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Simple Summary: CAR T cell therapies have been successful at treating patients with blood cancers and are now FDA-approved therapies for various types of leukemias and lymphomas. However, there are many challenges to using CAR T cells to treat patients with solid tumors. In fact, no CAR T cell product is currently FDA-approved in this context. Optimism remains for this promising therapy to treat solid tumors in the future. Many different strategies are being employed to improve the efficacy of next-generation T cell products. This review focuses specifically on one key problem with current CAR T cell products for solid tumors: persistence. We describe the emerging strategies being used to improve this element of CAR T cell therapy. CAR T cells require optimization to be effective in patients with solid tumors. There are many barriers affecting their ability to succeed. One barrier is persistence, as to achieve an optimal antitumor response, infused CAR T cells must engraft and persist. This singular variable is impacted by a multitude of factors—the CAR T cell design, lymphodepletion regimen used, expansion method to generate the T cell product, and more. Additionally, external agents can be utilized to augment CAR T cells, such as the addition of novel cytokines, pharmaceutical drugs that bolster memory formation, or other agents during either the ex vivo expansion process or after CAR T cell infusion to support them in the oppressive tumor microenvironment. This review highlights many strategies being used to optimize T cell persistence as well as future directions for improving the persistence of infused cells. [ABSTRACT FROM AUTHOR]

Simple Summary: This research is suggested to address the significant psychological distress that cancer patients often experience during diagnosis and treatment, which can adversely affect their outcomes and care. Despite advancements in cancer treatments extending survival rates, the emergence of depression and anxiety as common comorbidities underscores the need for targeted interventions to improve patient well-being. The study aims to investigate the prevalence of depression and anxiety among cancer patients and identify some of the associated risk factors. Advancements in cancer treatment and early detection have extended survival rates, transforming many cancers into chronic conditions. However, cancer diagnosis and treatment can trigger significant psychological distress, including depression and anxiety, impacting patient outcomes and care. This study aimed to examine the prevalence of and identify the risk factors for depression and anxiety among cancer patients. A cross-sectional study was conducted, including patients under the care of the oncology department at a tertiary medical center between June 2021 and October 2023. Depression and anxiety were assessed using the Patient-Reported Outcomes Measurement Information System (PROMIS) short forms. Logistic regression analysis identified risk factors for depression and anxiety. The study population included 159 patients, with 40.3% reporting worsening mental health, but only about half of them received therapy. Among the study participants, 22.6% experienced symptoms of depression and 30.2% experienced symptoms of anxiety. Single-cancer patients and those with metastases were at increased risk for depression, while those with a disease duration of more than a year and patients with female-specific cancer were more likely to experience anxiety. Given the high prevalence of mental health deterioration in cancer patients, closer monitoring and validated assessment tools are essential to improve depression and anxiety diagnosis and facilitate early interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: Diabetes and cancer are major global health problems that cause significant illness and death. Many cancer patients also have diabetes, which complicates their treatment, especially if surgery is needed. This review highlights the link between diabetes and cancer. It looks into how cancer treatments can worsen blood sugar control, examines the risks that surgery holds for patients with both conditions, and outlines the strategies that can be used to manage diabetes around the time of surgery. More research is needed to provide new strategies that can reduce complications following surgery in patients with diabetes and cancer. Background: Both diabetes and cancer are major global health issues that are among the leading causes of morbidity and mortality. There is a high prevalence of diabetes among cancer patients, many of whom require a surgical procedure. This review focuses on the operative complications in patients with diabetes and cancer, and the perioperative management of diabetes in cancer patients. Methodology: A literature search of articles in English—published between January 2010 and May 2024—was carried out using the databases PubMed, MEDLINE, Google Scholar, and the Cochrane Database of Systematic Reviews. The search primarily focused on the operative complications in patients with diabetes and cancer, and perioperative management strategies. Results: The relationship between cancer and diabetes is complex; cancer patients have a high risk of developing diabetes, while diabetes is a risk factor for certain cancers. In addition, various cancer therapies can induce or worsen diabetes in susceptible patients. Many individuals with cancer and diabetes require surgery, and due to underlying diabetes, they may have elevated risks for operative complications. Optimal perioperative management for these patients includes managing perioperative glycemia and other comorbid illnesses, adjusting diabetic and cancer treatments, optimizing nutrition, minimizing the duration of fasting, supporting early mobilization, and providing patient education to enable self-management. Conclusions: While evidence is limited, optimal perioperative management for patients with both diabetes and cancer is necessary in order to reduce surgical complications. Future studies are needed to develop evidence-informed perioperative strategies and improve outcomes for these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Elderly cancer patients represent a population particularly susceptible to nutritional alterations, which can have an impact on overall survival and chemotherapy tolerance. The effects of nutritional interventions in this frail population have not been adequately examined in previous review studies. We conducted a systematic review of the existing literature on the effects of oral nutritional supplements (ONSs) and dietary counseling during chemotherapy in older oncology patients. Various types of ONS were investigated, including multimodal intervention with tailored nutritional counseling, whey protein supplements, amino acids supplements (including immune nutrition supplements), and fish oil omega-3-enriched supplements. ONSs showed promise in reducing chemotherapy side-effects and improving nutritional status in older cancer patients, but further studies are needed to explore their efficacy on chemotherapy adherence and overall survival. Further studies are needed to investigate the effects of ONS considering chronological age and frailty criteria, different dietary habits, and specific nutritional assessment like Bioelectrical Impedance Analysis. This study aims to review existing literature on the effect of oral nutritional supplements (ONSs) during chemotherapy in older cancer patients. Electronic databases were searched for relevant studies up to March 2024. The risk of bias in the included studies was evaluated using the Cochrane tool. Eligible studies included randomized, prospective, and retrospective studies evaluating the effect of ONSs in elderly (median age > 65 years) cancer patients during chemotherapy. Data regarding chemotherapy adherence, toxicity, overall survival, and nutritional status were extracted. A total of ten studies, involving 1123 patients, were included. A meta-analysis of the results was not conducted due to the scarcity and heterogeneity of results. Some ONSs were associated with reduced incidence of chemotherapy side-effects, particularly oral mucositis, and improved nutritional status. There was limited or no evidence regarding the impact of ONSs on chemotherapy adherence or overall survival. Various types of ONS were investigated, including multimodal intervention with tailored nutritional counseling, whey protein supplements, amino acids supplements (including immune nutrition supplements), and fish oil omega-3-enriched supplements. ONSs showed promise in reducing chemotherapy side-effects and improving nutritional status in older cancer patients, but further studies are needed to explore their efficacy on chemotherapy adherence and overall survival. Future research should consider both chronological age and frailty criteria, account for dietary habits, and use specific nutritional assessment like Bioelectrical Impedance Analysis. [ABSTRACT FROM AUTHOR]

Simple Summary: Cutaneous squamous cell carcinoma and basal cell carcinoma are the most common cancers worldwide and surgical excision is the first-line treatment. Brachytherapy, which delivers a high dose of radiation to tumor tissue while sparing healthy tissue, represents a curative and conservative alternative in certain situations, particularly in elderly patients. Since the withdrawal of iridium wires from the market, brachytherapy has mainly been performed with high-dose-rate iridium-192 (HDR). Few studies and recommendations exist on HDR brachytherapy. Our study aims to evaluate the efficacy of HDR brachytherapy in terms of local control, survival, toxicity, and quality of life in patients with facial periorificial cutaneous squamous cell carcinoma or basal cell carcinoma treated in our center between 2015 and 2021. While treatment of localized cutaneous squamous cell carcinoma (SCC) and basal cell carcinoma (BCC) is based on surgery, brachytherapy, which delivers a high dose of radiation to tumor tissue while sparing healthy tissue, is an alternative. Since the withdrawal of iridium wires from the market, brachytherapy has mainly been performed with high-dose-rate iridium-192 (HDR). This study evaluated the efficacy of HDR brachytherapy in terms of local control, survival, toxicity, and quality of life in patients with facial periorificial cutaneous SCC or BCC treated in our center between 2015 and 2021. Sixty-seven patients were treated for SCC (n = 49) or BCC (n = 18), on the nose (n = 29), lip (n = 28), eyelid (n = 7), or ear (n = 3). The majority had Tis or T1 tumors (73.1%). After a median follow-up of 28 months, 8 patients had a local recurrence. The local control rate at 3 years was 87.05% (95% CI 74.6–93.7). All patients developed grade 1–2 acute radio-mucositis or radiodermatitis and one experienced reversible grade 3 acute radio-mucositis. Of the 27 patients who completed the quality-of-life questionnaire, 77.8% recommended the treatment. This study confirms that HDR brachytherapy for facial cutaneous carcinomas provides good local control, good tolerance, and satisfactory functional outcome. [ABSTRACT FROM AUTHOR]

Simple Summary: Individualized medicine means understanding how each tumor is different from normal cells and how each tumor is different from other tumors, including profiling mutations, non-mutational epigenetic changes, and differences in gene expression. This allows the discovery of key processes each tumor absolutely depends on for survival and growth, which are intrinsic weaknesses. This profiling means selecting treatments to specifically target each tumor's survival-dependent pathways, killing them. Tip60 is a master controller of processes that maintain genome stability and signaling regulating gene expression. While disrupted in many cancers, Tip60 is essential for cell survival, and inhibiting Tip60 kills tumors. While we understand some key aspects of the molecular roles Tip60 plays, much more remains to be discovered. A more complete understanding of the diverse roles and functions of Tip60 in cancer, and how targeting Tip60 kills cancer cells, will lead to better treatments for patients and increased survival. Precision (individualized) medicine relies on the molecular profiling of tumors' dysregulated characteristics (genomic, epigenetic, transcriptomic) to identify the reliance on key pathways (including genome stability and epigenetic gene regulation) for viability or growth, and then utilises targeted therapeutics to disrupt these survival-dependent pathways. Non-mutational epigenetic changes alter cells' transcriptional profile and are a key feature found in many tumors. In contrast to genetic mutations, epigenetic changes are reversable, and restoring a normal epigenetic profile can inhibit tumor growth and progression. Lysine acetyltransferases (KATs or HATs) protect genome stability and integrity, and Tip60 is an essential acetyltransferase due to its roles as an epigenetic and transcriptional regulator, and as master regulator of the DNA double-strand break response. Tip60 is commonly downregulated and mislocalized in many cancers, and the roles that mislocalized Tip60 plays in cancer are not well understood. Here we categorize and discuss Tip60-regulated genes, evaluate Tip60-interacting proteins based on cellular localization, and explore the therapeutic potential of Tip60-targeting compounds as epigenetic inhibitors. Understanding the multiple roles Tip60 plays in tumorigenesis will improve our understanding of tumor progression and will inform therapeutic options, including informing potential combinatorial regimes with current chemotherapeutics, leading to improvements in patient outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: With advanced bioinformatic and sequencing technologies, many non-coding RNAs have been found to harbor non-canonical open reading frames (ncORFs). Some studies suggest that many ncORF-encoded microproteins or micropeptides possess important roles in cancer biology, yet the functional roles of these ncORF-encoded peptides are mostly unknown. The purpose of this review is to provide a comprehensive overview of existing knowledge on ncORF-encoded microproteins in cancer biology and highlight their roles as potential prognostic and therapeutic targets in cancer. Cancer develops from abnormal cell growth in the body, causing significant mortalities every year. To date, potent therapeutic approaches have been developed to eradicate tumor cells, but intolerable toxicity and drug resistance can occur in treated patients, limiting the efficiency of existing treatment strategies. Therefore, searching for novel genes critical for cancer progression and therapeutic response is urgently needed for successful cancer therapy. Recent advances in bioinformatics and proteomic techniques have allowed the identification of a novel category of peptides encoded by non-canonical open reading frames (ncORFs) from historically non-coding genomic regions. Surprisingly, many ncORFs express functional microproteins that play a vital role in human cancers. In this review, we provide a comprehensive description of different ncORF types with coding capacity and technological methods in discovering ncORFs among human genomes. We also summarize the carcinogenic role of ncORFs such as pTINCR and HOXB-AS3 in regulating hallmarks of cancer, as well as the roles of ncORFs such as HOXB-AS3 and CIP2A-BP in cancer diagnosis and prognosis. We also discuss how ncORFs such as AKT-174aa and DDUP are involved in anti-cancer drug response and the underestimated potential of ncORFs as therapeutic targets. [ABSTRACT FROM AUTHOR]

