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Simple Summary: Pancreatic cancer is one of the most lethal forms of malignancies; therefore, new treatment strategies are required to increase the patients' survival. It has been established that different cell types that surround pancreatic cancer cells, thus forming the tumor microenvironment, are responsible for tumorigenicity and inefficacy of treatments, including immunotherapy. In the present review, we aim to summarize current knowledge regarding the molecular mechanisms underpinning the interaction of cancer cells with cells of their microenvironment and discuss associated strategies to improve treatment results. Pancreatic cancer demonstrates an ever-increasing incidence over the last years and represents one of the top causes of cancer-associated mortality. Cells of the tumor microenvironment (TME) interact with cancer cells in pancreatic ductal adenocarcinoma (PDAC) tumors to preserve cancer cells' metabolism, inhibit drug delivery, enhance immune suppression mechanisms and finally develop resistance to chemotherapy and immunotherapy. New strategies target TME genetic alterations and specific pathways in cell populations of the TME. Complex molecular interactions develop between PDAC cells and TME cell populations including cancer-associated fibroblasts, myeloid-derived suppressor cells, pancreatic stellate cells, tumor-associated macrophages, tumor-associated neutrophils, and regulatory T cells. In the present review, we aim to fully explore the molecular landscape of the pancreatic cancer TME cell populations and discuss current TME targeting strategies to provide thoughts for further research and preclinical testing. [ABSTRACT FROM AUTHOR]

Simple Summary: Lung squamous cell carcinoma (LSCC) is refractory to various therapies for non-small cell cancer. The expression and significance of B7-H3 in the tumor microenvironment (TME) and its relationship with other immune checkpoint molecules have not yet been investigated. We used high-throughput quantitative multiplex immunohistochemistry to examine B7-H3 expression in the TME. We investigated the relationship between B7-H3 expression and prognosis as well as changes in the TME with B7-H3 expression. The correlation between B7-H3 and programmed cell death-ligand 1 (PD-L1) expression in single cells was also examined. A quantitative analysis of protein expression in macrophages and cancer cells revealed that PD-L1-positive cells expressed higher levels of B7-H3 than that of PD-L1-negative cells. Our findings demonstrate a correlation between B7-H3 and PD-L1 expression in the same cells, indicating that therapies targeting B7-H3 could provide additional efficacy in patients refractory to PD-L1-targeting therapies. Lung squamous cell carcinoma (LSCC) is refractory to various therapies for non-small cell cancer; therefore, new therapeutic approaches are required to improve the prognosis of LSCC. Although immunotherapies targeting B7 family molecules were explored as treatments for several cancer types, the expression and significance of B7-H3 in the tumor microenvironment (TME) and its relationship with other immune checkpoint molecules have not yet been investigated in detail. We used high-throughput quantitative multiplex immunohistochemistry to examine B7-H3 expression in the TME. We investigated the relationship between B7-H3 expression and prognosis as well as changes in the TME with B7-H3 expression using 110 surgically resected pathological specimens retrospectively. We examined the correlation between B7-H3 and programmed cell death-ligand 1 (PD-L1) expression in single cells. High B7-H3 expression in tumor cells was associated with a better prognosis and a significant increase in the number of CD163+PD-L1+ macrophages. Quantitative analysis revealed that there is a positive correlation between B7-H3 and PD-L1 expression in tumor and stromal cells, as well as in intratumoral tumor-infiltrating lymphocytes and tumor-associated macrophages in the same cells. CD68+, CD163+, and CK+ cells with PD-L1+ phenotypes had higher B7-H3 expression compared to PD-L1− cells. Our findings demonstrate a correlation between B7-H3 and PD-L1 expression in the same cells, indicating that therapies targeting B7-H3 could provide additional efficacy in patients refractory to PD-L1-targeting therapies. [ABSTRACT FROM AUTHOR]

Simple Summary: Guidelines from oncologic societies recommend high-dose systemic corticosteroids as the primary therapy with or without biologics for moderate to severe colitis secondary to immune checkpoint inhibitors; budesonide is a gut selective steroid that undergoes first past metabolism with less systemic adverse events in comparison to systemic steroids, although its use has not been studied or established for colitis secondary to immune checkpoint inhibitors. Budesonide employed for other gastrointestinal diseases, such as inflammatory bowel disease, is associated with decreased infections and metabolic side effects. In our analysis, we observed that budesonide may be an effective strategy to treat and prevent the recurrence of colitis with similar results as systemic corticosteroids in this immunocompromised cancer patient population. Background: Current treatment guidelines for moderate to severe colitis (IMC) secondary to immune checkpoint inhibitors (ICI) recommend systemic corticosteroids as the primary therapy in conjunction with biologics, namely infliximab and/or vedolizumab. We aimed to explore the efficacy and safety of oral budesonide in the treatment of IMC. Methods: We performed a retrospective analysis at MD Anderson Cancer Center of adult cancer patients with a confirmed (based on clinical, radiographic and laboratory assessment) diagnosis of IMC between 1 January 2015 and 31 November 2022, treated with budesonide. Data collection included demographics, oncologic history, IMC-related information and outcomes up to 6 months after the last dose of ICI. Results: Our sample (n = 69) comprised primarily of Caucasian (76.8%) females (55.1%). The majority of patients received combination therapy with anti-PD-1/L1 and anti-CTLA-4 (49.3%), and the most common malignancy treated was melanoma (37.6%). The median grade of diarrhea was 3 and of colitis was 2. Of the 50 patients who underwent endoscopic evaluation, a majority had non-ulcerative inflammation (64%) and active colitis on histology (78%). Budesonide was used as primary treatment at onset of IMC in 56.5% patients, as well as a bridging therapy from systemic corticosteroids in 33.3%. Less than half of the patients (44.9%) required additional therapies such as biologics or fecal microbiota transplant. Additionally, 75.3% of patients achieved full remission of IMC and 24.6% had a recurrence of IMC. ICI was resumed in 31.9% of patients and 17.4% received other forms of cancer therapies. Conclusions: Budesonide may be an effective strategy to treat and prevent the recurrence of IMC. The remission rates observed in our analysis with budesonide alone are comparable to systemic corticosteroids. Patients that require an extended duration of steroid exposure and those with moderate to severe colitis may benefit from budesonide given its lower risk of infection and complications. Furthermore, we observe that budesonide may serve as a successful bridge from systemic corticosteroids with subsequent biologic treatment. Larger prospective studies are necessary to determine the role of budesonide as well as its safety profile. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) remains one of the leading causes of cancer mortality. Treatment of HCC remains challenging, especially for those with advanced stages or those with postoperative recurrence. Molecular research of signaling pathways to afford new options of treatments is urgent. Moreover, among the various signaling pathways, the Sonic hedgehog (SHH) signaling pathway is implicated in multiple aspects of HCC, including cancer development, growth, invasiveness, recurrence, metastasis, the tumor microenvironment, and the maintenance of its cancer stem cells. The SHH signaling pathway also contributes to the resistance of HCC to chemotherapy, target therapy, and radiation therapy. This narrative review of the update studies reappraises the roles of SHH signaling in HCC. A deeper understanding of the SHH signaling pathway is crucial. It may provide more insights into the regulatory processes to establish novel treatments for HCC. HCC remains one of the leading causes of cancer-related death globally. The main challenges in treatments of hepatocellular carcinoma (HCC) primarily arise from high rates of postoperative recurrence and the limited efficacy in treating advanced-stage patients. Various signaling pathways involved in HCC have been reported. Among them, the Sonic hedgehog (SHH) signaling pathway is crucial. The presence of SHH ligands is identified in approximately 60% of HCC tumor tissues, including tumor nests. PTCH-1 and GLI-1 are detected in more than half of HCC tissues, while GLI-2 is found in over 84% of HCC tissues. The SHH signaling pathway (including canonical and non-canonical) is involved in different aspects of HCC, including hepatocarcinogenesis, tumor growth, tumor invasiveness, progression, and migration. The SHH signaling pathway also contributes to recurrence, metastasis, modulation of the cancer microenvironment, and sustaining cancer stem cells. It also affects the resistance of HCC cells to chemotherapy, target therapy, and radiotherapy. Reappraisal of the roles of the SHH signaling pathway in HCC may trigger some novel therapies for HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Survival for many pediatric cancers has improved over recent decades. However, for pediatric patients with solid tumors that fail to respond to standard therapies, or relapse after initial response, outcomes generally remain poor, indicating a need for novel and improved treatments. Many cancers have an impaired ability to repair DNA damage, which in excess can become toxic to cells. As such, one potential approach for these challenging cancers is to target the DNA damage repair pathways of cancer cells, with the goal of inducing a lethal amount of DNA damage. This article reviews the current research efforts into targeting DNA damage repair pathways in pediatric extracranial solid tumors. It reviews the biology of DNA damage repair pathways, the biology of several extracranial pediatric cancers, the preclinical research investigating targeting the DNA damage repair in pediatric cancers, and the clinical trials using these agents in patients. This article also reviews the ability to harness a patient's immune system to kill cancer cells, and the research that has been done investigating ways in which DNA damage can activate the anti-tumor immune response. DNA damage is fundamental to tumorigenesis, and the inability to repair DNA damage is a hallmark of many human cancers. DNA is repaired via the DNA damage repair (DDR) apparatus, which includes five major pathways. DDR deficiencies in cancers give rise to potential therapeutic targets, as cancers harboring DDR deficiencies become increasingly dependent on alternative DDR pathways for survival. In this review, we summarize the DDR apparatus, and examine the current state of research efforts focused on identifying vulnerabilities in DDR pathways that can be therapeutically exploited in pediatric extracranial solid tumors. We assess the potential for synergistic combinations of different DDR inhibitors as well as combinations of DDR inhibitors with chemotherapy. Lastly, we discuss the immunomodulatory implications of targeting DDR pathways and the potential for using DDR inhibitors to enhance tumor immunogenicity, with the goal of improving the response to immune checkpoint blockade in pediatric solid tumors. We review the ongoing and future research into DDR in pediatric tumors and the subsequent pediatric clinical trials that will be critical to further elucidate the efficacy of the approaches targeting DDR. [ABSTRACT FROM AUTHOR]

