasis are the major obstacles in cancer therapy. Therefore, introducing new therapeutic agents for cancer remains a priority to increase the range of effective treatments. Terpenoids, a large group of secondary metabolites, are derived from plant sources and are composed of several isoprene units. The high diversity of terpenoids has drawn attention to their potential anticancer and pharmacological activities. Some terpenoids exhibit an anticancer effect by triggering various stages of cancer progression, for example, suppressing the early stage of tumorigenesis via induction of cell cycle arrest, inhibiting cancer cell differentiation and activating apoptosis. At the late stage of cancer development, certain terpenoids are able to inhibit angiogenesis and metastasis via modulation of different intracellular signaling pathways. Significant progress in the identification of the mechanism of action and signaling pathways through which terpenoids exert their anticancer effects has been highlighted. Hence, in this review, the anticancer activities of twenty-five terpenoids are discussed in detail. In addition, this review provides insights on the current clinical trials and future directions towards the development of certain terpenoids as potential anticancer agents.

Abstract: Simple Summary Timely palliative care is palliative care personalized based on patients’ needs and delivered at the optimal time and setting. It involves a systematic process to identify patients with high supportive care needs and referring these individuals to specialist palliative care in a timely manner based on standardized referral criteria. Timely palliative care brings together several important advances, including systematic symptom screening, electronic health records, and outpatient/telehealth palliative care to deliver personalized, patient-centered care towards improving patient outcomes. Empiric studies found that patients could be referred more frequently and in a timely fashion when standardized referral criteria are used. Implementation of timely palliative care at each institution requires visionary leadership, commitment of oncology teams, a robust palliative care clinic, a customized set of referral criteria and preferably an integrated electronic health record system. Abstract Timely palliative care is a systematic process to identify patients with high supportive care needs and to refer these individuals to specialist palliative care in a timely manner based on standardized referral criteria. It requires four components: (1) routine screening of supportive care needs at oncology clinics, (2) establishment of institution-specific consensual criteria for referral, (3) a system in place to trigger a referral when patients meet criteria, and (4) availability of outpatient palliative care resources to deliver personalized, timely patient-centered care aimed at improving patient and caregiver outcomes. In this review, we discuss the conceptual underpinnings, rationale, barriers and facilitators for timely palliative care referral. Timely palliative care provides a more rational use of the scarce palliative care resource and maximizes the impact on patients who are offered the intervention. Several sets of referral criteria have been proposed to date for outpatient palliative care referral. Studies examining the use of these referral criteria consistently found that timely palliative care can lead to a greater number of referrals and earlier palliative care access than routine referral. Implementation of timely palliative care at each institution requires oncology leadership support, adequate palliative care infrastructure, integration of electronic health record and customization of referral criteria.

Abstract: Simple Summary Growing evidence indicates that blood-count-based compound scores could be used as prognostic biomarkers in cancer as reflectors of uncontrolled inflammation in the tumor microenvironment. Several markers have been developed in this regard, including the recent pan-immune-inflammation value (PIV) that incorporates the levels of blood neutrophil, monocyte, platelet, and lymphocytes. In this paper, we reviewed the association between PIV and overall survival or progression-free survival in cancer from the published studies to date. We observed that higher PIV levels were an adverse prognostic factor consistently across several clinical scenarios, including non-metastatic or metastatic disease and treatment with targeted therapy or immunotherapy. In contrast, the data were limited in patients treated with chemotherapy or patients with non-metastatic disease. The available evidence demonstrates that PIV could be a readily available biomarker for prognosis prediction in cancer. However, further research is needed to explore the promise of PIV as a prognostic biomarker in cancer. Abstract Background: Prognostic scores derived from the blood count have garnered significant interest as an indirect measure of the inflammatory pressure in cancer. The recently developed pan-immune-inflammation value (PIV), an equation including the neutrophil, platelet, monocyte, and lymphocyte levels, has been evaluated in several cohorts, although with variations in the tumor types, disease stages, cut-offs, and treatments. Therefore, we evaluated the association between survival and PIV in cancer, performing a systematic review and meta-analysis. Methods: We conducted a systematic review from the Pubmed, Medline, and Embase databases to filter the published studies until 17 May 2022. The meta-analyses were performed with the generic inverse-variance method with a random-effects model. Results: Fifteen studies encompassing 4942 patients were included. In the pooled analysis of fifteen studies, the patients with higher PIV levels had significantly increased risk of death than those with lower PIV levels (HR: 2.00, 95% CI: 1.51–2.64, p < 0.001) and increased risk of progression or death (HR: 1.80, 95% CI: 1.39–2.32, p < 0.001). Analyses were consistent across several clinical scenarios, including non-metastatic or metastatic disease, different cut-offs (500, 400, and 300), and treatment with targeted therapy or immunotherapy (p < 0.001 for each). Conclusion: The available evidence demonstrates that PIV could be a prognostic biomarker in cancer. However, further research is needed to explore the promise of PIV as a prognostic biomarker in patients with non-metastatic disease or patients treated without immunotherapy or targeted therapy.