Simple Summary: Immunotherapy has been introduced as a standard of care for several cancers, and its use is on the rise. However, the enhanced immune system frequently causes immune-related adverse events. Depending on the affected organ and tissue and the severity of the toxicity, immunotherapy is generally held, and steroids or immunosuppressive agents are introduced, impacting cancer treatment. Therefore, prompt identification of toxicity at an early stage and multidisciplinary management are mandatory. Since imaging is crucial to guide clinicians in managing immune-related adverse events, this imaging-based review presents the most frequent complications identifiable on imaging. Clues for identification and the most important differential diagnoses are discussed to enhance knowledge among imaging specialists and clinicians regarding these complications. Immunotherapy has revolutionized oncology care, improving patient outcomes in several cancers. However, these therapies are also associated with typical immune-related adverse events due to the enhanced inflammatory and immune response. These toxicities can arise at any time during treatment but are more frequent within the first few months. Any organ and tissue can be affected, ranging from mild to life-threatening. While some manifestations are common and more often mild, such as dermatitis and colitis, others are rarer and more severe, such as myocarditis. Management depends on the severity, with treatment being held for >grade 2 toxicities. Steroids are used in more severe cases, and immunosuppressive treatment may be considered for non-responsive toxicities, along with specific organ support. A multidisciplinary approach is mandatory for prompt identification and management. The diagnosis is primarily of exclusion. It often relies on imaging features, and, when possible, cytologic and/or pathological analyses are performed for confirmation. In case of clinical suspicion, imaging is required to assess the presence, extent, and features of abnormalities and to evoke and rule out differential diagnoses. This imaging-based review illustrates the diverse system-specific toxicities associated with immune checkpoint inhibitors and chimeric antigen receptor T-cells with a multidisciplinary perspective. Clinical characteristics, imaging features, cytological and histological patterns, as well as the management approach, are presented with insights into radiological tips to distinguish these toxicities from the most important differential diagnoses and mimickers—including tumor progression, pseudoprogression, inflammation, and infection—to guide imaging and clinical specialists in the pathway of diagnosing immune-related adverse events. [ABSTRACT FROM AUTHOR]

Simple Summary: Image-guided solid tumor ablation therapy is an expanding practice designed to effectively target and eradicate malignant tissue through noninvasive or minimally invasive techniques. There exist several ablation systems that can utilize localized heating or mechanical stress to induce cell death of malignant cells. The provider selects a technique based on patient comorbidities, the type of malignancy, the size and location of the tumor, and the desired goal of therapy. Over the past two decades, several studies have validated the safety and efficacy of these techniques in humans to be used as an alternative to medical and surgical therapy or as an adjunct in a hybrid treatment plan. Compared to conventional surgical therapies, these procedures are better tolerated, with reduced morbidity and mortality, providing options to patients that are not surgical candidates. This article reviews the new and common techniques in solid tumor ablation and the research supporting their use in oncological treatment. Image-guided solid tumor ablation methods have significantly advanced in their capability to target primary and metastatic tumors. These techniques involve noninvasive or percutaneous insertion of applicators to induce thermal, electrochemical, or mechanical stress on malignant tissue to cause tissue destruction and apoptosis of the tumor margins. Ablation offers substantially lower risks compared to traditional methods. Benefits include shorter recovery periods, reduced bleeding, and greater preservation of organ parenchyma compared to surgical intervention. Due to the reduced morbidity and mortality, image-guided tumor ablation offers new opportunities for treatment in cancer patients who are not candidates for resection. Currently, image-guided ablation techniques are utilized for treating primary and metastatic tumors in various organs with both curative and palliative intent, including the liver, pancreas, kidneys, thyroid, parathyroid, prostate, lung, breast, bone, and soft tissue. The invention of new equipment and techniques is expanding the criteria of eligible patients for therapy, as now larger and more high-risk tumors near critical structures can be ablated. This article provides an overview of the different imaging modalities, noninvasive, and percutaneous ablation techniques available and discusses their applications and associated complications across various organs. [ABSTRACT FROM AUTHOR]

Simple Summary: Near-infrared photoimmunotherapy (NIR-PIT) is a recently developed cancer therapy that uses NIR light and conjugates of a tumor-targeting monoclonal antibody and phthalocyanine dye. In clinical practice, frontal and cylindrical diffusers are used for NIR illumination. However, the light illumination of a narrow space is technically difficult with such diffusers. Therefore, we evaluated the usefulness of a lateral illumination system using lateral emitting laser (LEL) fiber. The LEL fiber was capable of illuminating only a certain area in a lateral direction. NIR-PIT with an LEL fiber showed cytotoxic effects in vitro and suppressed tumor proliferation in vivo. Moreover, the LEL fiber delivered NIR light to an entire tumor more uniformly than a frontal diffuser in a narrow-space model. These results suggest that the LEL fiber can be used for NIR-PIT and is suitable for NIR light illumination in a narrow space. Near-infrared photoimmunotherapy (NIR-PIT) is a new cancer therapy that uses NIR light and conjugates of a tumor-targeting monoclonal antibody and phthalocyanine dye. In clinical practice, frontal and cylindrical diffusers are the only options for NIR illumination. However, illumination in a narrow space is technically difficult with such diffusers. Therefore, we evaluated a lateral illumination system using a lateral emitting laser (LEL) fiber. The LEL fiber illuminated a certain area in a lateral direction. NIR-PIT with an LEL fiber reduced luciferase activity in a light-dose-dependent manner in A431-GFP-luc cells in vitro and significantly suppressed tumor proliferation in a xenograft mouse model. To evaluate the usefulness of the LEL fiber in the illumination of a narrow space, a tumor was illuminated from the inside of a cylinder, mimicking a narrow space, and the fluorescence intensity in the tumor was monitored. In the frontal diffuser, NIR light was unevenly delivered and little light reached a distal tumor area from the illuminated side. By contrast, the LEL fiber allowed a uniform illumination of the entire tumor, and a loss of fluorescence was observed even in distal areas. These findings suggested that the LEL fiber can be used for NIR-PIT and is suitable for NIR light illumination in a narrow space. [ABSTRACT FROM AUTHOR]

Simple Summary: B7H4 emerges as a promising therapeutic target exhibiting negative costimulatory activity and whose expression is aberrant in a wide range of solid tumours. This molecule has obtained increased attention as the immune checkpoint is highly expressed in immune "cold" tumours in which the presence of PD-1 and PD-L1- is minimal, making these tumours unresponsive to most currently used immunotherapies. Deficient expression of B7H4 in normal tissue and its overexpression in malignant neoplasms makes B7H4 an attractive immunotherapy agent with potentially lower toxicity than anti-PD-1 and PD-L1 treatment. Numerous clinical trials have evaluated B7H4 targeting immunotherapy using various treatment modalities, including monoclonal antibodies, bispecific antibodies, antibody-drug conjugates, and CAR T cells. In this review, we aimed to update the current state of knowledge regarding B7H4's role in tumour promotion and immune evasion and summarise results from clinical trials assessing immunotherapies targeting B7H4 in solid tumours. Anti-cancer immunotherapies entirely changed the therapeutic approach to oncological patients. However, despite the undeniable success of anti-PD-1, PD-L1, and CTLA-4 antibody treatments, their effectiveness is limited either by certain types of malignancies or by the arising problem of cancer resistance. B7H4 (aliases B7x, B7H4, B7S1, VTCN1) is a member of a B7 immune checkpoint family with a distinct expression pattern from classical immune checkpoint pathways. The growing amount of research results seem to support the thesis that B7H4 might be a very potent therapeutic target. B7H4 was demonstrated to promote tumour progression in immune "cold" tumours by promoting migration, proliferation of tumour cells, and cancer stem cell persistence. B7H4 suppresses T cell effector functions, including inflammatory cytokine production, cytolytic activity, proliferation of T cells, and promoting the polarisation of naïve CD4 T cells into induced Tregs. This review aimed to summarise the available information about B7H4, focusing in particular on clinical implications, immunological mechanisms, potential strategies for malignancy treatment, and ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer care is being increasingly driven by biomarker testing. Many biomarkers are traditionally measured on a sample from a patient tumor such as a biopsy. More recently, "liquid biopsy" has emerged as a blood test to complement or replace traditional tissue-based testing. In this report, we explore one of the first case series of rapid liquid biopsy performed within a hospital setting. The results include a median 3-day time to results, compared to approximately 14 days using traditional centralized reference labs. Additional details of the cohort are shared to highlight the utility of point of care liquid biopsy. Liquid biopsy is rapidly becoming an indispensable tool in the oncologist's arsenal; however, this technique remains elusive in a publicly funded healthcare system, and real-world evidence is needed to demonstrate utility and feasibility. Here, we describe the first experience of an in-house point of care liquid biopsy program at a Canadian community hospital. A retrospective review of consecutive cases that underwent plasma-based next-generation sequencing (NGS) was conducted. Liquid biopsy was initiated at the discretion of clinicians. Sequencing followed a point of care workflow using the Genexus™ integrated sequencer and the Oncomine precision assay, performed by histotechnologists. Results were reported by the attending pathologist. Eligible charts were reviewed for outcomes of interest, including the intent of the liquid biopsy, results of the liquid biopsy, and turnaround time from blood draw to results available. A total of 124 cases, with confirmed or suspected cancer, underwent liquid biopsy between January 2021 and November 2023. The median turnaround time for liquid biopsy results was 3 business days (range 1–12 days). The sensitivity of liquid biopsies was 71%, compared to tissue testing in cases with matched tissue results available for comparison. Common mutations included EGFR (29%), in 86 lung cancer patients, and PIK3CA (22%), identified in 13 breast cancer patients. Healthcare providers ordered liquid biopsies to inform diagnostic investigations and treatment decisions, and to determine progression or resistance mechanisms, as these reasons often overlapped. This study demonstrates that rapid in-house liquid biopsy using point of care methodology is feasible. The technique facilitates precision treatment and offers many additional advantages for cancer care. [ABSTRACT FROM AUTHOR]

