Search

Simple Summary: The primary treatment for operable pancreatic cancer involves surgery followed by adjuvant therapy, with an increasing use of perioperative or neoadjuvant chemotherapy. We performed a network meta-analysis to assess the comparative efficacy of various treatment approaches for resectable pancreatic cancer. A total of 24 studies were incorporated, comparing 21 treatments with surgery in isolation. Eleven treatments showed superior efficacy compared to surgery alone. Excluding Asian studies, the perioperative regimen of gemcitabine combined with nab-paclitaxel was the most effective regimen. The findings endorse the utilization of perioperative and multi-agent chemotherapy as the favored intervention for operable PC in Western nations. The primary treatment for operable pancreatic cancer (PC) involves surgery followed by adjuvant therapy. Nevertheless, perioperative or neoadjuvant chemotherapy (CT) may be used to mitigate the likelihood of recurrence and mortality. This network meta-analysis (NMA) assesses the comparative efficacy of various treatment approaches for resectable PC. A thorough search was carried out on January 31, 2023, encompassing PubMed/MEDLINE, Cochrane Library, and Embase databases. We incorporated randomized clinical trials (RCTs) that compared surgical interventions with or without (neo)adjuvant or perioperative therapies for operable PC. We conducted a fixed-effects Bayesian NMA. We presented the effect sizes in terms of hazard ratios (HRs) for overall survival (OS) along with 95% credible intervals (95% CrIs). The treatment was deemed statistically superior when the 95% credible interval (CrI) did not encompass a null value (hazard ratio < 1). Treatment rankings were established based on the surface under the cumulative ranking curve (SUCRA). A total of 24 studies were incorporated, comparing 21 treatments with surgery in isolation. Eleven treatments showed superior efficacy compared to surgery alone, with HRs ranging from 0.38 for perioperative treatments to 0.73 for adjuvant 5-fluorouracil. After the exclusion of studies conducted in Asia, it was found that the perioperative regimen of gemcitabine combined with nab-paclitaxel was the most effective regimen (SUCRA, p = 0.99). The findings endorse the utilization of perioperative CT, especially multi-agent CT, as the favored intervention for operable PC in Western nations. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC) accounts for 90% of pancreatic cancers. It is considered one of the deadliest cancers due to its high metastatic potential and drug resistance. This review discusses various targets and nanoparticle-based delivery systems developed, tested, and approved for the effective diagnosis and targeted treatment of PDAC. Pancreatic ductal adenocarcinoma (PDAC), one of the deadliest cancers, presents significant challenges in diagnosis and treatment due to its aggressive, metastatic nature and lack of early detection methods. A key obstacle in PDAC treatment is the highly complex tumor environment characterized by dense stroma surrounding the tumor, which hinders effective drug delivery. Nanotechnology can offer innovative solutions to these challenges, particularly in creating novel drug delivery systems for existing anticancer drugs for PDAC, such as gemcitabine and paclitaxel. By using customization methods such as incorporating conjugated targeting ligands, tumor-penetrating peptides, and therapeutic nucleic acids, these nanoparticle-based systems enhance drug solubility, extend circulation time, improve tumor targeting, and control drug release, thereby minimizing side effects and toxicity in healthy tissues. Moreover, nanoparticles have also shown potential in precise diagnostic methods for PDAC. This literature review will delve into targeted mechanisms, pathways, and approaches in treating pancreatic cancer. Additional emphasis is placed on the study of nanoparticle-based delivery systems, with a brief mention of those in clinical trials. Overall, the overview illustrates the significant advances in nanomedicine, underscoring its role in transcending the constraints of conventional PDAC therapies and diagnostics. [ABSTRACT FROM AUTHOR]

Simple Summary: This review examines the available data that have been reported on diversity within the field of hepatobiliary and pancreas surgery in the United States. The authors review the barriers surmounted by successful hepatobiliary and pancreas surgeons from backgrounds that are historically underrepresented in medicine. The authors found that barriers exist at each point of training: starting from admission into medical school, continuing into surgical residency programs and surgical fellowship programs, and into surgical practice. A pattern emerged that revealed the attrition of underrepresented students at each progression toward hepatobiliary and pancreas surgical practice. The authors further review challenges inherent to workforce homogeneity and introduce evidence-based solutions that promote the achievement of excellence via diversity, equity, and inclusion in hepatopancreatobiliary surgery and beyond. Diversity is a catalyst for progress that prevents institutional stagnation and, by extension, averts descent to mediocrity. This review focuses on the available data concerning hepatopancreatobiliary (HPB) surgical workforce demographics and identifies evidence-based strategies that may enhance justice, equity, diversity, and inclusion for HPB surgeons and their patients. We report that the current United States HPB surgical workforce does not reflect the population it serves. We review data describing disparity-perpetuating hurdles confronting physicians from minority groups underrepresented in medicine at each stage of training. We further examine evidence showing widespread racial and socioeconomic disparities in HPB surgical care and review the effects of workforce diversity and physician–patient demographic concordance on healthcare outcomes. Evidence-based mitigators of structural racism and segregation are reviewed, including tailored interventions that can address social determinants of health toward the achievement of true excellence in HPB surgical care. Lastly, select evidence-based data driving surgical workforce solutions are reviewed, including intentional compensation plans, mentorship, and sponsorship. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer, including primarily pancreatic ductal adenocarcinoma (PDAC), represents a highly lethal disease and an increasingly common cause of cancer mortality worldwide. Diagnostics and treatment of PDAC represent a great challenge for modern medicine. PDAC is a highly malignant diagnosis, characterised by rapid local progression and distant metastasis formation. The screening of disease in general population is not cost effective but may be considered in high-risk groups. Recently, there has been great interest in developing new PDAC serum biomarkers: diagnostic, prognostic, and predictive. The most common management of early stage PDAC is radical surgery, which is rarely possible upon diagnosis. There is a strong need for further research to improve PDAC early detection and management. Pancreatic cancer is one of the leading causes off cancer-related deaths globally. In Europe, this type of cancer has the lowest survival rate of all cancers. A majority of patients have unresectable or even metastatic disease. In addition, actual therapeutic options are not curative, and surgical treatment is associated with high post-operative morbidity and a lack of uniform translation of surgical success into long-term survival. Moreover, there is no screening for the general population which is recommended, and the overall poor prognosis in pancreatic cancer is related to late clinical detection. Therefore, early diagnosis and early treatment of pancreatic cancer are particularly critical. In this review, we summarize the most significant gaps and opportunities in the diagnosis and treatment of pancreatic cancer to emphasize need for improvement of early detection and the therapeutic efficacy of the available treatment for this cancer. Novel, inclusive, and intentional research is needed to produce improvements in pancreatic cancer in mm the world. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic tumours usually require surgical removal. With advancing technology, these operations can be performed using laparoscopic and robotic techniques, which reduce surgical trauma to patients compared to conventional open surgery. In theory, robotic surgery should yield better outcomes due to its superior precision and control. Our study provided more evidence in support of this theory after comparing 62 patients who had laparoscopic surgery with 61 patients who had robotic surgery for the removal of their pancreatic tumours. We found that robotic surgeries resulted in fewer cases of conversion to open operations and fewer complications. Technical limitations of laparoscopic distal pancreatectomy (LDP), in comparison to robotic distal pancreatectomy (RDP), may translate to high conversion rates and morbidity. LDP and RDP procedures performed between December 2008 and January 2023 in our tertiary referral hepatobiliary and pancreatic centres were analysed and compared with regard to short-term outcomes. A total of 62 consecutive LDP cases and 61 RDP cases were performed. There was more conversion to open surgeries in the laparoscopic group compared with the robotic group (21.0% vs. 1.6%, p = 0.001). The LDP group also had a higher rate of postoperative complications (43.5% vs. 23.0%, p = 0.005). However, there was no significant difference between the two groups in terms of major complication or pancreatic fistular after operations (p = 0.20 and p = 0.71, respectively). For planned spleen-preserving operations, the RDP group had a shorter mean operative time (147 min vs. 194 min, p = 0.015) and a reduced total length of hospital stay compared with the LDP group (4 days vs. 7 days, p = 0.0002). The failure rate for spleen preservation was 0% in RDP and 20% (n = 5/25) in the LDP group (p = 0.009). RDP offered a better method for splenic preservation with Kimura's technique compared with LDP to avoid the risk of splenic infarction and gastric varices related to ligation and division of splenic pedicles. RDP should be the standard operation for the resection of pancreatic tumours at the body and tail of the pancreas without involving the celiac axis or common hepatic artery. [ABSTRACT FROM AUTHOR]

