New Frontiers in Pancreatic Cancer Management: Current Treatment Options and the Emerging Role of Neoadjuvant Therapy.

Pancreatic ductal adenocarcinoma (PDAC) ranks among the 15 most prevalent cancers globally, characterized by aggressive growth and late-stage diagnosis. Advances in imaging and surgical techniques have redefined the classification of pancreatic PDAC into resectable, borderline resectable, and locally advanced pancreatic cancer. While surgery remains the most effective treatment, only 20% of patients are eligible at diagnosis, necessitating innovative strategies to improve outcomes. Therefore, traditional treatment paradigms, primarily surgical resection for eligible patients, are increasingly supplemented by neoadjuvant therapies (NAT), which include chemotherapy, radiotherapy, or a combination of both. By administering systemic therapy prior to surgery, NAT aims to reduce tumor size and increase the feasibility of complete surgical resection, thus enhancing overall survival rates and potentially allowing more patients to undergo curative surgeries. Recent advances in treatment protocols, such as FOLFIRINOX and gemcitabine-nab-paclitaxel, now integral to NAT strategies, have shown promising results in increasing the proportion of patients eligible for surgery by effectively reducing tumor size and addressing micrometastatic disease. Additionally, they offer improved response rates and survival benefits compared to traditional regimes. Despite these advancements, the role of NAT continues to evolve, necessitating ongoing research to optimize treatment regimens, minimize adverse effects, and identify patient populations that would benefit most from these approaches. Through a detailed analysis of current literature and recent clinical trials, this review highlights the transformative potential of NAT in managing PDAC, especially in patients with borderline resectable or locally advanced stages, promising a shift towards more personalized and effective management strategies for PDAC.

Laparoscopic versus open liver resection for colorectal liver metastasis: an umbrella review.

Introduction: This study comprehensively compared laparoscopic liver resection (LLR) to open liver resection (OLR) in treating colorectal cancer liver metastasis (CRLM). Methods: A systematic review of relevant literature was conducted to assess a range of crucial surgical and oncological outcomes. Results: Findings indicate that minimally invasive surgery (MIS) did not significantly prolong the duration of surgery compared to open liver resection and notably demonstrated lower blood transfusion rates and reduced intraoperative blood loss. While some studies favored MIS for its lower complication rates, others did not establish a statistically significant difference. One study identified a lower post-operative mortality rate in the MIS group. Furthermore, MIS consistently correlated with shorter hospital stays, indicative of expedited post-operative recovery. Concerning oncological outcomes, while certain meta-analyses reported a lower rate of cancer recurrence in the MIS group, others found no significant disparity. Overall survival and disease-free survival remained comparable between the MIS and open liver resection groups. Conclusion: The analysis emphasizes the potential advantages of LLR in terms of surgical outcomes and aligns with existing literature findings in this field. Systematic review registration: [website], identifier [registration number].

Surgical Resection in Colorectal Liver Metastasis: An Umbrella Review.

Surgical resection is the gold standard for treating synchronous colorectal liver metastases (CRLM). The resection of the primary tumor and metastatic lesions can follow different sequences: "simultaneous", "bowel-first", and "liver-first". Conservative approaches, such as parenchymal-sparing surgery and segmentectomy, may serve as alternatives to major hepatectomy. A comprehensive search of Medline, Epistemonikos, Scopus, and the Cochrane Library was conducted. Studies evaluating patients who underwent surgery for CRLM and reported survival results were included. Other secondary outcomes were analyzed, including disease-free survival, perioperative complications and mortality, and recurrence rates. Quality assessment was performed using the AMSTAR-2 method. No significant differences in overall survival, disease-free survival, and secondary outcomes were observed when comparing simultaneous to "bowel-first" resections, despite a higher rate of perioperative mortality in the former group. The 5-year OS was significantly higher for simultaneous resection compared to "liver-first" resection. No significant differences in OS and DFS were noted when comparing "liver-first" to "bowel-first" resection, or anatomic to non-anatomic resection. Our umbrella review validates simultaneous surgery as an effective oncological approach for treating SCRLM, though the increased risk of perioperative morbidity highlights the importance of selecting suitable patients. Non-anatomic resections might be favored to preserve liver function and enable future surgical interventions.