Simple Summary: The premise that certain checkpoint inhibitors are effective anti-cancer treatments beyond their immune modulatory capabilities influences current cancer research and clinical practice as well as future drug versus therapy development. We propose ways and means to enhance immunotherapy in cancer care by combining anti-PD1/L1 with various therapeutic modalities according to an appropriate scientific theory, e.g., stem cell origin of cancer, and based on available clinical evidence, e.g., randomized clinical trials. Although immunotherapy has revolutionized cancer care, there is still an urgent need to enhance its efficacy and ensure its safety. A correct cancer theory and proper scientific method empower pertinent cancer research and enable effective and efficient drug versus therapy development for patient care. In this perspective, we revisit the concept of immune privilege in a cancer cell versus normal cell, as well as in a cancer stem cell versus normal stem cell. We re-examine whether effective immunotherapies are efficacious due to their anti-cancer and/or immune modulatory mechanisms. We reassess why checkpoint inhibitors (CPIs) are not equal. We reconsider whether one can attribute the utility of immunotherapy to specific cancer subtypes and its futility to certain tumor/immune compartments, components, and microenvironments. We propose ways and means to advance immunotherapy beyond CPIs by combining anti-PD1/L1 with various other treatment modalities according to an appropriate scientific theory, e.g., stem cell origin of cancer, and based on available clinical evidence, e.g., randomized clinical trials. We predict that a stem cell theory of cancer will facilitate the design of better and safer immunotherapy with improved selection of its use for the right patient with the right cancer type at the right time to optimize clinical benefits and minimize potential toxic effects and complications. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, we have explored the impact of a promising new cancer treatment modality called proton therapy (PT) and compared it to traditional X-ray based photon therapy (XRT) for head and neck cancers. Proton therapy is effective because it can be delivered with precision, thus causing fewer side effects. We demonstrate in this study that, when using proton therapy, there was a significant reduction (75%) in the production of small extracellular vesicles, commonly known as exosomes, from cancer cells, which usually suppress the immune system. XRT did not reduce exosome production. Exosomes from both PT and XRT had similar inhibitory effects on immune cells. Our findings suggest that proton therapy might be better at reducing the immune-suppressing effects of cancer exosomes by producing fewer of them. Proton therapy (PT) is emerging as an effective and less toxic alternative to conventional X-ray-based photon therapy (XRT) for patients with advanced head and neck squamous cell carcinomas (HNSCCs) owing to its clustered dose deposition dosimetric characteristics. For optimal efficacy, cancer therapies, including PT, must elicit a robust anti-tumor response by effector and cytotoxic immune cells in the tumor microenvironment (TME). While tumor-derived exosomes contribute to immune cell suppression in the TME, information on the effects of PT on exosomes and anti-tumor immune responses in HNSCC is not known. In this study, we generated primary HNSCC cells from tumors resected from HNSCC patients, irradiated them with 5 Gy PT or XRT, and isolated exosomes from cell culture supernatants. HNSCC cells exposed to PT produced 75% fewer exosomes than XRT- and non-irradiated HNSCC cells. This effect persisted in proton-irradiated cells for up to five days. Furthermore, we observed that exosomes from proton-irradiated cells were identical in morphology and immunosuppressive effects (suppression of IFN-γ release by peripheral blood mononuclear cells) to those of photon-irradiated cells. Our results suggest that PT limits the suppressive effect of exosomes on cancer immune surveillance by reducing the production of exosomes that can inhibit immune cell function. [ABSTRACT FROM AUTHOR]

Simple Summary: The heterogeneous expression of signaling molecules within the tumor, including kinases, is the major contributor to the acquisition of drug resistance and poor survival observed in small-cell lung cancer (SCLC). The addition of immunotherapy to chemotherapy has only marginally prolonged survival in patients with extensive-stage SCLC (ES-SCLC). Recent clinical trials have combined immunotherapy with the pharmacological inhibitors of kinases often dysregulated in SCLC. However, the regime has not been effective in the long term. Here, we review studies and clinical trials exploring dysregulated kinases in SCLC progression and resistance to chemotherapies and immunotherapies. We also discuss the possibility of repurposing kinase inhibitors against SCLC that have already demonstrated promising results for other types of cancers. SCLC is refractory to conventional therapies; targeted therapies and immunological checkpoint inhibitor (ICI) molecules have prolonged survival only marginally. In addition, ICIs help only a subgroup of SCLC patients. Different types of kinases play pivotal roles in therapeutics-driven cellular functions. Therefore, there is a significant need to understand the roles of kinases in regulating therapeutic responses, acknowledge the existing knowledge gaps, and discuss future directions for improved therapeutics for recalcitrant SCLC. Here, we extensively review the effect of dysregulated kinases in SCLC. We further discuss the pharmacological inhibitors of kinases used in targeted therapies for recalcitrant SCLC. We also describe the role of kinases in the ICI-mediated activation of antitumor immune responses. Finally, we summarize the clinical trials evaluating the potential of kinase inhibitors and ICIs. This review overviews dysregulated kinases in SCLC and summarizes their potential as targeted therapeutic agents. We also discuss their clinical efficacy in enhancing anticancer responses mediated by ICIs. [ABSTRACT FROM AUTHOR]

Simple Summary: This comprehensive review focuses on the role of epigenetics in oral squamous cell carcinoma (OSCC), a prevalent type of oral cancer. The review highlights the importance of epigenetic changes, including DNA methylation, histone modifications, and miRNAs, in OSCC development and progression. Aberrant DNA methylation of tumor suppressor genes (TSGs) promotes tumor growth, making gene methylation patterns potential biomarkers for OSCC detection. Histone modifications, such as acetylation, methylation, phosphorylation, and ubiquitination, impact gene expression by modifying chromatin structure. Dysregulated miRNAs also contribute to OSCC progression. Epigenetic-targeted therapies, such as DNMT and HDAC inhibitors, show promise in modifying abnormal gene expression patterns, potentially leading to improved treatment outcomes for OSCC. However, challenges remain in biomarker identification and developing effective combination treatments. Understanding and targeting these epigenetic processes offer potential strategies to overcome drug resistance and improve OSCC treatment efficacy. Overall, the review highlights the potential of understanding and targeting epigenetic processes to overcome challenges and improve the efficacy of OSCC treatment, offering valuable insights for society in the diagnosis and treatment of oral cancer. Oral squamous cell carcinoma (OSCC) is a prevalent and significant type of oral cancer that has far-reaching health implications worldwide. Epigenetics, a field focused on studying heritable changes in gene expression without modifying DNA sequence, plays a pivotal role in OSCC. Epigenetic changes, encompassing DNA methylation, histone modifications, and miRNAs, exert control over gene activity and cellular characteristics. In OSCC, aberrant DNA methylation of tumor suppressor genes (TSG) leads to their inactivation, subsequently facilitating tumor growth. As a result, distinct patterns of gene methylation hold promise as valuable biomarkers for the detection of OSCC. Oral cancer treatment typically involves surgery, radiation therapy, and chemotherapy, but even with these treatments, cancer cells cannot be effectively targeted and destroyed. Researchers are therefore exploring new methods to target and eliminate cancer cells. One promising approach is the use of epigenetic modifiers, such as DNA methyltransferase (DNMT) inhibitors and histone deacetylase (HDAC) inhibitors, which have been shown to modify abnormal epigenetic patterns in OSCC cells, leading to the reactivation of TSGs and the suppression of oncogenes. As a result, epigenetic-targeted therapies have the potential to directly alter gene expression and minimize side effects. Several studies have explored the efficacy of such therapies in the treatment of OSCC. Although studies have investigated the efficacy of epigenetic therapies, challenges in identifying reliable biomarkers and developing effective combination treatments are acknowledged. Of note, epigenetic mechanisms play a significant role in drug resistance in OSCC and other cancers. Aberrant DNA methylation can silence tumor suppressor genes, while alterations in histone modifications and chromatin remodeling affect gene expression related to drug metabolism and cell survival. Thus, understanding and targeting these epigenetic processes offer potential strategies to overcome drug resistance and improve the efficacy of cancer treatments in OSCC. This comprehensive review focuses on the complex interplay between epigenetic alterations and OSCC cells. This will involve a deep dive into the mechanisms underlying epigenetic modifications and their impact on OSCC, including its initiation, progression, and metastasis. Furthermore, this review will present the role of epigenetics in the treatment and diagnosis of OSCC. [ABSTRACT FROM AUTHOR]

Simple Summary: According to the stem cell theory of cancer, we should be judicious with immunotherapy in cancer care. When we do not realize that cancer originates from a stem cell and has stem-ness capabilities, immunotherapy could be gratifying for the wrong reasons and challenging with a cautionary tale. A simple way to understand the immune system is to separate the self from non-self. If it is self, the immune system tolerates and spares. If it is non-self, the immune system attacks and destroys. Consequently, if cancer has a stem cell origin and is a stem cell disease, we have a serious problem and a major dilemma with immunotherapy. Because many refractory cancers are more self than non-self, immunotherapy may become an uphill battle and pyrrhic victory in cancer care. In this article, we elucidate cancer immunity. We demonstrate for whom, with what, as well as when and how to apply immunotherapy in cancer care. We illustrate that a stem cell theory of cancer affects our perspectives and narratives of cancer. Without a pertinent theory about cancer's origin and nature, we may unwittingly perform misdirected cancer research and prescribe misguided cancer treatments. In the ongoing saga of immunotherapy, we are at a critical juncture. Because of the allure and promises of immunotherapy, we will be treating more patients not immediately threatened by their cancer. They may have more to lose than to gain, if we have a misconception and if we are on a wrong mission with immunotherapy. According to the stem cell theory of cancer, we should be careful with immunotherapy. When we do not know or realize that cancer originates from a stem cell and has stem-ness capabilities, we may cause more harm than good in some patients and fail to separate the truth from the myth about immunotherapy in cancer care. [ABSTRACT FROM AUTHOR]

Simple Summary: Research has clearly shown a connection between the respiratory tract microbiome and lung cancer. The composition and metabolism of the bacterial community in lung cancer patients differ from those in healthy individuals. Further large-scale studies are needed to understand the microbiome's role in lung cancer, including identifying bacterial species, deciphering mechanisms and relationships with the macro-organisms, and addressing analysis-related issues. Large-scale research is also needed on the lung mycobiome and virome. Identifying microorganisms involved in oncogenic processes could improve lung cancer patient screening, diagnosis, and therapeutic options. This review presents the current state of knowledge on the role of the respiratory tract microbiome in lung carcinogenesis. We highlight what we know and what we don' yet know about the human lung oncobiome. The importance of microbiota in developing and treating diseases, including lung cancer (LC), is becoming increasingly recognized. Studies have shown differences in microorganism populations in the upper and lower respiratory tracts of patients with lung cancer compared to healthy individuals, indicating a link between dysbiosis and lung cancer. However, it is not only important to identify "which bacteria are present" but also to understand "how" they affect lung carcinogenesis. The interactions between the host and lung microbiota are complex, and our knowledge of this relationship is limited. This review presents research findings on the bacterial lung microbiota and discusses the mechanisms by which lung-dwelling microorganisms may directly or indirectly contribute to the development of lung cancer. These mechanisms include influences on the host immune system regulation and the local immune microenvironment, the regulation of oncogenic signaling pathways in epithelial cells (causing cell cycle disorders, mutagenesis, and DNA damage), and lastly, the MAMPs-mediated path involving the effects of bacteriocins, TLRs signaling induction, and TNF release. A better understanding of lung microbiota's role in lung tumor pathology could lead to identifying new diagnostic and therapeutic biomarkers and developing personalized therapeutic management for lung cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Upper tract urothelial cancer is an aggressive malignancy that requires prompt treatment in the form of removal of the kidney and ureter with a bladder cuff, especially for invasive disease. The ideal surgical technique should offer a complete cancer clearance, including the ability to remove lymph glands with a short recovery period. The three techniques currently available include open, laparoscopic, and robotic approaches. This review compares the three techniques both on cancer clearance and survival by analyzing the existing literature. We found the robotic technique to be similar or slightly superior to either the open or laparoscopic approach for overall survival, cancer-specific survival, lymph node removal rates, and the rates of risk for residual cancer (positive margins). However, the risk of recurrent tumours in the bladder was identified to be higher in robotic surgery compared to the open approach. The study determines that the robotic approach offers comparable outcomes to the open and laparoscopic approaches, which are well established but for which the overall quality of evidence has been poor. Introduction and Aims: The optimal approach for nephroureterectomy in patients with suspected UTUC remains a point of debate. In this review, we compare the oncological outcomes of robotic nephroureterectomy (RNU) with open (ONU) or laparoscopic nephroureterectomy (LNU). Methods: All randomized trials and observational studies comparing RNU with ONU and/or LNU for suspected non-metastatic UTUC are included in this review. The systematic review was performed in accordance with the Cochrane Guidelines and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA). The primary outcome measures were overall survival (OS), cancer-specific survival (CSS), disease-free survival (DFS), and intravesical recurrence-free survival (IV-RFS). The secondary outcome measures were the lymph node dissection (LND) rates, positive margin rates, and the proportion of patients receiving bladder intravesical chemotherapy. Results: We identified 8172 references through our electronic searches and 8 studies through manual searching. A total of 15 studies met the inclusion criteria. The total number of patients in the review was 18,964. RNU had superior OS compared to LNU (HR: 0.81 (95% CI: 0.71, 0.93), p-0.002 (very low certainty)). RNU and ONU had similar OS (HR: 0.83 (95% CI: 0.52, 1.34), p-0.44 (very low certainty)). One study reported an independent association of RNU as a worse predictor of IV-RFS when compared to ONU (HR-1.73 (95% CI: 1.22, 2.45)). The LND rates were higher in the RNU cohort when compared to the LNU cohort (RR 1.24 (95% CI: 1.03, 1.51), p-0.03 (low certainty)). The positive margin rate was lower in the RNU cohort when compared to the ONU cohort (RR 0.29 (95% CI: 0.08, 0.86), p-0.03 (low certainty)). Conclusion: RNU offers comparable oncological efficacy to ONU, except for intravesical recurrence-free survival (IV-RFS). RNU has fewer positive surgical margin rates compared to ONU in well-balanced studies. RNU appears to outperform LNU for certain oncological parameters, such as OS and the proportion of patients who receive lymph node dissections. The quality of evidence comparing surgical techniques for UTUC has remained poor in the last decade. [ABSTRACT FROM AUTHOR]