Simple Summary: The current devices and methods for dosimetry of personalized photodynamic therapy of tumors have several disadvantages. For instance, they are unable to evaluate the entire tumor volume at great depth, and they lack the capacity to provide an accurate estimate of the effective light dose. Furthermore, they are limited by their ability to evaluate either only the photosensitizer concentration or only the hemoglobin oxygenation at a specific point on the tissue surface or the average value based on the finite tissue volume at little depth. Despite the advances in photodynamic therapy, the development of a precise and dependable methodology to ascertain the optimal light dosage for a given tumor remains a significant challenge. This is due to the pivotal role of light dosage in determining the efficacy of treatment outcomes. Significance: Despite the widespread use of photodynamic therapy in clinical practice, there is a lack of personalized methods for assessing the sufficiency of photodynamic exposure on tumors, depending on tissue parameters that change during light irradiation. This can lead to different treatment results. Aim: The objective of this article was to conduct a comprehensive review of devices and methods employed for the implicit dosimetric monitoring of personalized photodynamic therapy for tumors. Methods: The review included 88 peer-reviewed research articles published between January 2010 and April 2024 that employed implicit monitoring methods, such as fluorescence imaging and diffuse reflectance spectroscopy. Additionally, it encompassed computer modeling methods that are most often and successfully used in preclinical and clinical practice to predict treatment outcomes. The Internet search engine Google Scholar and the Scopus database were used to search the literature for relevant articles. Results: The review analyzed and compared the results of 88 peer-reviewed research articles presenting various methods of implicit dosimetry during photodynamic therapy. The most prominent wavelengths for PDT are in the visible and near-infrared spectral range such as 405, 630, 660, and 690 nm. Conclusions: The problem of developing an accurate, reliable, and easily implemented dosimetry method for photodynamic therapy remains a current problem, since determining the effective light dose for a specific tumor is a decisive factor in achieving a positive treatment outcome. [ABSTRACT FROM AUTHOR]

Simple Summary: This research explores the accidental leakage of substances from veins during cancer treatments like chemotherapy and radiotherapy, a problem known as extravasation. The study aims to understand the causes, risks, symptoms, and long-term effects of extravasation and to find better ways to prevent and manage it. New technologies and methods, such as advanced imaging and smart catheters, are highlighted as potential solutions. By identifying gaps in the current knowledge and suggesting future research areas, this study aims to improve patient safety and treatment outcomes, offering valuable insights for healthcare professionals and emphasizing the need for continued innovation in cancer care. Extravasation, the unintended leakage of intravenously administered substances, poses significant challenges in cancer treatment, particularly during chemotherapy and radiotherapy. This comprehensive review explores the pathophysiology, incidence, risk factors, clinical presentation, diagnosis, prevention strategies, management approaches, complications, and long-term effects of extravasation in cancer patients. It also outlines future directions and research opportunities, including identifying gaps in the current knowledge and proposing areas for further investigation in extravasation prevention and management. Emerging technologies and therapies with the potential to improve extravasation prevention and management in both chemotherapy and radiotherapy are highlighted. Such innovations include advanced vein visualization technologies, smart catheters, targeted drug delivery systems, novel topical treatments, and artificial intelligence-based image analysis. By addressing these aspects, this review not only provides healthcare professionals with insights to enhance patient safety and optimize clinical practice but also underscores the importance of ongoing research and innovation in improving outcomes for cancer patients experiencing extravasation events. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer significantly affects physical and mental health, evoking intense emotions and forcing life changes. Emotional responses to cancer treatment have an intrinsic connection with time, in particular with the positive memories of how life looked before the disease and the often grim and hopeless outlook on the future. This study found that patients in chemotherapy experience increased focus on the present, decreased focus on the future, and a sense of unpredictability, with a relatively short temporal horizon measured in weeks and months, not years. These experiences are prevalent regardless of the type of cancer, the length of treatment, and the sociodemographic background. It can be concluded that changed temporal experience during chemotherapy is a factor that can have an impact on patients' well-being and ability to cope with the disease. Understanding the impact of cancer on the experience of time is crucial in the context of hope and recovery. This study, a follow-up to a previous qualitative study of ovarian cancer patients – explored two types of such experiences—the memory of past happiness and the limited future planning. A sociodemographic questionnaire with nine questions about the experience of time was used on a convenience sample of 202 patients with various cancers, predominantly women with breast, ovarian, and cervical cancer. It was found that the respondents experienced increased focus on the present, decreased focus on the future, and a sense of unpredictability, with a relatively short temporal horizon measured in weeks and months, not years. Almost half of the respondents (46%) measured time during treatment by the rhythm of chemotherapy and check-ups, which thus appeared as the most meaningful events. The increase in the frequency with which patients underwent chemotherapy mildly affected their focus on the present (R = 0.25, p < 0.05), likely because of the discomfort of the side effects. The correlations between age and time in treatment, on the one hand, and the experience of time, on the other, were negligible. Changed temporal experience during chemotherapy is a factor that can have an impact on patients' well-being and ability to cope with the disease. It thus should be taken into account when planning oncology care. [ABSTRACT FROM AUTHOR]

Simple Summary: This review assesses the integration of nanotechnology and immunotherapy, with a specific focus on the utilization of nanomaterials to modulate the immune system in conditions such as cancer and autoimmunity. Liposomes, polymers, and inorganic nanoparticles (NPs) are versatile nanomaterials capable of effectively transporting immunomodulatory molecules. Their interactions with immune cells have contributed to the development of checkpoint inhibitors, improved cancer vaccines, and the optimization of adoptive cell therapies. These approaches enable the fine-tuning of immune responses with minimal adverse effects. Positioned at the forefront of the convergence of nanotechnology and immunology, nanomaterial-based platforms have the potential to revolutionize patient-centered immunotherapy. These systems are used in the transformative era of disease management by prioritizing safety, personalization, and compliance with regulations. Immunotherapy is a rapidly advancing field of research in the treatment of conditions such as cancer and autoimmunity. Nanomaterials can be designed for immune system manipulation, with precise targeted delivery and improved immunomodulatory efficacy. Here, we elaborate on various strategies using nanomaterials, including liposomes, polymers, and inorganic NPs, and discuss their detailed design intricacies, mechanisms, and applications, including the current regulatory issues. This type of nanomaterial design for targeting specific immune cells or tissues and controlling release kinetics could push current technological frontiers and provide new and innovative solutions for immune-related disorders and diseases without off-target effects. These materials enable targeted interactions with immune cells, thereby enhancing the effectiveness of checkpoint inhibitors, cancer vaccines, and adoptive cell therapies. Moreover, they allow for fine-tuning of immune responses while minimizing side effects. At the intersection of nanotechnology and immunology, nanomaterial-based platforms have immense potential to revolutionize patient-centered immunotherapy and reshape disease management. By prioritizing safety, customization, and compliance with regulatory standards, these systems can make significant contributions to precision medicine, thereby significantly impacting the healthcare landscape. [ABSTRACT FROM AUTHOR]

Simple Summary: This review discusses the importance of advancements in cancer diagnosis and treatment, emphasizing the need for early detection methods. It highlights the role of DNA methylation, an epigenetic change, as a promising marker for detecting cancer. This review explains how DNA methylation patterns differ between cancerous and healthy cells, influencing gene expression and contributing to genomic instability. It also delves into the challenges and methods associated with detecting DNA methylation, particularly in cell-free DNA (cfDNA) from bodily fluids, known as liquid biopsies. Different tests for single-cancer detection, such as colorectal, lung, and bladder cancer, as well as multi-cancer detection tests, are discussed along with their methodologies and clinical applications. Biological factors influencing DNA methylation, such as age, gender, and environmental influences, are also explored. The conclusion emphasizes the potential of cfDNA methylation analysis in cancer diagnostics but acknowledges the current limitations and challenges, highlighting the need for further research and advancements in methodology and understanding. In current clinical practice, effective cancer testing and screening paradigms are limited to specific types of cancer, exhibiting varying efficiency, acceptance, and adherence. Cell-free DNA (cfDNA) methylation profiling holds promise in providing information about the presence of malignity regardless of its type and location while leveraging blood-based liquid biopsies as a method to obtain analytical samples. However, technical difficulties, costs and challenges resulting from biological variations, tumor heterogeneity, and exogenous factors persist. This method exploits the mechanisms behind cfDNA release but faces issues like fragmentation, low concentrations, and high background noise. This review explores cfDNA methylation's origins, means of detection, and profiling for cancer diagnostics. The critical evaluation of currently available multi-cancer early detection methods (MCEDs) as well as tests targeting single genes, emphasizing their potential and limits to refine strategies for early cancer detection, are explained. The current methodology limitations, workflows, comparisons of clinically approved liquid biopsy-based methylation tests for cancer, their utilization in companion diagnostics as well as the biological limitations of the epigenetics approach are discussed, aiming to help healthcare providers as well as researchers to orient themselves in this increasingly complex and evolving field of diagnostics. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple tumor types feature frequent overexpression of somatostatin receptor type 2 (SSTR2). In addition to its well-established role in determining the primary diagnosis, a PET/CT can be helpful in the radiation treatment of these tumors. It has the potential to improve recognition of the tumor burden compared to CT or MRI alone. In a blinded comparative interobserver study, we anonymized 47 patients with various tumors with SSTR2 expression and instructed four radiation oncologists to independently contour the macroscopic tumor volume using MRI alone and subsequently with the addition of DOTA-conjugated PET/CT. This study showed that for meningioma and skull base paraganglioma (SBPGL), there was a better consensus and certainty between the observers, with the opposite trend for pituitary neuroendocrine tumors (PitNET). For PitNET and meningioma, the addition of PET/CT led to higher sensitivity between the observers compared to CT and MRI alone, suggesting the benefits of integrating DOTA-conjugated PET/CT for target definition. The overexpression of somatostatin receptor type 2 (SSTR2) is a property of various tumor types. Hybrid imaging utilizing [68Ga]1,4,7,10-tetraazacyclododecane-1,4,7,10-tetra-acetic acid (DOTA) may improve the differentiation between tumor and healthy tissue. We conducted an experimental study on 47 anonymized patient cases including 30 meningiomas, 12 PitNET and 5 SBPGL. Four independent observers were instructed to contour the macroscopic tumor volume on planning MRI and then reassess their volumes with the additional information from DOTA-PET/CT. The conformity between observers and reference volumes was assessed. In total, 46 cases (97.9%) were DOTA-avid and included in the final analysis. In eight cases, PET/CT additional tumor volume was identified that was not detected by MRI; these PET/CT findings were potentially critical for the treatment plan in four cases. For meningiomas, the interobserver and observer to reference volume conformity indices were higher with PET/CT. For PitNET, the volumes had higher conformity between observers with MRI. With regard to SBGDL, no significant trend towards conformity with the addition of PET/CT information was observed. DOTA PET/CT supports accurate tumor recognition in meningioma and PitNET and is recommended in SSTR2-expressing tumors planned for treatment with highly conformal radiation. [ABSTRACT FROM AUTHOR]