Use of Fluorescence Imaging in Liver Transplant Surgery.

Liver transplant surgery is a complex procedure that demands high knowledge of surgical anatomy and the precise recognition and preservation of structures. To address this, the use of fluorescence imaging has facilitated the identification of anatomical structures such as biliary ducts, arteries, and liver segmentation. Indocyanine green is among the most commonly utilized fluorescent agents, not just during surgery but also in the pre- and postoperative phases, where it is used to assess graft failure by measuring the plasma disappearance rate. New advancements such as artificial intelligence paired with fluorescence imaging have the potential to enhance patient outcomes. Additionally, technologies such as augmented reality and mixed reality could be integrated into surgical procedures, broadening the scope of possibilities for improving patient safety.

Robotic Vascular Resection in Pancreatic Ductal Adenocarcinoma: A Systematic Review.

(1) Background: This study comprehensively compared robotic pancreatic surgery with vascular resection (RPS-VR) to other surgical procedures in the treatment of pancreatic ductal adenocarcinoma (PDAC). (2) Methods: A systematic review of relevant literature was conducted to assess a range of crucial surgical and oncological outcomes. (3) Results: Findings indicate that robotic surgery with vascular resections (VRs) significantly prolongs the duration of surgery compared to other surgical procedures, and they notably demonstrate an equal hospital stay. While some studies reported a lower conversion rate and a higher rate of blood loss and blood transfusion in the RPS-VR group, others found no significant disparity. Furthermore, RPS-VR consistently correlated with comparable recurrence rates, free margins R0, postoperative mortality, and complication rates. Concerning the last one, certain reviews reported a higher rate of major complications. Overall survival and disease-free survival remained comparable between the RPS-VR and other surgical techniques in treating PDAC. (4) Conclusions: The analysis emphasizes how RPS-VR is a resembling approach in terms of surgical outcomes and aligns with existing literature findings in this field.

Liver transplantation vs liver resection in HCC: promoting extensive collaborative research through a survival meta-analysis of meta-analyses.

Background: HCC is a major global health concern, necessitating effective treatment strategies. This study conducts a meta-analysis of meta-analyses comparing liver resection (LR) and liver transplantation (LT) for HCC. Methods: The systematic review included meta-analyses comparing liver resection vs. liver transplantation in HCC, following PRISMA guidelines. Primary outcomes included 5-year overall survival (OS) and disease-free survival (DFS). AMSTAR-2 assessed study quality. Citation matrix and hierarchical clustering validated the consistency of the included studies. Results: A search identified 10 meta-analyses for inclusion. The median Pearson correlation coefficient for citations was 0.59 (IQR 0.41-0.65). LT showed better 5-year survival and disease-free survival in all HCC (OR): 0.79; 95% CI: 0.67-0.93, I^2:57% and OR: 0.44; 95% CI: 0.25-0.75, I^2:96%). Five-year survival in early HCC and ITT was 0.63 (95% CI: 0.50-0.78, I^2:0%) and 0.60 (95% CI: 0.39-0.92, I^2:0%). Salvage LT vs. Primary LT did not differ between 5-year survival and disease-free survival (OR: 0.62; 95% CI: 0.33-1.15, I^2:0% and 0.93; 95% CI: 0.82-1.04, I^2:0%). Conclusion: Overall, the study underscores the superior survival outcomes associated with LT over LR in HCC treatment, supported by comprehensive meta-analysis and clustering analysis. There was no difference in survival or recurrence rate between salvage LT and primary LT. Therefore, considering the organ shortage, HCC can be resected and transplanted in case of recurrence.

Unraveling Biomarker Signatures in Triple-Negative Breast Cancer: A Systematic Review for Targeted Approaches.