Simple Summary: Hepatocellular carcinoma (HCC) is the third main cause of cancer-related deaths worldwide, posing a significant global health problem. Surgical management offers the best chance of cure, making it crucial to accurately identify eligible patients and ensure optimal treatment. This paper discusses the ongoing debate regarding criteria expansion and highlights novel techniques for downstaging the tumor and optimizing the future liver remnant, aiming to enable patients to become eligible for surgical therapy. Moreover, the exploration of minimally invasive surgery, improved visualization techniques, and improved hemorrhage prevention techniques showcase promising advancements in HCC surgery that may reduce operative time, surgical stress, and morbidity. This review provides valuable updates for researchers and healthcare professionals, and the findings may shape future research directions, leading to improved outcomes and potentially expanding the pool of eligible patients for curative surgical interventions. Hepatocellular carcinoma (HCC) is a leading cause of cancer-related deaths worldwide. Surgical management, including hepatic resection, liver transplantation, and ablation, offers the greatest potential for a curative approach. This review aims to discuss recent advancements in HCC surgery and identify unresolved issues in the field. Treatment selection relies on the BCLC staging system, with surgical therapies primarily recommended for early-stage disease. Recent studies have shown that patients previously considered unresectable, such as those with portal vein tumor thrombus and uncomplicated portal hypertension, may benefit from hepatic resection. Minimally invasive surgery and improved visualization techniques are also explored, alongside new techniques for optimizing future liver remnant, ex vivo resection, and advancements in hemorrhage control. Liver transplantation criteria, particularly the long-standing Milan criteria, are critically examined. Alternative criteria proposed and tested in specific regions are presented. In the context of organ shortage, bridging therapy plays a critical role in preventing tumor progression and maintaining patients eligible for transplantation. Lastly, we explore emerging ablation modalities, comparing them with the current standard, radiofrequency ablation. In conclusion, this comprehensive review provides insights into recent trends and future prospects in the surgical management of HCC, highlighting areas that require further investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer (PCa) is a highly aggressive and deadly form of cancer with a low five-year survival rate. This paper explores the role of pharmacologic anthropology in understanding and addressing health disparities related to PCa. Pharmacologic anthropology examines how cultural, social, economic, and behavioral factors affect the use and effectiveness of pharmaceutical treatments. In the context of PCa, it helps us understand why different population groups experience disparities in PCa outcomes. By adopting this interdisciplinary approach, researchers, healthcare providers, and policymakers can better understand the complex dynamics of PCa health disparities. This understanding can lead to culturally sensitive interventions, improved communication between patients and providers, increased community engagement, and policies that enhance access to quality care for all PCa patients. Pancreatic cancer (PCa) remains a formidable global health challenge, with high mortality rates and limited treatment options. While advancements in pharmacology have led to improved outcomes for various cancers, PCa continues to exhibit significant health disparities, disproportionately affecting certain populations. This paper explores the intersection of pharmacology and anthropology in understanding the health disparities associated with PCa. By considering the socio-cultural, economic, and behavioral factors that influence the development, diagnosis, treatment, and outcomes of PCa, pharmacologic anthropology provides a comprehensive framework to address these disparities and improve patient care. [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: Pancreatic cancer remains one of the deadliest cancers and has a dismal survival rate. The disease is known to be resistant to chemo- and radiotherapy, and surgery can only be curative in a small percentage of patients. It is thought that the thick tissue (stroma) surrounding the cancer cells is the main factor in the resistance to systemic therapy. Photodynamic therapy (PDT) is a new treatment that uses a specific light to activate a smart molecule to cause cancer cell death. Emerging evidence suggests that PDT may offer a solution that can alter the stroma and kill pancreatic cancer cells. The aim of this review is to summarise the literature and explore the effect of PDT on the stroma within pancreatic cancer in order to improve our understanding of this new therapy and its application. Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest solid malignancies, with a five-year survival of less than 10%. The resistance of the disease and the associated lack of therapeutic response is attributed primarily to its dense, fibrotic stroma, which acts as a barrier to drug perfusion and permits tumour survival and invasion. As clinical trials of chemotherapy (CT), radiotherapy (RT), and targeted agents have not been successful, improving the survival rate in unresectable PDAC remains an urgent clinical need. Photodynamic stromal depletion (PSD) is a recent approach that uses visible or near-infrared light to destroy the desmoplastic tissue. Preclinical evidence suggests this can resensitise tumour cells to subsequent therapies whilst averting the tumorigenic effects of tumour–stromal cell interactions. So far, the pre-clinical studies have suggested that PDT can successfully mediate the destruction of various stromal elements without increasing the aggressiveness of the tumour. However, the complexity of this interplay, including the combined tumour promoting and suppressing effects, poses unknowns for the clinical application of photodynamic stromal depletion in PDAC. [ABSTRACT FROM AUTHOR]

Simple Summary: Early-onset rectal cancer (EORC) patients are more likely to undergo neoadjuvant therapies due to the advanced stage of cancer at diagnosis. The response to therapies in this group of patients is still unknown. The aim of this study was to explore the effect of age of onset on the pathological response to neoadjuvant therapies in locally advanced RC patients. A higher rate of incomplete response was reported in EORC patients and early age of onset presented as a risk factor for a worse response in a multivariable analysis. The results of this study call for a different multimodal strategy in EORC patients. The incidence of rectal cancer (RC) is increasing in the population aged ≤ 49 (early-onset RC-EORC). EORC patients are more likely to present with locally advanced disease at diagnosis than late-onset RC (LORC; aged ≥ 50) patients. As a consequence, more EORC patients undergo neoadjuvant therapies. The response to treatment in EORC patients is still unknown. This study aims to explore the effect of age of onset on the pathological response to neoadjuvant therapies in sporadic locally advanced RC (LARC) patients. Based on an institutional prospectively maintained database, LARC patients undergoing neoadjuvant therapies and radical surgery between January 2010 and December 2022 were allocated to the EORC and LORC groups. The primary endpoint was the rate of incomplete response (Dworak 0–2). A total of 326 LORC and 79 EORC patients were included. Pre-neoadjuvant tumor features were comparable. A significantly higher rate of incomplete response was observed in EORC patients (49% vs. 35%; p = 0.028). From multivariable analysis, early age of onset, smoking and extramural invasion presented as independent risk factors for a worse response. This study demonstrates that an early age of onset is related to a worse response and calls for different multimodal strategies in this group of patients. [ABSTRACT FROM AUTHOR]

Simple Summary: A bottleneck in oncology is the translation of results from preclinical models to the clinics. The rate of anticancer drugs that are effective in preclinical studies but fail in clinical trials is more than 95%. In order to test new immunotherapies and to identify the most effective combination of anticancer drugs, next-generation mouse models have been developed. These "humanized mouse models" support the growth of patient-derived tumors and the development of a human immune system. This review provides an overview of next-generation humanized mouse models and how they can be used to advance precision cancer medicine and immuno-oncology clinical trial design. Cancer immunotherapy has brought significant clinical benefits to numerous patients with malignant disease. However, only a fraction of patients experiences complete and durable responses to currently available immunotherapies. This highlights the need for more effective immunotherapies, combination treatments and predictive biomarkers. The molecular properties of a tumor, intratumor heterogeneity and the tumor immune microenvironment decisively shape tumor evolution, metastasis and therapy resistance and are therefore key targets for precision cancer medicine. Humanized mice that support the engraftment of patient-derived tumors and recapitulate the human tumor immune microenvironment of patients represent a promising preclinical model to address fundamental questions in precision immuno-oncology and cancer immunotherapy. In this review, we provide an overview of next-generation humanized mouse models suitable for the establishment and study of patient-derived tumors. Furthermore, we discuss the opportunities and challenges of modeling the tumor immune microenvironment and testing a variety of immunotherapeutic approaches using human immune system mouse models. [ABSTRACT FROM AUTHOR]

Simple Summary: Colorectal cancer is becoming more common in adults under 50. This trend has been observed worldwide, the reasons for which are unclear. Research has suggested that young patients present with more advanced diseases compared to their older counterparts yet have similar survival. How young patients respond to current treatments is unknown as they represent a small proportion of studies to date. The aim of this study is to evaluate disease-specific features and survival of patients diagnosed with colorectal cancer under 50 years of age. Increased understanding of the characteristics of early-age onset colorectal cancer will help to design age-specific preventative, diagnostic, and treatment strategies for these patients and to inform public health policies and initiatives. Background: The incidence of colorectal cancer (CRC) is increasing in the young (under 50). Defining the clinicopathological features and cancer-specific outcomes of patients with early-onset CRC is important to optimize screening and treatment strategies. This study evaluated disease-specific features and oncological outcomes of patients with early-onset CRC. Methods: Anonymized data from an international collaboration were analyzed. The inclusion criteria for this study were patients aged <50 years with stage I-III disease surgically resected with curative intent. Overall and disease-free survival were calculated using the Kaplan–Meier method. Results: A total of 3378 patients were included, with a median age of 43 (18–49) and a slight male preponderance (54.3%). One-third had a family history of colorectal cancer. Almost all (>95%) of patients were symptomatic at diagnosis. The majority (70.1%) of tumors were distal to the descending colon. Approximately 40% were node positive. Microsatellite instability was demonstrated in one in five patients, representing 10% of rectal and 27% of colon cancers. A defined inherited syndrome was diagnosed in one-third of those with microsatellite instability. Rectal cancer displayed a worse prognosis stage for stage. Five-year disease-free survival for stage I, II, and III colon cancer was 96%, 91%, and 68%, respectively. The equivalent rates for rectal cancer were 91%, 81%, and 62%. Conclusions and relevance: The majority of EOCRC would be captured with flexible sigmoidoscopy. Extending screening to young adults and public health education initiatives are potential interventions to improve survivorship. [ABSTRACT FROM AUTHOR]