Abstract: Simple Summary Advanced gastric cancer remains a malignancy with a poor prognosis, with a median survival of about 12–15 months. In recent years, immune checkpoint inhibitors have emerged as a new standard of care for several malignancies, including advanced gastric cancer, and have demonstrated good clinical benefit in some populations. In this review paper, we describe the current status of immunotherapy in gastric cancer, with a focus on molecular and immunological profiles, biomarkers, major clinical trials, and novel immunotherapies. Abstract Immune checkpoint inhibitors (ICIs) such as anti-programmed cell death-1 (PD-1) or programmed cell death ligand-1 (PD-L1) monoclonal antibodies have prolonged survival in various types of malignancies, including advanced gastric cancer (AGC). Nivolumab, a monoclonal anti-PD-1 antibody, showed an improvement in overall survival at a later-line therapy in unselected AGC patients in the ATTRACTION-2 study or in combination with chemotherapy as first-line therapy in the global CheckMate-649 study. Another monoclonal anti-PD-1 antibody, pembrolizumab, showed single agent activity in tumors with high microsatellite instability or high tumor mutational burden. Furthermore, a recent KEYNOTE-811 study demonstrated significant improvement in response rate with pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC. Based on these results, ICIs are now incorporated into standard treatment for AGC patients. As a result of pivotal clinical trials, three anti-PD-1 antibodies were approved for AGC: nivolumab combined with chemotherapy as first-line treatment or nivolumab monotherapy as third- or later-line treatment in Asian countries; pembrolizumab for previously treated microsatellite instability-high (MSI-H) or tumor mutational burden-high AGC, or pembrolizumab combined with trastuzumab and chemotherapy for HER2-positive AGC in the United States; and dostarlimab for previously treated MSI-H AGC in the United States. However, a substantial number of patients have showed resistance to ICIs, highlighting the importance of the better selection of patients or further combined immunotherapy. This review focused on molecular and immunological profiles, pivotal clinical trials of ICIs with related biomarkers, and investigational immunotherapy for AGC.

Abstract: Simple Summary Cancer is considered as a large group of diseases involving abnormal cell growth, which results in an alarming rise in the mortality rate at the worldwide level. Presently, the main point of interest in pharmaceutical research is the development of the novel and efficient anticancer drugs based on natural sources. In this regard, plants, and some microbial species, due to their composition, ecology, phytochemical, and ethnopharmacological properties, play a significant role. Accordingly, a series of plant-derived bioactive compounds are in the clinical development phase against cancer. The present review highlights the significance of several medicinal plants, plant extracts, and their bioactive compounds for their potential anticancer activities. The presented results can be useful for researchers in developing novel anticancer drugs, public health specialists, and for the public in general. Abstract Cancer is one of the major deadly diseases globally. The alarming rise in the mortality rate due to this disease attracks attention towards discovering potent anticancer agents to overcome its mortality rate. The discovery of novel and effective anticancer agents from natural sources has been the main point of interest in pharmaceutical research because of attractive natural therapeutic agents with an immense chemical diversity in species of animals, plants, and microorganisms. More than 60% of contemporary anticancer drugs, in one form or another, have originated from natural sources. Plants and microbial species are chosen based on their composition, ecology, phytochemical, and ethnopharmacological properties. Plants and their derivatives have played a significant role in producing effective anticancer agents. Some plant derivatives include vincristine, vinblastine, irinotecan, topotecan, etoposide, podophyllotoxin, and paclitaxel. Based on their particular activity, a number of other plant-derived bioactive compounds are in the clinical development phase against cancer, such as gimatecan, elomotecan, etc. Additionally, the conjugation of natural compounds with anti-cancerous drugs, or some polymeric carriers particularly targeted to epitopes on the site of interest to tumors, can generate effective targeted treatment therapies. Cognizance from such pharmaceutical research studies would yield alternative drug development strategies through natural sources which could be economical, more reliable, and safe to use.