Simple Summary: While immune checkpoint blockade (ICB) therapy is used successfully to treat various cancers, many patients develop immune-related adverse side effects (irAEs), which can be severe enough to cause decreases in quality of life and, in some cases, may result in treatment cessation. Here, we review current studies investigating the potential utility of the molecules MIF and CD74 as predictive biomarkers for ICB response and irAE development. We also discuss evidence for the circadian expression of MIF. Finally, we aim to highlight areas where future research will be beneficial in establishing the value of MIF and CD74 as biomarkers of ICB response. Immune checkpoint blockade (ICB) therapy is used to treat a wide range of cancers; however, some patients are at risk of developing treatment resistance and/or immune-related adverse events (irAEs). Thus, there is a great need for the identification of reliable predictive biomarkers for response and toxicity. The cytokine MIF (macrophage migration inhibitory factor) and its cognate receptor CD74 are intimately connected with cancer progression and have previously been proposed as prognostic biomarkers for patient outcome in various cancers, including solid tumors such as malignant melanoma. Here, we assess their potential as predictive biomarkers for response to ICB therapy and irAE development. We provide a brief overview of their function and roles in the context of cancer and autoimmune disease. We also review the evidence showing that MIF and CD74 may be of use as predictive biomarkers of patient response to ICB therapy and irAE development. We also highlight that careful consideration is required when assessing the potential of serum MIF levels as a biomarker due to its reported circadian expression in human plasma. Finally, we suggest future directions for the establishment of MIF and CD74 as predictive biomarkers for ICB therapy and irAE development to guide further research in this field. [ABSTRACT FROM AUTHOR]

Simple Summary: This manuscript systematically reviews the role of positron emission tomography (PET) in the assessment of toxicity associated with chimeric antigen receptor T-cell therapy (CAR T-cell therapy). CAR T-cell therapy, a revolutionary form of immunotherapy, activates immune mechanisms against malignant cells. By doing so, it can also provoke immune-mediated responses against healthy tissues. These responses exhibit diverse clinical, radiological, and functional manifestations across multiple physiological systems. Adverse events include cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome. Both can cause life-threatening complications. Given the critical imperative of timely identification and vigilant monitoring of these adverse events to enable targeted interventions, PET has emerged as an indispensable imaging biomarker facilitating their detection, prediction, and surveillance. Hence, our investigation is specifically tailored to examine the utility of PET in evaluating adverse events induced by CAR T-cell therapy. The utilization of chimeric antigen receptor (CAR) T-cell therapy to target cluster of differentiation (CD)19 in cancer immunotherapy has been a recent and significant advancement. Although this approach is highly specific and selective, it is not without complications. Therefore, a systematic review was conducted to assess the current state of positron emission tomography (PET) in evaluating the adverse effects induced by CAR T-cell therapy. A thorough search of relevant articles was performed in databases such as PubMed, Scopus, and Web of Science up until March 2024. Two reviewers independently selected articles and extracted data, which was then organized and categorized using Microsoft Excel. The risk of bias and methodological quality was assessed. In total, 18 articles were examined, involving a total of 753 patients, in this study. A wide range of utilities were analyzed, including predictive, correlative, and diagnostic utilities. While positive outcomes were observed in all the mentioned areas, quantitative analysis of the included studies was hindered by their heterogeneity and use of varying PET-derived parameters. This study offers a pioneering exploration of this promising field, with the goal of encouraging further and more focused research in upcoming clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: This review highlights the profound impact of digital pathology (DP) and artificial intelligence (AI) on advancing cancer diagnosis and treatment. DP enables pathologists to access, analyze, and share high-resolution images, enhancing diagnostic accuracy and fostering remote collaboration. AI further refines cancer diagnosis by automating tasks and facilitating spatial analysis of the tumor microenvironment (TME), leading to the discovery of novel biomarkers. Immunoscore (IS), an AI-assisted immune assay, exhibits robust potential in improving cancer diagnosis, prognosis, and treatment selection, surpassing traditional staging systems. Integrating DP and AI, particularly the IS biomarker, into clinical practice promises to enhance personalized cancer therapy. The research underscores a pivotal leap forward in pathology, stressing the imperative of incorporating AI-driven technologies for improved cancer patient care and outcomes. This exploration aims to provide insights into the transformative potential of DP in cancer management, influencing the clinical community towards more effective diagnostic and therapeutic strategies. (1) Background: Digital pathology (DP) is transforming the landscape of clinical practice, offering a revolutionary approach to traditional pathology analysis and diagnosis. (2) Methods: This innovative technology involves the digitization of traditional glass slides which enables pathologists to access, analyze, and share high-resolution whole-slide images (WSI) of tissue specimens in a digital format. By integrating cutting-edge imaging technology with advanced software, DP promises to enhance clinical practice in numerous ways. DP not only improves quality assurance and standardization but also allows remote collaboration among experts for a more accurate diagnosis. Artificial intelligence (AI) in pathology significantly improves cancer diagnosis, classification, and prognosis by automating various tasks. It also enhances the spatial analysis of tumor microenvironment (TME) and enables the discovery of new biomarkers, advancing their translation for therapeutic applications. (3) Results: The AI-driven immune assays, Immunoscore (IS) and Immunoscore-Immune Checkpoint (IS-IC), have emerged as powerful tools for improving cancer diagnosis, prognosis, and treatment selection by assessing the tumor immune contexture in cancer patients. Digital IS quantitative assessment performed on hematoxylin–eosin (H&E) and CD3+/CD8+ stained slides from colon cancer patients has proven to be more reproducible, concordant, and reliable than expert pathologists' evaluation of immune response. Outperforming traditional staging systems, IS demonstrated robust potential to enhance treatment efficiency in clinical practice, ultimately advancing cancer patient care. Certainly, addressing the challenges DP has encountered is essential to ensure its successful integration into clinical guidelines and its implementation into clinical use. (4) Conclusion: The ongoing progress in DP holds the potential to revolutionize pathology practices, emphasizing the need to incorporate powerful AI technologies, including IS, into clinical settings to enhance personalized cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: This review summarizes the pivotal role of tumor-infiltrating immune cells (TIICs) within the tumor microenvironment (TME) and their impact on cancer prognosis and treatment response. By analyzing TIICs alongside tumor mutation burden (TMB) and immune checkpoint inhibitor (ICI) scores, this study reveals insights into cancer's immune landscapes. Understanding TIICs' influence enables tailored cancer treatments, aiding postoperative care, therapy decisions, and personalized medicine choices. We effectively examined the predictive and prognostic value of TIICs alongside TMB and ICI scores in identifying the diverse immunological environments of cancer. Several approaches discussed in this review provide more accurate predictions of patient outcomes and treatment responses. These models can help identify individuals who may derive greater benefit from adjuvant or neoadjuvant treatment. In summary, we believe that the major contribution of TIICs in cancer will have a substantial positive impact on postoperative follow-up, therapy, interventions, and the ability to make educated decisions regarding personalized cancer treatments. This comprehensive study underscores the significant role of TIICs in combating tumor-mediated immunosuppression and fostering antitumor immune responses, promising improved cancer prognosis and therapeutic outcomes. TIICs are critical components of the TME and are used to estimate prognostic and treatment responses in many malignancies. TIICs in the tumor microenvironment are assessed and quantified by categorizing immune cells into three subtypes: CD66b+ tumor-associated neutrophils (TANs), FoxP3+ regulatory T cells (Tregs), and CD163+ tumor-associated macrophages (TAMs). In addition, many cancers have tumor-infiltrating M1 and M2 macrophages, neutrophils (Neu), CD4+ T cells (T-helper), CD8+ T cells (T-cytotoxic), eosinophils, and mast cells. A variety of clinical treatments have linked tumor immune cell infiltration (ICI) to immunotherapy receptivity and prognosis. To improve the therapeutic effectiveness of immune-modulating drugs in a wider cancer patient population, immune cells and their interactions in the TME must be better understood. This study examines the clinicopathological effects of TIICs in overcoming tumor-mediated immunosuppression to boost antitumor immune responses and improve cancer prognosis. We successfully analyzed the predictive and prognostic usefulness of TIICs alongside TMB and ICI scores to identify cancer's varied immune landscapes. Traditionally, immune cell infiltration was quantified using flow cytometry, immunohistochemistry, gene set enrichment analysis (GSEA), CIBERSORT, ESTIMATE, and other platforms that use integrated immune gene sets from previously published studies. We have also thoroughly examined traditional limitations and newly created unsupervised clustering and deconvolution techniques (SpatialVizScore and ProTICS). These methods predict patient outcomes and treatment responses better. These models may also identify individuals who may benefit more from adjuvant or neoadjuvant treatment. Overall, we think that the significant contribution of TIICs in cancer will greatly benefit postoperative follow-up, therapy, interventions, and informed choices on customized cancer medicines. [ABSTRACT FROM AUTHOR]

Simple Summary: This work challenges the traditional principles of cancer therapy: simply targeting and blocking the regulatory pathways of rapidly proliferating tumors is a serious mistake. Since tumor initiation and growth may be attributed to a patient's genomic instability and damage, genotoxic medications are inappropriate as they cause additional genomic damage in both patients and their cancers. Tumor cells are not enemies to be killed, but rather they are ill human cells which have the remnants of same genome stabilizer pathways like healthy cells. Within tumors, there is a combat for the improvement of their genomic defects. Moreover, tumors ask for help in their kamikaze action by recruiting immune competent cells into their environment. We should learn by watching the genome repairing activities within tumors, in the peritumoral region and in the whole body, and may follow them with supportive care. Successful cancer therapy does not remain a dream to be realized in the far future, but we should set about a cancer cure without delay. Background: In tumors, somatic mutagenesis presumably drives the DNA damage response (DDR) via altered regulatory pathways, increasing genomic instability and proliferative activity. These considerations led to the standard therapeutic strategy against cancer: the disruption of mutation-activated DNA repair pathways of tumors.Purpose: Justifying that cancer cells are not enemies to be killed, but rather that they are ill human cells which have the remnants of physiologic regulatory pathways. Results: 1. Genomic instability and cancer development may be originated from a flaw in estrogen signaling rather than excessive estrogen signaling; 2. Healthy cells with genomic instability exhibit somatic mutations, helping DNA restitution; 3. Somatic mutations in tumor cells aim for the restoration of DNA damage, rather than further genomic derangement; 4. In tumors, estrogen signaling drives the pathways of DNA stabilization, leading to apoptotic death; 5. In peritumoral cellular infiltration, the genomic damage of the tumor induces inflammatory cytokine secretion and increased estrogen synthesis. In the inflammatory cells, an increased growth factor receptor (GFR) signaling confers the unliganded activation of estrogen receptors (ERs); 6. In breast cancer cells responsive to genotoxic therapy, constitutive mutations help the upregulation of estrogen signaling and consequential apoptosis. In breast tumors non-responsive to genotoxic therapy, the possibilities for ER activation via either liganded or unliganded pathways are exhausted, leading to farther genomic instability and unrestrained proliferation. Conclusions: Understanding the real character and behavior of human tumors at the molecular level suggests that we should learn the genome repairing methods of tumors and follow them by supportive therapy, rather than provoking additional genomic damages. [ABSTRACT FROM AUTHOR]

