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Magnetic resonance imaging (MRI) has been shown to be associated with prognosis in some tumors; however, the correlation in pancreatic ductal adenocarcinoma (PDAC) remains inconclusive. In this retrospective study, we ultimately included 136 patients and analyzed quantitative MRI parameters that are associated with prognosis and recurrence patterns in PDAC using survival analysis and competing risks models; all the patients have been operated on with histopathology and immunohistochemical staining for further evaluation. In intravoxel incoherent motion diffusion-weighted imaging (DWI), we found that pure-diffusion coefficient D value was an independent risk factor for overall survival (OS) (HR: 1.696, 95% CI: 1.003-2.869, p = 0.049) and recurrence-free survival (RFS) (HR: 2.066, 95% CI: 1.252-3.409, p = 0.005). A low D value (≤1.08 × 10 -3 mm 2 /s) was significantly associated with a higher risk of local recurrence (SHR: 5.905, 95% CI: 2.107-16.458, p = 0.001). Subgroup analysis revealed that patients with high D and f values had significantly better outcomes with adjuvant chemotherapy. Distant recurrence patients in the high-D value group who received chemotherapy may significantly improve their OS and RFS. It was found that preoperative multiparametric quantitative MRI correlates with prognosis and recurrence patterns in PDAC. Diffusion coefficient D value can be used as a noninvasive biomarker for predicting prognosis and recurrence patterns in PDAC.

Simple Summary: The quality of life is influenced by individual's characteristics and values, personal's beliefs, physical and mental health and the quality of relationship to others. The researchers want to investigate how the quality of life of primary caregivers changes during care for patient with palliative care needs. It is a prospective longitudinal study that assesses the different aspects of the quality of life of caregivers in care process of palliative care. The caregiver burden which increased during the care of patient have a great and negative impact on quality of life as decrease significantly physical, psycho-emotional and social aspects of this. The primary caregiver is feeling the perception of deteriorating general health. Background/Objectives: The quality of life is a complex concept that is insufficiently assessed in clinical practice. It is influenced by different factors, as follows: the individual's characteristics, personal values and beliefs, physical and mental state, and relationship to other members of their community. The quality of life of the primary caregiver influences their health and the quality of their care interventions. This study aims to investigate how the quality of life of caregivers changes during palliative patients' care. Methods: This is a prospective longitudinal study that assesses the different aspects of the quality of life of primary caregivers who care for patients with palliative needs. The tool used in this study was the Medical Outcomes Scale-Short Form 36 (MOS-SF36). Results: This study included 140 caregivers, of which 63 were involved in the care of patients with cancer and 77 were involved in the care of patients with non-oncological diseases. Almost 9 out of 10 caregivers were a family member of the patient and over two-thirds of these were women. The caregivers of patients with non-malignant diseases had a decreased quality of life in the following aspects: limitations in their usual role due to emotional problems, social functioning, energy, and their perception of their general health. In the group of oncological patients, the caregivers displayed limitations in their daily role due to physical health, emotional problems, and social functioning. Conclusions: The large number of responsibilities, the long time spent caring, and the uncertainty about the evolution of the disease as well as the marginalization and lack of time for oneself are some of the elements that increase caregiver burden. Along with this, the quality of life of caregivers decreases significantly in different aspects, such as physical, psycho-emotional, and social, with the perception of deteriorating general health. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal malignancy characterised by late diagnosis and poor prognosis, with current diagnostic and prognostic strategies proving insufficient. Liquid biopsy techniques, including circulating tumor DNA (ctDNA), circulating tumor cells (CTCs), exosomes, and proteomics, present potential avenues for enhancing PDAC diagnosis, prognosis, and management. A review of literature from 2019 to 2024 identified 49 relevant studies focusing on these biomarkers. Investigations into ctDNA, particularly in detecting mutant KRAS, have shown some diagnostic and prognostic potential, though its efficacy in early-stage disease remains limited. CTCs, whilst highly specific, exhibit similarly restricted diagnostic utility in early disease, and studies have yielded inconsistent prognostic findings. Exosomal research identifies diverse biomarkers with promising diagnostic and prognostic value. Importantly, proteomics demonstrates superior accuracy in PDAC diagnosis, including early-stage detection, and significant prognostic capacity, especially when combined with CA19-9 analysis. This review highlights the significance of continued research into liquid biopsy techniques to improve PDAC management and outcomes. Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy characterised by late diagnosis and poor prognosis. Despite advancements, current diagnostic and prognostic strategies remain limited. Liquid biopsy techniques, including circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), circulating tumour exosomes, and proteomics, offer potential solutions to improve PDAC diagnosis, prognostication, and management. A systematic search of Ovid MEDLINE identified studies published between 2019 and 2024, focusing on liquid biopsy biomarkers for PDAC. A total of 49 articles were included. ctDNA research shows some promise in diagnosing and prognosticating PDAC, especially through detecting mutant KRAS in minimal residual disease assays. CTC analyses had low sensitivity for early-stage PDAC and inconsistent prognostic results across subpopulations. Exosomal studies revealed diverse biomarkers with some diagnostic and prognostic potential. Proteomics, although relatively novel, has demonstrated superior accuracy in PDAC diagnosis, including early detection, and notable prognostic capacity. Proteomics combined with CA19-9 analysis has shown the most promising results to date. An update on multi-cancer early detection testing, given its significance for population screening, is also briefly discussed. Liquid biopsy techniques offer promising avenues for improving PDAC diagnosis, prognostication, and management. In particular, proteomics shows considerable potential, yet further research is needed to validate existing findings and comprehensively explore the proteome using an unbiased approach. [ABSTRACT FROM AUTHOR]

Simple Summary: Inflammation-based prognostic markers have been recognized as useful in a range of oncologic conditions. Given the high mortality rate associated with pancreatic ductal adenocarcinoma (PDAC), the demand for accurate prognostic tools is significant. Nonetheless, the literature still shows conflicting results regarding the effectiveness of the various available scoring systems. Our data confirm that NLR and PNI are useful biomarkers regarding overall survival in PDAC. Especially in advanced disease stages, they seem to be of considerable benefit as easily accessible tools for prognosis prediction. Purpose: Prognostic inflammation-based parameters have been reported as useful tools in various oncologic diseases. Pancreatic ductal adenocarcinoma (PDAC) is characterized by a high mortality rate, making reliable prognostic markers highly desirable. However, there is still inconsistency in the literature regarding the efficacy of the different available scores. Methods: A total of 207 patients, who underwent primary resection of PDAC from January 2000 to December 2018 at the University Hospital of Erlangen, were included in this retrospective single-center study. Different biomarkers, including the preoperative neutrophil–lymphocyte ratio (NLR), the platelet–lymphocyte ratio (PLR), the c-reactive protein (CRP)–albumin ratio (CAR), the lymphocyte–CRP ratio (LCR), the prognostic nutritional index (PNI) and the modified Glasgow prognostic score (mGPS) were analyzed for their ability to predict overall survival (OS). Results: In our cohort, the median overall survival was 20.7 months. Among the investigated biomarkers, NLR and PNI were identified as independent prognostic markers (Hazard Ratio (HR) 1.6 (1.0–2.5), p = 0.048 and HR 0.6 (0.4–0.9), p = 0.018), whereas PLR, CAR, LCR and mGPS did not reach significance in the multivariate analysis. Subgroup analysis revealed that the prognostic value of NLR and PNI is particularly evident in locally advanced tumor stages (pT3/4 and pN+). Conclusions: The NLR and PNI could serve as valuable tools for estimating prognosis in patients with PDAC undergoing pancreatic resection in curative intention, especially in locally advanced tumor stages. However, conflicting results in the current literature highlight the need for further prospective studies to validate these findings. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is challenging to treat due to late diagnosis and limited options. Surgery, the main treatment, often leads to poor long-term outcomes, prompting exploration of alternative approaches like neoadjuvant therapy (NAT) and total neoadjuvant therapy (TNT). While NAT aims to improve surgical success and overall survival, there is room for enhancement, leading to consideration of neoadjuvant strategies combining full-dose chemotherapy and radiotherapy in TNT. TNT, integrating chemotherapy and radiotherapy before surgery, could increase the likelihood of successful surgery and cure for locally advanced cases. This article explores different TNT strategies, categorized based on radiotherapy techniques, offering a thorough analysis of their effectiveness in borderline resectable and locally advanced pancreatic cancer. The central question remains: does more treatment before surgery always yield better results? Pancreatic ductal adenocarcinoma (PDAC) poses a significant challenge in oncology due to its advanced stage upon diagnosis and limited treatment options. Surgical resection, the primary curative approach, often results in poor long-term survival rates, leading to the exploration of alternative strategies like neoadjuvant therapy (NAT) and total neoadjuvant therapy (TNT). While NAT aims to enhance resectability and overall survival, there appears to be potential for improvement, prompting consideration of alternative neoadjuvant strategies integrating full-dose chemotherapy (CT) and radiotherapy (RT) in TNT approaches. TNT integrates chemotherapy and radiotherapy prior to surgery, potentially improving margin-negative resection rates and enabling curative resection for locally advanced cases. The lingering question: is more always better? This article categorizes TNT strategies into six main groups based on radiotherapy (RT) techniques: (1) conventional chemoradiotherapy (CRT), (2) the Dutch PREOPANC approach, (3) hypofractionated ablative intensity-modulated radiotherapy (HFA-IMRT), and stereotactic body radiotherapy (SBRT) techniques, which further divide into (4) non-ablative SBRT, (5) nearly ablative SBRT, and (6) adaptive ablative SBRT. A comprehensive analysis of the literature on TNT is provided for both borderline resectable pancreatic cancer (BRPC) and locally advanced pancreatic cancer (LAPC), with detailed sections for each. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer is a common illness. It can spread to the liver in about a quarter of people with colorectal cancer, known as metastases. Previously, people with liver metastases did not survive for long. Thankfully, this is changing. As we understand more about the underlying causes and genetics of the disease, we can tailor treatments to patients on a more individual basis. Treatments like chemotherapy have made a difference in patients' survival, and now newer treatments like immunotherapy can have even greater benefits. Surgery is also changing, with more advanced techniques allowing for better recovery for patients and more aggressive surgery. It is important for surgeons to consider a large number of individual factors when making decisions with patients about their treatment—this is what we mean by "precision surgery". The incidence of colorectal cancer and colorectal liver metastases (CRLM) is increasing globally due to an interaction of environmental and genetic factors. A minority of patients with CRLM have surgically resectable disease, but for those who have resection as part of multimodal therapy for their disease, long-term survival has been shown. Precision surgery—the idea of careful patient selection and targeting of surgical intervention, such that treatments shown to be proven to benefit on a population level are the optimal treatment for each individual patient—is the new paradigm of care. Key to this is the understanding of tumour molecular biology and clinically relevant mutations, such as KRAS, BRAF, and microsatellite instability (MSI), which can predict poorer overall outcomes and a poorer response to systemic therapy. The emergence of immunotherapy and hepatic artery infusion (HAI) pumps show potential to convert previously unresectable disease to resectable disease, in addition to established systemic and locoregional therapies, but the surgeon must be wary of poor-quality livers and the spectre of post-hepatectomy liver failure (PHLF). Volume modulation, a cornerstone of hepatic surgery for a generation, has been given a shot in the arm with the advent of liver venous depletion (LVD) ensuring significantly more hypertrophy of the future liver remnant (FLR). The optimal timing of liver resection for those patients with synchronous disease is yet to be truly established, but evidence would suggest that those patients requiring complex colorectal surgery and major liver resection are best served with a staged approach. In the operating room, parenchyma-preserving minimally invasive surgery (MIS) can dramatically reduce the surgical insult to the patient and lead to better perioperative outcomes, with quicker return to function. [ABSTRACT FROM AUTHOR]