Abstract: Simple Summary This study investigates the latest achievements, challenges, and future research directions of deep learning techniques for lung cancer and pulmonary nodule detection. Hopefully, these research findings will help scientists, investigators, and clinicians develop new and effective medical imaging tools to improve lung nodule diagnosis accuracy, sensitivity, and specificity. Abstract Medical imaging tools are essential in early-stage lung cancer diagnostics and the monitoring of lung cancer during treatment. Various medical imaging modalities, such as chest X-ray, magnetic resonance imaging, positron emission tomography, computed tomography, and molecular imaging techniques, have been extensively studied for lung cancer detection. These techniques have some limitations, including not classifying cancer images automatically, which is unsuitable for patients with other pathologies. It is urgently necessary to develop a sensitive and accurate approach to the early diagnosis of lung cancer. Deep learning is one of the fastest-growing topics in medical imaging, with rapidly emerging applications spanning medical image-based and textural data modalities. With the help of deep learning-based medical imaging tools, clinicians can detect and classify lung nodules more accurately and quickly. This paper presents the recent development of deep learning-based imaging techniques for early lung cancer detection.

Abstract: Simple Summary The current meta-analysis highlighted that proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) could impact immune checkpoint inhibitors (ICIs) efficacy in NSCLC patients, highlighting the need for a deeper comprehension of factors involved in treatment response or resistance. Since the number of indications and NSCLC patients receiving ICIs is supposed to increase further soon, identifying the impact of these agents on NSCLC immunotherapy represents a compelling and urgent need regarding NSCLC. Abstract (1) Background: In recent years, immunotherapy has revolutionized the treatment landscape of non-small cell lung cancer (NSCLC), representing a therapeutic breakthrough in this field. Antacid agents such as proton pump inhibitors (PPIs) and histamine-2-receptor antagonists (H2RAs) are commonly prescribed for extended periods in NSCLC patients, and these drugs have the potential to modify the efficacy of immune checkpoint inhibitors (ICIs). (2) Materials and Methods: Herein, we conducted a systematic review and meta-analysis to investigate the impact of PPIs and H2RAs on progression-free survival (PFS) and overall survival (OS) among patients receiving immunotherapy for metastatic NSCLC. Effect measures for OS were Hazard Ratios (HRs) and 95% Confidence Intervals (CIs), which were extracted from available studies. Forest plots were used to assess HRs to describe the relationship between treatment and OS in the specified cohorts of patients. (3) Results: Six studies were included in the analysis, involving 2267 patients. The pooled HRs for OS and PFS were 1.4 (95% CI, 1.25–1.58) and 1.29 (95% CI, 1.17–1.43), respectively, suggesting that PPIs and H2RAs administration was negatively associated with PFS and OS. (4) Conclusion: Concomitant antacid use could modify the activity of ICIs in NSCLC patients.