Simple Summary: Small cell lung cancer (SCLC) remains a difficult-to-treat disease and is associated with a poor prognosis in most patients. Discovering biomarkers and developing targeted treatment options for patients with SCLC has been challenging though there are emerging therapies that are showing promise. A better understanding of the underlying biology and specific molecular targets in SCLC has led to newer drug strategies and combinations that can hopefully lead to better outcomes for our patients. Small cell lung cancer is an aggressive subtype of lung cancer with limited treatment options. Precision medicine has revolutionized cancer treatment for many tumor types but progress in SCLC has been slower due to the lack of targetable biomarkers. This review article provides an overview of emerging strategies for precision therapy in SCLC. Targeted therapies include targeted kinase inhibitors, monoclonal antibodies, angiogenesis inhibitors, antibody–drug conjugates, PARP inhibitors, and epigenetic modulators. Angiogenesis inhibitors and DNA-damaging agents, such as PARP and ATR inhibitors, have been explored in SCLC with limited success to date although trials are ongoing. The potential of targeting DLL3, a NOTCH ligand, through antibody–drug conjugates, bispecific T-cell engagers, and CAR T-cell therapy, has opened up new therapeutic options moving forward. Additionally, new research in epigenetic therapeutics in reversing transcriptional repression, modulating anti-tumor immunity, and utilizing antibody–drug conjugates to target cell surface-specific targets in SCLC are also being investigated. While progress in precision therapy for SCLC has been challenging, recent advancements provide optimism for improved treatment outcomes. However, several challenges remain and will need to be addressed, including drug resistance and tumor heterogeneity. Further research and biomarker-selected clinical trials are necessary to develop effective precision therapies for SCLC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Epithelial-to-mesenchymal transition (EMT) is a complex program by which epithelial cells lose epithelial characteristics whilst acquiring mesenchymal features. EMT was coined in the 1980s and initially thought to involve a binary switch between epithelial and mesenchymal states. However, mounting work suggests that EMT involves intermediate states or hybrid epithelial/mesenchymal (E/M) phenotypes. In the context of many cancers, such as breast cancers, these hybrid states retain characteristics of both epithelial and mesenchymal cells, and have been linked to poor survival, metastasis, and resistance to treatment. In this Review, the authors examine the complex layers of molecular interactions governing EMT in cancer. The underlying drivers of these states, namely EMT-transcription factors, epigenetic regulators, and non-coding RNAs, as well as the influence of EMT on the immune response, are discussed, and in doing so, this Review outlines valuable mechanistic insights for the reversion of EMT and potential avenues for therapeutic intervention. Cellular plasticity in cancer enables adaptation to selective pressures and stress imposed by the tumor microenvironment. This plasticity facilitates the remodeling of cancer cell phenotype and function (such as tumor stemness, metastasis, chemo/radio resistance), and the reprogramming of the surrounding tumor microenvironment to enable immune evasion. Epithelial plasticity is one form of cellular plasticity, which is intrinsically linked with epithelial–mesenchymal transition (EMT). Traditionally, EMT has been regarded as a binary state. Yet, increasing evidence suggests that EMT involves a spectrum of quasi-epithelial and quasi-mesenchymal phenotypes governed by complex interactions between cellular metabolism, transcriptome regulation, and epigenetic mechanisms. Herein, we review the complex cross-talk between the different layers of epithelial plasticity in cancer, encompassing the core layer of transcription factors, their interacting epigenetic modifiers and non-coding RNAs, and the manipulation of cancer immunogenicity in transitioning between epithelial and mesenchymal states. In examining these factors, we provide insights into promising therapeutic avenues and potential anti-cancer targets. [ABSTRACT FROM AUTHOR]

Simple Summary: As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, extracellular matrix (ECM), and soluble molecules forming the widely recognized tumor microenvironment. The main components of the tumor microenvironment include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), ECM, and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). The tumor microenvironment has been suggested to play a central role in tumor progression and treatment resistance. Accumulated evidence indicates that tumor maintenance, progression, and treatment resistance are determined by components of the microenvironment. Thus, targeting the components of the tumor microenvironment may have a therapeutic impact on melanoma treatment. The main topic of this paper deals with the main components of the tumor microenvironment and their impact as therapeutic targets in melanoma treatment. The role of the tumor microenvironment in tumor growth and therapy has recently attracted more attention in research and drug development. The ability of the microenvironment to trigger tumor maintenance, progression, and resistance is the main cause for treatment failure and tumor relapse. Accumulated evidence indicates that the maintenance and progression of tumor cells is determined by components of the microenvironment, which include stromal cells (endothelial cells, fibroblasts, mesenchymal stem cells, and immune cells), extracellular matrix (ECM), and soluble molecules (chemokines, cytokines, growth factors, and extracellular vesicles). As a solid tumor, melanoma is not only a tumor mass of monolithic tumor cells, but it also contains supporting stroma, ECM, and soluble molecules. Melanoma cells are continuously in interaction with the components of the microenvironment. In the present review, we focus on the role of the tumor microenvironment components in the modulation of tumor progression and treatment resistance as well as the impact of the tumor microenvironment as a therapeutic target in melanoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy for non-small cell lung cancer (NSCLC) is a clinical reality with impressive efficacy for some patients. However, less than half of them will benefit from this therapeutic regime, and finding indicators of response is necessary for selecting the patients likely to respond. So far, detection of PD-L1 in tumors by immunohistochemistry is the only validated predictive biomarker. In recent years, certain changes in the tumor cells (intrinsic alterations), including mutations, epigenetic changes and metabolic rewiring, have been shown to modify the type of tumor microenvironment (TME) where such a tumor grows. This TME may determine response or refractoriness to immunotherapy. Examples of key mutations are KRAS, SKT11(LKB1), KEAP1 and TP53, as well as co-mutations of these genes. Reshaping the TME with novel strategies in these particular TMEs could increase the efficacy of immunotherapy in lung cancer patients. Despite the great clinical success of immunotherapy in lung cancer patients, only a small percentage of them (<40%) will benefit from this therapy alone or combined with other strategies. Cancer cell-intrinsic and cell-extrinsic mechanisms have been associated with a lack of response to immunotherapy. The present study is focused on cancer cell-intrinsic genetic, epigenetic, transcriptomic and metabolic alterations that reshape the tumor microenvironment (TME) and determine response or refractoriness to immune checkpoint inhibitors (ICIs). Mutations in KRAS, SKT11(LKB1), KEAP1 and TP53 and co-mutations of these genes are the main determinants of ICI response in non-small-cell lung cancer (NSCLC) patients. Recent insights into metabolic changes in cancer cells that impose restrictions on cytotoxic T cells and the efficacy of ICIs indicate that targeting such metabolic restrictions may favor therapeutic responses. Other emerging pathways for therapeutic interventions include epigenetic modulators and DNA damage repair (DDR) pathways, especially in small-cell lung cancer (SCLC). Therefore, the many potential pathways for enhancing the effect of ICIs suggest that, in a few years, we will have much more personalized medicine for lung cancer patients treated with immunotherapy. Such strategies could include vaccines and chimeric antigen receptor (CAR) cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Gastric cancer (GC) ranks as one of the most life-threatening malignancies worldwide, and over one billion new cases and 783,000 deaths were reported last year. The incidence of GC is exceptionally high in Asian countries. Multiple oncogenic signaling pathways are aberrantly activated and implicated in gastric carcinogenesis, leading to the malignant phenotype acquisition. G-protein-coupled receptor (GPCR) signaling is one of them, and the aberrant activation of GPCRs and G proteins promotes GC progression. The activated GPCRs/G proteins might serve as useful biomarkers for early diagnosis, prognostic prediction, and even clinically therapeutic targets. This review summarized the recent research progress of GPCRs and highlighted their mechanisms in tumorigenesis, especially in GC initiation and progression. G-protein-coupled receptors (GPCRs) belong to a cell surface receptor superfamily responding to a wide range of external signals. The binding of extracellular ligands to GPCRs activates a heterotrimeric G protein and triggers the production of numerous secondary messengers, which transduce the extracellular signals into cellular responses. GPCR signaling is crucial and imperative for maintaining normal tissue homeostasis. High-throughput sequencing analyses revealed the occurrence of the genetic aberrations of GPCRs and G proteins in multiple malignancies. The altered GPCRs/G proteins serve as valuable biomarkers for early diagnosis, prognostic prediction, and pharmacological targets. Furthermore, the dysregulation of GPCR signaling contributes to tumor initiation and development. In this review, we have summarized the research progress of GPCRs and highlighted their mechanisms in gastric cancer (GC). The aberrant activation of GPCRs promotes GC cell proliferation and metastasis, remodels the tumor microenvironment, and boosts immune escape. Through deep investigation, novel therapeutic strategies for targeting GPCR activation have been developed, and the final aim is to eliminate GPCR-driven gastric carcinogenesis. [ABSTRACT FROM AUTHOR]

Simple Summary: DNA damage response (DDR)-related proteins contribute to tumorigenesis, tumor progression, and drug resistance. Pharmacological inhibition of DDR-related proteins, such as checkpoint kinase 1 (Chk1), exerts antitumor effects but has serious side effects. Therefore, we attempted to specifically kill cancer cells with low concentrations of drugs by simultaneously inhibiting two DDR-related proteins. In this study, we demonstrated that the combined treatment with ataxia telangiectasia-mutated serine/threonine kinase (ATM) inhibitor (ATMi) and Chk1 inhibitor (Chk1i) exerts synergistic antitumor effects and induces cancer-specific synthetic lethality at low doses. The ATMi and Chk1i combination synergistically promotes CDK1 activation, resulting in the induction of apoptosis with enhanced cell cycle progression in cancer cells. Considering that the combined treatment exerts antitumor effects at one-tenth the concentrations described in previous reports, with high antitumor efficacy and few side effects it could be an effective treatment approach. Genetic abnormalities induce the DNA damage response (DDR), which enables DNA repair at cell cycle checkpoints. Although the DDR is thought to function in preventing the onset and progression of cancer, DDR-related proteins are also thought to contribute to tumorigenesis, tumor progression, and drug resistance by preventing irreparable genomic abnormalities from inducing cell death. In the present study, the combination of ataxia telangiectasia-mutated serine/threonine kinase (ATM) and checkpoint kinase 1 (Chk1) inhibition exhibited synergistic antitumor effects and induced synergistic lethality in colorectal cancer cells at a low dose. The ATM and Chk1 inhibitors synergistically promoted the activation of cyclin-dependent kinase 1 by decreasing the phosphorylation levels of T14 and Y15. Furthermore, the combined treatment increased the number of sub-G1-stage cells, phospho-histone H2A.X-positive cells, and TdT-mediated dUTP nick-end labeling-positive cells among colon cancer cells, suggesting that the therapy induces apoptosis. Finally, the combined treatment exhibited a robust antitumor activity in syngeneic tumor model mice. These findings should contribute to the development of new treatments for colorectal cancer that directly exploit the genomic instability of cancer cells. [ABSTRACT FROM AUTHOR]