Simple Summary: The elusive nature of pancreatic cancer frequently results in late diagnoses, which in turn leads to unfavorable treatment outcomes. The existing screening methods lack reliability, and conventional treatments demonstrate limited efficacy. Recent studies have revealed that pancreatic cancer cells interact with their surroundings, specifically through small particles called extracellular vesicles (EVs). These EVs, secreted from cells, carry important molecules, such as miRNAs, proteins, mRNAs, and lipids, that influence cancer growth, metastasis, and response to treatment. Understanding this intercellular communication among cells and microenvironment may help to find a new potential target for novel therapeutic strategies. Pancreatic cancer is a prevalent lethal gastrointestinal cancer that generally does not show any symptoms until it reaches advanced stages, resulting in a high mortality rate. People at high risk, such as those with a family history or chronic pancreatitis, do not have a universally accepted screening protocol. Chemotherapy and radiotherapy demonstrate limited effectiveness in the management of pancreatic cancer, emphasizing the urgent need for innovative therapeutic strategies. Recent studies indicated that the complex interaction among pancreatic cancer cells within the dynamic microenvironment, comprising the extracellular matrix, cancer-associated cells, and diverse immune cells, intricately regulates the biological characteristics of the disease. Additionally, mounting evidence suggests that EVs play a crucial role as mediators in intercellular communication by the transportation of different biomolecules, such as miRNA, proteins, DNA, mRNA, and lipids, between heterogeneous cell subpopulations. This communication mediated by EVs significantly impacts multiple aspects of pancreatic cancer pathogenesis, including proliferation, angiogenesis, metastasis, and resistance to therapy. In this review, we delve into the pivotal role of EV-associated miRNAs in the progression, metastasis, and development of drug resistance in pancreatic cancer as well as their therapeutic potential as biomarkers and drug-delivery mechanisms for the management of pancreatic cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: This study suggests that GLR, along with other factors like CA 19-9 levels and symptoms, can help predict long-term survival outcomes in PDAC patients following surgical resection, aiding in the identification of high-risk individuals who may benefit from closer monitoring or more aggressive treatment approaches. Background: We retrospectively evaluated the usefulness of an elevated glucose-to-lymphocyte ratio (GLR) as a sensitive prognostic biomarker of disease-specific survival in 338 patients who underwent surgical resection of pancreatic ductal adenocarcinoma (PDAC). Methods: The optimal GLR cutoff value was determined using the method of Contal and O'Quigley. Patient demographics, clinical information, and imaging data were analyzed to identify preoperative predictors of long-term survival outcomes. Results: Elevated GLR correlated significantly with aggressive tumor biologic behaviors, such as a high carbohydrate antigen (CA) 19-9 level (p = 0.003) and large tumor size (p = 0.011). Multivariate analysis identified (1) GLR > 92.72 [hazard ratio (HR) = 2.475, p < 0.001], (2) CA 19-9 level > 145.35 (HR = 1.577, p = 0.068), and (3) symptoms (p = 0.064) as independent predictors of long-term, cancer-specific survival. These three risk factors were used to group patients into groups 1 (0 factors), 2 (1–2 factors), and 3 (3 factors), which corresponded to significantly different 5-year overall survival rates (50.2%, 34.6%, and 11.7%, respectively; p < 0.001). Conclusions: An elevated preoperative GLR is associated with aggressive tumor characteristics and is an independent predictor of poor postoperative prognosis in patients with PDAC. Further prospective studies are required to verify these findings. [ABSTRACT FROM AUTHOR]

Simple Summary: Interest in stratification of prognosis for patients with colorectal liver metastases is growing. Numerous clinical prediction models have been developed for this purpose in recent years, either with the aid of traditional statistical methods or by using the aid of artificial intelligence techniques. We herein provide an overview of relevant studies discussing the different types of predictors proven to be of importance and critically assess the variable model development and validation techniques as well as the performance of the reported models. Colorectal liver metastasis (CRLM) is a disease entity that warrants special attention due to its high frequency and potential curability. Identification of "high-risk" patients is increasingly popular for risk stratification and personalization of the management pathway. Traditional regression-based methods have been used to derive prediction models for these patients, and lately, focus has shifted to artificial intelligence-based models, with employment of variable supervised and unsupervised techniques. Multiple endpoints, like overall survival (OS), disease-free survival (DFS) and development or recurrence of postoperative complications have all been used as outcomes in these studies. This review provides an extensive overview of available clinical prediction models focusing on the prognosis of CRLM and highlights the different predictor types incorporated in each model. An overview of the modelling strategies and the outcomes chosen is provided. Specific patient and treatment characteristics included in the models are discussed in detail. Model development and validation methods are presented and critically appraised, and model performance is assessed within a proposed framework. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) continues to be a significant challenge in cancer management, with predictions indicating it will become the second leading cause of cancer-related death by 2030. The persistent poor outcomes in PDAC are partly attributed to a complex tumor microenvironment (TME) that inhibits anti-tumor immunity, restricts the penetration of therapeutics, and facilitates cancer dissemination. Only a few aspects of the TME are routinely documented in the clinical setting, but this may evolve as new TME-directed therapies are developed. In this review, we cover relevant aspects of modern PDAC management, summarize TME-related biomarkers and clinical trials, and discuss the potential challenges associated with evaluating the TME in a clinical context. Advances in our understanding of pancreatic ductal adenocarcinoma (PDAC) and its tumor microenvironment (TME) have the potential to transform treatment for the hundreds of thousands of patients who are diagnosed each year. Whereas the clinical assessment of cancer cell genetics has grown increasingly sophisticated and personalized, current protocols to evaluate the TME have lagged, despite evidence that the TME can be heterogeneous within and between patients. Here, we outline current protocols for PDAC diagnosis and management, review novel biomarkers, and highlight potential opportunities and challenges when evaluating the PDAC TME as we prepare to translate emerging TME-directed therapies to the clinic. [ABSTRACT FROM AUTHOR]

Simple Summary: Finding the best treatment for cancer remains one of the biggest scientific challenges in the 21st century. Available cancer treatments have issues like drug resistance and severe side effects, indicating the need for alternative therapies, especially for patients who do not respond well to regular methods like chemotherapy or surgery. Recently, a new approach, bacteria-mediated cancer therapy, has gained attention. A specific bacterium called Pseudomonas aeruginosa mannose-sensitive-hemagglutinin (PA-MSHA) has shown promise in inhibiting the growth of various cancers, like breast and lung cancer. It works by halting tumor cell growth and prompting their natural death. Clinical studies suggest that PA-MSHA can boost the effectiveness of chemotherapy and activate the immune system against cancer, with mild side effects like fever and skin irritation. This review aims to summarize the current knowledge about the usage of PA-MSHA for cancer treatment, from laboratory studies to clinical trials, understanding both its benefits and potential drawbacks. Cancer is a leading cause of death worldwide, for which finding the optimal therapy remains an ongoing challenge. Drug resistance, toxic side effects, and a lack of specificity pose significant difficulties in traditional cancer treatments, leading to suboptimal clinical outcomes and high mortality rates among cancer patients. The need for alternative therapies is crucial, especially for those resistant to conventional methods like chemotherapy and radiotherapy or for patients where surgery is not possible. Over the past decade, a novel approach known as bacteria-mediated cancer therapy has emerged, offering potential solutions to the limitations of conventional treatments. An increasing number of in vitro and in vivo studies suggest that the subtype of highly virulent Pseudomonas aeruginosa bacterium called Pseudomonas aeruginosa mannose-sensitive-hemagglutinin (PA-MSHA) can successfully inhibit the progression of various cancer types, such as breast, lung, and bladder cancer, as well as hepatocellular carcinoma. PA-MSHA inhibits the growth and proliferation of tumor cells and induces their apoptosis. Proposed mechanisms of action include cell-cycle arrest and activation of pro-apoptotic pathways regulated by caspase-9 and caspase-3. Moreover, clinical studies have shown that PA-MSHA improved the effectiveness of chemotherapy and promoted the activation of the immune response in cancer patients without causing severe side effects. Reported adverse reactions were fever, skin irritation, and pain, attributed to the overactivation of the immune response. This review aims to summarize the current knowledge obtained from in vitro, in vivo, and clinical studies available at PubMed, Google Scholar, and ClinicalTrials.gov regarding the use of PA-MSHA in cancer treatment in order to further elucidate its pharmacological and toxicological properties. [ABSTRACT FROM AUTHOR]

Simple Summary: The evolution of optical imaging in identifying normal from malignant tissues offers great advantages in terms of speed and accuracy of diagnosis. Our results demonstrate that spectroscopic techniques can create informative and rapid tools that can be used to assess axillary lymph node status in breast cancer patients and guide further surgical decision-making. Assessment of regional lymph node status in breast cancer is of important staging and prognostic value. Even though formal histological examination is the currently accepted standard of care, optical imaging techniques have shown promising results in disease diagnosis. In the present article, we review six spectroscopic techniques and focus on their use as alternative tools for breast cancer lymph node assessment. Elastic scattering spectroscopy (ESS) seems to offer a simple, cost-effective, and reproducible method for intraoperative diagnosis of breast cancer lymph node metastasis. Optical coherence tomography (OCT) provides high-resolution tissue scanning, along with a short data acquisition time. However, it is relatively costly and experimentally complex. Raman spectroscopy proves to be a highly accurate method for the identification of malignant axillary lymph nodes, and it has been further validated in the setting of head and neck cancers. Still, it remains time-consuming. Near-infrared fluorescence imaging (NIRF) and diffuse reflectance spectroscopy (DFS) are related to significant advantages, such as deep tissue penetration and efficiency. Fourier-transform infrared spectroscopy (FTIR) is a promising method but has significant drawbacks. Nonetheless, only anecdotal reports exist on their clinical use for cancerous lymph node detection. Our results indicate that optical imaging methods can create informative and rapid tools to effectively guide surgical decision-making. [ABSTRACT FROM AUTHOR]