Abstract: Simple Summary Radon represents the main risk factor of lung cancer in non-smokers and the second one in smoking patients. In Europe, there are several radon-prone areas, but regulatory policies may vary between countries. Radon causes DNA damage and high genomic tumor instability, but its exact carcinogenesis mechanism in lung cancer remains unknown. Molecular drivers in NSCLC are more often described in non-smoker patients and a potential association between radon exposure and oncogenic-driven NSCLC has been postulated. This is an updated review on indoor radon exposure and its role in lung cancer carcinogenesis, especially focusing on its potential relation with NSCLC with driver genomic alterations. We want to contribute to rising knowledge and awareness on this still silent but preventable lung cancer risk factor. Abstract Lung cancer is a public health problem and the first cause of cancer death worldwide. Radon is a radioactive gas that tends to accumulate inside homes, and it is the second lung cancer risk factor after smoking, and the first one in non-smokers. In Europe, there are several radon-prone areas, and although the 2013/59 EURATOM directive is aimed to regulate indoor radon exposition, regulating measures can vary between countries. Radon emits alpha-ionizing radiation that has been linked to a wide variety of cytotoxic and genotoxic effects; however, the link between lung cancer and radon from the genomic point of view remains poorly described. Driver molecular alterations have been recently identified in non-small lung cancer (NSCLC), such as somatic mutations (EGFR, BRAF, HER2, MET) or chromosomal rearrangements (ALK, ROS1, RET, NTRK), mainly in the non-smoking population, where no risk factor has been identified yet. An association between radon exposure and oncogenic NSCLC in non-smokers has been hypothesised. This paper provides a practical, concise and updated review on the implications of indoor radon in lung cancer carcinogenesis, and especially of its potential relation with NSCLC with driver genomic alterations.

Abstract: Simple Summary Human health is significantly affected by microbial infections. One of the largest determinants of the outcomes of such infections is the host immune response. Too weak of a response can lead to enhanced spread by the pathogen, while an overstimulated response can lead to immune-induced tissue damage. Thus, to effectively treat infected individuals, it is critical to understand the regulators that control inflammatory responses. Recently, it has become widely accepted that estrogens, a class of sex hormones, are capable of dramatically altering the responses of host cells to microbes. In this review, we discuss how estrogens change the host immune response, as well as how these changes can alter the outcome of the infection for the individual. Abstract Sex hormones, such as estrogen and testosterone, are steroid compounds with well-characterized effects on the coordination and development of vertebrate reproductive systems. Since their discovery, however, it has become clear that these “sex hormones” also regulate/influence a broad range of biological functions. In this review, we will summarize some current findings on how estrogens interact with and regulate inflammation and immunity. Specifically, we will focus on describing the mechanisms by which estrogens alter immune pathway activation, the impact of these changes during infection and the development of long-term immunity, and how different types of estrogens and their respective concentrations mediate these outcomes.

Abstract: Simple Summary Matrix stiffness is recognized as a critical factor in cancer progression. Recent studies have shown that matrix stiffening is caused by the accumulation, contraction, and crosslinking of the extracellular matrix by cancer and stromal cells. Cancer and stromal cells respond to matrix stiffness, which determines the phenotypes of these cells. In addition, matrix stiffness activates and/or inactivates specific transcription factors in cancer and stromal cells to regulate cancer progression. In this review, we discuss the mechanisms of cancer stiffening and progression that are regulated by transcription factors responding to matrix stiffness. Abstract Matrix stiffness is critical for the progression of various types of cancers. In solid cancers such as mammary and pancreatic cancers, tumors often contain abnormally stiff tissues, mainly caused by stiff extracellular matrices due to accumulation, contraction, and crosslinking. Stiff extracellular matrices trigger mechanotransduction, the conversion of mechanical cues such as stiffness of the matrix to biochemical signaling in the cells, and as a result determine the cellular phenotypes of cancer and stromal cells in tumors. Transcription factors are key molecules for these processes, as they respond to matrix stiffness and are crucial for cellular behaviors. The Yes-associated protein (YAP)/transcriptional coactivator with PDZ-binding motif (TAZ) is one of the most studied transcription factors that is regulated by matrix stiffness. The YAP/TAZ are activated by a stiff matrix and promotes malignant phenotypes in cancer and stromal cells, including cancer-associated fibroblasts. In addition, other transcription factors such as β-catenin and nuclear factor kappa B (NF-κB) also play key roles in mechanotransduction in cancer tissues. In this review, the mechanisms of stiffening cancer tissues are introduced, and the transcription factors regulated by matrix stiffness in cancer and stromal cells and their roles in cancer progression are shown.