Simple Summary: The immune system can fight foreign invaders by different means, expressed by different classes of immunity. There are two main classes: antibodies and cell-mediated immunity. Studies directed at how distinct classes of immunity are differentially generated and regulated have been ongoing for the better part of a century. Various quantitative variables of immunization, such as antigen doses, are critical, and were first identified more than fifty years ago. It was shown that lower and higher doses, respectively, lead to cell-mediated and antibody responses. The importance of these variables has stood the test of time. We argue here for a framework, the Threshold Hypothesis, that is consistent with these variables and accounts for their central role in determining the class of immunity generated. This framework leads to an understanding of many observations in the fields of tumor immunology and immunity against pathogens uniquely contained by cell-mediated attack. This understanding relies on the generalization that cancers are uniquely susceptible to cell-mediated attack. This confidence in the threshold mechanism led me to propose non-invasive and efficacious strategies to prevent and treat cancer and infectious diseases caused by pathogens uniquely susceptible to cell-mediated immunity. Different frameworks, which are currently employed to understand how immune responses are regulated, can account for different observations reported in the classical literature. I have argued that the predominant frameworks, employed over the last two/three decades to analyze the circumstances that determine whether an immune response is generated or this potential is ablated, and that determine the class of immunity an antigen induces, are inconsistent with diverse classical observations. These observations are "paradoxical" within the context of these frameworks and, consequently, tend to be ignored by most contemporary researchers. One such observation is that low and high doses of diverse types of antigen result, respectively, in cell-mediated and IgG antibody responses. I suggest these paradoxes render these frameworks implausible. An alternative framework, The Threshold Hypothesis, accounts for the paradoxical observations. Some frameworks are judged more plausible when found to be valuable in understanding findings in fields beyond their original compass. I explore here how the Threshold Hypothesis, initially based on studies with chemically well-defined and "simple antigens", most often a purified protein, can nevertheless shed light on diverse classical and more recent observations in the fields of immunity against cancer and against infectious agents, thus revealing common, immune mechanisms. Most cancers and some pathogens are best contained by cell-mediated immunity. The success of the Threshold Hypothesis has encouraged me to employ it as a basis for proposing strategies to prevent and to treat cancer and those infectious diseases caused by pathogens best contained by a cell-mediated attack. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is the second leading cause of death worldwide, accounting for nearly one in six deaths. One of the key underlying factors distinguishing a cancer cell from a normal cell is the pattern of expression of genes. Proteins that regulate gene expression, called transcription factors, are abnormally regulated in cancer cells, particularly a group of proteins called STATs. This causes cancer cells to survive, proliferate excessively, and escape killing by the immune system. Since normal cells can survive adequately without full STAT function, targeting these proteins is an attractive approach for a new generation of more effective and less toxic cancer therapies. In this review, we summarize the current knowledge of STAT function in cancer and the advances and challenges in developing drugs to target them. Despite advances in our understanding of molecular aspects of oncogenesis, cancer remains a leading cause of death. The malignant behavior of a cancer cell is driven by the inappropriate activation of transcription factors. In particular, signal transducers and activators of transcription (STATs), which regulate many critical cellular processes such as proliferation, apoptosis, and differentiation, are frequently activated inappropriately in a wide spectrum of human cancers. Multiple signaling pathways converge on the STATs, highlighting their importance in the development and progression of oncogenic diseases. STAT3 and STAT5 are two members of the STAT protein family that are the most frequently activated in cancers and can drive cancer pathogenesis directly. The development of inhibitors targeting STAT3 and STAT5 has been the subject of intense investigations in the last decade, although effective treatment options remain limited. In this review, we investigate the specific roles of STAT3 and STAT5 in normal physiology and cancer biology, discuss the opportunities and challenges in pharmacologically targeting STAT proteins and their upstream activators, and offer insights into novel therapeutic strategies to identify STAT inhibitors as cancer therapeutics. [ABSTRACT FROM AUTHOR]

Simple Summary: This review article explores the forefront of research and technology in the detection and isolation of circulating tumor cells (CTCs) for liquid biopsy applications. Traditional biopsies, which necessitate tissue samples, are invasive and often challenging for patients. In contrast, liquid biopsies provide a less invasive alternative, enabling the continuous monitoring of the cancer's progression and the effectiveness of treatments. Recent advancements have significantly enhanced our understanding of CTCs, underscoring their critical role in cancer research and patient management. This article aims to highlight these technological innovations and their potential to transform cancer diagnosis, prognosis, and personalized therapy, offering new hope for improved patient outcomes in the fight against cancer. Cancer remains a leading cause of mortality worldwide, with metastasis significantly contributing to its lethality. The metastatic spread of tumor cells, primarily through the bloodstream, underscores the importance of circulating tumor cells (CTCs) in oncological research. As a critical component of liquid biopsies, CTCs offer a non-invasive and dynamic window into tumor biology, providing invaluable insights into cancer dissemination, disease progression, and response to treatment. This review article delves into the recent advancements in CTC research, highlighting their emerging role as a biomarker in various cancer types. We explore the latest technologies and methods for CTC isolation and detection, alongside novel approaches to characterizing their biology through genomics, transcriptomics, proteomics, and epigenetic profiling. Additionally, we examine the clinical implementation of these findings, assessing how CTCs are transforming the landscape of cancer diagnosis, prognosis, and management. By offering a comprehensive overview of current developments and potential future directions, this review underscores the significance of CTCs in enhancing our understanding of cancer and in shaping personalized therapeutic strategies, particularly for patients with metastatic disease. [ABSTRACT FROM AUTHOR]

Simple Summary: Developing cancer during adolescence or young adulthood adds extra challenges to an already difficult period of development. This can cause a 'biographical disruption,' in the sense that people miss out on key milestones they might reasonably have expected to achieve during the period, and this can affect their emotional wellbeing. While research shows that young people may experience various degrees of emotional distress, less is known about the emotional experiences and barriers young people experience when accessing help and support. We interviewed two groups of young people who were within 6 months of diagnosis and 3–5 years after treatment. We found three themes that described emotional health experiences: the emotional impact of cancer; personal barriers to support; and support to improve mental health. Differences were identified across the treatment journey, in which we were able to propose therapies and interventions that could be used to help improve psychological outcomes. The biographical disruption that occurs in adolescents and young adults following a cancer diagnosis can affect various important psychosocial domains including relationships with family and friends, sexual development, vocational and educational trajectories, and physical and emotional wellbeing. While there is evidence of the physical impact of cancer during this period, less is known about the impact on emotional wellbeing and especially on the barriers for young people accessing help and support. We aimed to obtain a more in-depth understanding of young people's experiences of their diagnosis, treatment, psychological impact, and range of resources they could or wanted to access for their mental health. We conducted an in-depth qualitative study using semi-structured interviews with 43 young people who had developed cancer aged 16 to 39 years and were either within 6 months of diagnosis or 3–5 years after treatment had ended. Framework analysis identified three themes: the emotional impact of cancer (expressed through anxiety, anger, and fear of recurrence); personal barriers to support through avoidance; and support to improve mental health through mental health services or adolescent and young adult treatment teams. We showed the barriers young people have to access care, particularly participant avoidance of support. Interrupting this process to better support young people and provide them with flexible, adaptable, consistent, long-term psychological support has the potential to improve their quality of life and wellbeing. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer is a complex disease caused by a slew of genetic mutations discovered through advances in sequencing technologies such as next-generation sequencing. While this technology has been useful, it can only retrieve genomic information through short reads or sequences, which is a limitation. A new sequencing technology known as third-generation sequencing overcomes this limitation by using much longer reads. This is a game changer for cancer research, diagnosis and treatment. Third-generation sequencing enables the decipherment of complex genomic rearrangements, resulting in a better understanding of how cancer develops, as well as the examination of the entire transcriptome, revealing isoforms that could be used in diagnostics or treatment. Third-generation sequencing enhances cancer genome assembly, detects epigenetic changes, and can provide a comprehensive picture of a patient's specific cancer aberrations. This has the potential to lead to more effective treatments with fewer adverse effects. This review provides a rigorous scientific analysis of the advantages and limitations of third-generation sequencing, emphasizing its potential for the future of cancer research and personalized medicine. Although this is still a developing technology, it has enormous potential for research and clinical applications, ultimately leading to improved cancer diagnosis and treatment. Cancer is a multifaceted disease arising from numerous genomic aberrations that have been identified as a result of advancements in sequencing technologies. While next-generation sequencing (NGS), which uses short reads, has transformed cancer research and diagnostics, it is limited by read length. Third-generation sequencing (TGS), led by the Pacific Biosciences and Oxford Nanopore Technologies platforms, employs long-read sequences, which have marked a paradigm shift in cancer research. Cancer genomes often harbour complex events, and TGS, with its ability to span large genomic regions, has facilitated their characterisation, providing a better understanding of how complex rearrangements affect cancer initiation and progression. TGS has also characterised the entire transcriptome of various cancers, revealing cancer-associated isoforms that could serve as biomarkers or therapeutic targets. Furthermore, TGS has advanced cancer research by improving genome assemblies, detecting complex variants, and providing a more complete picture of transcriptomes and epigenomes. This review focuses on TGS and its growing role in cancer research. We investigate its advantages and limitations, providing a rigorous scientific analysis of its use in detecting previously hidden aberrations missed by NGS. This promising technology holds immense potential for both research and clinical applications, with far-reaching implications for cancer diagnosis and treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: We have recently witnessed several milestones in the treatment of various cancers with immunotherapy through modulating the activity of the immune system to suppress and destroy cancer cells. One main factor involved in the anti-cancer immune system is cytotoxic immune cells known as T cells. T cells can recognize pathogenic cancer cells and launch targeted destruction attacks. However, these T cells may become non-functional due to their close association with cancer cells within the tumor microenvironment. Cancer cell activity can ultimately suppress T-cell function. New approaches that prevent the inactivation of T cells by cancer cells would result in recovery of the T-cell functions, cancer regression, and overall survival. Targeting cancer cells specifically to prevent T-cell inactivation would result in tumor disappearance, inhibition of metastasis, and the reversal of resistance to therapy. Therefore, this proposed alternative approach is promising as it is applicable to numerous cancers, including those that are resistant to treatment. During the last decade, we have witnessed several milestones in the treatment of various resistant cancers including immunotherapeutic strategies that have proven to be superior to conventional treatment options, such as chemotherapy and radiation. This approach utilizes the host's immune response, which is triggered by cancer cells expressing tumor-associated antigens or neoantigens. The responsive immune cytotoxic CD8+ T cells specifically target and kill tumor cells, leading to tumor regression and prolongation of survival in some cancers; however, some cancers may exhibit resistance due to the inactivation of anti-tumor CD8+ T cells. One mechanism by which the anti-tumor CD8+ T cells become dysfunctional is through the activation of the inhibitory receptor programmed death-1 (PD-1) by the corresponding tumor cells (or other cells in the tumor microenvironment (TME)) that express the programmed death ligand-1 (PD-L1). Hence, blocking the PD-1/PD-L1 interaction via specific monoclonal antibodies (mAbs) restores the CD8+ T cells' functions, leading to tumor regression. Accordingly, the Food and Drug Administration (FDA) has approved several checkpoint antibodies which act as immune checkpoint inhibitors. Their clinical use in various resistant cancers, such as metastatic melanoma and non-small-cell lung cancer (NSCLC), has shown significant clinical responses. We have investigated an alternative approach to prevent the expression of PD-L1 on tumor cells, through targeting the oncogenic transcription factor Yin Yang 1 (YY1), a known factor overexpressed in many cancers. We report the regulation of PD-L1 by YY1 at the transcriptional, post-transcriptional, and post-translational levels, resulting in the restoration of CD8+ T cells' anti-tumor functions. We have performed bioinformatic analyses to further explore the relationship between both YY1 and PD-L1 in cancer and to corroborate these findings. In addition to its regulation of PD-L1, YY1 has several other anti-cancer activities, such as the regulation of proliferation and cell viability, invasion, epithelial–mesenchymal transition (EMT), metastasis, and chemo-immuno-resistance. Thus, targeting YY1 will have a multitude of anti-tumor activities resulting in a significant obliteration of cancer oncogenic activities. Various strategies are proposed to selectively target YY1 in human cancers and present a promising novel therapeutic approach for treating unresponsive cancer phenotypes. These findings underscore the distinct regulatory roles of YY1 and PD-L1 (CD274) in cancer progression and therapeutic response. [ABSTRACT FROM AUTHOR]