Simple Summary: Genetic information is seldom incorporated in formulating radiation treatment recommendations for patients with cancer, even though genetic information is now well established to be prognostic and predictive of cancer outcomes and response to systemic therapy. With the increasing accessibility to and use of genetic testing, tumor, and germline genetic data have the potential to inform clinical decisions by improving the efficacy of radiation treatment and ensuring the safety of treatment delivery. This review summarizes the biological underpinning of "radio-sensitizing genes", discusses the clinical basis and evidence for identifying genetic mutations as radiation response biomarkers, and proposes future directions for research as well as clinical implementation. Radiation treatment (RT) is a mainstay treatment for many types of cancer. Recommendations for RT and the radiation plan are individualized to each patient, taking into consideration the patient's tumor pathology, staging, anatomy, and other clinical characteristics. Information on germline mutations and somatic tumor mutations is at present rarely used to guide specific clinical decisions in RT. Many genes, such as ATM, and BRCA1/2, have been identified in the laboratory to confer radiation sensitivity. However, our understanding of the clinical significance of mutations in these genes remains limited and, as individual mutations in such genes can be rare, their impact on tumor response and toxicity remains unclear. Current guidelines, including those from the National Comprehensive Cancer Network (NCCN), provide limited guidance on how genetic results should be integrated into RT recommendations. With an increasing understanding of the molecular underpinning of radiation response, genomically-guided RT can inform decisions surrounding RT dose, volume, concurrent therapies, and even omission to further improve oncologic outcomes and reduce risks of toxicities. Here, we review existing evidence from laboratory, pre-clinical, and clinical studies with regard to how genetic alterations may affect radiosensitivity. We also summarize recent data from clinical trials and explore potential future directions to utilize genetic data to support clinical decision-making in developing a pathway toward personalized RT. [ABSTRACT FROM AUTHOR]

Simple Summary: The high mortality of pancreatic cancer (PaC) is due to different reasons: a lack of specific symptoms, an unlikely diagnosis, therapies' paucity, and drug resistance onset. For this reason, it is of paramount importance to develop new strategies to cure this incurable malignancy. Exosomes are secreted by all kinds of cells and used for intercellular communications. They are also used by cancer cells to induce drug resistance. Understanding how PaC cells use exosomes in drug resistance onset represents a supplemental weapon to cure PaC patients. Pancreatic cancer (PaC) is one of the most lethal tumors worldwide, difficult to diagnose, and with inadequate therapeutical chances. The most used therapy is gemcitabine, alone or in combination with nanoparticle albumin-bound paclitaxel (nab-paclitaxel), and the multidrug FOLFIRINOX. Unfortunately, PaC develops resistance early, thus reducing the already poor life expectancy of patients. The mechanisms responsible for drug resistance are not fully elucidated, and exosomes seem to be actively involved in this phenomenon, thanks to their ability to transfer molecules regulating this process from drug-resistant to drug-sensitive PaC cells. These extracellular vesicles are released by both normal and cancer cells and seem to be essential mediators of intercellular communications, especially in cancer, where they are secreted at very high numbers. This review illustrates the role of exosomes in PaC drug resistance. This manuscript first provides an overview of the pharmacological approaches used in PaC and, in the last part, focuses on the mechanisms exploited by the exosomes released by cancer cells to induce drug resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: Lipids are the main structural component of cellular membranes; they play an essential role in cellular functions. For the growth and progression of cancer, tumor cells require lipid-related metabolic and structural adaptations, such as altered lipid membrane composition, which is in part regulated by lipid flippases. Type IV P-type ATPases (P4-ATPases), the main class of flippases, are responsible for membrane lipid asymmetry, and thus they are closely involved in cancer-related lipid changes. Lately, flippases have gained more attention regarding the pathobiology of human disease. This review focuses on recent publications discussing the role of P4-ATPases in cancer development, progression, and prospective treatment. Adaptations of cancer cells for survival are remarkable. One of the most significant properties of cancer cells to prevent the immune system response and resist chemotherapy is the altered lipid metabolism and resulting irregular cell membrane composition. The phospholipid distribution in the plasma membrane of normal animal cells is distinctly asymmetric. Lipid flippases are a family of enzymes regulating membrane asymmetry, and the main class of flippases are type IV P-type ATPases (P4-ATPases). Alteration in the function of flippases results in changes to membrane organization. For some lipids, such as phosphatidylserine, the changes are so drastic that they are considered cancer biomarkers. This review will analyze and discuss recent publications highlighting the role that P4-ATPases play in the development and progression of various cancer types, as well as prospects of targeting P4-ATPases for anti-cancer treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) is a morbid malignancy with discouraging survival rates. Enthusiasm for pre-operative therapy (chemotherapy, radiation, chemoradiation) in the treatment of PDAC has grown, with many clinical guidelines recommending its use in patients with borderline resectable tumors. The purpose of this review is to discuss important surgical considerations for the use of pre-operative therapy in patients with pancreatic cancer undergoing curative intent surgery. These considerations include accurately determining tumor resectability, vascular resection, reconstruction when tumors involve surrounding vascular structures, and implementing pre-operative fitness programs to improve treatment outcomes. We also discuss methods to evaluate the response of PDAC to pre-operative therapy such as CA 19-9 levels, imaging studies, and others that are currently being studied for potential use in the future. Preoperative therapy can provide many benefits to patients with pancreatic cancer undergoing surgery, but a comprehensive understanding of several surgical considerations is needed. Pancreatic ductal adenocarcinoma (PDAC) is a challenging disease process with a 5-year survival rate of only 11%. Neoadjuvant therapy in patients with localized pancreatic cancer has multiple theoretical benefits, including improved patient selection for surgery, early delivery of systemic therapy, and assessment of response to therapy. Herein, we review key surgical considerations when selecting patients for neoadjuvant therapy and curative-intent resection. Accurate determination of resectability at diagnosis is critical and should be based on not only anatomic criteria but also biologic and clinical criteria to determine optimal treatment sequencing. Borderline resectable or locally advanced pancreatic cancer is best treated with neoadjuvant therapy and resection, including vascular resection and reconstruction when appropriate. Lastly, providing nutritional, prehabilitation, and supportive care interventions to improve patient fitness prior to surgical intervention and adequately address the adverse effects of therapy is critical. [ABSTRACT FROM AUTHOR]

Simple Summary: In this study, X-ray Photoelectron Spectroscopy (XPS) is used as a fast technique to characterize the composition of nanosized small extracellular vesicles (EVs), with the aim of evaluating its possible application in cancer screening and diagnosis. This spectroscopic technique is an ideal approach to characterize membranes due to its sensitivity and its penetration depth, in the nanometric range, meaning that the results will mainly correspond to the membrane composition, with little interference from the biomolecules in the EV´s lumen. We propose the use of XPS to analyze the membranes of small extracellular vesicles isolated from bodily fluids of cancer patients and compared them to those of healthy cells and donors. Notably, we have focused our analysis on the N chemical environment of EV membranes, as this can be related to previous complex chemical analyses of lipid and protein contents in EVs. We provide preliminary results on a fast and non-invasive novel strategy, as a method or tool for research-based EV investigations with potential application in cancer screening and monitoring. Small extracellular vesicle (EV) membranes display characteristic protein-lipidic composition features that are related to their cell of origin, providing valuable clues regarding their parental cell composition and real-time state. This could be especially interesting in the case of cancer cell-derived EVs, as their membranes could serve as valuable tools in liquid biopsy applications and to detect changes in the tumor malignancy. X-Ray Photoelectron Spectroscopy (XPS) is a powerful surface analysis technique able to detect every chemical element present, being also sensitive to their chemical environment. Here we explore the use of XPS as a fast technique to characterize EV membrane composition, with possible application in cancer research. Notably, we have focused on the nitrogen environment as an indicator of the relative abundance of pyridine-type bonding, primary, secondary and tertiary amines. Specifically, we have analyzed how tumoral and healthy cells have different nitrogen chemical environments that can indicate the presence or absence of malignancy. In addition, a collection of human serum samples from cancer patients and healthy donors was also analyzed. The differential XPS analysis of EVs collected from patients confirmed that the patterns of amine evolution could be related to markers of cancer disease, opening the possibility of their use as a non-invasive blood biomarker. [ABSTRACT FROM AUTHOR]

Simple Summary: The choice of the surgical and therapeutic approach for patients suffering from neuroendocrine liver metastases (NELM) plays a central role in the therapeutic strategy. Whilst debulking surgery is widely accepted as an alternative approach for eligible patients, its prognostic influence remains a point of discussion. With the advent of minimally invasive liver surgery (MILS), its applicability for the treatment of neuroendocrine tumors has scarcely been described. Here, we aimed to investigate different surgical strategies in the multimodal treatment of NELM, including minimally invasive approaches. Tumor debulking showed comparable survival outcomes to curative intended liver surgery, and MILS was not inferior to open liver surgery in terms of survival rates and as such should be recommended also in patients with NELM. Indications for liver resection in patients with gastroenteropancreatic neuroendocrine tumors (GEP-NET) vary from liver resection with curative intent to tumor debulking or tissue sampling for histopathological characterization. With increasing expertise, the number of minimally invasive liver surgeries (MILS) in GEP-NET patients has increased. However, the influence on the oncological outcome has hardly been described. The clinicopathological data of patients who underwent liver resection for hepatic metastases of GEP-NET at the Department of Surgery, Charité—Universitätsmedizin Berlin, were analyzed. Propensity score matching (PSM) was performed to compare MILS with open liver surgery (OLS). In total, 22 patients underwent liver surgery with curative intent, and 30 debulking surgeries were analyzed. Disease-free survival (DFS) was longer than progression-free survival (PFS) (10 vs. 24 months), whereas overall survival (OS) did not differ significantly (p = 0.588). Thirty-nine (75%) liver resections were performed as OLS, and thirteen (25%) as MILS. After PSM, a shorter length of hospital stay was found for the MILS group (14 vs. 10 d, p = 0.034), while neither DFS/PFS nor OS differed significantly. Both curative intended and cytoreductive resection of hepatic GEP-NET metastases achieved excellent outcomes. MILS led to a reduced length of hospital, while preserving a good oncological outcome. [ABSTRACT FROM AUTHOR]

Simple Summary: Gastrointestinal (GI) cancers are a common cancer, affecting both men and women, normally diagnosed through tissue biopsies in combination with imaging techniques and standardized biomarkers leading to patient selection for local or systemic therapies. Liquid biopsies (LBs)—due to their non-invasive nature as well as low risk—are the current focus of cancer research and could be a promising tool for early cancer detection and treatment surveillance, thus leading to better patient outcomes. In this review, we provide an overview of different types of LBs enabling early detection and monitoring of GI cancers and their clinical application. Worldwide, gastrointestinal (GI) cancers account for a significant amount of cancer-related mortality. Tests that allow an early diagnosis could lead to an improvement in patient survival. Liquid biopsies (LBs) due to their non-invasive nature as well as low risk are the current focus of cancer research and could be a promising tool for early cancer detection. LB involves the sampling of any biological fluid (e.g., blood, urine, saliva) to enrich and analyze the tumor's biological material. LBs can detect tumor-associated components such as circulating tumor DNA (ctDNA), extracellular vesicles (EVs), and circulating tumor cells (CTCs). These components can reflect the status of the disease and can facilitate clinical decisions. LBs offer a unique and new way to assess cancers at all stages of treatment, from cancer screenings to prognosis to management of multidisciplinary therapies. In this review, we will provide insights into the current status of the various types of LBs enabling early detection and monitoring of GI cancers and their use in in vitro diagnostics. [ABSTRACT FROM AUTHOR]