Abstract: Simple Summary Glioblastoma is the most common tumour that originates in the brain in adults. Most of the published data on glioblastoma are from patients in clinical trials who tend to be younger and fitter than the average patient. We therefore looked at patient demographic, tumour characteristics, and treatments received in a group of 490 real-world patients with glioblastoma to evaluate their survival, and to investigate whether we could find any factors that were associated with longer survival. Overall, the average survival of patients was 9 months. Patients tended to live longer if they were younger, had surgery, if they had further treatment after surgery (chemo- or radio-therapy), or if they had a tumour marker called MGMT promotor methylation. Abstract Background: IDH-wildtype glioblastoma is the most common malignant primary brain tumour in adults. As there is limited information on prognostic factors outside of clinical trials; thus, we conducted a retrospective study to characterise the glioblastoma population at our centre. Methods: Demographic, tumour molecular profiles, treatment, and survival data were collated for patients diagnosed with glioblastoma at our centre between July 2011 and December 2015. We used multivariate proportional hazard model associations with survival. Results: 490 patients were included; 60% had debulking surgery and 40% biopsy only. Subsequently, 56% had standard chemoradiotherapy, 25% had non-standard chemo/radio-therapy, and 19% had no further treatment. Overall survival was 9.2 months. In the multivariate analysis, longer survival was associated with debulking surgery vs. biopsy alone (14.9 vs. 8 months) (HR 0.54 [95% CI 0.41–0.70]), subsequent treatment after diagnosis (HR 0.12 [0.08–0.16]) (standard chemoradiotherapy [16.9 months] vs. non-standard regimens [9.2 months] vs. none [2.0 months]), tumour MGMT promotor methylation (HR 0.71 [0.58–0.87]), and younger age (hazard ratio vs. age < 50: 1.70 [1.26–2.30] for ages 50–59; 3.53 [2.65–4.70] for ages 60–69; 4.82 [3.54–6.56] for ages 70+). Conclusions: The median survival for patients with glioblastoma is less than a year. Younger age, debulking surgery, treatment with chemoradiotherapy, and MGMT promotor methylation are independently associated with longer survival.

Abstract: Simple Summary Ovarian cancer is a highly lethal female malignancy with high rates of advanced stage and recurrent disease. Ovarian cancer is characterized as poorly responsive to immunotherapy. This is hypothesized to be secondary to its highly immunosuppressive and phenotypically “cold” tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are an integral component of the ovarian cancer TME, and predominantly display an M2 protumor phenotype. Ovarian cancer cells and TAMs interact via a complex network of signaling cytokines. Ovarian cancer TAMs are linked to tumor metastasis, angiogenesis, chemoresistance, and poor prognosis. Due to their profound role, TAMs represent a therapeutic target for ovarian cancer immunotherapy. Strategies for targeting TAMs include increasing phagocytosis, decreasing recruitment, decreasing macrophage survival, and repolarizing TAMs to an antitumor phenotype. Abstract The tumor microenvironment (TME) has been implicated to play an important role in the progression of ovarian cancer. One of the most important components of the TME is tumor associated macrophages (TAMs). Phenotypically, macrophages are broadly categorized as M1 pro-inflammatory or M2 anti-inflammatory, based on the cytokines and chemokines that they secrete. The tumor microenvironment is associated with macrophages of an M2 phenotype which suppress the surrounding immune environment, assist tumor cells in evading immune targeting, and support tumor growth and metastasis. Contrarily, M1 macrophages help mount an immune response against tumors, and are associated with a more favorable prognosis in solid tumors. One of the characteristic indicators of a poor prognosis in ovarian cancer is the overrepresentation of M2-type TAMs. As such, therapeutic modalities targeting TME and TAMs are of increasing interest. Pharmacological approaches to eliminate TAMs, include decreasing macrophage survival and recruitment and increasing phagocytosis, have been underwhelming. Clinical strategies targeting these macrophage subtypes via repolarization to an M1 antitumoral state deserve increasing attention, and may serve as a new modality for immunotherapy.