Simple Summary: Oral cancer is a major cause of death worldwide. The major challenges associated with the conventionally used treatment modalities include the recurrence of the cancer and the adverse effects of the chemotherapeutic drugs. Natural products play a very important role in drug discovery and have potential effects against various cancers in general and oral cancer in particular. The major problem with natural products is their poor bioavailability, which limits their therapeutic application. Therefore, an attempt is made to comprehensively utilize various formulation strategies that can help in improving the bioavailability of various anticancer natural compounds. In this work, we have presented recent advancements in novel strategies for natural product delivery that lead to the significant enhancement of bioavailability, in vivo activity, and fewer adverse events for the prevention and treatment of oral cancer. Oral cancer is emerging as a major cause of mortality globally. Oral cancer occupies a significant proportion of the head and neck, including the cheeks, tongue, and oral cavity. Conventional methods in the treatment of cancer involve surgery, radiotherapy, and immunotherapy, and these have not proven to completely eradicate cancerous cells, may lead to the reoccurrence of oral cancer, and possess numerous adverse side effects. Advancements in novel drug delivery approaches have gained popularity in cancer management with an increase in the number of cases associated with oral cancer. Natural products are potent sources for drug discovery, especially for anticancer drugs. Natural product delivery has major challenges due to its low solubility, poor absorption, inappropriate size, instability, poor permeation, and first-pass metabolism. Therefore, it is of prime importance to investigate novel treatment approaches for the delivery of bioactive natural products. Nanotechnology is an advanced method of delivering cancer therapy with minimal damage to normal cells while targeting cancer cells. Therefore, the present review elaborates on the advancements in novel strategies for natural product delivery that lead to the significant enhancement of bioavailability, in vivo activity, and fewer adverse events for the prevention and treatment of oral cancer. Various approaches to accomplish the desired results involve size reduction, surface property modification, and polymer attachment, which collectively result in the higher stability of the formulation. [ABSTRACT FROM AUTHOR]

Simple Summary: The study was the first to screen seven genes and identify the set of genes using twelve machine learning algorithms that predict the progression from oral leukoplakia to oral squamous cell carcinoma. We verified these genes by RT-qPCR experiments and speculated on the possible molecular mechanisms through the results. These genes could be used as biomarkers for early diagnosis and predicting patients with a high risk of malignant transformation. This will aid in early intervention, improve the patient prognosis, and reduce the incidences of oral squamous cell carcinoma. The aim of the study is to identify key genes during the progression from oral leukoplakia (OL) to oral squamous cell carcinoma (OSCC) and predict effective diagnoses. Weighted gene co-expression network analysis (WGCNA) and differential expression analysis were performed to identify seven genes associated with the progression from OL to OSCC. Twelve machine learning algorithms including k-nearest neighbor (KNN), neural network (NNet), and extreme gradient boosting (XGBoost) were used to construct multi-gene models, which revealed that each model had good diagnostic efficacy. The functional mechanism or the pathways associated with these genes were evaluated using enrichment analysis, subtype clustering, and immune infiltration analysis. The enrichment analysis revealed that the genes enriched were associated with the cell cycle, cell division, and intracellular energy metabolism. The immunoassay results revealed that the genes primarily affected the infiltration of proliferating T cells and macrophage polarization. Finally, a nomogram and Kaplan–Meier survival analysis were used to predict the prognostic efficacy of key genes in OSCC patients. The results showed that genes could predict the prognosis of the patients, and patients in the high-risk group had a poor prognosis. Our study identified that the seven key genes, including DHX9, BCL2L12, RAD51, MELK, CDC6, ANLN, and KIF4A, were associated with the progression from OL to OSCC. These genes had good diagnostic efficacy and could be used as potential biomarkers for the prognosis of OSCC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: This review aims at analyzing an emergent topic regarding the possible combined use of poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi), anticancer drugs approved to treat tumors with defective repair of DNA damage, and immunostimulating agents, like Immune Checkpoint Inhibitors (ICIs), that represent the current treatment of a variety of malignancies. Preclinical investigation shows how PARPi, by positively impacting anti-tumor immune response through DNA damage-related mechanisms, might render cancer cells more responsive to immunotherapies, especially in the setting of genomic instability. In addition to well-recognized mechanisms that may be elicited by PARPi, recent experimental evidence is summarized further supporting the potential synergistic effects of PARPi and ICIs. We believe that an in-depth analysis of the tumor genome as well as of the characteristics of the tumor microenvironment at a single-patient level, along with an implementation of clinical trials that are presently at an early-stage, can contribute to identify more effective and individually-tailored treatments. Poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi) induce cytotoxic effects as single agents in tumors characterized by defective repair of DNA double-strand breaks deriving from BRCA1/2 mutations or other abnormalities in genes associated with homologous recombination. Preclinical studies have shown that PARPi-induced DNA damage may affect the tumor immune microenvironment and immune-mediated anti-tumor response through several mechanisms. In particular, increased DNA damage has been shown to induce the activation of type I interferon pathway and up-regulation of PD-L1 expression in cancer cells, which can both enhance sensitivity to Immune Checkpoint Inhibitors (ICIs). Despite the recent approval of ICIs for a number of advanced cancer types based on their ability to reinvigorate T-cell-mediated antitumor immune responses, a consistent percentage of treated patients fail to respond, strongly encouraging the identification of combination therapies to overcome resistance. In the present review, we analyzed both established and unexplored mechanisms that may be elicited by PARPi, supporting immune reactivation and their potential synergism with currently used ICIs. This analysis may indicate novel and possibly patient-specific immune features that might represent new pharmacological targets of PARPi, potentially leading to the identification of predictive biomarkers of response to their combination with ICIs. [ABSTRACT FROM AUTHOR]

Simple Summary: The aim of this study is to discover and characterize novel small cell lung cancer (SCLC) subtypes and further identify their relationship with existing SCLC subtypes. We identified SCLC-M (mesenchymal) tumors as SCLC subtypes that are distinctive of SCLC-I (inflamed) tumors. SCLC-M tumors showed elevated epithelial-to-mesenchymal transformation (EMT) activity but a low level of anticancer immune activity also with unfavorable clinical outcomes. Gene expression- and immunohistochemistry-based prediction suggests that SCLC-M tumors comprise approximately 5% of primary SCLC tumors. Given these unique molecular and clinical features, SCLC-M tumors should be taken into account in the clinical settings of SCLC management. While molecular subtypes of small cell lung cancers (SCLC) based on neuroendocrine (NE) and non-NE transcriptional regulators have been established, the association between these molecular subtypes and recently recognized SCLC-inflamed (SCLC-I) tumors is less understood. In this study, we used gene expression profiles of SCLC primary tumors and cell lines to discover and characterize SCLC-M (mesenchymal) tumors distinct from SCLC-I tumors for molecular features, clinical outcomes, and cross-species developmental trajectories. SCLC-M tumors show elevated epithelial-to-mesenchymal transformation (EMT) and YAP1 activity but a low level of anticancer immune activity and worse clinical outcomes than SCLC-I tumors. The prevalence of SCLC-M tumors was 3.2–7.4% in primary SCLC cohorts, which was further confirmed by immunohistochemistry in an independent cohort. Deconvoluted gene expression of tumor epithelial cells showed that EMT and increased immune function are tumor-intrinsic characteristics of SCLC-M and SCLC-I subtypes, respectively. Cross-species analysis revealed that human primary SCLC tumors recapitulate the NE-to-non-NE progression murine model providing insight into the developmental relationships among SCLC subtypes, e.g., early NE (SCLC-A and -N)- vs. late non-NE tumors (SCLC-M and -P). Newly identified SCLC-M tumors are biologically and clinically distinct from SCLC-I tumors which should be taken into account for the diagnosis and treatment of the disease. [ABSTRACT FROM AUTHOR]

Simple Summary: DNA-damage repair (DDR) gene alterations are a hallmark for cancer. The exploitation of DDR alterations has improved outcomes in breast, ovarian, pancreatic, and prostate cancers. However, little is known about the role of DDR alterations, leading to a homologous recombination deficiency (HRD) state in lung cancer. In this review, we discuss the existing literature examining the role of DDR alterations as both predictive biomarkers of response to therapy and as therapeutic targets in lung cancer. Lung cancer remains the second most commonly diagnosed cancer worldwide and the leading cause of cancer-related mortality. The mapping of genomic alterations and their role in lung-cancer progression has been followed by the development of new therapeutic options. Several novel drugs, such as targeted therapy and immunotherapy, have significantly improved outcomes. However, many patients with lung cancer do not benefit from existing therapies or develop progressive disease, leading to increased morbidity and mortality despite initial responses to treatment. Alterations in DNA-damage repair (DDR) genes represent a cancer hallmark that impairs a cell's ability to prevent deleterious mutation accumulation and repair. These alterations have recently emerged as a therapeutic target in breast, ovarian, prostate, and pancreatic cancers. The role of DDR alterations remains largely unknown in lung cancer. Nevertheless, recent research efforts have highlighted a potential role of some DDR alterations as predictive biomarkers of response to treatment. Despite the failure of PARP inhibitors (main class of DDR targeting agents) to improve outcomes in lung cancer patients, there is some evidence suggesting a role of PARP inhibitors and other DDR targeting agents in benefiting a distinct subset of lung cancer patients. In this review, we will discuss the existing literature on DDR alterations and homologous recombination deficiency (HRD) state as predictive biomarkers and therapeutic targets in both non-small cell lung and small cell lung cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer (CRC) is one of the deadliest cancers worldwide, and this is mainly due to the fact that advanced, metastatic CRC is poorly responsive to current pharmacologic treatment. Therefore, studies aimed at dissecting the mechanisms driving CRC progression are worth pursuing in order to improve the treatment of the metastatic disease. We here analyzed whether hepcidin, a peptide hormone involved in the growth of cancer cells in many organs, identifies some subsets of CRC with advanced and aggressive course. By integrating results of in vitro/ex vivo studies with data of bioinformatics databases, we show that CRC cells express high levels of hepcidin and provide data supporting the role of hepcidin in promoting a tumor microenvironment that sustains CRC cell growth and metastasis. Overall, these novel findings could help develop therapeutic strategies to combat metastatic CRC. Advanced, metastatic colorectal cancer (CRC) is associated with high rate of mortality because of its poor responsiveness to chemotherapy/immunotherapy. Recent studies have shown that hepcidin, a peptide hormone produced mainly by hepatocytes, is expressed by and enhances the growth of tumor cells. We here assessed whether hepcidin expression helps identify subsets of CRC with advanced and aggressive course. By integrating results of in vitro/ex vivo studies with data of bioinformatics databases, we initially showed that hepcidin RNA and protein expression was more pronounced in tissue samples taken from the tumor area, as compared to the macroscopically unaffected, adjacent, colonic mucosa of CRC patients. The induction of hepcidin in the colonic epithelial cell line HCEC-1ct by interleukin (IL)-6, IL-21 and IL-23 occurred via a Stat3-dependent mechanism and, in primary CRC cells, hepcidin co-localized with active Stat3. In CRC tissue, hepcidin content correlated mainly with macrophage accumulation and IL-10 and CD206 expression, two markers of regulatory macrophages. Consistently, both IL-10 and CD206 were up-regulated by hepcidin in blood mononuclear cells. The highest levels of hepcidin were found in metastatic CRC and survival analysis showed that high expression of hepcidin associated with poor prognosis. Moreover, hepcidin expression correlated with markers of epithelial-to-mesenchymal transition and the silencing of hepcidin in CRC cells reduced epithelial-to-mesenchymal transition markers. These findings indicate that hepcidin is markedly induced in the advanced stages of CRC and suggest that it could serve as a prognostic biomarker in CRC. [ABSTRACT FROM AUTHOR]