Triple-negative breast cancer (TNBC) is one of the most aggressive subtypes of breast cancer, marked by poor outcomes and dismal prognosis. Due to the absence of targetable receptors, chemotherapy still represents the main therapeutic option. Therefore, current research is now focusing on understanding the specific molecular pathways implicated in TNBC, in order to identify novel biomarker signatures and develop targeted therapies able to improve its clinical management. With the aim of identifying novel molecular features characterizing TNBC, elucidating the mechanisms by which these molecular biomarkers are implicated in the tumor development and progression, and assessing the impact on cancerous cells following their inhibition or modulation, we conducted a literature search from the earliest works to December 2023 on PubMed, Scopus, and Web Of Science. A total of 146 studies were selected. The results obtained demonstrated that TNBC is characterized by a heterogeneous molecular profile. Several biomarkers have proven not only to be characteristic of TNBC but also to serve as potential effective therapeutic targets, holding the promise of a new era of personalized treatments able to improve its prognosis. The pre-clinical findings that have emerged from our systematic review set the stage for further investigation in forthcoming clinical trials.

Exploring the Multifaceted Landscape of MASLD: A Comprehensive Synthesis of Recent Studies, from Pathophysiology to Organoids and Beyond.

Non-alcoholic fatty liver disease (NAFLD) is a widespread contributor to chronic liver disease globally. A recent consensus on renaming liver disease was established, and metabolic dysfunction-associated steatotic liver disease, MASLD, was chosen as the replacement for NAFLD. The disease's range extends from the less severe MASLD, previously known as non-alcoholic fatty liver (NAFL), to the more intense metabolic dysfunction-associated steatohepatitis (MASH), previously known as non-alcoholic steatohepatitis (NASH), characterized by inflammation and apoptosis. This research project endeavors to comprehensively synthesize the most recent studies on MASLD, encompassing a wide spectrum of topics such as pathophysiology, risk factors, dietary influences, lifestyle management, genetics, epigenetics, therapeutic approaches, and the prospective trajectory of MASLD, particularly exploring its connection with organoids.

From CySkin to ProxySKIN: Design, Implementation and Testing of a Multi-Modal Robotic Skin for Human-Robot Interaction.

The Industry 5.0 paradigm has a human-centered vision of the industrial scenario and foresees a close collaboration between humans and robots. Industrial manufacturing environments must be easily adaptable to different task requirements, possibly taking into account the ergonomics and production line flexibility. Therefore, external sensing infrastructures such as cameras and motion capture systems may not be sufficient or suitable as they limit the shop floor reconfigurability and increase setup costs. In this paper, we present the technological advancements leading to the realization of ProxySKIN, a skin-like sensory system based on networks of distributed proximity sensors and tactile sensors. This technology is designed to cover large areas of the robot body and to provide a comprehensive perception of the surrounding space. ProxySKIN architecture is built on top of CySkin, a flexible artificial skin conceived to provide robots with the sense of touch, and arrays of Time-of-Flight (ToF) sensors. We provide a characterization of the arrays of proximity sensors and we motivate the design choices that lead to ProxySKIN, analyzing the effects of light interference on a ToF, due to the activity of other sensing devices. The obtained results show that a large number of proximity sensors can be embedded in our distributed sensing architecture and incorporated onto the body of a robotic platform, opening new scenarios for complex applications.

Age and liver graft: a systematic review with meta-regression.

Increasing organ shortage results in extended criteria donors (ECD) being used to face the growing demand for liver grafts. The demographic change leads to greater use of elderly donors for liver transplantation, historically considered marginal donors. Age is still considered amongst ECD in liver transplantation as it could affect transplant outcomes. However, what is the cutoff for donor age is still unclear and debated. A search of PubMed, Scopus and Cochrane Library was performed. The primary outcome was 1-year graft survival (GS). The secondary outcome was overall biliary complications and 3-5 years of graft and overall survival. A meta-regression model was used to analyse the temporal trend relation in the survival outcome. The meta-analysis included 11 studies. Hazard ratios for 1-year (age cutoff of 70 and 80,) and 5-year GS (I2:0%) were similar irrespectively of the age group. The meta-regression analysis showed a significant correlation between the 1-year graft survival and the year of publication. (coef. 0.00027, 95% CI - 0.0001 to - 0.0003 p = 0.0009). Advanced-age donors showed an increased risk of overall biliary complications with an odd ratio (OR) of 1.89 (95% CI 1-3.65). Liver grafts potentially discharged because of high-risk failure show encouraging results, and GS in ECD has progressively improved with a temporal trend. Currently, the criteria of marginality vary amongst centres. Age alone cannot be considered amongst the extended criteria. First of all, because of the positive results in terms of septuagenarian graft survival. Moreover, the potential elderly donor-related adjunctive risk can be balanced by reducing other risk factors. A prospective multicentre study should investigate a multi-factorial model based on donor criteria, recipient features and new functional biomarkers to predict graft outcome, as proper donor-recipient matching seems to be the critical point for good outcomes.