Abstract: Simple Summary Anoikis is a programmed cell death process resulting from the loss of interaction between cells and the extracellular matrix. Therefore, it is necessary to overcome anoikis when tumor cells acquire metastatic potential. In lung cancer, the composition of the extracellular matrix, cell adhesion-related membrane proteins, cytoskeletal regulators, and epithelial–mesenchymal transition are involved in the process of anoikis, and the initiation of apoptosis signals is a critical step in anoikis. Inversely, activation of growth signals counteracts anoikis. This review summarizes the regulators of lung cancer-related anoikis and explores potential drug applications targeting anoikis. Abstract Tumor metastasis occurs in lung cancer, resulting in tumor progression and therapy failure. Anoikis is a mechanism of apoptosis that combats tumor metastasis; it inhibits the escape of tumor cells from the native extracellular matrix to other organs. Deciphering the regulators and mechanisms of anoikis in cancer metastasis is urgently needed to treat lung cancer. Several natural and synthetic products exhibit the pro-anoikis potential in lung cancer cells and in vivo models. These products include artonin E, imperatorin, oroxylin A, lupalbigenin, sulforaphane, renieramycin M, avicequinone B, and carbenoxolone. This review summarizes the current understanding of the molecular mechanisms of anoikis regulation and relevant regulators involved in lung cancer metastasis and discusses the therapeutic potential of targeting anoikis in the treatment of lung cancer metastasis.

Abstract: Simple Summary DNA damage is one of the hallmarks of cancer. Epithelial ovarian cancer (EOC) —especially the high-grade serous subtype—harbors a defect in at least one DNA damage response (DDR) pathway. Defective DDR results from a variety of lesions affecting homologous recombination (HR) and nonhomologous end joining (NHEJ) for double strand breaks, base excision repair (BER), and nucleotide excision repair (NER) for single strand breaks and mismatch repair (MMR). Apart from the EOC, mutations in the DDR genes, such as BRCA1 and BRCA2, are common in prostate cancer as well. Among them, BRCA2 lesions are found in 12% of metastatic castration-resistant prostate cancers, but very rarely in primary prostate cancer. Better understanding of the DDR pathways is essential in order to optimize the therapeutic choices, and has led to the design of biomarker-driven clinical trials. Poly(ADP-ribose) polymerase (PARP) inhibitors are now a standard therapy for EOC patients, and more recently have been approved for the metastatic castration-resistant prostate cancer with alterations in DDR genes. They are particularly effective in tumours with HR deficiency. Abstract DNA damage repair (DDR) defects are common in different cancer types, and these alterations can be exploited therapeutically. Epithelial ovarian cancer (EOC) is among the tumours with the highest percentage of hereditary cases. BRCA1 and BRCA2 predisposing pathogenic variants (PVs) were the first to be associated with EOC, whereas additional genes comprising the homologous recombination (HR) pathway have been discovered with DNA sequencing technologies. The incidence of DDR alterations among patients with metastatic prostate cancer is much higher compared to those with localized disease. Genetic testing is playing an increasingly important role in the treatment of patients with ovarian and prostate cancer. The development of poly (ADP-ribose) polymerase (PARP) inhibitors offers a therapeutic strategy for patients with EOC. One of the mechanisms of PARP inhibitors exploits the concept of synthetic lethality. Tumours with BRCA1 or BRCA2 mutations are highly sensitive to PARP inhibitors. Moreover, the synthetic lethal interaction may be exploited beyond germline BRCA mutations in the context of HR deficiency, and this is an area of ongoing research. PARP inhibitors are in advanced stages of development as a treatment for metastatic castration-resistant prostate cancer. However, there is a major concern regarding the need to identify reliable biomarkers predictive of treatment response. In this review, we explore the mechanisms of DDR, the potential for genomic analysis of ovarian and prostate cancer, and therapeutics of PARP inhibitors, along with predictive biomarkers.