Simple Summary: The prevalence of colorectal cancer (CRC) and inflammatory bowel disease (IBD) is increasing worldwide. Understanding what factors foster these diseases' development can help reduce their burden. Viral infections have been suggested to be involved in the genesis of these diseases, but the data is contradictory. The present study analyzed 11,413 articles on the topic and identified 196 that could provide information on the relationship between a viral infection and these gastrointestinal diseases. The Epstein–Barr virus (EBV, HHV-4) was strongly associated with IBD, and cytomegalovirus (HHV-5) with both CRC and IBD. Gastrointestinal diseases (GDs) include colorectal cancer (CRC), gastric cancer (GC), and inflammatory bowel disease (IBD). CRC and GC are typically diagnosed at later stages of development, reducing patients' chances of survival. IBD is characterized by chronic intestinal inflammation and is a significant risk factor for the development of CRC. Chronic bacterial infections have been shown to promote some GDs, but the role of viruses in the etiology of these diseases is less clear. The present meta-analysis retrieved literature on the viral prevalence in GD patients, measuring the GD risk in odd ratios. By quantifying the study heterogeneity, the literature bias was fundamentally included in the analysis. The analysis also included 11 metagenomic studies. Our meta-analysis retrieved 11,413 studies, with 196 suitable for analysis. HHV-4 (Epstein–Barr virus) was identified as a significant risk factor for the development of IBD, and HHV-5 (cytomegalovirus) as a risk factor for both CRC and IBD. Polyomaviruses and the Hepatitis B virus were also, less strongly, involved in the risk of CRC and IBD. No relations withstanding the literature bias were identified for GC. The study discusses these findings, as well as the role of other viruses in the etiology of CRC and IBD. [ABSTRACT FROM AUTHOR]

Simple Summary: Diffuse intrinsic pontine glioma (DIPG) is a neuro-radiologically defined tumor of the brainstem, primarily affecting children, with most diagnoses occurring between 5 and 7 years of age. Surgical removal in DIPGs is not feasible. Subsequent tumor progression is almost universal and no biomarker for predicting the course of the disease has entered into clinical practice so far. Under these premises, it is essential to develop reliable biomarkers that are able to improve outcomes and stratify patients using non-invasive methods to determine tumor profiles. We designed a study assessing circulating miRNA expression by a high-throughput platform and divided patients into training and validation phases in order to disclose a potential signature with clinical impact. Our results for the first time have proved the usefulness of blood-circulating nucleic acids as powerful, easy-to-assay molecular markers of disease status in DIPG. Diffuse midline gliomas (DMGs) originate in the thalamus, brainstem, cerebellum and spine. This entity includes tumors that infiltrate the pons, called diffuse intrinsic pontine gliomas (DIPGs), with a rapid onset and devastating neurological symptoms. Since surgical removal in DIPGs is not feasible, the purpose of this study was to profile circulating miRNA expression in DIPG patients in an effort to identify a non-invasive prognostic signature with clinical impact. Using a high-throughput platform, miRNA expression was profiled in serum samples collected at the time of MRI diagnosis and prior to radiation and/or systemic therapy from 47 patients enrolled in clinical studies, combining nimotuzumab and vinorelbine with concomitant radiation. With progression-free survival as the primary endpoint, a semi-supervised learning approach was used to identify a signature that was also tested taking overall survival as the clinical endpoint. A signature comprising 13 circulating miRNAs was identified in the training set (n = 23) as being able to stratify patients by risk of disease progression (log-rank p = 0.00014; HR = 7.99, 95% CI 2.38–26.87). When challenged in a separate validation set (n = 24), it confirmed its ability to predict progression (log-rank p = 0.00026; HR = 5.51, 95% CI 2.03–14.9). The value of our signature was also confirmed when overall survival was considered (log-rank p = 0.0021, HR = 4.12, 95% CI 1.57–10.8). We have identified and validated a prognostic marker based on the expression of 13 circulating miRNAs that can shed light on a patient's risk of progression. This is the first demonstration of the usefulness of nucleic acids circulating in the blood as powerful, easy-to-assay molecular markers of disease status in DIPG. This study provides Class II evidence that a signature based on 13 circulating miRNAs is associated with the risk of disease progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the most commonly diagnosed cancer in American women, and metastasis accounts for the majority of breast cancer-related deaths. The common metastatic sites for breast cancer includes the bones, lungs, brain, and liver. Breast cancer brain metastasis (BCBM) patients have dismal prognoses, primarily due to the lack of understanding of the molecular mechanisms driving breast cancer cell colonization to the brain. In breast cancer, truncated glioma-associated oncogene homolog 1, tGLI1, promotes preferential metastasis to the brain through the upregulation of the cancer stem cell subpopulation and the activation of astrocytes. Whether tGLI1 is an actionable therapeutic target for any cancer type has not yet been investigated. Herein, we identified an FDA-approved antifungal, ketoconazole (KCZ), and its novel derivative, KCZ-7, to antagonize tGLI1 transcriptional activity, suppress cancer stem cells, and inhibit BCBM, rendering tGLI1, for the first time, as an actionable therapeutic target for the prevention and treatment of BCBM. The goal of this study is to identify pharmacological inhibitors that target a recently identified novel mediator of breast cancer brain metastasis (BCBM), truncated glioma-associated oncogene homolog 1 (tGLI1). Inhibitors of tGLI1 are not yet available. To identify compounds that selectively kill tGLI1-expressing breast cancer, we screened 1527 compounds using two sets of isogenic breast cancer and brain-tropic breast cancer cell lines engineered to stably express the control, GLI1, or tGLI1 vector, and identified the FDA-approved antifungal ketoconazole (KCZ) to selectively target tGLI1-positive breast cancer cells and breast cancer stem cells, but not tGLI1-negative breast cancer and normal cells. KCZ's effects are dependent on tGLI1. Two experimental mouse metastasis studies have demonstrated that systemic KCZ administration prevented the preferential brain metastasis of tGLI1-positive breast cancer and suppressed the progression of established tGLI1-positive BCBM without liver toxicities. We further developed six KCZ derivatives, two of which (KCZ-5 and KCZ-7) retained tGLI1-selectivity in vitro. KCZ-7 exhibited higher blood–brain barrier penetration than KCZ/KCZ-5 and more effectively reduced the BCBM frequency. In contrast, itraconazole, another FDA-approved antifungal, failed to suppress BCBM. The mechanistic studies suggest that KCZ and KCZ-7 inhibit tGLI1's ability to bind to DNA, activate its target stemness genes Nanog and OCT4, and promote tumor proliferation and angiogenesis. Our study establishes the rationale for using KCZ and KCZ-7 for treating and preventing BCBM and identifies their mechanism of action. [ABSTRACT FROM AUTHOR]

Simple Summary: Multi-parametric magnetic resonance imaging (mpMRI) is regarded as an essential tool for identifying prostate cancer (PCa) in suspected cases. However, unnecessary biopsies continue to be performed in real clinics, especially for prostate imaging reporting and data system version 2 (PI-RADS v2) score-3 lesions, corresponding to the "gray zone". To aid the diagnosis of PCa, as well as of clinically significant PCa (csPCa), in patients with PI-RADSv2 score-3 lesions, we evaluated the clinical utility of the prostate health index (PHI). When a biopsy was restricted to those patients with PI-RADSv2 score-3 lesions and a PHI of ≥30, 34.4% of unnecessary biopsies could be avoided at the cost of missing 8.3% of overall PCa cases. However, there were no cases of missed csPCa diagnosis. The combination of PHI and PI-RADSv2 score-3 lesions offered higher accuracy in the diagnosis of PCa as well as of csPCa. The risk of prostate cancer (PCa) in prostate imaging reporting and data system version 2 (PI-RADSv2) score-3 lesions is equivocal; it is regarded as an intermediate status of presented PCa. In this study, we evaluated the clinical utility of the prostate health index (PHI) for the diagnosis of PCa and clinically significant PCa (csPCa) in patients with PI-RADSv2 score-3 lesions. The study cohort included patients who underwent a transrectal ultrasound (TRUS)-guided, cognitive-targeted biopsy for PI-RADSv2 score-3 lesions between November 2018 and April 2021. Before prostate biopsy, the prostate-specific antigen (PSA) derivatives, such as total PSA (tPSA), [-2] proPSA (p2PSA) and free PSA (fPSA) were determined. The calculation equation of PHI is as follows: [(p2PSA/fPSA) × tPSA ½]. Using a receiver operating characteristic (ROC) curve analysis, the values of PSA derivatives measured by the area under the ROC curve (AUC) were compared. For this study, csPCa was defined as Gleason grade 2 or higher. Of the 392 patients with PI-RADSv2 score-3 lesions, PCa was confirmed in 121 (30.9%) patients, including 59 (15.1%) confirmed to have csPCa. Of all the PSA derivatives, PHI and PSA density (PSAD) showed better performance in predicting overall PCa and csPCa, compared with PSA (all p < 0.05). The AUC of the PHI for predicting overall PCa and csPCa were 0.807 (95% confidence interval (CI): 0.710–0.906, p = 0.001) and 0.819 (95% CI: 0.723–0.922, p < 0.001), respectively. By the threshold of 30, PHI was 91.7% sensitive and 46.1% specific for overall PCa, and was 100% sensitive for csPCa. Using 30 as a threshold for PHI, 34.4% of unnecessary biopsies could have been avoided, at the cost of 8.3% of overall PCa, but would include all csPCa. [ABSTRACT FROM AUTHOR]

Simple Summary: Head and neck cancer develops from premalignant lesions. The key issue is to recognize potentially harmful precursor lesions. Fluorescence in Situ Hybridization (FISH)-based detection of copy number variations (CNV) of chromosomes 1 and 7 can help to differentiate between low-risk and high-risk lesions. Dual-target FISH for chromosomes 1 and 7 in 87 glottic, laryngeal premalignancies was performed. Lesions were evaluated by (1) establishing the chromosome 7/1 ratio (CR-FISH), based on the absolute number of signals of both chromosomes in 100 nuclei, and (2) by the assessment of the percentage of aberrant nuclei, counted in a total of 100 (PAN-FISH). The latter approach combined with histopathological assessment was the best predictive model for progression. The defined evaluation criteria for FISH diagnostics and the proposed prognostic model may help in clinical decision making on treatment strategies in patients with laryngeal precursor lesions. Background: The definition of objective, clinically applicable evaluation criteria for FISH 1c/7c in laryngeal precursor lesions for the detection of chromosome instability (CI). Copy Number Variations (CNV) for chromosomes 1 and 7 reflect the general ploidy status of premalignant head and neck lesions and can therefore be used as a marker for CI. Methods: We performed dual-target FISH for chromosomes 1 and 7 centromeres on 4 µm formalin-fixed, paraffin-embedded tissue sections of 87 laryngeal premalignancies to detect CNVs. Thirty-five normal head and neck squamous cell samples were used as a control. First, the chromosome 7:1 ratio (CR) was evaluated per lesion. The normal range of CRs (≥0.84 ≤ 1.16) was based on the mean CR +/− 3 x SD found in the normal population. Second, the percentage of aberrant nuclei, harboring > 2 chromosomes of chromosome 1 and/or 7 (PAN), was established (cut-off value for abnormal PAN ≥ 10%). Results: PAN showed a stronger correlation with malignant progression than CR (resp. OR 5.6, p = 0.001 and OR 3.8, p = 0.009). PAN combined with histopathology resulted in a prognostic model with an area under the ROC curve (AUC) of 0.75 (s.e. 0.061, sensitivity 71%, specificity 70%). Conclusions: evaluation criteria for FISH 1c/7c based on PAN ≥ 10% provide the best prognostic information on the risk of malignant progression of premalignant laryngeal lesions as compared with criteria based on the CR. FISH 1c/7c detection can be applied in combination with histopathological assessment. [ABSTRACT FROM AUTHOR]