Simple Summary: The gold standard for detecting cancer and profiling tumors is tissue biopsies. Despite this, tissue biopsies have been associated with many limitations leading to the desire for less invasive and more accurate solutions. One very attractive candidate for the diagnosis and prognosis of cancer in patients is provided by liquid biopsies. The number of analytes circulating in the blood that may be used for liquid biopsy testing is enormous making it a promising technique for the clinical management of oncological patients. The goal of this study is to discuss in detail the clinical relevance of liquid biopsies, as well as the opportunities they might offer for cancer prognosis, diagnosis and monitoring. The isolation process and clinical use of the biological components of the liquid biopsy will also be explained, with specific focus placed on novel procedures that can be developed as well as the approach's future possibilities. Cancer is among the leading causes of death worldwide. Early diagnosis and prognosis are vital to improve patients' outcomes. The gold standard of tumor characterization leading to tumor diagnosis and prognosis is tissue biopsy. Amongst the constraints of tissue biopsy collection is the sampling frequency and the incomplete representation of the entire tumor bulk. Liquid biopsy approaches, including the analysis of circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), circulating miRNAs, and tumor-derived extracellular vesicles (EVs), as well as certain protein signatures that are released in the circulation from primary tumors and their metastatic sites, present a promising and more potent candidate for patient diagnosis and follow up monitoring. The minimally invasive nature of liquid biopsies, allowing frequent collection, can be used in the monitoring of therapy response in real time, allowing the development of novel approaches in the therapeutic management of cancer patients. In this review we will describe recent advances in the field of liquid biopsy markers focusing on their advantages and disadvantages. [ABSTRACT FROM AUTHOR]

Simple Summary: Prostate cancer is a highly heterogenous disease with respect to molecular, morphological and clinical features. Therefore, one of the major tasks in its management is to define the risk subgroups that would guide the treatment approach. Amino acid metabolism-related genes are involved in several aspects of prostate cancer progression. In this publication, we show that their expression is highly aberrant in prostate cancer, which could be potentially exploited for the establishment of disease progression parameters and therapeutic targets. We show that among the variables studied, the Gleason score was the strongest prognostic factor of progression-free survival in multivariate analysis. Additionally, the expression of SERINC3 and CSAD genes strongly differentiated between better and worse prognosis (low and high risk) for high and low Gleason scores, respectively. These results offer a suggestion for potential biomarkers of prostate cancer progression in patients that are stratified by the Gleason score. Prostate cancer is among the leading cancers according to both incidence and mortality. Due to the high molecular, morphological and clinical heterogeneity, the course of prostate cancer ranges from slow growth that usually does not require immediate therapeutic intervention to aggressive and fatal disease that spreads quickly. However, currently available biomarkers cannot precisely predict the course of a disease, and novel strategies are needed to guide prostate cancer management. Amino acids serve numerous roles in cancers, among which are energy production, building block reservoirs, maintenance of redox homeostasis, epigenetic regulation, immune system modulation and resistance to therapy. In this article, by using The Cancer Genome Atlas (TCGA) data, we found that the expression of amino acid metabolism-related genes is highly aberrant in prostate cancer, which holds potential to be exploited in biomarker design or in treatment strategies. This change in expression is especially evident for catabolism genes and transporters from the solute carrier family. Furthermore, by using recursive partitioning, we confirmed that the Gleason score is strongly prognostic for progression-free survival. However, the expression of the genes SERINC3 (phosphatidylserine and sphingolipids generation) and CSAD (hypotaurine generation) can refine prognosis for high and low Gleason scores, respectively. Therefore, our results hold potential for novel prostate cancer progression biomarkers. [ABSTRACT FROM AUTHOR]

Simple Summary: In cancer therapy, mitochondrial metabolism has emerged as a particularly attractive target, especially for malignancies such as pancreatic ductal adeno carcinoma (PDAC) that are resistant to treatment. Along with other treatment approaches, including targeting glutamine and fatty acid metabolism and inhibiting the tricarboxylic acid (TCA) cycle precursors, mitochondrial oxidative phosphorylation (OXPHOS) is still a key target in cancer therapy. To the advantage of PDAC patients, innovative and more effective therapeutics will be possible with a greater understanding of how pancreatic cancer cells control mitochondrial metabolism, and their role in PDAC progression through modulating cellular dynamics, bioenergetics, immune education, and retrograde signaling. Pancreatic ductal adenocarcinoma (PDAC), the fourteenth most common malignancy, is a major contributor to cancer-related death with the utmost case fatality rate among all malignancies. Functional mitochondria, regardless of their complex ecosystem relative to normal cells, are essential in PDAC progression. Tumor cells' potential to produce ATP as energy, despite retaining the redox potential optimum, and allocating materials for biosynthetic activities that are crucial for cell growth, survival, and proliferation, are assisted by mitochondria. The polyclonal tumor cells with different metabolic profiles may add to carcinogenesis through inter-metabolic coupling. Cancer cells frequently possess alterations in the mitochondrial genome, although they do not hinder metabolism; alternatively, they change bioenergetics. This can further impart retrograde signaling, educate cell signaling, epigenetic modifications, chromatin structures, and transcription machinery, and ultimately satisfy cancer cellular and nuclear demands. To maximize the tumor microenvironment (TME), tumor cells remodel nearby stromal cells and extracellular matrix. These changes initiate polyclonality, which is crucial for growth, stress response, and metastasis. Here, we evaluate all the intrinsic and extrinsic pathways drawn by mitochondria in carcinogenesis, emphasizing the perspectives of mitochondrial metabolism in PDAC progression and treatment. [ABSTRACT FROM AUTHOR]

Simple Summary: Aptamer is a targeting tool with many unique advantages, therefore many experts screened corresponding aptamers in various hematologic malignancies for diagnosis and targeted treatment. In this review, we try to summarize the research progress of aptamers in the diagnosis and treatment of hematologic malignancies to provide support for the application of aptamers in hematologic malignancies. Currently, research for hematological malignancies is very intensive, with many breakthroughs. Among them, aptamer-based targeted therapies could be counted. Aptamer is a targeting tool with many unique advantages (easy synthesis, low toxicity, easy modification, low immunogenicity, nano size, long stability, etc.), therefore many experts screened corresponding aptamers in various hematological malignancies for diagnosis and treatment. In this review, we try to summarize and provide the recent progress of aptamer research in the diagnosis and treatment of hematologic malignancies. Until now, 29 aptamer studies were reported in hematologic malignancies, of which 12 aptamers were tested in vivo and the remaining 17 aptamers were only tested in vitro. In this case, 11 aptamers were combined with chemotherapeutic drugs for the treatment of hematologic malignancies, 4 aptamers were used in combination with nanomaterials for the diagnosis and treatment of hematologic malignancies, and some studies used aptamers for the targeted transportation of siRNA and miRNA for targeted therapeutic effects. Their research provides multiple approaches to achieve more targeted goals. These findings show promising and encouraging future for both hematological malignancies basic and clinical trials research. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) remains one of the most lethal cancers worldwide, with a poor prognosis and an increasing incidence. Recently, the tumor microenvironment, including its neural component, has gained the attention of cancer researchers. Neural regulation of pancreatic cancer carcinogenesis is, however, poorly understood. Only lately have the diversified autonomic nerve fibers been noticed in cancer research. Targeting sympathetic and parasympathetic nerves in various malignancies, including PDAC, may bring new therapies into clinical practice. Omnipresent perineural invasion in pancreatic cancer is associated with a poor prognosis. Moreover, novel quantification with a distinction between perineural and endoneural invasion could help stratify the risk of relapse and mortality for patients with this cancer. Newly described biologic phenomena—cancer-related axonogenesis and neurogenesis—are understudied in pancreatic cancer. This review aims to summarize and integrate the role of nerves in PDAC. Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive primary malignancy of the pancreas, with a dismal prognosis and limited treatment options. It possesses a unique tumor microenvironment (TME), generating dense stroma with complex elements cross-talking with each other to promote tumor growth and progression. Diversified neural components makes for not having a full understanding of their influence on its aggressive behavior. The aim of the study was to summarize and integrate the role of nerves in the pancreatic tumor microenvironment. The role of autonomic nerve fibers on PDAC development has been recently studied, which resulted in considering the targeting of sympathetic and parasympathetic pathways as a novel treatment opportunity. Perineural invasion (PNI) is commonly found in PDAC. As the severity of the PNI correlates with a poorer prognosis, new quantification of this phenomenon, distinguishing between perineural and endoneural invasion, could feature in routine pathological examination. The concepts of cancer-related neurogenesis and axonogenesis in PDAC are understudied; so, further research in this field may be warranted. A better understanding of the interdependence between the neural component and cancer cells in the PDAC microenvironment could bring new nerve-oriented treatment options into clinical practice and improve outcomes in patients with pancreatic cancer. In this review, we aim to summarize and integrate the current state of knowledge and future challenges concerning nerve–cancer interactions in PDAC. [ABSTRACT FROM AUTHOR]

Simple Summary: Individualized diagnostics approaches in modern cancer therapy require predictive and prognostic biomarkers that are easily accessible and stratify patients for optimal and individualized treatment. Pancreatic ductal adenocarcinoma (PDAC) is still a life-threatening disease mainly because of its late diagnosis in advanced stages or rapid progress even in patients with curative resection of the primary tumor. Moreover, patients with liver metastases exhibit an even worse prognosis. Hence, this retrospective multi-center study aims to identify biomarkers in perioperative serum of PDAC patients predicting early liver metastasis. A highly sensitive biomarker analysis was performed using two different methodological approaches. Olink® analysis, which was also used to validate LEGENDplexTM results, identified significant differences in proteins involved in chemotaxis and migration of immune cells as well as cell growth in serum of patients with early versus late onset of liver metastasis. Further studies with larger cohorts are required to validate these findings for clinical translation. Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive solid malignancies with poor survival rates. Only 20% of the patients are eligible for R0-surgical resection, presenting with early relapses, mainly in the liver. PDAC patients with hepatic metastases have a worse outcome compared to patients with metastases at other sites. Early detection of hepatic spread bears the potential to improve patient outcomes. Thus, this study sought for serum-based perioperative biomarkers allowing discrimination of early (EHMS ≤ 12 months) and late hepatic metastatic spread (LHMS > 12 months). Serum samples from 83 resectable PDAC patients were divided into EHMS and LHMS and analyzed for levels of inflammatory mediators by LEGENDplexTM, which was validated and extended by Olink® analysis. CA19-9 serum levels served as control. Results were correlated with clinicopathological data. While serum CA19-9 levels were comparable, Olink® analysis confirmed distinct differences between both groups. It revealed significantly elevated levels of factors involved in chemotaxis and migration of immune cells, immune activity, and cell growth in serum of LHMS-patients. Overall, Olink® analysis identified a comprehensive biomarker panel in serum of PDAC patients that could provide the basis for predicting LHMS. However, further studies with larger cohorts are required for its clinical translation. [ABSTRACT FROM AUTHOR]