Abstract: Simple Summary NHS-Galleri is a randomised controlled trial that will assess how well a blood test can reduce the number of late-stage cancers by helping to find cancers early. The test looks at patterns in blood samples to detect a cancer signal. NHS-Galleri has enrolled over 140,000 people, invited from the general population of England aged 50–77 years who did not have or were not being investigated for cancer. Blood is being collected up to three times: first when people join the study and again 12 and 24 months later. Half the participants (chosen at random) will have their blood tested and half will have their blood stored. Participants will not be told whether their blood will be tested or stored. Participants with a cancer signal detected result will be sent for further diagnostic testing in the NHS. The trial will help the NHS decide whether to introduce screening using this test. Abstract We report the design of the NHS-Galleri trial (ISRCTN91431511), aiming to establish whether a multi-cancer early detection (MCED) test that screens asymptomatic individuals for cancer can reduce late-stage cancer incidence. This randomised controlled trial has invited approximately 1.5 million persons and enrolled over 140,000 from the general population of England (50–77 years; ≥3 years without cancer diagnosis or treatment; not undergoing investigation for suspected cancer). Blood is being collected at up to three annual visits. Following baseline blood collection, participants are randomised 1:1 to the intervention (blood tested by MCED test) or control (blood stored) arm. Only participants in the intervention arm with a cancer signal detected have results returned and are referred for urgent investigations and potential treatment. Remaining participants in both arms stay blinded and return for their next visit. Participants are encouraged to continue other NHS cancer screening programmes and seek help for new or unusual symptoms. The primary objective is to demonstrate a statistically significant reduction in the incidence rate of stage III and IV cancers diagnosed in the intervention versus control arm 3–4 years after randomisation. NHS-Galleri will help determine the clinical utility of population screening with an MCED test.

Abstract: Simple Summary Hepatocellular carcinoma (HCC) constitutes a major health burden, accounting for >80% of primary liver cancers globally. Inflammation has come into the spotlight as a hallmark of cancer, and it is evident that tumor-associated inflammation drives the involvement of monocytes in tumor growth and metastasis. Tumor-associated macrophages (TAMs) actively participate in tumor-related inflammation, representing the main type of inflammatory cells in the tumor microenvironment, setting the crosstalk between tumor and stromal cells. Infiltrating TAMs exert either anti-tumorigenic (M1) or pro-tumorigenic (M2) functions. In most solid human tumors, increased TAM infiltration has been associated with enhanced tumor growth and metastasis, while other studies showcase that under certain conditions, TAMs exhibit cytotoxic and tumoricidal activity, inhibiting the progression of cancer. In this review, we summarize the current evidence on the role of macrophages in the pathogenesis and progression of HCC and we highlight their potential utilization in HCC prognosis and therapy. Abstract Hepatocellular carcinoma (HCC) constitutes a major health burden globally, and it is caused by intrinsic genetic mutations acting in concert with a multitude of epigenetic and extrinsic risk factors. Cancer induces myelopoiesis in the bone marrow, as well as the mobilization of hematopoietic stem and progenitor cells, which reside in the spleen. Monocytes produced in the bone marrow and the spleen further infiltrate tumors, where they differentiate into tumor-associated macrophages (TAMs). The relationship between chronic inflammation and hepatocarcinogenesis has been thoroughly investigated over the past decade; however, several aspects of the role of TAMs in HCC development are yet to be determined. In response to certain stimuli and signaling, monocytes differentiate into macrophages with antitumor properties, which are classified as M1-like. On the other hand, under different stimuli and signaling, the polarization of macrophages shifts towards an M2-like phenotype with a tumor promoting capacity. M2-like macrophages drive tumor growth both directly and indirectly, via the suppression of cytotoxic cell populations, including CD8+ T cells and NK cells. The tumor microenvironment affects the response to immunotherapies. Therefore, an enhanced understanding of its immunobiology is essential for the development of next-generation immunotherapies. The utilization of various monocyte-centered anticancer treatment modalities has been under clinical investigation, selectively targeting and modulating the processes of monocyte recruitment, activation and migration. This review summarizes the current evidence on the role of TAMs in HCC pathogenesis and progression, as well as in their potential involvement in tumor therapy, shedding light on emerging anticancer treatment methods targeting monocytes.