Simple Summary: The Hepatocellular Carcinoma (HCC) remains a major concern for the public health. The pandemic of metabolic syndrome in the Western societies and the considerable amounts of viral hepatitis in the underdeveloped countries keep fueling s the development of HCC. The hepatotropic viruses evade the NLRP3 inflammasome in order to sustain the chronicity of infection leading to cirrhosis while in the established tumors the activation of NLRP3 promotes several pro-tumorigenic effects. That leads to substantial economic burden for the societies and alternative therapeutic targets should be investigated. Reviewing past and more recent literature it can be deduced that the NLRP3 inflammasome could be an ideal therapeutic effects and it should be studied in more depth. The HCC constitutes one of the most frequent cancers, with a non-decreasing trend in disease mortality despite advances in systemic therapy and surgery. This trend is fueled by the rise of an obesity wave which is prominent the Western populations and has reshaped the etiologic landscape of HCC. Interest in the nucleotide-binding domain leucine-rich repeat containing (NLR) family member NLRP3 has recently been revived since it would appear that, by generating inflammasomes, it participates in several physiologic processes and its dysfunction leads to disease. The NLRP3 inflammasome has been studied in depth, and its influence in HCC pathogenesis has been extensively documented during the past quinquennial. Since inflammation comprises a major regulator of carcinogenesis, it is of paramount importance an attempt to evaluate the contribution of the NLRP3 inflammasome to the generation and management of HCC. The aim of this review was to examine the literature in order to determine the impact of the NLRP3 inflammasome on, and present a hypothesis about its input in, HCC. [ABSTRACT FROM AUTHOR]

Simple Summary: Aspirin and related drugs with anti-inflammatory effects have lung cancer prevention effects in laboratory studies and through their use in populations at risk for lung cancer. We studied aspirin plus zileuton compared to two placebo pills for 3 months in smokers. We studied genes associated with lung cancer, smoking, and lung disease. We used nasal swabs to collect nasal cells that were smoke exposed to look for changes in these genes. We found that most of the gene panels in the nasal cells related to smoking and lung cancer lung disease did not change in a favorable way, but we did see a favorable change in a gene panel representing abnormal squamous cells that may progress to lung cancer. We think this finding is of interest and can be studied further using deep lung biopsies to understand if this drug effect occurs where squamous cell lung cancer actually starts. The chemopreventive effect of aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) on lung cancer risk is supported by epidemiologic and preclinical studies. Zileuton, a 5-lipoxygenase inhibitor, has additive activity with NSAIDs against tobacco carcinogenesis in preclinical models. We hypothesized that cyclooxygenase plus 5-lipoxygenase inhibition would be more effective than a placebo in modulating the nasal epithelium gene signatures of tobacco exposure and lung cancer. We conducted a randomized, double-blinded study of low-dose aspirin plus zileuton vs. double placebo in current smokers to compare the modulating effects on nasal gene expression and arachidonic acid metabolism. In total, 63 participants took aspirin 81 mg daily plus zileuton (Zyflo CR) 600 mg BID or the placebo for 12 weeks. Nasal brushes from the baseline, end-of-intervention, and one-week post intervention were profiled via microarray. Aspirin plus zilueton had minimal effects on the modulation of the nasal or bronchial gene expression signatures of smoking, lung cancer, and COPD but favorably modulated a bronchial gene expression signature of squamous dysplasia. Aspirin plus zileuton suppressed urinary leukotriene but not prostaglandin E2, suggesting shunting through the cyclooxygenase pathway when combined with 5-lipoxygenase inhibition. Continued investigation of leukotriene inhibitors is needed to confirm these findings, understand the long-term effects on the airway epithelium, and identify the safest, optimally dosed agents. [ABSTRACT FROM AUTHOR]

Simple Summary: Magnetic resonance imaging (MRI)-associated prostate-specific antigen density (mPSAD) and MRI predictive models have been proposed for improving the selection of candidates for prostate biopsy among men with suspected prostate cancer (PCa). While the calculation of mPSAD only requires a simple division, the individual risk assessment of PCa using the available risk calculators is also a swift process. We aim to compare the clinical usefulness of mPSAD and an MRI predictive model that utilises the same predictors as the recently developed and externally validated Barcelona MRI predictive model (MRI-PMbdex). This study is a head-to-head comparison between mPSAD and MRI-PMbdex. The MRI-PMbdex was created from 2432 men with suspected PCa; this cohort comprised the development and external validation cohorts of the Barcelona MRI predictive model. Pre-biopsy 3-Tesla multiparametric MRI (mpMRI) and 2 to 4-core transrectal ultrasound (TRUS)-guided biopsies for suspicious lesions and/or 12-core TRUS systematic biopsies were scheduled. Clinically significant PCa (csPCa), defined as Gleason-based Grade Group 2 or higher, was detected in 934 men (38.4%). The area under the curve was 0.893 (95% confidence interval [CI]: 0.880–0.906) for MRI-PMbdex and 0.764 (95% CI: 0.774–0.783) for mPSAD, with p < 0.001. MRI-PMbdex showed net benefit over biopsy in all men when the probability of csPCa was greater than 2%, while mPSAD did the same when the probability of csPCa was greater than 18%. Thresholds of 13.5% for MRI-PMbdex and 0.628 ng/mL2 for mPSAD had 95% sensitivity for csPCa and presented 51.1% specificity for MRI-PMbdex and 19.6% specificity for mPSAD, with p < 0.001. MRI-PMbdex exhibited net benefit over mPSAD in men with prostate imaging report and data system (PI-RADS) <4, while neither exhibited any benefit in men with PI-RADS 5. Hence, we can conclude that MRI-PMbdex is more accurate than mPSAD for the proper selection of candidates for prostate biopsy among men with suspected PCa, with the exception of men with a PI-RAD S 5 score, for whom neither tool exhibited clinical guidance to determine the need for biopsy. [ABSTRACT FROM AUTHOR]

Simple Summary: Oral cavity is the most common site of head and neck cancer which is ranked as the eighth most common cancer worldwide. Oral cancer treatment is often associated with significant morbidity and is sometimes ineffective. These cancers, mainly due to tobacco and alcohol consumption, can develop from oral potentially malignant disorders, the most common of which is oral leukoplakia. Some of these oral potentially malignant disorders disappear, while others will transform to oral cancer. Patients may also develop cancer in the field of cancerization. Unfortunately, except for the surgical excision of lesions with dysplasia, there is no effective intervention to effectively prevent transformation or cancer development in the field of cancerization. Moreover, no standardized biomarker has been clearly identified as sufficient to predict malignant transformation. In this article, several experts discuss the main challenges in oral cancer prevention, in particular the need (i) to define new a new classification system integrating cellular and molecular features aiming (ii) at better identifying patients at high risk of malignant transformation, and (iii) at developing treatment strategies to prevent their malignant transformation of oral potentially malignant disorders. Oral potentially malignant disorders (OPMD) may precede oral squamous cell carcinoma (OSCC). Reported rates of malignant transformation of OPMD range from 3 to 50%. While some clinical, histological, and molecular factors have been associated with a high-risk OPMD, they are, to date, insufficiently accurate for treatment decision-making. Moreover, this range highlights differences in the clinical definition of OPMD, variation in follow-up periods, and molecular and biological heterogeneity of OPMD. Finally, while treatment of OPMD may improve outcome, standard therapy has been shown to be ineffective to prevent OSCC development in patients with OPMD. In this perspective paper, several experts discuss the main challenges in oral cancer prevention, in particular the need to (i) to define an OPMD classification system by integrating new pathological and molecular characteristics, aiming (ii) to better identify OPMD at high risk of malignant transformation, and (iii) to develop treatment strategies to eradicate OPMD or prevent malignant transformation. [ABSTRACT FROM AUTHOR]

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. 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 FROM AUTHOR]

Simple Summary: Incisional tissue biopsy is highly invasive, but it remains the current practice for oral cancer diagnosis through histopathological interpretation. To reduce biopsy invasiveness without compromising diagnosis, we pioneered a multigene RT-qPCR method for cancer detection using only a tiny 1 mm3 minimally invasive biopsy. Here we presented international multicohort validation of our second-generation method which involved new genes from matrix/stroma and immune regulations enabling sensitive, quantitative and precise oral cancer detection in otherwise ambiguous oral lesions. Background: Heterogeneity in oral potentially malignant disorder (OPMD) poses a problem for accurate prognosis that impacts on treatment strategy and patient outcome. A holistic assessment based on gene expression signatures from both the tumour cells and their microenvironment is necessary to provide a more precise prognostic assessment than just tumour cell signatures alone. Methods: We reformulated our previously established multigene qPCR test, quantitative Malignancy Index Diagnostic System (qMIDS) with new genes involved in matrix/stroma and immune modulation of the tumour microenvironment. An algorithm calculates and converts a panel of 16 gene mRNA expression levels into a qMIDS index to quantify risk of malignancy for each sample. Results: The new qMIDSV2 assay was validated in a UK oral squamous cell carcinoma (OSCC) cohort (n = 282) of margin and tumour core samples demonstrating significantly better diagnostic performance (AUC = 0.945) compared to previous qMIDSV1 (AUC = 0.759). Performance of qMIDSV2 were independently validated in Chinese (n = 35; AUC = 0.928) and Indian (n = 95; AUC = 0.932) OSCC cohorts. Further, 5-year retrospective analysis on an Indian dysplastic lesion cohort (n = 30) showed that qMIDSV2 was able to significantly differentiate between lesions without transformation and those with malignant transformation. Conclusions: This study validated a novel multi-gene qPCR test on a total of 535 tissue specimens from UK, China and India, demonstrating a rapid minimally invasive method that has a potential application for dysplasia risk stratification. Further study is required to establish if qMIDSV2 could be used to improve OPMD patient management, guide treatment strategy and reduce oral cancer burden. [ABSTRACT FROM AUTHOR]

Simple Summary: Defective DNA damage response (DDR) is a hallmark of cancer leading to genomic instability. Up to 15–20% of colorectal cancers carry alterations in DDR. However, the role of DDR alterations as a prognostic factor and as a therapeutic target must be elucidated. To date, disappointing results have been obtained in different clinical trials mainly due to poor molecular selection of patients. Several challenges must be overcome before these compounds may have an impact on colorectal cancer. For instance, although some preclinical evidence showed the vulnerability of a subset of CRCs to PARP inhibitors, no specific clinical or molecular biomarkers have been validated to select patients. Moreover, different DDR alterations may not equally confer platinum sensitivity in CRC patients. Further efforts are needed in both preclinical and clinical settings to exploit DDR alterations as therapeutic targets and to eventually discover PARP or other DDR inhibitors (e.g., Wee1) with clinical benefit on colorectal cancer patients. Major advances have been made in CRC treatment in recent years, especially in molecularly driven therapies and immunotherapy. Despite this, a large number of advanced colorectal cancer patients do not benefit from these treatments and their prognosis remains poor. The landscape of DNA damage response (DDR) alterations is emerging as a novel target for treatment in different cancer types. PARP inhibitors have been approved for the treatment of ovarian, breast, pancreatic, and prostate cancers carrying deleterious BRCA1/2 pathogenic variants or homologous recombination repair (HRR) deficiency (HRD). Recent research reported on the emerging role of HRD in CRC and showed that alterations in these genes, either germline or somatic, are carried by up to 15–20% of CRCs. However, the role of HRD is still widely unknown, and few data about their clinical impact are available, especially in CRC patients. In this review, we report preclinical and clinical data currently available on DDR inhibitors in CRC. We also emphasize the predictive role of DDR mutations in response to platinum-based chemotherapy and the potential clinical role of DDR inhibitors. More preclinical and clinical trials are required to better understand the impact of DDR alterations in CRC patients and the therapeutic opportunities with novel DDR inhibitors. [ABSTRACT FROM AUTHOR]