Simple Summary: A highly desirable approach to diagnose a human disease quickly and easily is to identify a chemical, protein, or antibody in a biofluid like blood or urine that is uniquely associated with the disease state and can serve as a diagnostic biomarker. Metabolomics is the study of the set of metabolites or small molecular-weight compounds found in cells, tissues, organs, and organisms. Thus, metabolomics is being widely applied to a variety of human diseases including various cancers to identify potential metabolite biomarkers for disease diagnosis and personalized medicine. Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related death and has the lowest five-year survival rate primarily due to the lack of an early diagnosis. A total of 24 metabolomics studies have been reported in the scientific literature that aimed to identify diagnostic biomarkers for PDAC. We analyzed the outcomes from these 24 studies in detail and observed a high level of inconsistencies in the identified metabolites that we attributed to a variety of experimental factors. Despite this negative outcome, we did identify a set of 10 metabolites that were consistently detected by several clinical studies and have the potential to serve as PDAC biomarkers and warrant further investigation. Clinical metabolomics is a rapidly expanding field focused on identifying molecular biomarkers to aid in the efficient diagnosis and treatment of human diseases. Variations in study design, metabolomics methodologies, and investigator protocols raise serious concerns about the accuracy and reproducibility of these potential biomarkers. The explosive growth of the field has led to the recent availability of numerous replicate clinical studies, which permits an evaluation of the consistency of biomarkers identified across multiple metabolomics projects. Pancreatic ductal adenocarcinoma (PDAC) is the third-leading cause of cancer-related death and has the lowest five-year survival rate primarily due to the lack of an early diagnosis and the limited treatment options. Accordingly, PDAC has been a popular target of clinical metabolomics studies. We compiled 24 PDAC metabolomics studies from the scientific literature for a detailed meta-analysis. A consistent identification across these multiple studies allowed for the validation of potential clinical biomarkers of PDAC while also highlighting variations in study protocols that may explain poor reproducibility. Our meta-analysis identified 10 metabolites that may serve as PDAC biomarkers and warrant further investigation. However, 87% of the 655 metabolites identified as potential biomarkers were identified in single studies. Differences in cohort size and demographics, p-value choice, fold-change significance, sample type, handling and storage, data collection, and analysis were all factors that likely contributed to this apparently large false positive rate. Our meta-analysis demonstrated the need for consistent experimental design and normalized practices to accurately leverage clinical metabolomics data for reliable and reproducible biomarker discovery. [ABSTRACT FROM AUTHOR]

Simple Summary: Nerve–cancer cross-talk has increasingly become a focus of the oncology field, particularly in gastrointestinal (GI) cancers. The indispensable roles of the nervous system in GI tumorigenesis and malignancy have been dissected by epidemiological, experimental animal and mechanistic data. Herein, we review and integrate recent discoveries linking the nervous system to GI cancer initiation and progression, and focus on the molecular mechanisms by which nerves and neural receptor pathways drive GI malignancy. Our understanding of the fascinating connection between nervous system and gastrointestinal (GI) tumorigenesis has expanded greatly in recent years. Recent studies revealed that neurogenesis plays an active part in GI tumor initiation and progression. Tumor-driven neurogenesis, as well as neurite outgrowth of the pre-existing peripheral nervous system (PNS), may fuel GI tumor progression via facilitating cancer cell proliferation, chemoresistance, invasion and immune escape. Neurotransmitters and neuropeptides drive the activation of various oncogenic pathways downstream of neural receptors within cancer cells, underscoring the importance of neural signaling pathways in GI tumor malignancy. In addition, neural infiltration also plays an integral role in tumor microenvironments, and contributes to an environment in favor of tumor angiogenesis, immune evasion and invasion. Blockade of tumor innervation via denervation or pharmacological agents may serve as a promising therapeutic strategy against GI tumors. In this review, we summarize recent findings linking the nervous system to GI tumor progression, set the spotlight on the molecular mechanisms by which neural signaling fuels cancer aggressiveness, and highlight the importance of targeting neural mechanisms in GI tumor therapy. [ABSTRACT FROM AUTHOR]

Simple Summary: The indolent nature of some cancers makes early detection challenging, as such significant effort is placed on identifying circulating cancer biomarkers using minimally invasive, highly sensitive diagnostic assays. Biological fluids contain small extracellular vesicles including exosomes, which have many tissue origins. Cancer cells increase production and release of exosomes in the circulation to deliver biologically active compounds that can reprogram recipient cells, which potentially represent a valuable source of biomarkers. In this review, we evaluate the biogenesis of exosomes to understand how cancer cells alter their production and how their molecular cargoes interact with the microenvironment. Next, we provide a comprehensive inventory of techniques available for exosome purification, as this represents the most critical aspect for sensitive and specific evaluation of their biomarker content. Finally, we provide a current evaluation of their use as human cancer biomarkers. Although diagnostic and therapeutic treatments of cancer have tremendously improved over the past two decades, the indolent nature of its symptoms has made early detection challenging. Thus, inter-disciplinary (genomic, transcriptomic, proteomic, and lipidomic) research efforts have been focused on the non-invasive identification of unique "silver bullet" cancer biomarkers for the design of ultra-sensitive molecular diagnostic assays. Circulating tumor biomarkers, such as CTCs and ctDNAs, which are released by tumors in the circulation, have already demonstrated their clinical utility for the non-invasive detection of certain solid tumors. Considering that exosomes are actively produced by all cells, including tumor cells, and can be found in the circulation, they have been extensively assessed for their potential as a source of circulating cell-specific biomarkers. Exosomes are particularly appealing because they represent a stable and encapsulated reservoir of active biological compounds that may be useful for the non-invasive detection of cancer. T biogenesis of these extracellular vesicles is profoundly altered during carcinogenesis, but because they harbor unique or uniquely combined surface proteins, cancer biomarker studies have been focused on their purification from biofluids, for the analysis of their RNA, DNA, protein, and lipid cargoes. In this review, we evaluate the biogenesis of normal and cancer exosomes, provide extensive information on the state of the art, the current purification methods, and the technologies employed for genomic, transcriptomic, proteomic, and lipidomic evaluation of their cargoes. Our thorough examination of the literature highlights the current limitations and promising future of exosomes as a liquid biopsy for the identification of circulating tumor biomarkers. [ABSTRACT FROM AUTHOR]

Simple Summary: In pancreatic cancer, immunotherapy and targeted therapies have not brought about the therapeutic revolution that has been observed in other malignancies. Among the reasons to explain this difference is the possibly crucial role played by the pancreatic tumor microenvironment, which has unique features and is different from that of other neoplasms. The aim of this review is to provide a comprehensive overview of the distinctive tumor immune microenvironment of pancreatic cancer and to summarize existing data about the use of immunotherapy and immune biomarkers in this cancer. The advent of immunotherapy and targeted therapies has dramatically changed the outcomes of patients affected by many malignancies. Pancreatic cancer (PC) remains one the few tumors that is not treated with new generation therapies, as chemotherapy still represents the only effective therapeutic strategy in advanced-stage disease. Agents aiming to reactivate the host immune system against cancer cells, such as those targeting immune checkpoints, failed to demonstrate significant activity, despite the success of these treatments in other tumors. In many cases, the proportion of patients who derived benefits in early-phase trials was too small and unpredictable to justify larger studies. The population of PC patients with high microsatellite instability/mismatch repair deficiency is currently the only population that may benefit from immunotherapy; nevertheless, the prevalence of these alterations is too low to determine a real change in the treatment scenario of this tumor. The reasons for the unsuccess of immunotherapy may lie in the extremely peculiar tumor microenvironment, including distinctive immune composition and cross talk between different cells. These unique features may also explain why the biomarkers commonly used to predict immunotherapy efficacy in other tumors seem to be useless in PC. In the current paper, we provide a comprehensive and up-to-date review of immunotherapy in PC, from the analysis of the tumor immune microenvironment to immune biomarkers and treatment outcomes, with the aim to highlight that simply transferring the knowledge acquired on immunotherapy in other tumors might not be a successful strategy in patients affected by PC. [ABSTRACT FROM AUTHOR]

Simple Summary: Multidrug resistance (MDR) is a major cause of breast cancer (BC) chemotherapy failure. Long noncoding RNAs (lncRNAs) have been shown closely related to the chemoresistance of BC. In this work, the mechanisms of lncRNA-mediated MDR in BC were elaborated from eight sections, including apoptosis, autophagy, DNA repair, cell cycle, drug efflux, epithelial-mesenchymal transition, epigenetic modification and the tumor microenvironment. Additionally, we also discuss the clinical significance of lncRNAs, which may be biomarkers for diagnosis, therapy and prognosis. Breast cancer (BC) is a highly heterogeneous disease and presents a great threat to female health worldwide. Chemotherapy is one of the predominant strategies for the treatment of BC; however, multidrug resistance (MDR) has seriously affected or hindered the effect of chemotherapy. Recently, a growing number of studies have indicated that lncRNAs play vital and varied roles in BC chemoresistance, including apoptosis, autophagy, DNA repair, cell cycle, drug efflux, epithelial-mesenchymal transition (EMT), epigenetic modification and the tumor microenvironment (TME). Although thousands of lncRNAs have been implicated in the chemoresistance of BC, a systematic review of their regulatory mechanisms remains to be performed. In this review, we systematically summarized the mechanisms of MDR and the functions of lncRNAs mediated in the chemoresistance of BC from the latest literature. These findings significantly enhance the current understanding of lncRNAs and suggest that they may be promising prognostic biomarkers for BC patients receiving chemotherapy, as well as therapeutic targets to prevent or reverse chemoresistance. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is one of the most heterogeneous and aggressive tumours that exist. The median survival of diagnosed patients is limited. For all these reasons, it is necessary to develop new disease markers that allow guidelines for clinical action to improve the average survival of patients with pancreatic cancer. The incidence and prevalence of pancreatic adenocarcinoma have increased in recent years. Pancreatic cancer is the seventh leading cause of cancer death, but it is projected to become the second leading cause of cancer-related mortality by 2040. Most patients are diagnosed in an advanced stage of the disease, with very limited 5-year survival. The discovery of different tissue markers has elucidated the underlying pathophysiology of pancreatic adenocarcinoma and allowed stratification of patient risk at different stages and assessment of tumour recurrence. Due to the invasive capacity of this tumour and the absence of screening markers, new immunohistochemical and serological markers may be used as prognostic markers for recurrence and in the study of possible new therapeutic targets because the survival of these patients is low in most cases. The present article reviews the currently used main histopathological and serological markers and discusses the main characteristics of markers under development. [ABSTRACT FROM AUTHOR]