Simple Summary: In this manuscript, we review the progress in knowledge made over the last decade, which, thanks to the commitment of many academics and researchers, has clarified many aspects relating to ferroptosis and its connections with cancer. Ferroptosis is currently regarded as a distinct type of regulated cell death (RCD), characterized by iron-dependent oxidative stress and the accumulation of lethal oxidized lipids. With a focus on the recent literature, the connection between iron homeostasis, oxidative stress and lipid metabolism is highlighted, which overall regulates ferroptotic cellular death. Moreover, special attention is devoted to the possible activation of this RCD pathway as a mechanism of tumor suppression. Its in-depth understanding from a regulatory and molecular perspective could provide important information for the development of new candidate drugs for the treatment of tumors resistant to conventional therapies. Based on the multifaceted molecular machinery that tightly controls iron cellular homeostasis, this review delves into its paradoxical, potentially dangerous role in biological systems, with a special focus on double-edged sword correlations with cancer. Indeed, though iron is a vital micronutrient and a required cofactor participating in several essential cell functions, its tendency to cause oxidative stress can be related both to cancer risk and to the activation of cancer cell death pathways. In this scenario, ferroptosis refers to an iron-dependent form of regulated cell death (RCD) powered by an overload of lethal peroxides sharing distinctive oxidized phospholipid profiles. As a unique cell death pathway, ferroptosis is both morphologically and mechanistically different from other types of programmed cell death involving executioner family proteins. The accumulation of cytotoxic lipid peroxides encompasses a cellular antagonism between ferroptosis execution and defense systems, with iron-dependent death occurring when ferroptosis-promoting activities significantly exceed the cellular antioxidant defenses. The most recent molecular breakthroughs in the execution of ferroptosis have aroused great consideration in tumor biology, as targeting ferroptosis can provide new tools for exploring therapeutic strategies for tumor suppression. Mutations and death/survival pathway alterations, as well as distinctive metabolic regulations of cancer cells, including the propensity to generate ROS, are seen as features that can render cancer cells unprotected to ferroptosis, thereby exposing vulnerabilities which deserve further attention to be regarded as targetable for cancers with limited therapeutic options. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer remains one of the leading causes of death worldwide due to widespread metastasis. Circulating tumor cells (CTCs) were first detected in 1886 and have been thought of as seeds of metastasis. However, emerging evidence has shown that CTCs can be used for early disease detection and as predictors of disease prognosis and treatment response. This review discusses recent findings regarding the detection and characterization of CTCs. Integrating these findings into routine clinical workflows promises to revolutionize the diagnosis and treatment of cancer. Circulating tumor cells (CTCs) are cells released from the primary and metastatic tumor and intravasate into the blood or lymphatic vessels, where they are transported to distant sites and act as seeds that initiate cancer metastases or the development of further lesions. Recent advances in CTC research have shown their relevance as prognostic markers for early and metastatic disease detection, predictive biomarkers for relapse, and response to medical intervention or therapy. The rapidly evolving landscape of CTC biology has opened new avenues for understanding cancer progression, metastasis, and treatment response. Additionally, translating these findings into clinical applications holds promise for improving cancer diagnostics, prognosis, and personalized therapeutic strategies. This review discusses the significance of CTCs in cancer research and their associated challenges. We explore recent developments in the detection and characterization of CTCs and their implications in cancer research and clinical practice. [ABSTRACT FROM AUTHOR]

Simple Summary: Hyperthermia (HT) is a commonly used technique applied as an effective sensitizer during cancer therapy. However, the localized heating of the tumor due to supraphysiological temperature may cause serious side effects towards normal tissues. Thus, new methods are needed to improve the precision of HT. Nanotechnology has allowed for the development of many promising tools to revolutionize traditional thermotherapy. Here, we showed that magnetic nanoparticles (MNPs) following activation by altered magnetic field not only destroy tumor cells but also cause increased blood flow to and oxygenation of cancer tissue. Moreover, we present the current state of knowledge regarding the combination of MNPs-based hyperthermia with traditional and innovative cancer therapies as well perspectives on its implementation within clinics. Hyperthermia (HT) is an anti-cancer therapy commonly used with radio and chemotherapies based on applying heat (39–45 °C) to inhibit tumor growth. However, controlling heat towards tumors and not normal tissues is challenging. Therefore, nanoparticles (NPs) are used in HT to apply heat only to tumor tissues to induce DNA damage and the expression of heat shock proteins, which eventually result in apoptosis. The aim of this review article is to summarize recent advancements in HT with the use of magnetic NPs to locally increase temperature and promote cell death. In addition, the recent development of nanocarriers as NP-based drug delivery systems is discussed. Finally, the efficacy of HT combined with chemotherapy, radiotherapy, gene therapy, photothermal therapy, and immunotherapy is explored. [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: Alternative splicing is a pivotal regulatory mechanism in gene expression, generating multiple RNA species and influencing protein isoform diversity and function, as well as regulatory RNA networks. Histone post-translational modifications can affect alternative splicing and mediate diverse interactions between histones and splicing factors, adding complexity to the transcriptional landscape. Alternative splicing of epigenetic 'reader' proteins is of growing interest in cancer etiology and other pathologies, providing insights into effective new therapeutic strategies, including RNA-based approaches and small-molecule targeting of splicing abnormalities. Epigenetic 'reader' proteins, which have evolved to interact with specific chromatin modifications, play pivotal roles in gene regulation. There is growing interest in the alternative splicing mechanisms that affect the functionality of such epigenetic readers in cancer etiology. The current review considers how deregulation of epigenetic processes and alternative splicing events contribute to pathophysiology. An A–Z guide of epigenetic readers is provided, delineating the antagonistic 'yin-yang' roles of full-length versus spliced isoforms, where this is known from the literature. The examples discussed underscore the key contributions of epigenetic readers in transcriptional regulation, early development, and cancer. Clinical implications are considered, offering insights into precision oncology and targeted therapies focused on epigenetic readers that have undergone alternative splicing events during disease pathogenesis. This review underscores the fundamental importance of alternative splicing events in the context of epigenetic readers while emphasizing the critical need for improved understanding of functional diversity, regulatory mechanisms, and future therapeutic potential. [ABSTRACT FROM AUTHOR]

Simple Summary: Glutamine, vital for the body's functions, is pivotal in cancer metabolism as it influences tumor growth. However, cancer cells' complex adaptive metabolic dynamics raise concerns about potential limitations in glutamine antagonism strategies to impede tumor growth. Similarly, while glutamine supplementation shows promise in supporting cancer patients, careful considerations are necessary to address possible interactions with ongoing treatments and concerns about inadvertent tumor growth stimulation. Recent studies have shed light on the effects of glutamine on the epigenetic regulation of cancer cells and the enhancement of anti-cancer immune functions, providing valuable insights for potential therapeutic advancements. Understanding the intricacies and challenges of glutamine interventions is essential for optimizing their potential benefits in cancer treatment and patient well-being. Glutamine, a multifaceted nonessential/conditionally essential amino acid integral to cellular metabolism and immune function, holds pivotal importance in the landscape of cancer therapy. This review delves into the intricate dynamics surrounding both glutamine antagonism strategies and glutamine supplementation within the context of cancer treatment, emphasizing the critical role of glutamine metabolism in cancer progression and therapy. Glutamine antagonism, aiming to disrupt tumor growth by targeting critical metabolic pathways, is challenged by the adaptive nature of cancer cells and the complex metabolic microenvironment, potentially compromising its therapeutic efficacy. In contrast, glutamine supplementation supports immune function, improves gut integrity, alleviates treatment-related toxicities, and improves patient well-being. Moreover, recent studies highlighted its contributions to epigenetic regulation within cancer cells and its potential to bolster anti-cancer immune functions. However, glutamine implementation necessitates careful consideration of potential interactions with ongoing treatment regimens and the delicate equilibrium between supporting normal cellular function and promoting tumorigenesis. By critically assessing the implications of both glutamine antagonism strategies and glutamine supplementation, this review aims to offer comprehensive insights into potential therapeutic strategies targeting glutamine metabolism for effective cancer management. [ABSTRACT FROM AUTHOR]

Simple Summary: Although immune check point inhibitors have been established as a new paradigm in cancer treatment, they have shown no clinical benefit in immune excluded or dessert tumors. Dendritic cells promote and coordinate the immune system. Dendritic cell vaccination enriches tumor milieu and potentiates patient systemic antitumoral responses. In this work we review the strengths and weaknesses of dendritic cell vaccines in different solid tumors regarding their role to improve their clinical efficacy. To date, dendritic cell vaccines have induced immune responses in patients without a significant impact on outcome. Improvements in vaccine formulations, selection of patients and combinations with other antitumoral therapies are needed to increase patients' survival. Cancer immunotherapy modulates the immune system, overcomes immune escape and stimulates immune defenses against tumors. Dendritic cells (DCs) are professional promoters of immune responses against tumor antigens with the outstanding ability to coordinate the innate and adaptive immune systems. Evidence suggests that there is a decrease in both the number and function of DCs in cancer patients. Therefore, they represent a strong scaffold for therapeutic interventions. DC vaccination (DCV) is safe, and the antitumoral responses induced are well established in solid tumors. Although the addition of checkpoint inhibitors (CPIs) to chemotherapy has provided new options in the treatment of cancer, they have shown no clinical benefit in immune desert tumors or in those tumors with dysfunctional or exhausted T-cells. In this way, DC-based therapy has demonstrated the ability to modify the tumor microenvironment for immune enriched tumors and to potentiate systemic host immune responses as an active approach to treating cancer patients. Application of DCV in cancer seeks to obtain long-term antitumor responses through an improved T-cell priming by enhancing previous or generating de novo immune responses. To date, DCV has induced immune responses in the peripheral blood of patients without a significant clinical impact on outcome. Thus, improvements in vaccines formulations, selection of patients based on biomarkers and combinations with other antitumoral therapies are needed to enhance patient survival. In this work, we review the role of DCV in different solid tumors with their strengths and weaknesses, and we finally mention new trends to improve the efficacy of this immune strategy. [ABSTRACT FROM AUTHOR]