Simple Summary: The treatment of periampullary tumors is becoming increasingly multimodal. Surgical interventions must be weighed against alternative therapeutic options, including ablative radiation and systemic chemotherapy. An operation should not jeopardize the receipt of adjuvant therapies. Therefore, a multiparametric risk assessment is crucial for patients who are potential surgical candidates. If pancreatoduodenectomy (PD) is feasible, a series of perioperative checkpoints are keys to a rapid recovery. The aim of our review is to itemize the pre-, intra-, and post-operative pathways of PD, with the intent of providing clinicians with an up-to-date perioperative roadmap. Pancreaticoduodenectomy (PD) is a mainstay in the management of periampullary tumors. Treatment algorithms increasingly employ a multimodal strategy, which includes neoadjuvant and adjuvant therapies. However, the successful treatment of a patient is contingent on the execution of a complex operation, whereby minimizing postoperative complications and optimizing a fast and complete recovery are crucial to the overall success. In this setting, risk reduction and benchmarking the quality of care are essential frameworks through which modern perioperative PD care must be delivered. The postoperative course is primarily influenced by pancreatic fistulas, but other patient- and hospital-associated factors, such as frailty and the ability to rescue from complications, also affect the outcomes. A comprehensive understanding of the factors influencing surgical outcomes allows the clinician to risk stratify the patient, thereby facilitating a frank discussion of the morbidity and mortality of PD. Further, such an understanding allows the clinician to practice based on the most up-to-date evidence. This review intends to provide clinicians with a roadmap to the perioperative PD pathway. We review key considerations in the pre-, intra-, and post-operative periods. [ABSTRACT FROM AUTHOR]

Simple Summary: Intrahepatic cholangiocarcinoma is an aggressive primary liver cancer originating in the intrahepatic bile ducts. While surgical resection is the only curative treatment, many patients present with locally advanced, unresectable, or metastatic disease, and few are candidates for curative-intent resection. In this review, we examine locoregional therapy approaches and summarize the current literature. Current locoregional therapies include thermal ablation, transarterial chemoembolization, transarterial radioembolization, external beam radiotherapy, stereotactic body radiotherapy, hepatic arterial infusion of chemotherapy, irreversible electroporation, and brachytherapy. These therapies are most often offered to patients with unresectable primary or recurrent intrahepatic cholangiocarcinoma, and studies on each modality have shown these locoregional approaches to be effective for prolonging overall survival. The findings of this review also further inform the need for future research regarding the efficacy of these treatments in comparison to each other due to the limited literature on optimal treatment strategies. Intrahepatic cholangiocarcinoma (ICC) has a poor prognosis, and surgical resection (SR) offers the only potential for cure. Unfortunately, only a small proportion of patients are eligible for resection due to locally advanced or metastatic disease. Locoregional therapies (LRT) are often used in unresectable liver-only or liver-dominant ICC. This review explores the role of these therapies in the treatment of ICC, including radiofrequency ablation (RFA), microwave ablation (MWA), transarterial chemoembolization (TACE), transarterial radioembolization (TARE), external beam radiotherapy (EBRT), stereotactic body radiotherapy (SBRT), hepatic arterial infusion (HAI) of chemotherapy, irreversible electroporation (IE), and brachytherapy. A search of the current literature was performed to examine types of LRT currently used in the treatment of ICC. We examined patient selection, technique, and outcomes of each type. Overall, LRTs are well-tolerated in the treatment of ICC and are effective in improving overall survival (OS) in this patient population. Further studies are needed to reduce bias from heterogenous patient populations and small sample sizes, as well as to determine whether certain LRTs are superior to others and to examine optimal treatment selection. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal carcinomas (PDACs) are difficult to diagnose at an early stage and carry a poor overall prognosis for patients. Many patients with PDACs have serious nutritional deficiencies relating to their cancer. Typically, the pancreas produces enzymes resulting in food digestion. However, patients with pancreatic cancer often have a limited ability to digest their food due to decreased enzyme function, known as pancreatic enzyme insufficiency (PEI). These patients then become malnourished, which lowers their quality of life and reduces their survival. Unfortunately, PEI in PDACs is sometimes missed by healthcare providers. This paper reviews past studies describing malnutrition in PDAC, focusing on PEI and its treatment. It focuses on guidelines and recommendations for the appropriate treatment of PEI. We also review knowledge gaps of healthcare professionals regarding PEI to enhance treatment uptake and improve future patients' quality of life. Pancreatic ductal adenocarcinoma (PDAC) is the most common malignancy of the pancreas and is associated with an extremely poor prognosis. Many PDAC patients suffer from profound nutritional complications such as nutrient deficiencies, weight loss, malnutrition, and cancer cachexia. These complications cause barriers to effective anticancer treatments, gravely influence their quality of life, and decrease their overall survival. Pancreatic exocrine insufficiency (PEI) is defined as impaired digestion due to inadequate secretion of pancreatic enzymes and is a common cause of malnutrition in PDAC. This review first summarizes the existing literature around malnutrition in PDAC, with a particular focus on PEI and its management with pancreatic enzyme replacement therapy (PERT). Second, we summarize existing guidelines and recommendations for the management of PEI among patients with PDAC. Lastly, we highlight potential gaps of knowledge of PEI among healthcare providers resulting in underdiagnosis and treatment, which may have implications for the quality of life and overall survival of PDAC patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic carcinoma is one of the malignancies with the highest cancer-specific mortality. While invading the microenvironment and the dense stroma, the immune system plays a key role in the pathological development, as well as in the treatment of pancreatic tumors. In this review, evidence-based treatment options, including standard oncological treatment and integrative therapies, such as hyperthermia, electroporation, intra-tumoral injections, phytochemical preparations or vitamins to improve the prognosis of patients with pancreatic cancer, are presented and discussed. Numerous clinical studies have been conducted to improve the outcomes of patients suffering from pancreatic cancer. Different approaches using targeted therapeutic strategies and precision medicine methods have been investigated, and synergies and further therapeutic advances may be achieved through combinations with integrative methods. For pancreatic tumors, a particular challenge is the presence of a microenvironment and a dense stroma, which is both a physical barrier to drug penetration and a complex entity being controlled by the immune system. Therefore, the state of immunological tolerance in the tumor microenvironment must be overcome, which is a considerable challenge. Integrative approaches, such as hyperthermia, percutaneous irreversible electroporation, intra-tumoral injections, phytotherapeutics, or vitamins, in combination with standard-oncological therapies, may potentially contribute to the control of pancreatic cancer. The combined application of standard-oncological and integrative methods is currently being studied in ongoing clinical trials. An actual overview is given here. [ABSTRACT FROM AUTHOR]

Simple Summary: Cancer-associated fibroblasts (CAFs) represent an important stromal cell population of pancreatic cancer in which multiple CAF subtypes have been identified. CAFs engage in a bidirectional crosstalk with cancer cells, continuously adapting their metabolism to external factors, such as chemotherapy. In this review, we summarize recently identified CAF subtypes in pancreatic cancer and discuss how CAFs shape cancer cell metabolism through several mechanisms, notably metabolite exchange, paracrine signaling, desmoplasia/hypoxia and acidosis. Despite extensive research, the 5-year survival rate of pancreatic cancer (PDAC) patients remains at only 9%. Patients often show poor treatment response, due partly to a highly complex tumor microenvironment (TME). Cancer-associated fibroblast (CAF) heterogeneity is characteristic of the pancreatic TME, where several CAF subpopulations have been identified, such as myofibroblastic CAFs (myCAFs), inflammatory CAFs (iCAFs), and antigen presenting CAFs (apCAFs). In PDAC, cancer cells continuously adapt their metabolism (metabolic switch) to environmental changes in pH, oxygenation, and nutrient availability. Recent advances show that these environmental alterations are all heavily driven by stromal CAFs. CAFs and cancer cells exchange cytokines and metabolites, engaging in a tight bidirectional crosstalk, which promotes tumor aggressiveness and allows constant adaptation to external stress, such as chemotherapy. In this review, we summarize CAF diversity and CAF-mediated metabolic rewiring, in a PDAC-specific context. First, we recapitulate the most recently identified CAF subtypes, focusing on the cell of origin, activation mechanism, species-dependent markers, and functions. Next, we describe in detail the metabolic crosstalk between CAFs and tumor cells. Additionally, we elucidate how CAF-driven paracrine signaling, desmoplasia, and acidosis orchestrate cancer cell metabolism. Finally, we highlight how the CAF/cancer cell crosstalk could pave the way for new therapeutic strategies. [ABSTRACT FROM AUTHOR]