Simple Summary: Mutations of the PIK3CA gene are thought to contribute to the development of head and neck squamous cell carcinomas (HNSCC), especially those associated with human papillomavirus infection. Furthermore, these mutations may help identify patients who can benefit from specific targeted therapies. This study presents a systematic review of the PIK3CA mutations profile in HNSCC. The results are compared with a cohort of Portuguese patients to study the possible associations with HPV status and patient survival. The Portuguese cohort harboured PIK3CA mutations in 39% of patients, and there were no significant associations with the HPV status or with the OS. In this original case series, there was a statistically significant interaction effect between HPV status and PIK3CA mutation regarding disease-free survival. In HPV-positive patients, the PIK3CA wild-type is associated with a significant 4.64 times increase in the hazard of recurrence or death. Additional studies are needed to clarify the implications of PIK3CA mutations for patient prognosis. PIK3CA mutations are believed to contribute to the pathogenesis of human papillomavirus (HPV)-associated head and neck squamous cell carcinomas (HNSCC). This study aims to establish the frequency of PIK3CA mutations in a Portuguese HNSCC cohort and to determine their association with the HPV status and patient survival. A meta-analysis of scientific literature also revealed widely different mutation rates in cohorts from different world regions and a trend towards improved prognosis among patients with PIK3CA mutations. DNA samples were available from 95 patients diagnosed with HNSCC at the Portuguese Institute of Oncology in Lisbon between 2010 and 2019. HPV status was established based on viral DNA detected using real-time PCR. The evaluation of PIK3CA gene mutations was performed by real-time PCR for four mutations (H1047L; E542K, E545K, and E545D). Thirty-seven cases were found to harbour PIK3CA mutations (39%), with the E545D mutation (73%) more frequently detected. There were no significant associations between the mutational status and HPV status (74% WT and 68% MUT were HPV (+); p = 0.489) or overall survival (OS) (3-year OS: WT 54% and MUT 65%; p = 0.090). HPV status was the only factor significantly associated with both OS and disease-free survival (DFS), with HPV (+) patients having consistently better outcomes (3-year OS: HPV (+) 65% and HPV (−) 36%; p = 0.007; DFS HPV (+) 83% and HPV (−) 43%; p = 0.001). There was a statistically significant interaction effect between HPV status and PIK3CA mutation regarding DFS (Interaction test: p = 0.026). In HPV (+) patients, PIK3CA wild-type is associated with a significant 4.64 times increase in the hazard of recurrence or death (HR = 4.64; 95% CI 1.02–20.99; p = 0.047). Overall, PIK3CA gene mutations are present in a large number of patients and may help define patient subsets who can benefit from therapies targeting the PI3K pathway. The systematic assessment of PIK3CA gene mutations in HNSCC patients will require further methodological standardisation. [ABSTRACT FROM AUTHOR]

Simple Summary: Osteosarcomas are heterogeneous bone tumors with complex genetic and chromosomic alterations. The numerous patients with metastatic osteosarcoma have a very poor prognosis, and only those who can have full surgical resection of the primary tumor and of all the macro metastasis can survive. Despite the recent improvements in prediction and early detection of metastasis, big efforts are still required to understand the specific mechanisms of osteosarcoma metastatic progression, in order to reveal novel therapeutic targets. Metastases of osteosarcomas are heterogeneous. They may grow simultaneously with the primary tumor, during treatment or shortly after, or a long time after the end of the treatment. They occur mainly in lungs but also in bone and various soft tissues. They can have the same histology as the primary tumor or show a shift towards a different differentiation path. However, the metastatic capacities of osteosarcoma cells can be predicted by gene and microRNA signatures. Despite the identification of numerous metastasis-promoting/predicting factors, there is no efficient therapeutic strategy to reduce the number of patients developing a metastatic disease or to cure these metastatic patients, except surgery. Indeed, these patients are generally resistant to the classical chemo- and to immuno-therapy. Hence, the knowledge of specific mechanisms should be extended to reveal novel therapeutic approaches. Recent studies that used DNA and RNA sequencing technologies highlighted complex relations between primary and secondary tumors. The reported results also supported a hierarchical organization of the tumor cell clones, suggesting that cancer stem cells are involved. Because of their chemoresistance, their plasticity, and their ability to modulate the immune environment, the osteosarcoma stem cells could be important players in the metastatic process. [ABSTRACT FROM AUTHOR]

Simple Summary: Immune therapy is designed to stimulate tumoricidal effects in a variety of solid tumors including breast carcinomas. However, the emergence of resistant clones leads to treatment failure. Understanding the molecular, cellular, and microenvironmental aberrations is crucial to uncovering underlying mechanisms and developing advanced strategies for preventing or combating these resistant malignancies. This review will summarize research findings revealing various mechanisms employed to hijack innate and adaptive immune surveillance mechanisms, develop hypoxic and tumor promoting metabolism, and foster an immune tolerance microenvironment. In addition, it will highlight potential targets for therapeutic approaches. Breast cancer is the most common malignancy among females in western countries, where women have an overall lifetime risk of >10% for developing invasive breast carcinomas. It is not a single disease but is composed of distinct subtypes associated with different clinical outcomes and is highly heterogeneous in both the molecular and clinical aspects. Although tumor initiation is largely driven by acquired genetic alterations, recent data suggest microenvironment-mediated immune evasion may play an important role in neoplastic progression. Beyond surgical resection, radiation, and chemotherapy, additional therapeutic options include hormonal deactivation, targeted-signaling pathway treatment, DNA repair inhibition, and aberrant epigenetic reversion. Yet, the fatality rate of metastatic breast cancer remains unacceptably high, largely due to treatment resistance and metastases to brain, lung, or bone marrow where tumor bed penetration of therapeutic agents is limited. Recent studies indicate the development of immune-oncological therapy could potentially eradicate this devastating malignancy. Evidence suggests tumors express immunogenic neoantigens but the immunity towards these antigens is frequently muted. Established tumors exhibit immunological tolerance. This tolerance reflects a process of immune suppression elicited by the tumor, and it represents a critical obstacle towards successful antitumor immunotherapy. In general, immune evasive mechanisms adapted by breast cancer encompasses down-regulation of antigen presentations or recognition, lack of immune effector cells, obstruction of anti-tumor immune cell maturation, accumulation of immunosuppressive cells, production of inhibitory cytokines, chemokines or ligands/receptors, and up-regulation of immune checkpoint modulators. Together with altered metabolism and hypoxic conditions, they constitute a permissive tumor microenvironment. This article intends to discern representative incidents and to provide potential innovative therapeutic regimens to reinstate tumoricidal immunity. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast cancer is the second most common cancer in women worldwide. The risk of developing breast cancer depends on various mechanisms, such as age, heredity, reproductive factors, physical inactivity, and obesity. Obesity increases the risk of breast cancer and worsens outcomes for breast cancer patients. The rate of obesity is increasing worldwide, stressing the need for awareness of the association between obesity and breast cancer. In this review, we outline the biomarkers—including cellular and soluble factors—in the breast, associated with obesity, that affect the risk of breast cancer and breast cancer prognosis. Through these biomarkers, we aim to better identify patients with obesity with a higher risk of breast cancer and an inferior prognosis. Obesity is associated with an increased risk of breast cancer, which is the most common cancer in women worldwide (excluding non-melanoma skin cancer). Furthermore, breast cancer patients with obesity have an impaired prognosis. Adipose tissue is abundant in the breast. Therefore, breast cancer develops in an adipose-rich environment. During obesity, changes in the local environment in the breast occur which are associated with breast cancer. A shift towards a pro-inflammatory state is seen, resulting in altered levels of cytokines and immune cells. Levels of adipokines, such as leptin, adiponectin, and resistin, are changed. Aromatase activity rises, resulting in higher levels of potent estrogen in the breast. Lastly, remodeling of the extracellular matrix takes place. In this review, we address the current knowledge on the changes in the breast adipose tissue in obesity associated with breast cancer initiation and progression. We aim to identify obesity-associated biomarkers in the breast involved in the interplay between obesity and breast cancer. Hereby, we can improve identification of women with obesity with an increased risk of breast cancer and an impaired prognosis. Studies investigating mammary adipocytes and breast adipose tissue in women with obesity versus women without obesity are, however, sparse and further research is needed. [ABSTRACT FROM AUTHOR]

Simple Summary: Circulating tumour cells (CTCs) have the potential to serve as a rich source of information for cancer diagnostic and therapeutic decisions. To fully exploit this minimally invasive diagnostic resource requires techniques that aid in enriching heterogenous populations of CTCs and markers to efficiently characterise these cells as tumour derived. In the present study we eva-luated the microfluidic enrichment of CTCs and a multi-marker staining methodology for the identification of heterogeneous CTCs in ovarian cancer (OC) patients and evaluation of PD-L1 expression. We showed, for the first time, the existence of hybrid CTCs with an epithelial/mesenchymal phenotype and their association with PD-L1 in OC. Incorporation of this method in future clinical trials can help predict immunotherapy responsiveness in OC patients. Detection of ovarian cancer (OC) circulating tumour cells (CTCs) is primarily based on targeting epithelial markers, thus failing to detect mesenchymal tumour cells. More importantly, the immune checkpoint inhibitor marker PD-L1 has not been demonstrated on CTCs from OC patients. An antibody staining protocol was developed and tested using SKOV-3 and OVCA432 OC cell lines. We targeted epithelial (cytokeratin (CK) and EpCAM), mesenchymal (vimentin), and OC-specific (PAX8) markers for detection of CTCs, and CD45/16 and CD31 were used for the exclusion of white blood and vascular endothelial cells, respectively. PD-L1 was used for CTC characterisation. CTCs were enriched using the Parsortix™ system from 16 OC patients. Results revealed the presence of CTCs in 10 (63%) cases. CTCs were heterogeneous, with 113/157 (72%) cells positive for CK/EpCAM (epithelial marker), 58/157 (37%) positive for vimentin (mesenchymal marker), and 17/157 (11%) for both (hybrid). PAX8 was only found in 11/157 (7%) CTCs. In addition, 62/157 (39%) CTCs were positive for PD-L1. Positivity for PD-L1 was significantly associated with the hybrid phenotype when compared with the epithelial (p = 0.007) and mesenchymal (p = 0.0009) expressing CTCs. Characterisation of CTC phenotypes in relation to clinical outcomes is needed to provide insight into the role that epithelial to mesenchymal plasticity plays in OC and its relationship with PD-L1. [ABSTRACT FROM AUTHOR]