The Role of mTOR Inhibitors after Liver Transplantation for Hepatocellular Carcinoma.

Liver transplantation is a treatment option for nonresectable patients with early-stage HCC, with more significant advantages when Milan criteria are fulfilled. An immunosuppressive regimen is required to reduce the risk of graft rejection after transplantation, and CNIs represent the drugs of choice in this setting. However, their inhibitory effect on T-cell activity accounts for a higher risk of tumour regrowth. mTOR inhibitors (mTORi) have been introduced as an alternative immunosuppressive approach to conventional CNI-based regimens to address both immunosuppression and cancer control. The PI3K-AKT-mTOR signalling pathway regulates protein translation, cell growth, and metabolism, and the pathway is frequently deregulated in human tumours. Several studies have suggested the role of mTORi in reducing HCC progression after LT, accounting for a lower recurrence rate. Furthermore, mTOR immunosuppression controls the renal damage associated with CNI exposure. Conversion to mTOR inhibitors is associated with stabilizing and recovering renal dysfunction, suggesting an essential renoprotective effect. Limitations in this therapeutic approach are related to their negative impact on lipid and glucose metabolism as well as on proteinuria development and wound healing. This review aims to summarize the roles of mTORi in managing patients with HCC undergoing LT. Strategies to overcome common adverse effects are also proposed.

Neoadjuvant Treatments for Pancreatic Ductal Adenocarcinoma: Where We Are and Where We Are Going.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) represents a challenging disease for the surgeon, oncologist, and radiation oncologist in both diagnostic and therapeutic settings. Surgery is currently the gold standard treatment, but the role of neoadjuvant treatment (NAD) is constantly evolving and gaining importance in resectable PDACs. The aim of this narrative review is to report the state of the art and future perspectives of neoadjuvant therapy in patients with PDAC. METHODS: A PubMed database search of articles published up to September 2022 was carried out. RESULTS: Many studies showed that FOLFIRINOX or Gemcitabine-nab-paclitaxel in a neoadjuvant setting had a relevant impact on overall survival (OS) for patients with locally advanced and borderline resectable PDAC without increasing post-operative complications. To date, there have not been many published multicentre randomised trials comparing upfront surgery with NAD in resectable PDAC patients, but the results obtained are promising. NAD in resectable PDAC showed long-term effective benefits in terms of median OS (5-year OS rate 20.5% in NAD group vs. 6.5% in upfront surgery). NAD could play a role in the treatment of micro-metastatic disease and lymph nodal involvement. In this scenario, given the low sensitivity and specificity for lymph-node metastases of radiological investigations, CA 19-9 could be an additional tool in the decision-making process. CONCLUSIONS: The future challenge could be to identify only selected patients who will really benefit from upfront surgery despite a combination of NAD and surgery.

Current Perspectives in Liver Transplantation for Perihilar Cholangiocarcinoma.

Cholangiocarcinoma (CCA) encompasses all malignant neoplasms arising from the epithelial cells of the biliary tree. About 40% of CCAs are perihilar, involving the bile ducts distal to the second-order biliary branches and proximal to the cystic duct implant. About two-thirds of pCCAs are considered unresectable at the time of diagnosis or exploration. When resective surgery is deemed unfeasible, liver transplantation (LT) could be an effective alternative. The overall survival rates after LT at 1 and 3 years are 91% and 81%, respectively. The overall five-year survival rate after transplantation is 73% (79% for patients with underlying PSC and 63% for de novo pCCA). Multicenter case series reported a 5-year disease-free survival rate of ~65%. However, different protocols, including neoadjuvant therapy, have been proposed. The scarcity of organ availability represents a crucial limiting factor in recommending LT preferentially in treating pCCA. Living donor transplantations and marginal cadaveric allografts have proven to be exciting options to overcome organ shortage. Management of jaundice and cholangitis is still challenging for these patients and could impact LT listing. Whether to adopt surgical resection or LT as standard-of-care in pCCA is still a matter of debate, and more prospective studies are needed.