Simple Summary: Racial disparities exist within colorectal cancer (CRC) incidence and mortality, with African Americans (AA) exhibiting a greater risk of developing and dying from the disease than European Americans (EA). This disparity is mirrored in scientific research, where an inadequate number of omic-based studies have sought to recruit AA populations, severely limiting the scope of subsequent findings. Aberrant DNA methylation is a hallmark of CRC, with global and region-specific differences being attributed to disease subtype, pathogenesis and survival. However, studies on cancerous tissue are limited in their ability to infer risk mechanisms occurring in healthy cells. Here, we explore the effects of aging, a well-known CRC risk factor, on DNA methylation in normal rectum of AA and EA subjects. Our findings highlight an interplay between race and age that impacts DNA methylation and, potentially, rectal cancer risk. Approximately 90% of colorectal cancer (CRC) develop over the age of 50, highlighting the important role of aging in CRC risk. African Americans (AAs) shoulder a greater CRC burden than European Americans (EA) and are more likely to develop CRC at a younger age. The effects of aging in AA and EA normal rectal tissue have yet to be defined. Here, we performed epigenome-wide DNA methylation analysis in the first, large-scale biracial cohort of normal rectum (n = 140 samples). We identified increased epigenetic age acceleration in EA than AA rectum (p = 3.91 × 10−4) using linear regression. We also identified differentially methylated regions (DMRs) associated with chronological aging in AA and EA, separately using DMRcate. Next, a consensus set of regions associated with cancer was identified through DMR analysis of two rectal cancer cohorts. The vast majority of AA DMRs were present in our analysis of aging in rectum of EA subjects, though rates of epigenetic drift were significantly greater in AA (p = 1.94 × 10−45). However, 3.66-fold more DMRs were associated with aging in rectum of EA subjects, many of which were also associated with rectal cancer. Our findings reveal a novel relationship between race, age, DNA methylation and rectal cancer risk that warrants further investigation. [ABSTRACT FROM AUTHOR]

Simple Summary: Early-onset colorectal cancer (EOCRC) is on the rise. Reasons are unknown and comparative results about long-term survival are still widely debated. This study aimed to explore the effect of early age of onset in a surgical population of sporadic colorectal cancer patients. Early age of onset resulted independently and is associated with worse oncologic outcomes also in stage I patients. This study suggested that EOCRC may have a more aggressive tumoral phenotype compared with late-onset CRC. A better understanding of the biology of EOCRC is needed to revise —and eventually modify—current strategies of treatment and surveillance. The incidence of colorectal cancer (CRC) is increasing in the population aged ≤ 49 (early-onset CRC-EOCRC). Recent studies highlighted the biological and clinical differences between EOCRC and late-onset CRC (LOCRC-age ≥ 50), while comparative results about long-term survival are still debated. This study aimed to investigate whether age of onset may impact on oncologic outcomes in a surgical population of sporadic CRC patients. Patients operated on for sporadic CRC from January 2010 to January 2022 were allocated to the EOCRC and LOCRC groups. The primary endpoint was the recurrence/progression-free survival (R/PFS). A total of 423 EOCRC and 1650 LOCRC was included. EOCRC had a worse R/PFS (p < 0.0001) and cancer specific survival (p < 0.0001) compared with LOCRC. At Cox regression analysis, age of onset, tumoral stage, signet ring cells, extramural/lymphovascular/perineural veins invasion, and neoadjuvant therapy were independent risk factors for R/P. The analysis by tumoral stage showed an increased incidence of recurrence in stage I EOCRC (p = 0.014), and early age of onset was an independent predictor for recurrence (p = 0.035). Early age of onset was an independent predictor for worse prognosis, this effect was stronger in stage I patients suggesting a potentially—and still unknown—more aggressive tumoral phenotype in EOCRC. [ABSTRACT FROM AUTHOR]

Simple Summary: PDAC remains as one of the deadliest types of cancer due to its late diagnosis, its inherent aggressiveness, and the low efficacy of routinely used treatments (from surgery or radiotherapy to systemic treatments). The search of new potential biomarkers is paramount in this context, where CA19-9 is still the only recommended biomarker for the management of this disease. Thus, the main goal of the present study was to assess the potential value as predictive/prognostic biomarkers of several cytokines and growth factors in serum, as well as circulating immune populations in a cohort of 64 PDAC patients. Despite its relative low incidence, PDAC is one of the most aggressive and lethal types of cancer, being currently the seventh leading cause of cancer death worldwide, with a 5-year survival rate of 10.8%. Taking into consideration the necessity to improve the prognosis of these patients, this research has been focused on the discovery of new biomarkers. For this purpose, patients with BL and resectable disease were recruited. Serum cytokines and growth factors were monitored at different time points using protein arrays. Immune cell populations were determined by flow cytometry in peripheral blood as well as by immunohistochemistry (IHC) in tumor tissues. Several cytokines were found to be differentially expressed between the study subgroups. In the BL disease setting, two different scores were proven to be independent prognostic factors for progression-free survival (PFS) (based on IL-10, MDC, MIF, and eotaxin-3) and OS (based on eotaxin-3, NT-3, FGF-9, and IP10). In the same context, CA19-9 was found to play a role as independent prognostic factor for OS. Eotaxin-3 and MDC cytokines for PFS, and eotaxin-3, NT-3, and CKβ8-1 for OS, were shown to be predictive biomarkers for nab-paclitaxel and gemcitabine regimen. Similarly, oncostatin, BDNF, and IP10 cytokines were proven to act as predictive biomarkers regarding PFS, for FOLFIRINOX regimen. In the resectable cohort, RANTES, TIMP-1, FGF-4, and IL-10 individually differentiated patients according to their cancer-associated survival. Regarding immune cell populations, baseline high levels of circulating B lymphocytes were related to a significantly longer OS, while these levels significantly decreased as progression occurred. Similarly, baseline high levels of helper lymphocytes (CD4+), low levels of cytotoxic lymphocytes (CD8+), and a high CD4/CD8 ratio, were related to a significantly longer PFS. Finally, high levels of CD4+ and CD8+ intratumoural infiltration was associated with significantly longer PFS. In conclusion, in this study we were able to identify several prognostic and predictive biomarker candidates in patients diagnosed of resectable or BL PDAC. [ABSTRACT FROM AUTHOR]