Simple Summary: Photodynamic therapy (PDT) is a cancer treatment that uses photogenerated reactive oxygen species (ROS) to damage target cells. The unique mechanism of action of PDT involves the systemic or local administration of a photosensitizing compound (photosensitizer), which is then activated by light of a specific energy. PDT induces a very strong local inflammatory response. A number of adaptive mechanisms are induced within the tumor, related to increased amino acid metabolism and damage to lymphatic vessels. In this review, we are describing the adaptive immune response induced by ROS and generated by PDT. Cancer is one of the most significant causes of death worldwide. Despite the rapid development of modern forms of therapy, results are still unsatisfactory. The prognosis is further worsened by the ability of cancer cells to metastasize. Thus, more effective forms of therapy, such as photodynamic therapy, are constantly being developed. The photodynamic therapeutic regimen involves administering a photosensitizer that selectively accumulates in tumor cells or is present in tumor vasculature prior to irradiation with light at a wavelength corresponding to the photosensitizer absorbance, leading to the generation of reactive oxygen species. Reactive oxygen species are responsible for the direct and indirect destruction of cancer cells. Photodynamically induced local inflammation has been shown to have the ability to activate an adaptive immune system response resulting in the destruction of tumor lesions and the creation of an immune memory. This paper focuses on presenting the latest scientific reports on the specific immune response activated by photodynamic therapy. We present newly discovered mechanisms for the induction of the adaptive response by analyzing its various stages, and the possible difficulties in generating it. We also present the results of research over the past 10 years that have focused on improving the immunological efficacy of photodynamic therapy for improved cancer therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The development of cancer proceeds when the intricate dynamics of the cell are destabilized. It is a multifaceted process, and the involvement of one particularly notorious cell type, cancer stem cells, has been increasingly observed. The WNT signaling pathway is a prominently deregulated pathway in cancer stem cells and has been suggested to maintain properties of self-renewal, tumor initiation, metastasis, and chemoresistance in these cells. MicroRNAs (miRNAs) are post-transcriptional gene regulators that can directly influence gene expression in cancer. As miRNAs hold the potential to be either oncogenic or tumor suppressors, they are found to be highly dysregulated in numerous cancers. Understanding the function of miRNAs in the context of cancer stem cells and the WNT signaling pathway may provide new insights into the treatment of cancer, which is a leading cause of death worldwide. Carcinogenesis is a complex process characterized by intricate changes in organ histology, biochemistry, epigenetics, and genetics. Within this intricate landscape, cancer stem cells (CSCs) have emerged as distinct cell types possessing unique attributes that significantly contribute to the pathogenesis of cancer. The WNT signaling pathway plays a critical role in maintaining somatic stem cell pluripotency. However, in cancer, overexpression of WNT mediators enhances the activity of β-catenin, resulting in phenomena such as recurrence and unfavorable survival outcomes. Notably, CSCs exhibit heightened WNT signaling compared to bulk cancer cells, providing intriguing insights into their functional characteristics. MicroRNAs (miRNAs), as post-transcriptional gene expression regulators, modulate various physiological processes in numerous diseases including cancer. Upregulation or downregulation of miRNAs can affect the production of pro-oncogenic or anti-oncogenic proteins, influencing cellular processes that maintain tissue homeostasis and promote either apoptosis or differentiation, even in cancer cells. In order to understand the dysregulation of miRNAs, it is essential to examine miRNA biogenesis and any possible alterations at each step. The potential of a miRNA as a biomarker in prognosis, diagnosis, and detection is being assessed using technologies such as next-generation sequencing. Extensive research has explored miRNA expression profiles in cancer, leading to their utilization as diagnostic tools and the development of personalized and targeted cancer therapies. This review delves into the role of miRNAs in carcinogenesis in relation to the WNT signaling pathway along with their potential as druggable compounds. [ABSTRACT FROM AUTHOR]

Simple Summary: A 10-year experience in cancer therapy using concomitant treatment of immunotherapy and percutaneous thermal ablation is shared in this article. Based on a retrospective cohort of 78 patients, the feasibility, safety and efficacy of such combined treatments were assessed. Most patients received immune checkpoint blocker monotherapy combined with radiofrequency or cryotherapy ablation. The feasibility and safety profile were found to be excellent, with complications equivalent to those reported when each treatment was performed separately. Overall, thermal ablation outcomes were found to be similar to standards for patients not on immunotherapy. Purpose: We report a 10-year experience in cancer therapy with concomitant treatment of percutaneous thermal ablation (PTA) and immune checkpoint blockers (ICBs). Material and methods: This retrospective cohort study included all patients at a single tertiary cancer center who had received ICBs at most 90 days before, or 30 days after, PTA. Feasibility and safety were assessed as the primary outcomes. The procedure-related complications and immune-related adverse events (irAEs) were categorized according to the Common Terminology Criteria for Adverse Events v5.0 (CTCAE). Efficacy was evaluated based on overall survival (OS), progression-free survival (PFS), and local progression-free survival (LPFS) according to the indication, ablation modality, neoplasm histology, and ICB type. Results: Between 2010 and 2021, 78 patients (57% male; median age: 61 years) were included. The PTA modality was predominantly cryoablation (CA) (61%), followed by radiofrequency ablation (RFA) (31%). PTA indications were the treatment of oligo-persistence (29%), oligo-progression (14%), and palliation of symptomatic lesions or prevention of skeletal-related events (SREs) (56%). Most patients received anti-PD1 ICB monotherapy with pembrolizumab (n = 35) or nivolumab (n = 24). The feasibility was excellent, with all combined treatment performed and completed as planned. Ten patients (13%) experienced procedure-related complications (90% grade 1–2), and 34 patients (44%) experienced an irAE (86% grade 1–2). The only factor statistically associated with better OS and PFS was the ablation indication, favoring oligo-persistence (p = 0.02). Tumor response was suggestive of an abscopal effect in four patients (5%). Conclusions: The concomitant treatment of PTA and ICBs within 2–4 weeks is feasible and safe for both palliative and local control indications. Overall, PTA outcomes were found to be similar to standards for patients not on ICB therapy. While a consistently reproducible abscopal effect remains elusive, the safety profile of concomitant therapy provides the framework for continued assessment as ICB therapies evolve. [ABSTRACT FROM AUTHOR]

Simple Summary: As a tumor grows, DNA fragments from cancer cells shed into the bloodstream. Known as circulating tumor DNA (ctDNA), these fragments can be used to inform on cancer diagnosis, treatment, and prognosis. However, despite the potential for these uninavasive liquid biopsies to revolutionize cancer monitoring and treatment, ctDNA can show poor genetic concordance between blood and the main tumor tissue, hampering its general clinical utility. For liquid biopsy technologies and ctDNA analyses to transform cancer care, from early screening and diagnosis through treatment and long-term follow-up, we need to better understand how to interpret the genetic diversity measured in the blood and how it can be used to describe the true composition of the tumor tissue. In this work we study the evolutionary processes that can lead to genetic discordance between a blood sample and the main tumor tissue and specifically, how tumor spatial heterogeneity shapes these genetic differences. We find that spatial heterogeneity in apoptosis and cellular shedding across different regions of a tumor can significantly bias the mutational composition of ctDNA and emphasize important directions for further theoretical and clinical investigation into the effect of the microenvironment on ctDNA origin and quantification. Circulating tumor DNA (ctDNA) monitoring, while sufficiently advanced to reflect tumor evolution in real time and inform cancer diagnosis, treatment, and prognosis, mainly relies on DNA that originates from cell death via apoptosis or necrosis. In solid tumors, chemotherapy and immune infiltration can induce spatially variable rates of cell death, with the potential to bias and distort the clonal composition of ctDNA. Using a stochastic evolutionary model of boundary-driven growth, we study how elevated cell death on the edge of a tumor can simultaneously impact driver mutation accumulation and the representation of tumor clones and mutation detectability in ctDNA. We describe conditions in which invasive clones are over-represented in ctDNA, clonal diversity can appear elevated in the blood, and spatial bias in shedding can inflate subclonal variant allele frequencies (VAFs). Additionally, we find that tumors that are mostly quiescent can display similar biases but are far less detectable, and the extent of perceptible spatial bias strongly depends on sequence detection limits. Overall, we show that spatially structured shedding might cause liquid biopsies to provide highly biased profiles of tumor state. While this may enable more sensitive detection of expanding clones, it could also increase the risk of targeting a subclonal variant for treatment. Our results indicate that the effects and clinical consequences of spatially variable cell death on ctDNA composition present an important area for future work. [ABSTRACT FROM AUTHOR]

Simple Summary: This review discussed the importance of the gut microbiome for cancer patients and how disturbances in the microbiome can lead to unwanted side effects during cancer treatment. The way in which a variety of foods can influence the microbiota and its abundance was described. Not only this, the effects of antibiotics can also modulate the abundance of the gut microbiome and its diversity. Alterations in the bacterial population can help achieve better immune responses and maintain the intestinal barrier's integrity. In this regard, this article also discussed several advanced approaches utilizing the advantages of probiotics along with immunotherapies. The gut microbiota composition can affect the tumor microenvironment and its interaction with the immune system, thereby having implications for treatment predictions. This article reviews the studies available to better understand how the gut microbiome helps the immune system fight cancer. To describe this fact, different mechanisms and approaches utilizing probiotics to improve advancements in cancer treatment will be discussed. Moreover, not only calorie intake but also the variety and quality of diet can influence cancer patients' immunotherapy treatment because dietary patterns can impair immunological activities either by stimulating or suppressing innate and adaptive immunity. Therefore, it is interesting and critical to understand gut microbiome composition as a biomarker to predict cancer immunotherapy outcomes and responses. Here, more emphasis will be given to the recent development in immunotherapies utilizing microbiota to improve cancer therapies, which is beneficial for cancer patients. [ABSTRACT FROM AUTHOR]

Simple Summary: In order to advance cancer research and personalized care, the Allegheny Health Network Cancer Institute (AHNCI) established a clinical data program (CDP) consisting of a comprehensive biobank and data repository. This includes details on socio-demographic characteristics, diagnosis, tumor characteristics, treatments, and prognosis. By understanding individual patient characteristics, such as genetics, lifestyle, and environmental factors, researchers can determine more effective treatments and preventive interventions. The CDP aids in predicting therapy responses and clinical outcomes through the utilization of cancer-related biomarkers across various disease sites. The CDP supports the initiative by providing comprehensive patient information, such as demographic characteristics, diagnosis details, and treatment responses, which, when combined with genomic data, can enhance the understanding of disease progression and treatment outcomes, thereby facilitating personalized care and precision medicine. Advancing cancer treatment relies on the rapid translation of new scientific discoveries to patient care. To facilitate this, an oncology biobank and data repository program, also referred to as the "Moonshot" program, was launched in 2021 within the Integrated Network Cancer Program of the Allegheny Health Network. A clinical data program (CDP) and biospecimen repository were established, and patient data and blood and tissue samples have been collected prospectively. To date, the study has accrued 2920 patients, predominantly female (61%) and Caucasian (90%), with a mean age of 64 ± 13 years. The most common cancer sites were the endometrium/uterus (12%), lung/bronchus (12%), breast (11%), and colon/rectum (11%). Of patients diagnosed with cancer, 34% were diagnosed at stage I, 25% at stage II, 26% at stage III, and 15% at stage IV. The CDP is designed to support our initiative in advancing personalized cancer research by providing a comprehensive array of patient data, encompassing demographic characteristics, diagnostic details, and treatment responses. The "Moonshot" initiative aims to predict therapy responses and clinical outcomes through cancer-related biomarkers. The CDP facilitates this initiative by fostering data sharing, enabling comparative analyses, and informing the development of novel diagnostic and therapeutic methods. [ABSTRACT FROM AUTHOR]