The Role of Growth Hormone and Insulin Growth Factor 1 in the Development of Non-Alcoholic Steato-Hepatitis: A Systematic Review.

Diabetic and obese patients have a high prevalence of non-alcoholic fatty liver disease (NAFLD). This condition groups a spectrum of conditions varying from simple steatosis to non-alcoholic steatohepatitis (NASH), with or without fibrosis. Multiple factors are involved in the development of NAFLD. However, details about its pathogenesis and factors that promote the progression to NASH are still missing. Growth hormone (GH) and insulin-like growth factor 1 (IGF-1) regulate metabolic, immune, and hepatic stellate cell functions. Increasing evidence suggests they may have roles in the progression from NAFLD to NASH. Following the PRISMA reporting guidelines, we conducted a systematic review to evaluate all clinical and experimental studies published in the literature correlating GH and IGF-1 to inflammation and fibrosis in NAFLD and NASH. Our results showed that GH and IGF-1 have a fundamental role in the pathogenesis of NASH, acting in slightly different ways to produce a synergic effect. Indeed, GH may mediate its protective effect in the pathogenesis of NASH by regulating lipogenesis pathways, while IGF-1 has the same effect by regulating cholesterol transport. Therefore, they could be used as therapeutic strategies in preventing NAFLD progression to NASH.

Artificial Intelligence in the Diagnosis of Hepatocellular Carcinoma: A Systematic Review.

Hepatocellular carcinoma ranks fifth amongst the most common malignancies and is the third most common cause of cancer-related death globally. Artificial Intelligence is a rapidly growing field of interest. Following the PRISMA reporting guidelines, we conducted a systematic review to retrieve articles reporting the application of AI in HCC detection and characterization. A total of 27 articles were included and analyzed with our composite score for the evaluation of the quality of the publications. The contingency table reported a statistically significant constant improvement over the years of the total quality score (p = 0.004). Different AI methods have been adopted in the included articles correlated with 19 articles studying CT (41.30%), 20 studying US (43.47%), and 7 studying MRI (15.21%). No article has discussed the use of artificial intelligence in PET and X-ray technology. Our systematic approach has shown that previous works in HCC detection and characterization have assessed the comparability of conventional interpretation with machine learning using US, CT, and MRI. The distribution of the imaging techniques in our analysis reflects the usefulness and evolution of medical imaging for the diagnosis of HCC. Moreover, our results highlight an imminent need for data sharing in collaborative data repositories to minimize unnecessary repetition and wastage of resources.

Gastro-intestinal emergency surgery: Evaluation of morbidity and mortality. Protocol of a prospective, multicenter study in Italy for evaluating the burden of abdominal emergency surgery in different age groups. (The GESEMM study).

Gastrointestinal emergencies (GE) are frequently encountered in emergency department (ED), and patients can present with wide-ranging symptoms. more than 3 million patients admitted to US hospitals each year for EGS diagnoses, more than the sum of all new cancer diagnoses. In addition to the complexity of the urgent surgical patient (often suffering from multiple co-morbidities), there is the unpredictability and the severity of the event. In the light of this, these patients need a rapid decision-making process that allows a correct diagnosis and an adequate and timely treatment. The primary endpoint of this Italian nationwide study is to analyze the clinicopathological findings, management strategies and short-term outcomes of gastrointestinal emergency procedures performed in patients over 18. Secondary endpoints will be to evaluate to analyze the prognostic role of existing risk-scores to define the most suitable scoring system for gastro-intestinal surgical emergency. The primary outcomes are 30-day overall postoperative morbidity and mortality rates. Secondary outcomes are 30-day postoperative morbidity and mortality rates, stratified for each procedure or cause of intervention, length of hospital stay, admission and length of stay in ICU, and place of discharge (home or rehabilitation or care facility). In conclusion, to improve the level of care that should be reserved for these patients, we aim to analyze the clinicopathological findings, management strategies and short-term outcomes of gastrointestinal emergency procedures performed in patients over 18, to analyze the prognostic role of existing risk-scores and to define new tools suitable for EGS. This process could ameliorate outcomes and avoid futile treatments. These results may potentially influence the survival of many high-risk EGS procedure.