Simple Summary: The progression of pancreatic cancer (PDAC) involves a series of events transforming the phenotype of cancer cells, namely epithelial-to-mesenchymal transition (EMT), which contributes to their invasiveness and spread. Although basic science studies, by in vitro and in vivo animal models strongly support the occurrence of EMT in PDAC, it remains perceived as something heretical in a clinical perspective. To turn this suspended perception, more translational data are needed, consolidating the notion of EMT as a hallmark of human PDAC. Clearly, the network of mechanisms involved its timing and regulation also requires further research, such as those aspects of EMT cancer cell at the intersection with stemness. The translational improvement provided by the identification of EMT markers suitable for deciphering the aggressive behavior of PDAC could eventually modify the clinical scenario, possibly contributing to the advancement in diagnosis and monitoring of its evolution and responsiveness to treatments. Owed to its aggressive yet subtle nature, pancreatic cancer remains unnoticed till an advanced stage so that in most cases the diagnosis is made when the cancer has already spread to other organs with deadly efficiency. The progression from primary tumor to metastasis involves an intricate cascade of events comprising the pleiotropic process of epithelial to mesenchymal transition (EMT) facilitating cancer spread. The elucidation of this pivotal phenotypic change in cancer cell morphology, initially heretic, moved from basic studies dissecting the progression of pancreatic cancer in animal models to move towards human disease, although no clinical translation of the concept emerged yet. Despite this transition, a full-blown mesenchymal phenotype may not be accomplished; rather, the plasticity of the program and its dependency on heterotopic signals implies a series of fluctuating modifications of cancer cells encompassing mesenchymal and epithelial features. Despite the evidence supporting the activation of EMT and MET during cancer progression, our understanding of the relationship between tumor microenvironment and EMT is not yet mature for a clinical application. In this review, we attempt to resume the knowledge on EMT and pancreatic cancer, aiming to include the EMT among the hallmarks of cancer that could potentially modify our clinical thinking with the purpose of filling the gap between the results pursued in basic research by animal models and those achieved in translational research by surrogate biomarkers, as well as their application for prognostic and predictive purposes. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic cancer is one of the most intractable malignant tumors worldwide, and is known for its refractory and poor prognosis. Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer. KRAS is the most commonly mutated oncogene in PDAC. It has been considered the "untargetable" oncogene for decades until the emergence of G12C inhibitors, which put an end to this dilemma by covalent binding to the switch-II pocket of the G12C mutant protein. However, G12C inhibitors showed remarkable efficacy against non-small-cell lung cancer (NSCLC), while the G12C mutation is rare in PDAC. Based on the successful experience of G12C inhibitors, targeting KRAS G12D/V, which forms the majority of KRAS mutations in PDAC, is gradually being regarded as a potential therapy. Pancreatic cancer is one of the most intractable malignant tumors worldwide, and is known for its refractory nature and poor prognosis. The fatality rate of pancreatic cancer can reach over 90%. In pancreatic ductal carcinoma (PDAC), the most common subtype of pancreatic cancer, KRAS is the most predominant mutated gene (more than 80%). In recent decades, KRAS proteins have maintained the reputation of being "undruggable" due to their special molecular structures and biological characteristics, making therapy targeting downstream genes challenging. Fortunately, the heavy rampart formed by KRAS has been broken down in recent years by the advent of KRASG12C inhibitors; the covalent inhibitors bond to the switch-II pocket of the KRASG12C protein. The KRASG12C inhibitor sotorasib has been received by the FDA for the treatment of patients suffering from KRASG12C-driven cancers. Meanwhile, researchers have paid close attention to the development of inhibitors for other KRAS mutations. Due to the high incidence of PDAC, developing KRASG12D/V inhibitors has become the focus of attention. Here, we review the clinical status of PDAC and recent research progress in targeting KRASG12D/V and discuss the potential applications. [ABSTRACT FROM AUTHOR]

Simple Summary: Proteostasis is a balance between protein formation and degradation. All cells maintain their proteome throughout their lifespan. Malignant cells rely on protein degradation mechanisms to replenish cellular supplies of amino acids. Interference with the protein degradation machinery has become an effective method of fighting hematological malignancies, i.e., using proteasome inhibitors in cases of multiple myeloma and other lymphomas. Newer modalities have emerged, including proteolysis-targeting chimeras (PROTACs), lysosome-targeting chimeras (LYTAC), and other techniques for protein degradation that lead to cellular apoptosis. The current review focuses on targeted protein degradation and its use in the treatment of hematological malignancies. Cells must maintain their proteome homeostasis by balancing protein synthesis and degradation. This is facilitated by evolutionarily-conserved processes, including the unfolded protein response and the proteasome-based system of protein clearance, autophagy, and chaperone-mediated autophagy. In some hematological malignancies, including acute myeloid leukemia, misfolding or aggregation of the wild-type p53 tumor-suppressor renders cells unable to undergo apoptosis, even with an intact p53 DNA sequence. Moreover, blocking the proteasome pathway triggers lymphoma cell apoptosis. Extensive studies have led to the development of proteasome inhibitors, which have advanced into drugs (such as bortezomib) used in the treatment of certain hematological tumors, including multiple myeloma. New therapeutic options have been studied making use of the so-called proteolysis-targeting chimeras (PROTACs), that bind desired proteins with a linker that connects them to an E3 ubiquitin ligase, resulting in proteasomal-targeted degradation. This review examines the mechanisms of protein degradation in the cells of the hematopoietic system, explains the role of dysfunctional protein degradation in the pathogenesis of hematological malignancies, and discusses the current and future advances of therapies targeting these pathways, based on an extensive search of the articles and conference proceedings from 2005 to April 2022. [ABSTRACT FROM AUTHOR]

Simple Summary: Radiation treatment plays a pivotal a role in the management of pancreatic cancer, mainly in the neoadjuvant setting for borderline resectable tumors and in the definitive setting for unresectable localized disease. Most of the studies on pancreatic cancer use photon-based radiation therapy modalities. However, there is a growing interest in the application of protons therapy for gastrointestinal cancers. This review summarizes the literature on the use of proton therapy in the management of pancreatic cancer. Radiation therapy plays a central role in the treatment of pancreatic cancer. While generally shown to be feasible, proton irradiation, particularly when an ablative dose is planned, remains a challenge, especially due to tumor motion and the proximity to organs at risk, like the stomach, duodenum, and bowel. Clinically, standard doses of proton radiation treatment have not been shown to be statistically different from photon radiation treatment in terms of oncologic outcomes and toxicity rates as per non-randomized comparative studies. Fractionation schedules and concurrent chemotherapy combinations are yet to be optimized for proton therapy and are the subject of ongoing trials. [ABSTRACT FROM AUTHOR]

Simple Summary: Oesophageal adenocarcinoma is a lethal malignancy with limited treatment options. Recent studies have identified oestrogen receptors (ERs) in this cancer, which could represent a new target for therapy. In this study, we used laboratory models of oesophageal adenocarcinoma to look for the presence of variant forms of ERs. We also assessed the response to treatment with a drug that acts through these ERs. We found that variant forms of ERs do exist in this malignancy and that some of the variants appear to be important in order for the cells to respond to treatment. This could be due to interactions between different ERs, or between ERs and other molecules that are known to be important in cancer growth. Our findings are encouraging in that drugs that act through ERs might be useful for patients with oesophageal adenocarcinoma in the future. Oesophageal adenocarcinoma is a rapidly increasing problem in which treatment options are limited. Previous studies have shown that oesophageal adenocarcinoma cells and tissues express oestrogen receptors (ERs) and show growth suppression and apoptosis in response to ER modulator agents such as tamoxifen. ERs are known to be expressed in a number of isoforms that act together to regulate cell growth and cell death. In this study, we used western blotting to profile the expression of ERα and ERβ isoforms, and expression of the oncologically related molecules p53, HER2, and EGFR, in a panel of oesophageal adenocarcinoma cell lines. The cytotoxicity of tamoxifen in the cell lines was determined with Annexin V-FITC flow cytometry, and correlations between cytotoxicity and receptor expression were assessed using Spearman's rank-order correlation. Oesophageal adenocarcinoma cell lines showed varying cytotoxicity in response to tamoxifen. The ER species ERα90, ERα50, and ERα46, as well as p53, were positively associated with a cytotoxic response. Conversely, ERα74, ERα70, and ERβ54 were associated with a lack of cytotoxic response. The ER species detected in oesophageal adenocarcinoma cells may work together to confer sensitivity to ER modulators in this disease, which could open up a new avenue for therapy in selected patients. [ABSTRACT FROM AUTHOR]

Endoscopic ultrasound-guided fine needle aspiration-biopsy is a safe and effective technique in diagnosing and staging of pancreatic ductal adenocarcinoma. However its predictive negative value does not exceed 50% to 60%. Unfortunately, the majority of pancreatic cancer patients have a metastatic and/or a locally advanced disease (i.e., not eligible for curative resection) which explains the limited access to pancreatic tissue specimens. Endoscopic ultrasound-guided fine needle aspiration-biopsy is the most widely used approach for cytological and histological material sampling in these situations used in up to two thirds of patients with pancreatic cancer. Based on this unique material, we and others developed strategies to improve the differential diagnosis between carcinoma and inflammatory pancreatic lesions by analysis of KRAS oncogene mutation, microRNA expression and methylation, as well as mRNA expression using both qRT-PCR and Low Density Array Taqman analysis. Indeed, differentiating pancreatic cancer from pseudotumoral chronic pancreatitis remains very difficult in current clinical practice, and endoscopic ultrasound-guided fine needle aspiration-biopsy analysis proved to be very helpful. In this review, we will compile the clinical and molecular advantages of using endoscopic ultrasound-guided fine needle aspiration-biopsy in managing pancreatic cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: As we are facing an increasing incidence of pancreatic neuroendocrine tumors (pNETs), it appears necessary to better classify this disease—and in 2017 the WHO classification introduced a new category of well differentiated grade 3 tumors. pNETs treatment requires some specific background and recent reviews on the multimodal management of this disease are missing. Indeed, those modalities constantly evolve and this review, focusing on Grade 1 and Grade 2 pNETs, aims to clarify both oncological and surgical treatment options from localized tumors to multi metastatic disease. Every aspect of the strategy are discussed in this review from the oncologist and the surgeon's point of view and with a special focus on a minimally invasive approach. Pancreatic neuroendocrine tumors (p-NETs) are rare tumors with a recent growing incidence. In the 2017 WHO classification, p-NETs are classified into well-differentiated (i.e., p-NETs grade 1 to 3) and poorly differentiated neuroendocrine carcinomas (i.e., p-NECs). P-NETs G1 and G2 are often non-functioning tumors, of which the prognosis depends on the metastatic status. In the localized setting, p-NETs should be surgically managed, as no benefit for adjuvant chemotherapy has been demonstrated. Parenchymal sparing resection, including both duodenum and pancreas, are safe procedures in selected patients with reduced endocrine and exocrine long-term dysfunction. When the p-NET is benign or borderline malignant, this surgical option is associated with low rates of severe postoperative morbidity and in-hospital mortality. This narrative review offers comments, tips, and tricks from reviewing the available literature on these different options in order to clarify their indications. We also sum up the overall current data on p-NETs G1 and G2 management. [ABSTRACT FROM AUTHOR]