Simple Summary: Gastric cancer is a major global health issue, ranking among the top causes of cancer-related deaths. Unfortunately, most patients are diagnosed in advanced stages, with only a 6% chance of surviving five years. Current treatment involves a specific drug combination, but predicting its effectiveness is challenging. This review explores the changing world of gastric cancer markers, focusing on Claudin 18.2 (CLDN18.2) as a promising target. Recent trials show that Zolbetuximab, a CLDN18.2-targeting drug, works well with chemotherapy for CLDN18.2-positive gastric cancer. Understanding how to choose these therapies is crucial as this new approach unfolds. This review aims to overview new strategies in managing CLDN18.2 positive advanced gastric cancer. Gastric cancer (GC) remains a formidable global health challenge, ranking among the top-five causes of cancer-related deaths worldwide. The majority of patients face advanced stages at diagnosis, with a mere 6% five-year survival rate. First-line treatment for metastatic GC typically involves a fluoropyrimidine and platinum agent combination; yet, predictive molecular markers have proven elusive. This review navigates the evolving landscape of GC biomarkers, with a specific focus on Claudin 18.2 (CLDN18.2) as an emerging and promising target. Recent phase III trials have unveiled the efficacy of Zolbetuximab, a CLDN18.2-targeting antibody, in combination with oxaliplatin-based chemotherapy for CLDN18.2-positive metastatic GC. As this novel therapeutic avenue unfolds, understanding the nuanced decision making regarding the selection of anti-CLDN18.2 therapies over other targeted agents in metastatic GC becomes crucial. This manuscript reviews the evolving role of CLDN18.2 as a biomarker in GC and explores the current status of CLDN18.2-targeting agents in clinical development. The aim is to provide concise insights into the potential of CLDN18.2 as a therapeutic target and guide future clinical decisions in the management of metastatic GC. [ABSTRACT FROM AUTHOR]

Simple Summary: Cuproptosis is a recently identified form of cell death induced by imbalanced copper levels. We aimed to explore the mechanism underlying copper-induced cell death. To achieve this, we surveyed the literature to understand the biochemical implications of cuproptosis in diseases, particularly in the context of cancer. The concept of copper ionophores, such as elesclomol and disulfiram, is highlighted as they elevate intracellular copper levels, triggering oxidative stress and ultimately leading to cell death–a potential avenue for cancer therapy. Furthermore, we will delve into the intricate relationship between copper, mitochondrial respiration, and protein lipoylation, shedding light on their connections in inducing cell death. Copper, an essential element for various biological processes, demands precise regulation to avert detrimental health effects and potential cell toxicity. This paper explores the mechanisms of copper-induced cell death, known as cuproptosis, and its potential health and disease implications, including cancer therapy. Copper ionophores, such as elesclomol and disulfiram, increase intracellular copper levels. This elevation triggers oxidative stress and subsequent cell death, offering potential implications in cancer therapy. Additionally, copper ionophores disrupt mitochondrial respiration and protein lipoylation, further contributing to copper toxicity and cell death. Potential targets and biomarkers are identified, as copper can be targeted to those proteins to trigger cuproptosis. The role of copper in different cancers is discussed to understand targeted cancer therapies using copper nanomaterials, copper ionophores, and copper chelators. Furthermore, the role of copper is explored through diseases such as Wilson and Menkes disease to understand the physiological mechanisms of copper. Exploring cuproptosis presents an opportunity to improve treatments for copper-related disorders and various cancers, with the potential to bring significant advancements to modern medicine. [ABSTRACT FROM AUTHOR]

Simple Summary: Heat shock proteins (HSPs) are extensively distributed throughout cells. They play a crucial role as molecular chaperones and regulate various cellular processes, such as metabolism, growth, differentiation, cell signaling, and programmed cell death. However, in cancers, HSPs are frequently overexpressed and associated with tumor advancement and metastasis, as well as in acquiring drug resistance against chemotherapeutic agents, leading to poor prognosis. Thus, the expression of HSPs can be modulated to imitate the cellular response against cancer cells by targeting the tumor microenvironment through different mechanisms. For instance, HSPs bind to antigens (peptides) associated with tumors, forming a complex that is easily recognized as an antigen-presenting cell (APC), leading to specific antitumor responses. This review summarizes and discusses recent advances, perspectives, and involvement of HSPs, including small and large HSPs, as well as the molecular mechanisms underlying tumor progression and metastasis. This study may offer new insights into the development of safer and more effective anticancer therapeutics. Heat shock proteins (HSPs) are developmentally conserved families of protein found in both prokaryotic and eukaryotic organisms. HSPs are engaged in a diverse range of physiological processes, including molecular chaperone activity to assist the initial protein folding or promote the unfolding and refolding of misfolded intermediates to acquire the normal or native conformation and its translocation and prevent protein aggregation as well as in immunity, apoptosis, and autophagy. These molecular chaperonins are classified into various families according to their molecular size or weight, encompassing small HSPs (e.g., HSP10 and HSP27), HSP40, HSP60, HSP70, HSP90, and the category of large HSPs that include HSP100 and ClpB proteins. The overexpression of HSPs is induced to counteract cell stress at elevated levels in a variety of solid tumors, including anticancer chemotherapy, and is closely related to a worse prognosis and therapeutic resistance to cancer cells. HSPs are also involved in anti-apoptotic properties and are associated with processes of cancer progression and development, such as metastasis, invasion, and cell proliferation. This review outlines the previously mentioned HSPs and their significant involvement in diverse mechanisms of tumor advancement and metastasis, as well as their contribution to identifying potential targets for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Simple Summary: Clinical management of some cancers requires immunotherapy using immune checkpoint inhibitors (ICI). ICI, however, can result in severe gastrointestinal toxicity, including ICI colitis. The main guidelines recommend the use of corticosteroids or some biologic drugs such as infliximab or vedolizumab. However, little space is given to Janus kinase (JAK)–signal transducer and activator of transcription (STAT) inhibitors. This review summarizes the primary evidence for using JAK-STAT inhibitors in managing ICI colitis. Tofacitinib has been provided in multiple case reports of being able to induce solid clinical remission of ICI colitis without concerns for the oncologic progression of the underlying neoplasm under immunotherapy treatment. Immunotherapy has emerged as a pivotal component in the treatment of various malignancies, encompassing lung, skin, gastrointestinal, and head and neck cancers. The foundation of this therapeutic approach lies in immune checkpoint inhibitors (ICI). While ICIs have demonstrated remarkable efficacy in impeding the neoplastic progression of these tumours, their use may give rise to substantial toxicity, notably in the gastrointestinal domain, where ICI colitis constitutes a significant aspect. The optimal positioning of Janus kinase (JAK)–signal transducer and activator of transcription (STAT) pathway inhibitors in the therapeutic management of ICI colitis remains unclear. Numerous reports have highlighted notable improvements in ICI colitis through the application of pan-JAK-STAT inhibitors, with tofacitinib, in particular, reporting evident clinical remission of colitis. The precise mechanism by which JAK-STAT inhibitors may impact the pathogenetic process of ICI colitis remains inadequately understood. However, there is speculation regarding their potential role in modulating memory resident CD8+ T lymphocytes. The elucidation of this mechanism requires further extensive and robust evidence, and ongoing JAK-STAT-based trials are anticipated to contribute valuable insights. [ABSTRACT FROM AUTHOR]

Simple Summary: PIM3 is a serine/threonine kinase linked to various oncogenic processes and often overexpressed in solid cancers such as pancreatic, liver, colon, stomach, and breast cancers. Upregulation of PIM3 is associated with poor patient prognosis, and its inhibition leads to reduced cell proliferation, invasion, and in vivo tumor growth; thus, PIM3 represents an emerging novel therapeutic target in cancer. Although pan-PIM inhibitors have entered clinical trials in hematological cancers, they were not potent or specific enough or exhibited side effects; thus, currently, there is no FDA-approved inhibitor for targeting all PIMs or PIM3. The development of selective and effective PIM3 inhibitors may have a significant clinical impact and a novel potential therapeutic strategy for PIM3-driven solid and hematological cancers. PIM3 (provirus-integrating Moloney site 3) is a serine/threonine kinase and belongs to the PIM family (PIM1, PIM2, and PIM3). PIM3 is a proto-oncogene that is frequently overexpressed in cancers originating from endoderm-derived tissues, such as the liver, pancreas, colon, stomach, prostate, and breast cancer. PIM3 plays a critical role in activating multiple oncogenic signaling pathways promoting cancer cell proliferation, survival, invasion, tumor growth, metastasis, and progression, as well as chemo- and radiation therapy resistance and immunosuppressive microenvironment. Genetic inhibition of PIM3 expression suppresses in vitro cell proliferation and in vivo tumor growth and metastasis in mice with solid cancers, indicating that PIM3 is a potential therapeutic target. Although several pan-PIM inhibitors entered phase I clinical trials in hematological cancers, there are currently no FDA-approved inhibitors for the treatment of patients. This review provides an overview of recent developments and insights into the role of PIM3 in various cancers and its potential as a novel molecular target for cancer therapy. We also discuss the current status of PIM-targeted therapies in clinical trials. [ABSTRACT FROM AUTHOR]

Simple Summary: In the complex world of cancer, iron and copper play essential roles as trace metal ions that are crucial for cancer cell survival. Disruption in their metabolic functions can be lethal to cancer cells, triggering ferroptosis and cuproptosis, respectively. Given an accelerated proliferation rate, cancer cells exhibit a heightened dependence on iron and copper, exposing vulnerabilities that could potentially be exploited to reverse drug resistance. Notably, mitochondria, the cellular powerhouses, play a crucial role in regulating both ferroptosis and cuproptosis. This review focuses on elucidating the key mechanisms behind ferroptosis and cuproptosis and summarizes recent clinical applications targeting dysfunctional iron and copper metabolic pathways. Drug resistance is a hallmark of cancer development that underscores a critical need to address it, underscoring the critical need to explore novel approaches. Understanding and targeting these metal-related processes offers promising approaches for developing innovative cancer therapies, making use of vulnerabilities specific to cancer cells. Iron (Fe) and copper (Cu), essential transition metals, play pivotal roles in various cellular processes critical to cancer biology, including cell proliferation, mitochondrial respiration, distant metastases, and oxidative stress. The emergence of ferroptosis and cuproptosis as distinct forms of non-apoptotic cell death has heightened their significance, particularly in connection with these metal ions. While initially studied separately, recent evidence underscores the interdependence of ferroptosis and cuproptosis. Studies reveal a link between mitochondrial copper accumulation and ferroptosis induction. This interconnected relationship presents a promising strategy, especially for addressing refractory cancers marked by drug tolerance. Harnessing the toxicity of iron and copper in clinical settings becomes crucial. Simultaneous targeting of ferroptosis and cuproptosis, exemplified by the combination of sorafenib and elesclomol-Cu, represents an intriguing approach. Strategies targeting mitochondria further enhance the precision of these approaches, providing hope for improving treatment outcomes of drug-resistant cancers. Moreover, the combination of iron chelators and copper-lowering agents with established therapeutic modalities exhibits a synergy that holds promise for the augmentation of anti-tumor efficacy in various malignancies. This review elaborates on the complex interplay between ferroptosis and cuproptosis, including their underlying mechanisms, and explores their potential as druggable targets in both cancer research and clinical settings. [ABSTRACT FROM AUTHOR]