Pancreatic ductal adenocarcinoma (PDAC) is the most prevalent form of pancreatic cancer and carries the worst prognosis of all common cancers. Five-year survival rates have not surpassed 6% for some decades and this lack of improvement in outcome urges a better understanding of the PDAC-specific features which contribute to this poor result. One of the most defining features of PDAC known to contribute to its progression is the abundance of non-tumor cells and material collectively known as the stroma. It is now well recognized that the different non-cancer cell types, signalling molecules, and mechanical properties within a tumor can have both tumor-promoting as well as-inhibitory effects. However, the net effect of this intratumour heterogeneity is not well understood. Heterogeneity in the stromal makeup between patients is even less well established. Such intertumour heterogeneity is likely to be affected by the relative contributions of individual stromal constituents, but how these contributions exactly relate to existing classifications that demarcate intertumour heterogeneity in PDAC is not fully known. In this review, we give an overview of the available evidence by delineating the elements of the PDAC stroma and their contribution to tumour growth. We do so by interpreting the heterogeneity at the gene expression level in PDAC, and how stromal elements contribute to, or interconnect, with this. [ABSTRACT FROM AUTHOR]

Pancreatic cancer is typically characterized by its aggressive tumor growth and dismal prognosis. Approximately 30% of patients with pancreatic cancer present with locally advanced disease, broadly defined as having a tumor-to-artery interface >180°, having an unreconstructable portal vein or superior mesenteric vein and no signs of metastatic disease. These patients are currently designated to palliative systemic chemotherapy, though median overall survival remains poor (approximately 11 months). Therefore, several innovative local therapies have been investigated as new treatment options for locally advanced pancreatic cancer (LAPC). This article provides an overview of available data with regard to morbidity and oncological outcome of novel local therapies for LAPC. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) with peritoneal dissemination is a highly lethal disease. Recently, promising activity of intraperitoneal chemotherapy with paclitaxel (i.p.-PTX) has been observed in patients with peritoneal dissemination. We conducted a retrospective comparative study to evaluate the clinical efficacy of i.p.-PTX combined with systemic chemotherapy versus standard systemic chemotherapy in PDAC patients with peritoneal dissemination. The median survival time was 10.2 months for patients in the standard therapy group and 17.9 months in the i.p.-PTX group; the difference between groups was statistically significant (p = 0.006). We have performed surgical resection (defined as conversion surgery) to responders to treatment. Conversion surgery was planned for 26% in the i.p.-PTX group and 8% in the standard therapy group. The median survival time (27.4 months) from initial treatment in patients who underwent conversion surgery was significantly longer than that in patients who did not undergo conversion surgery (11.3 months, p < 0.0001). Implementation of the i.p.-PTX regimen may improve survival in patients with PDAC with peritoneal dissemination. Background: Intraperitoneal chemotherapy using paclitaxel (i.p.-PTX) is expected to be a new therapeutic strategy for patients with pancreatic ductal adenocarcinoma (PDAC) and peritoneal dissemination. We evaluated the survival benefit of i.p.-PTX compared with standard systemic chemotherapy. Methods: Clinical data of 101 consecutive PDAC patients with peritoneal dissemination between 2007 and 2018 were analyzed. All patients were determined to have no other sites of distant organ metastasis to the lung, bone, or liver on contrast-enhanced CT imaging. Patients underwent staging laparoscopy or open laparotomy to confirm pathological evidence of peritoneal dissemination, and to exclude occult liver metastasis. Survival curves were estimated using the Kaplan–Meier method, and differences were compared using the log-rank test. Results: Forty-three patients were treated with i.p.-PTX (i.p.-PTX group) and forty-nine patients received standard systemic chemotherapy (Ctrl group). Nine patients did not receive any treatment (BSC group). The median survival time (MST) in the i.p.-PTX group was significantly longer than that in the Ctrl group (17.9 months vs. 10.2 months, p = 0.006). Negative peritoneal washing cytology was observed in 24 out of 43 patients in the i.p.-PTX group. The i.p.-PTX group tended to have a higher proportion of clinical responses than the Ctrl group (30% vs. 18%, p = 0.183). Conversion surgery was performed in 10 patients in the i.p.-PTX group and 2 patients in the Ctrl group after confirming disappearance of peritoneal dissemination with staging laparoscopy or open laparotomy (p = 0.005). The MST in patients who underwent surgical resection was significantly longer than that in patients who did not (27.4 months vs. 11.3 months; p < 0.0001). Conclusion: i.p.-PTX therapy provided improved survival in PDAC patients with peritoneal dissemination, and conversion surgery enhanced it in patients with favorable responses to chemotherapy. i.p.-PTX might become one of the treatment options to PDAC patients with peritoneal dissemination. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma is a devastating illness but guidelines consider it unresectable once metastasized. However, resection of the primary tumor is carried out in select cases and retrospective analyses indicate that this may improve survival. Even so, these analyses are limited to single centers or fail to account for biased patient selection. We overcome these limitations with a propensity score-matched SEER database analysis that reliably demonstrates surgery can extend overall survival. Furthermore, we identify prognostic factors that could aid the selection of patients for randomized controlled trials. Thus, this study paves the way for future work that aims to update treatment guidelines in accordance with surgical developments. Guidelines do not recommend resection surgery for oligometastatic pancreatic ductal adenocarcinoma (PDAC). However, reports in small samples of selected patients suggest that surgery extends survival. Thus, this study aims to gather evidence for the benefits of cancer-directed surgery (CDS) by analyzing a national cohort and identifying prognostic factors that aid the selection of candidates for CDS or recruitment into experimental trials. Data for patients with PDAC and hepatic metastasis were extracted from the population-based Surveillance, Epidemiology, and End Results database (SEER). The bias between CDS and non-CDS groups was minimized with Propensity Score Matching (PSM), and the prognostic role of CDS was investigated by comparing Kaplan-Meier estimators and Cox proportional hazard models. A total of 12,018 patients were extracted from the database, including 259 patients who underwent CDS that were 1:1 propensity score-matched with patients who did not receive CDS. CDS appeared to significantly prolong median overall survival from 5 to 10 months. Multivariate analysis revealed chemotherapy as a protective prognostic, whilst survival was impaired by old age and tumors that were poorly differentiated (Grades III–IV). These factors can be used to select patients likely to benefit from CDS treatment, which may facilitate recruitment into randomized controlled trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive neoplasm with a poor survival rate. This is mainly due to late detection, which substantially limits therapy options. A better understanding of the early phases of pancreatic carcinogenesis is fundamental for improving patient prognosis in the future. In this article, we focused on the tumor microenvironment (TME), which provides the biological niche for the development of PDAC from its most common precursor lesions, PanIN (pancreatic intraepithelial neoplasias). Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with a poor prognosis. A characteristic of PDAC is the formation of an immunosuppressive tumor microenvironment (TME) that facilitates bypassing of the immune surveillance. The TME consists of a desmoplastic stroma, largely composed of cancer-associated fibroblasts (CAFs), immunosuppressive immune cells, immunoregulatory soluble factors, neural network cells, and endothelial cells with complex interactions. PDAC develops from various precursor lesions such as pancreatic intraepithelial neoplasia (PanIN), intraductal papillary mucinous neoplasms (IPMN), mucinous cystic neoplasms (MCN), and possibly, atypical flat lesions (AFL). In this review, we focus on the composition of the TME in PanINs to reveal detailed insights into the complex restructuring of the TME at early time points in PDAC progression and to explore ways of modifying the TME to slow or even halt tumor progression. [ABSTRACT FROM AUTHOR]

Simple Summary: Breast and gynecological cancers, broadly termed as female-oriented cancers, are the primary cause of death among females in developed and developing countries. Tumor invasion and metastasis cause the aggressiveness of these cancer types. The occurrence and frequency of women's cancers are associated with genetics, personal lifestyle, body shape, age, menopause status, history of exposure to carcinogens or viruses, and geographical habitat. Moreover, ncRNAs, especially lncRNAs, play an essential role in regulating cellular functions within such cancers. LncRNAs can play dual roles. They can either exert tumor-suppressive or oncogenic functions in women's cancers. Accumulating evidence suggests that lncRNAs can be promising prognostic and diagnostic biomarkers and therapeutic targets in cancers. Thus, understanding the mechanism and role of lncRNAs might provide new opportunities for diagnosing and treating female-oriented cancers. In this review, we discuss the worldwide incidence of breast and gynecological cancers, including endometrial, cervical, ovarian, vaginal, vulvar cancers, and GTN among women. We further provide various perspectives on the association of some lncRNAs, i.e., HOTAIR, NEAT1, H19, MALAT1, and MEG3, in terms of invasion, proliferation, metastasis, apoptosis, and drug resistance of breast and gynecological cancers based on recent discoveries. Finally, we present insight and prospects into the potential of these lncRNAs for evaluating the prognosis, diagnosis, and treatment of such cancers. Recent advances in molecular biology have discovered the mysterious role of long non-coding RNAs (lncRNAs) as potential biomarkers for cancer diagnosis and targets for advanced cancer therapy. Studies have shown that lncRNAs take part in the incidence and development of cancers in humans. However, previously they were considered as mere RNA noise or transcription byproducts lacking any biological function. In this article, we present a summary of the progress on ascertaining the biological functions of five lncRNAs (HOTAIR, NEAT1, H19, MALAT1, and MEG3) in female-oriented cancers, including breast and gynecological cancers, with the perspective of carcinogenesis, cancer proliferation, and metastasis. We provide the current state of knowledge from the past five years of the literature to discuss the clinical importance of such lncRNAs as therapeutic targets or early diagnostic biomarkers. We reviewed the consequences, either oncogenic or tumor-suppressing features, of their aberrant expression in female-oriented cancers. We tried to explain the established mechanism by which they regulate cancer proliferation and metastasis by competing with miRNAs and other mechanisms involved via regulating genes and signaling pathways. In addition, we revealed the association between stated lncRNAs and chemo-resistance or radio-resistance and their potential clinical applications and future perspectives. [ABSTRACT FROM AUTHOR]

Simple Summary: Perineural invasion is a complicated process involving a series of cells and extracellular matrix components in the tumor microenvironment, particularly the crosstalk between cancer cells and neurons. Perineural invasion occurs in many malignant tumors, including gastric carcinoma, biliary tract tumor and pancreatic cancer. It is identified in approximately 80–100% of pancreatic cancer patients and is correlated with poor survival and decreased quality of life. Extensive studies have revealed the subtle molecule regulatory mechanisms during perineural invasion, as well as the potential causal link with pancreatic cancer-associated pain. Here, we introduce the underlying mechanism of perineural invasion and its possible relationship with the intractable pain in pancreatic cancer patients. Pancreatic ductal adenocarcinoma (PDAC) is one of the cancers with the highest incidence of perineural invasion (PNI), which often indicates a poor prognosis. Aggressive tumor cells invade nerves, causing neurogenic inflammation; the tumor microenvironment also induces nerves to undergo a series of structural and functional reprogramming. In turn, neurons and the surrounding glial cells promote the development of pancreatic cancer through autocrine and/or paracrine signaling. In addition, hyperalgesia in PDAC patients implies alterations of pain transmission in the peripheral and central nervous systems. Currently, the studies on this topic are relatively limited. This review will elaborate on the mechanisms of tumor–neural interactions and its possible relationship with pain from several aspects that have been focused on in recent years. [ABSTRACT FROM AUTHOR]