Simple Summary: Developing therapeutic resistance to monoclonal antibodies (mAbs) causes increasing failure in oral squamous cell carcinoma (OSCC) treatment. A clear understanding of the molecular basis for drug resistance will pave the way for OSCC management and a new effective therapeutic modality. This review elucidates the role played by EMT during the emergence of mAbs resistance and the configuration of the tumor microenvironment. The cancer cells that undergo the EMT process also cause significant energy substrate consumption which leads to a limited number and function of effective T-cells, eventually leading to immune evasion. This review firstly reveals the implicit crosstalk between the EMT, energy metabolism, and therapeutic resistance of mAbs. A focus on the rebalanced energy homeostasis in cancer cells and T-cells may provide a new perspective on the treatment of OSCC. Oral squamous cell carcinoma (OSCC) is a major type of cancer that accounts for over 90% of all oral cancer cases. Recently developed evidence-based therapeutic regimens for OSCC based on monoclonal antibodies (mAbs), such as cetuximab, pembrolizumab, and nivolumab, have attracted considerable attention worldwide due to their high specificity, low toxicity, and low rates of intolerance. However, the efficacy of those three mAbs remains poor because of the low rate of responders and acquired resistance within a short period of time. The epithelial–mesenchymal transition (EMT) process is fundamental for OSCC growth and metastasis and is also responsible for the poor response to mAbs. During EMT, cancer cells consume abundant energy substrates and create an immunosuppressive tumor microenvironment to support their growth and evade T cells. In this review, we provide an overview of the complex roles of major substrates and signaling pathways involved in the development of therapeutic resistance in OSCC. In addition, we summarize potential therapeutic strategies that may help overcome this resistance. This review aims to help oral oncologists and researchers aiming to manage OSCC and establish new treatment modalities. [ABSTRACT FROM AUTHOR]

Simple Summary: Expression of MERTK and/or AXL (members of the TAM family of receptor tyrosine kinases) provides a survival advantage for non-small cell lung cancer (NSCLC) cells and correlates with lymph node metastasis, drug resistance, and disease progression. TAM receptors on host tumor infiltrating cells also play important roles in the immunosuppressive tumor microenvironment. Thus, MERTK and AXL are attractive biologic targets for NSCLC treatment, and clinical trials have recently been launched exploring the efficacy of MERTK/AXL inhibitors in NSCLC. This timely review will address the potential clinical impact of these agents as well as potential side effects to be monitored with the use of these novel drugs. MERTK and AXL are members of the TAM family of receptor tyrosine kinases and are abnormally expressed in 69% and 93% of non-small cell lung cancers (NSCLCs), respectively. Expression of MERTK and/or AXL provides a survival advantage for NSCLC cells and correlates with lymph node metastasis, drug resistance, and disease progression in patients with NSCLC. The TAM receptors on host tumor infiltrating cells also play important roles in the immunosuppressive tumor microenvironment. Thus, MERTK and AXL are attractive biologic targets for NSCLC treatment. Here, we will review physiologic and oncologic roles for MERTK and AXL with an emphasis on the potential to target these kinases in NSCLCs with activating EGFR mutations. [ABSTRACT FROM AUTHOR]

Simple Summary: Squamous cell carcinomas affect different head and neck subsites and, although these tumors arise from the same epithelial lining and share risk factors, they differ in terms of clinical behavior and molecular carcinogenesis mechanisms. Differences between HPV-negative and HPV-positive tumors are those most frequently explored, but further data suggest that the molecular heterogeneity observed among head and neck subsites may go beyond HPV infection. In this review, we explore how alterations of DNA methylation and microRNA expression contribute to head and neck squamous cell carcinoma (HNSCC) development and progression. The association of these epigenetic alterations with risk factor exposure, early carcinogenesis steps, transformation risk, and prognosis are described. Finally, we discuss the potential application of the use of epigenetic biomarkers in HNSCC. Head and neck squamous cell carcinomas (HNSCC) are among the ten most frequent types of cancer worldwide and, despite all efforts, are still diagnosed at late stages and show poor overall survival. Furthermore, HNSCC patients often experience relapses and the development of second primary tumors, as a consequence of the field cancerization process. Therefore, a better comprehension of the molecular mechanisms involved in HNSCC development and progression may enable diagnosis anticipation and provide valuable tools for prediction of prognosis and response to therapy. However, the different biological behavior of these tumors depending on the affected anatomical site and risk factor exposure, as well as the high genetic heterogeneity observed in HNSCC are major obstacles in this pursue. In this context, epigenetic alterations have been shown to be common in HNSCC, to discriminate the tumor anatomical subsites, to be responsive to risk factor exposure, and show promising results in biomarker development. Based on this, this review brings together the current knowledge on alterations of DNA methylation and microRNA expression in HNSCC natural history, focusing on how they contribute to each step of the process and on their applicability as biomarkers of exposure, HNSCC development, progression, and response to therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: In the last decades, the widespread use of PSA as the standard tool for prostate cancer diagnosis led to a high rate of overdiagnosis and overtreatment. More recently, multiparametric magnetic resonance imaging (mpMRI) became part of the diagnostic pathway, and several next-generation PSA-based tests (PHI, PHI density, 4Kscore, STHLM3) have been proposed. The multivariable approach promises to help with a better stratification of PCa patients at initial diagnosis. In this study, we evaluated the performance of the prostate health index (PHI) and mpMRI for the prediction of positive biopsy and of high-grade PCa at radical prostatectomy (RP). Our findings suggested that PHI had a better ability than mpMRI to predict positive biopsy, whereas a comparable performance in the identification of pathological aggressive PCa was pointed out. Notably, PHI and PHI density might represent useful biomarkers to recognize high-grade PCa in patients with low or uncertain PI-RADS scores on mpMRI. Widespread use of PSA as the standard tool for prostate cancer (PCa) diagnosis led to a high rate of overdiagnosis and overtreatment. In this study, we evaluated the performance of the prostate health index (PHI) and multiparametric magnetic resonance imaging (mpMRI) for the prediction of positive biopsy and of high-grade PCa at radical prostatectomy (RP). To this end, we prospectively enrolled 196 biopsy-naïve patients who underwent mpMRI. A subgroup of 116 subjects with biopsy-proven PCa underwent surgery. We found that PHI significantly outperformed both PI-RADS score (difference in AUC: 0.14; p < 0.001) and PHI density (difference in AUC: 0.08; p = 0.002) in the ability to predict positive biopsy with a cut-off value of 42.7 as the best threshold. Conversely, comparing the performance in the identification of clinically significant prostate cancer (csPCa) at RP, we found that PHI ≥ 61.68 and PI-RADS score ≥ 4 were able to identify csPCa (Gleason score ≥ 7 (3 + 4)) both alone and added to a base model including age, PSA, fPSA-to-tPSA ratio and prostate volume. In conclusion, PHI had a better ability than PI-RADS score to predict positive biopsy, whereas it had a comparable performance in the identification of pathological csPCa. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite being effective initially, almost all patients eventually develop resistance to EGFR-tyrosine kinase inhibitors (TKI). Changes in the histology of the tumor have been increasingly recognized as a critical mechanism of resistance to EGFR-directed therapies. This article summarizes histologic changes known to impart resistance to EGFR TKIs and discusses novel pathways to develop effective novel therapies. With the advent of potent EGFR tyrosine kinase inhibitors (TKIs), the treatment landscape of EGFR-mutant lung adenocarcinomas has changed drastically in recent years. However, the development of resistance to EGFR TKIs remains a critical barrier to improving survival in these patients. Histologic transformations to small cell lung carcinoma, large cell neuroendocrine carcinoma, squamous cell carcinoma, and the sarcomatoid phenotype have been increasingly recognized as important mechanisms of resistance. In this article, we summarize the known biological bases for such phenotypic switches in regard to EGFR TKIs and describe novel pathways that might be harnessed to develop effective novel therapies for patients with EGFR-mutant non-small cell lung cancers. [ABSTRACT FROM AUTHOR]

Simple Summary: Interleukin-33 (IL-33) is often released from damaged cells, acting as a danger signal. IL-33 exerts its function by interacting with its receptor suppression of tumorigenicity 2 (ST2) that is constitutively expressed on most immune cells. Therefore, IL-33/ST2 signaling can modulate immune responses to participate actively in a variety of pathological conditions, such as cancer. Like a two-faced Janus, which faces opposite directions, IL-33/ST2 signaling may play contradictory roles on its impact on cancer progression through both immune and nonimmune cellular components. Accumulating evidence demonstrates both pro- and anti-tumorigenic properties of IL-33, depending on the complex nature of different tumor immune microenvironments. We summarize and discuss the most recent studies on the contradictory effects of IL-33 on cancer progression and treatment, with a goal to better understanding the various ways for IL-33 as a therapeutic target. Interleukin-33 (IL-33), a member of the IL-1 cytokine family, plays a critical role in maintaining tissue homeostasis as well as pathological conditions, such as allergy, infectious disease, and cancer, by promoting type 1 and 2 immune responses. Through its specific receptor ST2, IL-33 exerts multifaceted functions through the activation of diverse intracellular signaling pathways. ST2 is expressed in different types of immune cells, including Th2 cells, Th1 cells, CD8+ T cells, regulatory T cells (Treg), cytotoxic NK cells, group 2 innate lymphoid cells (ILC2s), and myeloid cells. During cancer initiation and progression, the aberrant regulation of the IL-33/ST2 axis in the tumor microenvironment (TME) extrinsically and intrinsically mediates immune editing via modulation of both innate and adaptive immune cell components. The summarized results in this review suggest that IL-33 exerts dual-functioning, pro- as well as anti-tumorigenic effects depending on the tumor type, expression levels, cellular context, and cytokine milieu. A better understanding of the distinct roles of IL-33 in epithelial, stromal, and immune cell compartments will benefit the development of a targeting strategy for this IL-33/ST2 axis for cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Simple Summary: Small-cell lung cancer carries a dismal prognosis with few long-term treatment options. The enzyme poly-(ADP)-ribose polymerase (PARP), which functions to repair DNA breaks, has emerged as a promising therapeutic target, with modest response rates in early clinical trials prompting investigation of predictive biomarkers and therapeutic combinations. This review summarizes the development and testing of PARP inhibitors in small-cell lung cancer with an emphasis on developing treatment combinations. These combinations can be divided into three categories: (1) contributing to DNA damage; (2) inhibiting the DNA damage response; and (3) activating the immune system. An evolving classification of small-cell lung cancer subtypes and gene expression patterns will guide PARP inhibitor biomarker identification to improve treatments for this challenging cancer. Despite recent advances in first-line treatment for small-cell lung cancer (SCLC), durable responses remain rare. The DNA repair enzyme poly-(ADP)-ribose polymerase (PARP) was identified as a therapeutic target in SCLC using unbiased preclinical screens and confirmed in human and mouse models. Early trials of PARP inhibitors, either alone or in combination with chemotherapy, showed promising but limited responses, suggesting that selecting patient subsets and treatment combinations will prove critical to further clinical development. Expression of SLFN11 and other components of the DNA damage response (DDR) pathway appears to select for improved responses. Combining PARP inhibitors with agents that damage DNA and inhibit DDR appears particularly effective in preclinical and early trial data, as well as strategies that enhance antitumor immunity downstream of DNA damage. A robust understanding of the mechanisms of DDR in SCLC, which exhibits intrinsic replication stress, will improve selection of agents and predictive biomarkers. The most effective combinations will target multiple nodes in the DNA damage/DDR/immune activation cascade to minimize toxicity from synthetic lethality. [ABSTRACT FROM AUTHOR]

Simple Summary: Proton radiation therapy is a more recent type of radiotherapy that uses proton beams instead of classical photon or X-rays beams. The clinical benefit of proton therapy is that it allows to treat tumors more precisely. As a result, proton radiotherapy induces less toxicity to healthy tissue near the tumor site. Despite the experience in the clinical use of protons, the response of cells to proton radiation, the radiobiology, is less understood. In this review, we describe the current knowledge about proton radiobiology. Clinical use of proton radiation has massively increased over the past years. The main reason for this is the beneficial depth-dose distribution of protons that allows to reduce toxicity to normal tissues surrounding the tumor. Despite the experience in the clinical use of protons, the radiobiology after proton irradiation compared to photon irradiation remains to be completely elucidated. Proton radiation may lead to differential damages and activation of biological processes. Here, we will review the current knowledge of proton radiobiology in terms of induction of reactive oxygen species, hypoxia, DNA damage response, as well as cell death after proton irradiation and radioresistance. [ABSTRACT FROM AUTHOR]