Metabolic Syndrome (MetS), Systemic Inflammatory Response Syndrome (SIRS), and Frailty: Is There any Room for Good Outcome in the Elderly Undergoing Emergency Surgery?

Background: Patients with MetS or SIRS experience higher rates of mortality and morbidity, across both cardiac and noncardiac surgery. Frailty assessment has acquired increasing importance in recent years as it predisposes elderly patients to a worse outcome. The aim of our study was to investigate the influence of MetS, SIRS, and with or without frailty on elderly patients undergoing emergency surgical procedures. Methods: We analyzed data of all patients with nonmalignant diseases requiring an emergency surgical procedure from January 2017 to December 2020. The occurrence of MetS was identified using modified definition criteria used by the NCEP-ATP III Expert Panel: obesity, hypertension, diabetes, or if medication for high triglycerides or for low HDL cholesterol was taken. Systemic inflammatory response syndrome (SIRS) was evaluated according to the original consensus study (Sepsis-1). The frailty profile was investigated by the 5-modified Frailty Index (5-mFI) and the Emergency Surgery Frailty Index (EmSFI). Postoperative complications have been reported and categorized according to the Clavien-Dindo (C-D) classification system. Morbidity and mortality have been mainly considered as the 30-day standard period definition. Results: Of the 2,318 patients included in this study, 1,010 (43.6%) fulfilled the criteria for MetS (MetsG group). Both 5-Items score and EmsFI showed greater fragility in patients with MetS. All patients with MetS showed more frequently a CACI index greater than 6. The occurrence of SIRS was higher in MetSG. LOS was longer in patients with MetS (MetSG 11.4 ± 12 days vs. n-MetSG 10.5 ± 10.2 days, p = 0.046). MetSG has a significantly higher rate of morbidity (353 (35.%) vs. 385 (29.4%), p = 0.005). The mortality rate in patients with MetS (98/1010, 10%) was similar to that in patients without it (129/1308, 10%). Considering patients with MetS who developed SIRS and those who had frailty or both, the occurrence of these conditions was associated with a higher rate of morbidity and mortality. Conclusion: Impact of MetS and SIRS on elderly surgical patient outcomes has yet to be fully elucidated. The present study showed a 43.6% incidence of MetS in the elderly population. In conclusion, age per se should be not considered anymore as the main variable to estimate patient outcomes, while MetS and Frailty should have always a pivotal role.

From endoscopic resection to pancreatoduodenectomy: a narrative review of treatment modalities for the tumors of the ampulla of Vater.

BACKGROUND AND OBJECTIVE: Tumors of the ampulla of Vater are a rare set of lesions that arise at the confluence of the common bile duct (CBD) and the pancreatic duct. They can be benign or malignant, often not easy to discriminate before treatment. Malignant tumors have low chances of survival (overall 5-year survival between 0% and 60%) and surgery is still the only curative option. Prognostic factors are being investigated to tailor therapeutic approach and improve outcomes. Due to their location in a complex anatomical region, all treatment options are challenging and associated with relevant morbidity. In this review we discuss different excisional techniques for the treatment of ampullary tumors (AT). METHODS: A review of medical databases (PubMed and Google Scholar) was conducted selecting most relevant articles in English language without a specific timeframe. After first selection, most relevant citations were identified through snowballing. KEY CONTENT AND FINDINGS: Pancreatoduodenectomy (PD) is the gold standard in malignant tumors, achieving the most radical treatment, at the price of worse perioperative morbidity/mortality and quality of life. Trans-duodenal ampullectomy (TDA) was developed before endoscopic resection (ER) and maintains a role only in selected patients. ER is now the first choice for benign lesions and expanding towards early stages malignant AT. CONCLUSIONS: Pancreatodudenectomy remains the best option for the radical excision of malignant AT, recently being offered also via minimally invasive approach. However, in early-stage malignant tumors, ER is gaining importance with foreseeable further expansion. Transduodenal ampullectomy still has a role in selected patients, such as unfit for PD when ER is not possible mainly due to anatomical abnormalities.