Simple Summary: The interactions between cancer cells and the surrounding blood vessels and peripheral nerves are critical in all the phases of tumor development. Accordingly, therapies that specifically target vessels and nerves represent promising anticancer approaches. The first aim of this review is to document the importance of blood vessels and peripheral nerves in both cancer onset and local or distant growth of tumoral cells. We then focus on the state-of-the-art therapies that limit cancer progression through the impairment of blood vessels and peripheral nerves. The mentioned literature is helpful for the scientific community to appreciate the recent advances in these two fundamental components of tumors. Cancer cells continuously interact with the tumor microenvironment (TME), a heterogeneous milieu that surrounds the tumor mass and impinges on its phenotype. Among the components of the TME, blood vessels and peripheral nerves have been extensively studied in recent years for their prominent role in tumor development from tumor initiation. Cancer cells were shown to actively promote their own vascularization and innervation through the processes of angiogenesis and axonogenesis. Indeed, sprouting vessels and axons deliver several factors needed by cancer cells to survive and proliferate, including nutrients, oxygen, and growth signals, to the expanding tumor mass. Nerves and vessels are also fundamental for the process of metastatic spreading, as they provide both the pro-metastatic signals to the tumor and the scaffold through which cancer cells can reach distant organs. Not surprisingly, continuously growing attention is devoted to the development of therapies specifically targeting these structures, with promising initial results. In this review, we summarize the latest evidence that supports the importance of blood vessels and peripheral nerves in cancer pathogenesis, therapy resistance, and innovative treatments. [ABSTRACT FROM AUTHOR]

Simple Summary: Due to their systemic nature, metastatic lesions are a major problem for curative cancer treatment. According to a common model for metastasis, tumor cells disseminate by local invasion, survival in the blood stream and extravasation into suitable tissue environments. At secondary sites, metastatic cells adapt, proliferate and foster vascularization to satisfy nutrient and oxygen demand. In recent years, tumors were shown to extensively communicate with cells in the local microenvironment and future metastatic sites by secreting small extracellular vesicles (sEVs, exosomes). sEVs deliver bioactive cargos, e.g., proteins, and in particular, several nucleic acid classes to reprogram target cells, which in turn facilitate tumor growth, cell motility, angiogenesis, immune evasion and establishment of pre-metastatic niches. sEV-cargos also act as biomarkers for diagnosis and prognosis. This review discusses how tumor cells utilize sEVs with nucleic acid cargos to progress through metastasis, and how sEVs may be employed for prognosis and treatment. Cancer is a complex disease, driven by genetic defects and environmental cues. Systemic dissemination of cancer cells by metastasis is generally associated with poor prognosis and is responsible for more than 90% of cancer deaths. Metastasis is thought to follow a sequence of events, starting with loss of epithelial features, detachment of tumor cells, basement membrane breakdown, migration, intravasation and survival in the circulation. At suitable distant niches, tumor cells reattach, extravasate and establish themselves by proliferating and attracting vascularization to fuel metastatic growth. These processes are facilitated by extensive cross-communication of tumor cells with cells in the primary tumor microenvironment (TME) as well as at distant pre-metastatic niches. A vital part of this communication network are small extracellular vesicles (sEVs, exosomes) with a size of 30–150 nm. Tumor-derived sEVs educate recipient cells with bioactive cargos, such as proteins, and in particular, major nucleic acid classes, to drive tumor growth, cell motility, angiogenesis, immune evasion and formation of pre-metastatic niches. Circulating sEVs are also utilized as biomarker platforms for diagnosis and prognosis. This review discusses how tumor cells facilitate progression through the metastatic cascade by employing sEV-based communication and evaluates their role as biomarkers and vehicles for drug delivery. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is one of the deadliest solid malignancies. Pancreatic ductal adenocarcinoma accounts for 90% of pancreatic cancer cases with minimal response to traditional chemotherapies. Protein tyrosine kinases have been shown to be hyperactivated in cancers and thus can serve as therapeutic targets. Patient-derived tumor xenografts (PDXs) in animal models such as mice are an appropriate resource to identify such activated kinases. PDXs models are excellent for the identification of therapeutic targets as compared to cell line models as they better reflect an in vivo environment. We identified ephrin type-B receptor 4 (EphB4) as hyperactivated in PDXs derived from pancreatic ductal adenocarcinoma. Pancreatic ductal adenocarcinoma is a recalcitrant tumor with minimal response to conventional chemotherapeutic approaches. Oncogenic signaling by activated tyrosine kinases has been implicated in cancers resulting in activation of diverse effector signaling pathways. Thus, the discovery of aberrantly activated tyrosine kinases is of great interest in developing novel therapeutic strategies in the treatment and management of pancreatic cancer. Patient-derived tumor xenografts (PDXs) in mice serve as potentially valuable preclinical models as they maintain the histological and molecular heterogeneity of the original human tumor. Here, we employed high-resolution mass spectrometry combined with immunoaffinity purification using anti-phosphotyrosine antibodies to profile tyrosine phosphoproteome across 13 pancreatic ductal adenocarcinoma PDX models. This analysis resulted in the identification of 1199 tyrosine-phosphorylated sites mapping to 704 proteins. The mass spectrometric analysis revealed widespread and heterogeneous activation of both receptor and non-receptor tyrosine kinases. Preclinical studies confirmed ephrin type-B receptor 4 (EphB4) as a potential therapeutic target based on the efficacy of human serum albumin-conjugated soluble EphB4 in mice bearing orthotopic xenografts. Immunohistochemistry-based validation using tissue microarrays from 346 patients with PDAC showed significant expression of EphB4 in >70% of patients. In summary, we present a comprehensive landscape of tyrosine phosphoproteome with EphB4 as a promising therapeutic target in pancreatic ductal adenocarcinoma. [ABSTRACT FROM AUTHOR]

Simple Summary: The increased incidence and global failure of ongoing therapies project pancreatic cancer as the second deadliest cancer worldwide. While our knowledge of pancreatic cancer cells' abilities and specificities has drastically improved based on multi-scaled omics, one must consider that much more remains to be uncovered on the role and impact of stromal cells and the established network of communication with tumor cells. This review article discusses how tumor cells communicate with the various cells composing the stroma and its implication in tumor cells' abilities, PDA (pancreatic ductal adenocarcinoma) carcinogenesis and therapeutic response. We will focus on extracellular vesicles-mediated crosstalk and how this multifaceted dialogue impacts both cellular compartments and its subsequent impact on PDA biology. Deciphering the interactions between tumor and stromal cells is a growing field of research to improve pancreatic cancer-associated therapies and patients' care. Indeed, while accounting for 50 to 90% of the tumor mass, many pieces of evidence reported that beyond their structural role, the non-tumoral cells composing the intra-tumoral microenvironment influence tumor cells' proliferation, metabolism, cell death and resistance to therapies, among others. Simultaneously, tumor cells can influence non-tumoral neighboring or distant cells in order to shape a tumor-supportive and immunosuppressive environment as well as influencing the formation of metastatic niches. Among intercellular modes of communication, extracellular vesicles can simultaneously transfer the largest variety of signals and were recently reported as key effectors of cell–cell communication in pancreatic cancer, from its development to its evolution as well as its ability to resist available treatments. This review focuses on extracellular vesicles-mediated communication between different cellular components of pancreatic tumors, from the modulation of cellular activities and abilities to their biological and physiological relevance. Taking into consideration the intra-tumoral microenvironment and its extracellular-mediated crosstalk as main drivers of pancreatic cancer development should open up new therapeutic windows. [ABSTRACT FROM AUTHOR]

Simple Summary: To improve clinical outcomes, early diagnosis is mandatory in cancer patients. Several diagnostic approaches have been proposed, however, the main drawback relies on the invasive procedures required. Extracellular vesicles (EVs) are bilayer lipid membrane structures released by almost all cells and transferred to remote sites via the bloodstream. The observation that their cargo reflects the cell of origin has opened a new frontier for non-invasive biomarker discovery in oncology. Moreover, since EVs can be recovered from different body fluids, their impact as a Correctdiagnostic tool has gained particular interest. Hence, in the last decade, several studies using different biological fluids have been performed, showing the valuable contributions of EVs as tumour biomarkers, and their improved diagnostic power when combined with currently available tumour markers. In this review, the most relevant data on the diagnostic relevance of EVs, alone or in combination with the well-established tumour markers, are discussed. Early diagnosis, along with innovative treatment options, are crucial to increase the overall survival of cancer patients. In the last decade, extracellular vesicles (EVs) have gained great interest in biomarker discovery. EVs are bilayer lipid membrane limited structures, released by almost all cell types, including cancer cells. The EV cargo, which consists of RNAs, proteins, DNA, and lipids, directly mirrors the cells of origin. EVs can be recovered from several body fluids, including blood, cerebral spinal fluid (CSF), saliva, and Broncho-Alveolar Lavage Fluid (BALF), by non-invasive or minimally invasive approaches, and are therefore proposed as feasible cancer diagnostic tools. In this review, methodologies for EV isolation and characterization and their impact as diagnostics for the central nervous system, head and neck, lung, and gastrointestinal cancers are outlined. For each of these tumours, recent data on the potential clinical applications of the EV's unique cargo, alone or in combination with currently available tumour biomarkers, have been deeply discussed. [ABSTRACT FROM AUTHOR]

Simple Summary: Circulating tumor cells (CTCs) found in the blood of pancreatic cancer patients show a worse prognosis to therapy if they are seen in clusters of cells with neutrophils or platelets or with other cell types than when they are seen as singlets. We wanted to investigate if there is a secondary mode of communication between the CTCs and neutrophils that causes them to associate. We describe for the first time an extravesicular (EV) mediated communication between CTCs and neutrophils that modulates early transcriptome changes that can cause neutrophils to partially degranulate and form associations. We also identify the protein cargo carried in such EVs and how when added to naïve neutrophils, they can modulate transcriptomic changes in neutrophils partially disarming them to form clusters rather than undergo specialized cell death, which is characterized by release of condensed chromatin (NETs) and granular contents termed as NETosis. Tumor cells dissociate from the primary site and enter into systemic circulation (circulating tumor cells, CTCs) either alone or as tumor microemboli (clusters); the latter having an increased predisposition towards forming distal metastases than single CTCs. The formation of clusters is, in part, created by contacts between cell–cell junction proteins and/or cytokine receptor pairs with other cells such as neutrophils, platelets, fibroblasts, etc. In the present study, we provide evidence for an extravesicular (EV) mode of communication between pancreatic cancer CTCs and neutrophils. Our results suggest that the EV proteome of CTCs contain signaling proteins that can modulate degranulation and granule mobilization in neutrophils and, also, contain tissue plasminogen activator and other proteins that can regulate cluster formation. By exposing naïve neutrophils to EVs isolated from CTCs, we further show how these changes are modulated in a dynamic fashion indicating evidence for a deeper EV based remodulatory effect on companion cells in clusters. [ABSTRACT FROM AUTHOR]