Simple Summary: Pancreatic ductal adenocarcinoma (PDAC), the most common form of pancreatic cancer, remains one of the most lethal diseases. Current evidence, discussed in this article, implicates an interplay between the oncogene KRAS, the transcriptional co-activator YES1-Associated Protein (YAP) and the proto-oncogenes of the Src family kinases (SFK) in the pathogenesis of PDAC and consequently, they represent potential targets for therapeutic intervention. Here, we focus on recent mechanistic and translational studies that identify a complex crosstalk between KRAS, YAP and SFK in PDAC initiation and maintenance. Additionally, we discuss strategies for targeting these crucial signaling nodes and the feedback loops emanating from them, with especial consideration to preventing the development of drug resistance. Pancreatic ductal adenocarcinoma (PDAC), the predominant form of pancreatic cancer, remains a devastating disease. The purpose of this review is to highlight recent literature on mechanistic and translational developments that advance our understanding of a complex crosstalk between KRAS, YAP and Src tyrosine kinase family (SFK) in PDAC development and maintenance. We discuss recent studies indicating the importance of RAS dimerization in signal transduction and new findings showing that the potent pro-oncogenic members of the SFK phosphorylate and inhibit RAS function. These surprising findings imply that RAS may not play a crucial role in maintaining certain subtypes of PDAC. In support of this interpretation, current evidence indicates that the survival of the basal-like subtype of PDAC is less dependent on RAS but relies, at least in part, on the activity of YAP/TAZ. Based on current evidence, we propose that SFK propels PDAC cells to a state of high metastasis, epithelial-mesenchymal transition (EMT) and reduced dependence on KRAS signaling, salient features of the aggressive basal-like/squamous subtype of PDAC. Strategies for PDAC treatment should consider the opposite effects of tyrosine phosphorylation on KRAS and SFK/YAP in the design of drug combinations that target these novel crosstalk mechanisms and overcome drug resistance. [ABSTRACT FROM AUTHOR]

Simple Summary: Patients diagnosed with pancreatic cancer have very few treatment options. In order to identify new treatment opportunities, and develop new drugs for clinical use, appropriate model systems that take into account the complexities of a tumor are required. In this review, we summarize the current and emerging opportunities to accurately model pancreatic cancer using organoid technologies. We highlight the need for continued development of these complex model systems in order to inform personalized treatment. Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal solid malignancies. While immortalized cancer cell lines and genetically engineered murine models have increased our understanding of PDAC tumorigenesis, they do not recapitulate inter- and intra-patient heterogeneity. PDAC patient derived organoid (PDO) biobanks have overcome this hurdle, and provide an opportunity for the high throughput screening of potential new therapies. This review provides a summary of the PDAC PDO biobanks established to date, and discusses how they have advanced our understanding of PDAC biology. Looking forward, the development of coculturing techniques for specific immune or stromal cell populations will enable a better understanding of the crosstalk that occurs within the tumor microenvironment, and the impact of this crosstalk on treatment response. [ABSTRACT FROM AUTHOR]

Simple Summary: The ubiquitin-proteasome system regulates multiple facets of protein homeostasis to modulate signal transduction in numerous biological processes. Not surprisingly, dysregulation of this delicately balanced system is frequently observed in cancer progression. In the past two decades, researchers in both academia and industry have made significant progress in developing small-molecule inhibitors targeting various components in the ubiquitin-proteasome system for cancer therapy. Here, we aim to provide a comprehensive summary of these efforts. Additionally, we overview the advancements of targeted protein degradation, a recently emerging drug discovery concept in cancer therapy. The ubiquitin-proteasome system (UPS) is a critical regulator of cellular protein levels and activity. It is, therefore, not surprising that its dysregulation is implicated in numerous human diseases, including many types of cancer. Moreover, since cancer cells exhibit increased rates of protein turnover, their heightened dependence on the UPS makes it an attractive target for inhibition via targeted therapeutics. Indeed, the clinical application of proteasome inhibitors in treatment of multiple myeloma has been very successful, stimulating the development of small-molecule inhibitors targeting other UPS components. On the other hand, while the discovery of potent and selective chemical compounds can be both challenging and time consuming, the area of targeted protein degradation through utilization of the UPS machinery has seen promising developments in recent years. The repertoire of proteolysis-targeting chimeras (PROTACs), which employ E3 ligases for the degradation of cancer-related proteins via the proteasome, continues to grow. In this review, we will provide a thorough overview of small-molecule UPS inhibitors and highlight advancements in the development of targeted protein degradation strategies for cancer therapeutics. [ABSTRACT FROM AUTHOR]

Simple Summary: Genomic instability is a major driving force of tumour development and evolution. Cells have developed sophisticated regulatory systems to preserve the stability of the genome and defects in these mechanisms can lead to the acquisition of mutations. In this review we look at the role of ubiquitination, a common post-translational modification, in the regulation of genomic integrity. Faithful DNA replication during cellular division is essential to maintain genome stability and cells have developed a sophisticated network of regulatory systems to ensure its integrity. Disruption of these control mechanisms can lead to loss of genomic stability, a key hallmark of cancer. Ubiquitination is one of the most abundant regulatory post-translational modifications and plays a pivotal role in controlling replication progression, repair of DNA and genome stability. Dysregulation of the ubiquitin proteasome system (UPS) can contribute to the initiation and progression of neoplastic transformation. In this review we provide an overview of the UPS and summarize its involvement in replication and replicative stress, along with DNA damage repair. Finally, we discuss how the UPS presents as an emerging source for novel therapeutic interventions aimed at targeting genomic instability, which could be utilized in the treatment and management of cancer. [ABSTRACT FROM AUTHOR]

Simple Summary: Multiple myeloma is a cancer of plasma cells causing bone fractures, anemia, renal insufficiency and hypercalcemia. Despite the introduction of new drugs in the past years, it still remains incurable and most patients die from the disease. Multiple myeloma cells are characterized by the production of high amounts of monoclonal antibodies. Therefore, maintaining protein homeostasis from synthesis through folding to degradation is crucial for multiple myeloma cells. While protein ubiquitination and organized degradation are typically considered critical for cellular health, an emerging strategy is to block these processes to induce cell death in disease-state cells characterized by protein over-production. Recent development of compounds that alter the ubiquitin proteasome pathway and drugs that affect ubiquitin-like modifications appear promising in both preclinically and in clinical trials. This review summarizes the impact of protein modifications such as ubiquitination and ubiquitin-like modifications in the biology of multiple myeloma and how it can be exploited to develop new effective therapies for multiple myeloma. Multiple myeloma is a genetically heterogeneous plasma cell malignancy characterized by organ damage and a massive production of (in-)complete monoclonal antibodies. Coping with protein homeostasis and post-translational regulation is therefore essential for multiple myeloma cells to survive. Furthermore, post-translational modifications such as ubiquitination and SUMOylation play key roles in essential pathways in multiple myeloma, including NFκB signaling, epigenetic regulation, as well as DNA damage repair. Drugs modulating the ubiquitin–proteasome system, such as proteasome inhibitors and thalidomide analogs, are approved and highly effective drugs in multiple myeloma. In this review, we focus on ubiquitin and ubiquitin-like modifications in the biology and current developments of new treatments for multiple myeloma. [ABSTRACT FROM AUTHOR]

Simple Summary: This review aims to highlight the potential of cold plasma, the fourth state of matter, as anti-cancer treatment for pancreatic cancer, and the importance of pancreatic stellate cells in the response to this treatment. Currently, a significant lack of basic research on cold plasma considering both pancreatic cancer and stellate cells exists. However, co-cultures of these populations can be advantageous, as they resemble the cell-to-cell interactions occurring in a tumor in response to therapy. Even more, these studies should be performed prior to clinical trials of cold plasma to avoid unforeseen responses to treatment. This review article provides a framework for future research of cold plasma therapies for pancreatic cancer, considering the critical role of pancreatic stellate cells in the disease and treatment outcome. Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease with low five-year survival rates of 8% by conventional treatment methods, e.g., chemotherapy, radiotherapy, and surgery. PDAC shows high resistance towards chemo- and radiotherapy and only 15–20% of all patients can have surgery. This disease is predicted to become the third global leading cause of cancer death due to its significant rise in incidence. Therefore, the development of an alternative or combinational method is necessary to improve current approaches. Cold atmospheric plasma (CAP) treatments could offer multiple advantages to this emerging situation. The plasma-derived reactive species can induce oxidative damage and a cascade of intracellular signaling pathways, which could lead to cell death. Previous reports have shown that CAP treatment also influences cells in the tumor microenvironment, such as the pancreatic stellate cells (PSCs). These PSCs, when activated, play a crucial role in the propagation, growth and survival of PDAC tumors. However, the effect of CAP on PSCs is not yet fully understood. This review focuses on the application of CAP for PDAC treatment and the importance of PSCs in the response to treatment. [ABSTRACT FROM AUTHOR]

Globally, the death rate of pancreatic ductal adenocarcinoma (PDAC) has doubled over 30 years and is likely to further increase, making PDAC a leading cause of cancer-related death in the coming years. PDAC is typically diagnosed at an advanced stage, and modified FOLFIRINOX or nab-paclitaxel and gemcitabine are the mainstay of systemic therapy. For elderly patients with good performance status, low-dose treatment can preserve quality of life without compromising cancer control or survival. Maintenance therapy should be considered in PDAC patients achieving disease control with systemic therapy. In particular, olaparib has demonstrated a progression-free survival benefit of 3.6 months in a subgroup of PDAC patients with germline BRCA1/2 mutations (ca. 10% of all PDAC). Pancreatic enzyme replacement therapy is often omitted in the treatment of patients with PDAC, with possibly deleterious consequences. Small intestinal bacterial overgrowth is highly prevalent in patients with PDAC and should be considered in the diagnostic algorithm of PDAC patients with bloating and diarrhea. Rivaroxaban has been associated with a reduced risk of thrombosis without an increase in major bleeding events, and its use should be considered in every patient with advanced PDAC undergoing systemic therapy. [ABSTRACT FROM AUTHOR]

The ubiquitin proteasome system (UPS) is the main cellular degradation machinery designed for controlling turnover of critical proteins involved in cancer pathogenesis, including hematological malignancies. UPS plays a functional role in regulating turnover of key proteins involved in cell cycle arrest, apoptosis and terminal differentiation. When deregulated, it leads to several disorders, including cancer. Several studies indicate that, in some subtypes of human hematological neoplasms such as multiple myeloma and Burkitt's lymphoma, abnormalities in the UPS made it an attractive therapeutic target due to pro-cancer activity. In this review, we discuss the aberrant role of UPS evaluating its impact in hematological malignancies. Finally, we also review the most promising therapeutic approaches to target UPS as powerful strategies to improve treatment of blood cancers. [ABSTRACT FROM AUTHOR]

Pancreatic cancer (PC) is anticipated to be second only to lung cancer as the leading cause of cancer-related deaths in the United States by 2030. Surgery remains the only potentially curative treatment for patients with pancreatic ductal adenocarcinoma (PDAC), the most common form of PC. Multiple recent preclinical studies focus on identifying effective treatments for PDAC, but the models available for these studies often fail to reproduce the heterogeneity of this tumor type. Data generated with such models are of unknown clinical relevance. Patient-derived xenograft (PDX) models offer several advantages over human cell line-based in vitro and in vivo models and models of non-human origin. PDX models retain genetic characteristics of the human tumor specimens from which they were derived, have intact stromal components, and are more predictive of patient response than traditional models. This review briefly describes the advantages and disadvantages of 2D cultures, organoids and genetically engineered mouse (GEM) models of PDAC, and focuses on the applications, characteristics, advantages, limitations, and the future potential of PDX models for improving the management of PDAC. [ABSTRACT FROM AUTHOR]

Background: Few studies have compared perioperative and oncological outcomes between minimally invasive pancreatoduodenectomy (MIPD) and open pancreatoduodenectomy (OPD) for pancreatic ductal adenocarcinoma (PDAC). Methods: A retrospective review of patients undergoing MIPD and OPD for PDAC from January 2011 to December 2017 was performed. Perioperative, oncological, and survival outcomes were analyzed before and after propensity score matching (PSM). Results: Data from 1048 patients were evaluated (76 MIPD, 972 OPD). After PSM, 73 patients undergoing MIPD were matched with 219 patients undergoing OPD. Operation times were longer for MIPD than OPD (392 vs. 327 min, p < 0.001). Postoperative hospital stays were shorter for MIPD patients than OPD patients (12.4 vs. 14.2 days, p = 0.040). The rate of overall complications and postoperative pancreatic fistula did not differ between the two groups. Adjuvant treatment rates were higher following MIPD (80.8% vs. 59.8%, p = 0.002). With the exception of perineural invasion, no differences were seen between the two groups in pathological outcomes. The median overall survival and disease-free survival rates did not differ between the groups. Conclusions: MIPD showed shorter postoperative hospital stays and comparable perioperative and oncological outcomes to OPD for selected PDAC patients. Future randomized studies will be required to validate these findings. [ABSTRACT FROM AUTHOR]

Smoking is highly associated with pancreatic cancer. Nicotine, the addictive component of tobacco, is involved in pancreatic cancer tumorigenesis, metastasis, and chemoresistance. This work aimed to describe the role of nicotine within the pancreatic cancer tumor microenvironment. Nicotine treatment was used in vitro to assess its effect on tumor-associated stromal cells and pancreatic cancer cells. Nicotine treatment was then used in a pancreatic cancer patient-derived xenograft model to study the effects in vivo. Nicotine induced secretion of interleukin 8 (IL-8) by tumor-associated stroma cells in an extracellular signal-regulated kinase (ERK)-dependent fashion. The secreted IL-8 and nicotine acted on the pancreatic cancer cell, resulting in upregulation of IL-8 receptor. Nicotine treatment of mice bearing pancreatic cancer patient-derived xenografts had significantly increased tumor mass, increased tumor-free weight loss, and decreased muscle mass. These represent important pathways through which nicotine acts within the tumor microenvironment and worsens pancreatic cancer-induced cachexia, potentially representing future therapeutic targets. [ABSTRACT FROM AUTHOR]

Tumor-derived cytokines are known to drive the catabolism of host tissues, including skeletal muscle. However, our understanding of the specific cytokines that initiate this process remains incomplete. In the current study, we conducted multiplex analyte profiling of cytokines in conditioned medium (CM) collected from human pancreatic cancer (PC) cells, human tumor-associated stromal (TAS) cells, and their co-culture. Of the factors identified, interleukin-8 (IL-8) is released at high levels from PC cells and PC/TAS co-culture and has previously been associated with low muscle mass in cancer patients. We, therefore, treated C2C12 myotubes with IL-8 which led to the activation of ERK1/2, STAT, and Smad signaling, and induced myotube atrophy. Moreover, the treatment of mice with IL-8 also induced significant muscle wasting, confirming the in vivo relevance of IL-8 on muscle. Mechanistically, IL-8-induced myotube atrophy is inhibited by treatment with the CXCR2 antagonist, SB225002, or by treatment with the ERK1/2 inhibitor, U0126. We further demonstrate that this axis mediates muscle atrophy induced by pancreatic cancer cell CM, as neutralization of IL-8 or treatment with SB225002 or U0126 significantly inhibit CM-induced myotube atrophy. Thus, these data support a key role of IL-8 released from human PC cells in initiating atrophy of muscle cells via CXCR2-ERK1/2. [ABSTRACT FROM AUTHOR]