Simple Summary: Approximately 60% of all melanomas are associated with a constitutive activating BRAF mutation. Inhibition of BRAF downstream signaling by targeted therapies significantly improved patient outcomes. However, most patients eventually develop resistance. Here we identified miR-129-5p as a novel tumor suppressor in BRAF mutated melanoma, which expression is increased during response to BRAF inhibition, but repressed in an EZH2 dependent manner during activated BRAF signaling. Overexpression of miR-129-5p decreases melanoma cell proliferation and improves response to BRAF inhibition by targeting SOX4. Taken together our results emphasize SOX4 as a potential therapeutic target in BRAF driven melanoma which could be attacked by pharmaceutically. Many melanomas are associated with activating BRAF mutation. Targeted therapies by inhibitors of BRAF and MEK (BRAFi, MEKi) show marked antitumor response, but become limited by drug resistance. The mechanisms for this are not fully revealed, but include miRNA. Wishing to improve efficacy of BRAFi and knowing that certain miRNAs are linked to resistance to BRAFi, we wanted to focus on miRNAs exclusively associated with response to BRAFi. We found increased expression of miR-129-5p during BRAFi treatment of BRAF- mutant melanoma cells. Parallel to emergence of resistance we observed mir-129-5p expression to become suppressed by BRAF/EZH2 signaling. In functional analyses we revealed that miR-129-5p acts as a tumor suppressor as its overexpression decreased cell proliferation, improved treatment response and reduced viability of BRAFi resistant melanoma cells. By protein expression analyses and luciferase reporter assays we confirmed SOX4 as a direct target of mir-129-5p. Thus, modulation of the miR-129-5p-SOX4 axis could serve as a promising novel strategy to improve response to BRAFi in melanoma. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastatic pancreatic ductal adenocarcinoma (mPDAC) has a dismal prognosis. In selected patients with limited metastatic disease, locoregional therapy, in addition to systemic chemotherapy, may improve survival. This systematic review sought to examine current evidence on the value of additional locoregional treatment, including resection, ablation and embolization, in patients with hepatic or pulmonary mPDAC. The results, although liable to substantial bias, demonstrated superior survival from metastatic diagnosis or treatment in a subset of patients after radical-intent local primary and metastatic treatment (hepatic mPDAC 7.8–19 months; pulmonary mPDAC 22.8–47 months) compared to chemotherapy or best supportive care (hepatic mPDAC 4.3–7.6 months; pulmonary mPDAC 11.8 months). However, as a consequence of the bias, definitive conclusions regarding the seemingly beneficial effect of locoregional treatment cannot be endorsed. Randomized controlled trials with strictly selected oligometastatic PDAC patients are required to deduce final recommendations on this notion. The prognosis of metastatic pancreatic ductal adenocarcinoma (mPDAC) remains universally poor, requiring new and innovative treatment approaches. In a subset of oligometastatic PDAC patients, locoregional therapy, in addition to systemic chemotherapy, may improve survival. The aim of this systematic review was to explore and evaluate the current evidence on locoregional treatments for mPDAC. A systematic literature search was conducted on locoregional techniques, including resection, ablation and embolization, for mPDAC with a focus on hepatic and pulmonary metastases. A total of 59 studies were identified, including 63,453 patients. Although subject to significant bias, radical-intent local therapy for both the primary and metastatic sites was associated with a superior median overall survival from metastatic diagnosis or treatment (hepatic mPDAC 7.8–19 months; pulmonary mPDAC 22.8–47 months) compared to control groups receiving chemotherapy or best supportive care (hepatic mPDAC 4.3–7.6 months; pulmonary mPDAC 11.8 months). To recruit patients that may benefit from these local treatments, selection appears essential. Most significant is the upfront possibility of local radical pancreatic and metastatic treatment. In addition, a patient's response to neoadjuvant systemic chemotherapy, performance status, metastatic disease load and, to a lesser degree, histological differentiation grade and tumor marker CA19-9 serum levels, are powerful prognostic factors that help identify eligible subjects. Although the exact additive value of locoregional treatments for mPDAC patients cannot be distillated from the results, locoregional primary pancreatic and metastatic treatment seems beneficial for a highly selected group of oligometastatic PDAC patients. For definite recommendations, well-designed prospective randomized controlled trials with strict in- and exclusion criteria are needed to validate these results. [ABSTRACT FROM AUTHOR]

Simple Summary: The survival after surgical removal of pancreatic cancer is remaining dismal with frequent cases of treatment failure by early cancer recurrence. There are currently no means to preoperatively identify those at risk for early recurrence. Circulating tumour cells (CTCs) have been shown to identify high-risk individuals in a variety of cancer types. We did explore the impact of CTC detection with the FDA-approved CellSearch® test on relapse and survival after removal of pancreatic cancer by surgery. CTCs were detected in about 7% of patients. The presence of CTCs in samples taken before the operation was associated with earlier cancer metastasis and shorter survival. The survival impact of CTCs was comparable to or exceeded the risk-factors that become available only after the operation like spread to lymph nodes or aggressive tissue growth patterns. We conclude that the detection of CTCs by this method warrants further exploration of its clinical application in presumed operable pancreatic cancer. In patients with presumed pancreatic ductal adenocarcinoma (PDAC), biomarkers that may open for personalised, risk-adapted treatment are lacking. The study analysed the impact of CTCs-presence on the patterns of recurrence and survival in 98 patients resected for PDAC with 5–10 years of follow-up. Preoperative samples were analysed by the CellSearch® system for EpCAM+/DAPI+/CK+/CD45-CTCs. CTCs were detected in 7 of the 98 patients. CTCs predicted a significantly shorter median disease-free survival (DFS) of 3.3 vs. 9.2 months and a median cancer specific survival (CSS)of 6.3 vs. 18.5 months. Relapse status was confirmed by imaging for 87 patients. Of these, 58 patients developed distant metastases (DM) and 29 developed isolated local recurrence (ILR) as the first sign of cancer relapse. All patients with CTCs experienced DM. pN-status and histological grade >2 were other independent risk factors for DM, but only CTCs predicted significantly shorter cancer-specific, disease-free and post-recurrence survival. Preoperative parameters did not affect clinical outcome. We conclude that CTC presence in resected PDAC patients predicted early distant metastasis and impaired survival. Preoperative CTCs alone or in combination with histopathological factors may guide initial treatment decisions in patients with resectable PDAC in the future. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer remains a highly lethal disease, with only ~10% of patients still alive five years after diagnosis, as most patients already have advanced, metastatic disease at the time of diagnosis. Therefore, new treatments are needed for these patients. We tested INCB057643, a novel bromodomain inhibitor, in a relevant mouse model of pancreatic cancer, and this compound improves survival and reduces metastasis. Pancreatic cancers are very dense, as the stroma within the tumor can account for up to 90% of the tumor mass and is responsible for the failure of many drugs. INCB057643 modulates the immune cells within the tumor so they can attack and kill tumor cells. INCB057643 also alters immune cells within the pancreas in a mouse model of pancreatitis, which is inflammation of the pancreas that can promote the development of pancreatic cancer. In pancreatic cancer the tumor microenvironment (TME) can account for up to 90% of the tumor mass. The TME drives essential functions in disease progression, invasion and metastasis. Tumor cells can use epigenetic modulation to evade immune recognition and shape the TME toward an immunosuppressive phenotype. Bromodomain inhibitors are a class of drugs that target BET (bromodomain and extra-terminal) proteins, impairing their ability to bind to acetylated lysines and therefore interfering with transcriptional initiation and elongation. INCB057643 is a new generation, orally bioavailable BET inhibitor that was developed for treating patients with advanced malignancies. KrasG12D/+; Trp53R172H/+; Pdx-1-Cre (KPC) mice mimic human disease, with similar progression and incidence of metastasis. Treatment of established tumors in KPC mice with INCB057643 increased survival by an average of 55 days, compared to the control group. Moreover, INCB057643 reduced metastatic burden in these mice. KPC mice treated with INCB057643, starting at 4 weeks of age, showed beneficial changes in immune cell populations in the pancreas and liver. Similarly, INCB057643 modified immune cell populations in the pancreas of KrasG12D/+; Pdx-1-Cre (KC) mice with pancreatitis, an inflammatory process known to promote pancreatic cancer progression. The data presented here suggest that the bromodomain inhibitor INCB057643 modulates the TME, reducing disease burden in two mouse models of pancreatic cancer. Furthermore, this work suggests that BRD4 may play a role in establishing the TME in the liver, a primary metastatic site for pancreatic cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Despite considerable improvements in diagnosis and treatment, drug resistance remains the main cause of death in BC. Multiple lines of evidence demonstrated that ncRNAs play a vital role in BC resistance. Here, we summarized the molecular mechanisms by which miRNAs and lncRNAs may impact the therapeutic response in BC, highlighting that these molecules can be further exploited as predictive biomarkers and therapeutic targets. By merging data from various studies, we concluded that several ncRNAs, such as miR-221, miR-222, miR-451, UCA1, and GAS5 are strong candidates for pharmacological interventions since they are involved in resistance to all forms of therapies in BC. Therefore, we believe that our review provides an important reservoir of molecules that may translate into clinically useful biomarkers, laying the ground for the adoption of ncRNAs within mainstream routine oncology clinical practice. Whether acquired or de novo, drug resistance remains a significant hurdle in achieving therapeutic success in breast cancer (BC). Thus, there is an urge to find reliable biomarkers that will help in predicting the therapeutic response. Stable and easily accessible molecules such as microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) are regarded as valuable prognostic biomarkers and therapeutic targets since they act as crucial regulators of the various mechanisms involved in BC drug resistance. Here, we reviewed the current literature on ncRNAs as mediators of resistance to systemic therapies in BC. Interestingly, upon integrating data results from individual studies, we concluded that miR-221, miR-222, miR-451, Urothelial Carcinoma Associated 1 (UCA1), and Growth arrest-specific 5 (GAS5) are strong candidates as prognostic biomarkers and therapeutic targets since they are regulating multiple drug resistance phenotypes in BC. However, further research around their clinical implications is needed to validate and integrate them into therapeutic applications. Therefore, we believe that our review may provide relevant evidence for the selection of novel therapeutic targets and prognostic biomarkers for BC and will serve as a foundation for future translational research in the field. [ABSTRACT FROM AUTHOR]

Epithelial–mesenchymal transitions (EMTs) generate hybrid phenotypes with an enhanced ability to adapt to diverse microenvironments encountered during the metastatic spread. Accordingly, EMTs play a crucial role in the biology of circulating tumor cells (CTCs) and contribute to their heterogeneity. Here, we review major EMT-driven properties that may help hybrid Epithelial/Mesenchymal CTCs to survive in the bloodstream and accomplish early phases of metastatic colonization. We then discuss how interrogating EMT in CTCs as a companion biomarker could help refine cancer patient management, further supporting the relevance of CTCs in personalized medicine. [ABSTRACT FROM AUTHOR]