Background: Patients with pancreatic cancer often develop cancer cachexia, a complex multifactorial syndrome with weight loss, muscle wasting and adipose tissue depletion with systemic inflammation causing physical impairment. In patients with locally advanced pancreatic cancer (LAPC) neoadjuvant treatment is routinely performed to allow a subsequent resection. Herein, we assess body composition and laboratory markers for cancer cachexia both before and after neoadjuvant chemoradiation (CRT). Methods: Subcutaneous fat (SCF), visceral fat (VF), skeletal muscle (SM), weight and laboratory parameters were determined longitudinally in 141 LAPC patients treated with neoadjuvant CRT. Changes during CRT were statistically analyzed and correlated with outcome and Kaplan–Meier curves were plotted. Different prognostic factors linked to cachexia were assessed by uni- and multivariable cox proportional hazards models. Results: There was a significant decrease in weight as well as SCF, VF and SM during CRT. The laboratory parameter C-reactive protein (CRP) increased significantly, whereas there was a significant decrease in leukocyte count, hemoglobin, albumin and cholinesterase as well as in the tumor marker CA 19.9. Cachectic weight loss, sarcopenia, reductions in body compartments SCF, VF and SM, and changes in laboratory markers as well as resection affected survival in univariable analysis. In multivariable analysis, weight loss >5% (HR 2.8), reduction in SM >5% (HR 5.5), an increase in CRP (HR 2.2) or CA 19.9 (HR 1.9), and resection (HR 0.4) remained independently associated with survival, whereas classical cachexia and sarcopenia did not. Interestingly, the subgroup of patients with cachectic weight loss >5% or SM reduction >5% during CRT did not benefit from resection (median survival 12 vs. 27 months). Conclusions: Persistent weight loss and muscle depletion during CRT as well as systemic inflammation after CRT impacted survival more than cachexia or sarcopenia according classical definitions. [ABSTRACT FROM AUTHOR]

Our poor understanding of the intricate biology of cancer and the limited availability of preclinical models that faithfully recapitulate the complexity of tumors are primary contributors to the high failure rate of novel therapeutics in oncology clinical studies. To address this need, patient-derived xenograft (PDX) platforms have been widely deployed and have reached a point of development where we can critically review their utility to model and interrogate relevant clinical scenarios, including tumor heterogeneity and clonal evolution, contributions of the tumor microenvironment, identification of novel drugs and biomarkers, and mechanisms of drug resistance. Colorectal cancer (CRC) constitutes a unique case to illustrate clinical perspectives revealed by PDX studies, as they overcome limitations intrinsic to conventional ex vivo models. Furthermore, the success of molecularly annotated "Avatar" models for co-clinical trials in other diseases suggests that this approach may provide an additional opportunity to improve clinical decisions, including opportunities for precision targeted therapeutics, for patients with CRC in real time. Although critical weaknesses have been identified with regard to the ability of PDX models to predict clinical outcomes, for now, they are certainly the model of choice for preclinical studies in CRC. Ongoing multi-institutional efforts to develop and share large-scale, well-annotated PDX resources aim to maximize their translational potential. This review comprehensively surveys the current status of PDX models in translational CRC research and discusses the opportunities and considerations for future PDX development. [ABSTRACT FROM AUTHOR]

Cachexia is a syndrome characterized by an ongoing loss of skeletal muscle mass associated with poor patient prognosis in non-small cell lung cancer (NSCLC). However, prognostic cachexia biomarkers in NSCLC are unknown. Here, we analyzed computed tomography (CT) images and tumor transcriptome data to identify potentially secreted cachexia biomarkers (PSCB) in NSCLC patients with low-muscularity. We integrated radiomics features (pectoralis muscle, sternum, and tenth thoracic (T10) vertebra) from CT of 89 NSCLC patients, which allowed us to identify an index for screening muscularity. Next, a tumor transcriptomic-based secretome analysis from these patients (discovery set) was evaluated to identify potential cachexia biomarkers in patients with low-muscularity. The prognostic value of these biomarkers for predicting recurrence and survival outcome was confirmed using expression data from eight lung cancer datasets (validation set). Finally, C2C12 myoblasts differentiated into myotubes were used to evaluate the ability of the selected biomarker, interleukin (IL)-8, in inducing muscle cell atrophy. We identified 75 over-expressed transcripts in patients with low-muscularity, which included IL-6, CSF3, and IL-8. Also, we identified NCAM1, CNTN1, SCG2, CADM1, IL-8, NPTX1, and APOD as PSCB in the tumor secretome. These PSCB were capable of distinguishing worse and better prognosis (recurrence and survival) in NSCLC patients. IL-8 was confirmed as a predictor of worse prognosis in all validation sets. In vitro assays revealed that IL-8 promoted C2C12 myotube atrophy. Tumors from low-muscularity patients presented a set of upregulated genes encoding for secreted proteins, including pro-inflammatory cytokines that predict worse overall survival in NSCLC. Among these upregulated genes, IL-8 expression in NSCLC tissues was associated with worse prognosis, and the recombinant IL-8 was capable of triggering atrophy in C2C12 myotubes. [ABSTRACT FROM AUTHOR]

Despite improvements to surgical procedures and novel combinations of drugs for adjuvant and neoadjuvant therapies for pancreatic adenocarcinoma, the recurrence rate after radical surgery is still high. Little is known about the role of surgery in the treatment of isolated recurrences of pancreatic cancer. The aim of this study was to review the current literature dealing with surgery for recurrent pancreatic cancer in order to examine its feasibility and effectiveness. An extensive literature review was conducted according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and 14 articles dealing with re-resections for recurrent pancreatic adenocarcinoma were analyzed, focusing on the characteristics of the primary neoplasm and its recurrence, the surgical procedures used, and patient outcomes. Data were retrieved on a total of 301 patients. The interval between surgery for primary pancreatic cancer and the detection of a recurrence ranged from 2 to 120 months. The recurrence was local or regional in 230 patients, and distant in 71. The median overall survival was 68.9 months (range 3–152) after resection of the primary tumor, and 26.0 months (range 0–112) after surgery for recurrent disease. The disease-free interval after the resection of recurrences was 14.2 months (range 4–29). Although data analysis was performed on a heterogeneous and limited number of patients, some of these may benefit from surgery for isolated recurrence of pancreatic adenocarcinoma. Further studies are needed to identify these cases. [ABSTRACT FROM AUTHOR]

Background: Surgical resection offers the best chance of survival in patients with pancreatic cancer, but those with locally advanced disease (LAPC) are usually not surgical candidates. This cohort often receives either neoadjuvant chemotherapy or chemoradiation (CRT), but unintended weight loss coupled with muscle wasting (sarcopenia) can often be observed. Here, we report on the predictive value of changes in weight and muscle mass in 147 consecutive patients with LAPC treated with neoadjuvant CRT. Methods: Clinicopathologic data were obtained via a retrospective chart review. The abdominal skeletal muscle area (SMA) at the third lumbar vertebral body was determined via computer tomographic (CT) scans as a surrogate for the muscle mass and skeletal muscle index (SMI) calculated. Uni- and multi-variable statistical tests were performed to assess for impact on survival. Results: Weight loss (14.5 vs. 20.3 months; p = 0.04) and loss of muscle mass (15.1 vs. 22.2 months; p = 0.007) were associated with poor outcomes. The highest survival was observed in patients who had neither cachectic weight loss nor sarcopenia (27 months), with improved survival seen in those who ultimately received a resection (23 vs. 10 months; p < 0.001). Cox regression revealed that either continued weight loss or continued muscle wasting (SMA reduction) was predictive of poor outcomes, whereas a sarcopenic SMI was not. Conclusions: Loss of weight and lean muscle in patients with LAPC is prognostic when persistent. Therefore, both should be assessed longitudinally and considered before surgery. [ABSTRACT FROM AUTHOR]

Pancreatic stellate cells (PSCs) are a key component of tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) and contribute to drug resistance. c-MET receptor tyrosine kinase activation plays an important role in tumorigenesis in different cancers including PDAC. In this study, effects of PSC conditioned medium (PCM) on c-MET phosphorylation (by immunocytochemistry enzyme-linked immunosorbent assay (ELISA)) and drug response (by sulforhodamine B assay) were investigated in five primary PDAC cells. In novel 3D-spheroid co-cultures of cyan fluorescence protein (CFP)-firefly luciferase (Fluc)-expressing primary human PDAC cells and green fluorescence protein (GFP)-expressing immortalized PSCs, PDAC cell growth and chemosensitivity were examined by luciferase assay, while spheroids' architecture was evaluated by confocal microscopy. The highest phospho-c-MET expression was detected in PDAC5 and its subclone sorted for "stage specific embryonic antigen-4" (PDAC5 (SSEA4)). PCM of cells pre-incubated with PDAC conditioned medium, containing increased hepatocyte growth factor (HGF) levels, made PDAC cells significantly more resistant to gemcitabine, but not to c-MET inhibitors. Hetero-spheroids containing both PSCs and PDAC5 (SSEA4) cells were more resistant to gemcitabine compared to PDAC5 (SSEA4) homo-spheroids. However, c-MET inhibitors (tivantinib, PHA-665752 and crizotinib) were equally effective in both spheroid models. Experiments with primary human PSCs confirmed the main findings. In conclusion, we developed spheroid models to evaluate PSC–PDAC reciprocal interaction, unraveling c-MET inhibition as an important therapeutic option against drug resistant PDAC. [ABSTRACT FROM AUTHOR]