Cholangiocarcinoma (CCC) is the most aggressive malignant tumor of the biliary tract. Perihilar CCC (pCCC) is the most common CCC and is burdened by a complicated diagnostic iter and its anatomical ...location makes surgical approach burden by poor results. Besides its clinical presentation, a multimodal diagnostic approach should be carried on by a tertiary specialized center to avoid miss-diagnosis. Preoperative staging must consider the extent of liver resection to avoid post-surgical hepatic failure. During staging iter, magnetic resonance can obtain satisfactory cholangiographic images, while invasive techniques should be used if bile duct samples are needed. Consistently, to improve diagnostic potential, bile duct drainage is not necessary in jaundice, while it is indicated in refractory cholangitis or when liver hypertrophy is needed. Once resecability criteria are identified, the extent of liver resection is secondary to the longitudinal spread of CCC. While in the past type IV pCCC was not considered resectable, some authors reported good results after their treatment. Conversely, in selected unresectable cases, liver transplantation could be a valuable option. Adjuvant chemotherapy is the standard of care for resected patients, while neoadjuvant approach has growing evidences. If curative resection is not achieved, radiotherapy can be added to chemotherapy. This multistep curative iter must be carried on in specialized centers. Hence, the aim of this review is to highlight the main steps and pitfalls of the diagnostic and therapeutic approach to pCCC with a peculiar attention to type IV pCCC.
The frequent use of marginal livers forces transplant centres to explore novel technologies to improve organ quality and outcomes after implantation. Organ perfusion techniques are therefore ...frequently discussed with an ever-increasing number of experimental and clinical studies. Two main approaches, hypothermic and normothermic perfusion, are the leading strategies to be introduced in clinical practice in many western countries today. Despite this success, the number of studies, which provide robust data on the underlying mechanisms of protection conveyed through this technology remains scarce, particularly in context of different stages of ischemia-reperfusion-injury (IRI). Prior to a successful clinical implementation of machine perfusion, the concept of IRI and potential key molecules, which should be addressed to reduce IRI-associated inflammation, requires a better exploration. During ischemia, Krebs cycle metabolites, including succinate play a crucial role with their direct impact on the production of reactive oxygen species (ROS) at mitochondrial complex I upon reperfusion. Such features are even more pronounced under normothermic conditions and lead to even higher levels of downstream inflammation. The direct consequence appears with an activation of the innate immune system. The number of articles, which focus on the impact of machine perfusion with and without the use of specific perfusate additives to modulate the inflammatory cascade after transplantation is very small. This review describes first, the subcellular processes found in mitochondria, which instigate the IRI cascade together with proinflammatory downstream effects and their link to the innate immune system. Next, the impact of currently established machine perfusion strategies is described with a focus on protective mechanisms known for the different perfusion approaches. Finally, the role of such dynamic preservation techniques to deliver specific agents, which appear currently of interest to modulate this posttransplant inflammation, is discussed together with future aspects in this field.
Machine perfusion (MP) is often referred to as one of the most promising advancements in liver transplantation research of the last few decades, with various techniques and modalities being evaluated ...in preclinical studies using animal models. However, low scientific rigor and subpar reporting standards lead to limited reproducibility and translational potential, hindering progress. This pre-registered systematic review (PROSPERO: CRD42021234667) aimed to provide a thematic overview of the preclinical research landscape on MP in liver transplantation using in vivo transplantation models and to explore methodological and reporting standards, using the ARRIVE (Animal Research: Reporting of In Vivo Experiments) score. In total 56 articles were included. Studies were evenly distributed across Asia, Europe, and the Americas. Porcine models were used in 57.1% of the studies, followed by rats (39.3%) and dogs (3.6%). In terms of graft type, 55.4% of the studies used donation after cardiac death grafts, while donation after brain death grafts accounted for 37.5%. Regarding MP modalities, the distribution was as follows: 41.5% of articles utilized hypothermic MP, 21.5% normothermic MP, 13.8% subnormothermic MP, and 16.9% utilized hypothermic oxygenated MP. The stringent documentation of ARRIVE elements concerning precise experimental execution, group size and selection, the choice of statistical methods, as well as adherence to the principles of the 3Rs, was notably lacking in the majority of publications, with less than 30% providing comprehensive details. Postoperative analgesia and antibiotics treatment were not documented in 82.1% of all included studies. None of the analyzed studies fully adhered to the ARRIVE Guidelines. In conclusion, the present study emphasizes the importance of adhering to reporting standards to promote reproducibility and adequate animal welfare in preclinical studies in machine perfusion. At the same time, it highlights a clear deficiency in this field, underscoring the need for further investigations into animal welfare-related topics.
•Targeting the Melanocortin pathway exerts multiple beneficial effects on injured lungs.•The use of marginal organs is increasing to cope with organ shortage in lung transplantation.•NDP-MSH, a ...synthetic melanocortin peptide, was administered during rat lung ex vivo perfusion.•NDP-MSH reduced inflammation and preserved ATP content in lungs exposed to ischemia/reperfusion.•NDP-MSH ameliorated hemodynamic and airway parameters in lungs procured from cardiac death donors.
The increasing use of marginal lungs for transplantation encourages novel approaches to improve graft quality. Melanocortins and their receptors (MCRs) exert multiple beneficial effects in pulmonary inflammation. We tested the idea that treatment with the synthetic α-melanocyte-stimulating hormone analogue Nle4,D-Phe7-α-MSH (NDP-MSH) during ex vivo lung perfusion (EVLP) could exert positive influences in lungs exposed to different injuries.
Rats were assigned to one of the following protocols (N = 10 each): 1) ischemia/reperfusion (IR) or 2) cardiac death (CD) followed by ex vivo perfusion. NDP-MSH treatment was performed in five rats of each protocol before lung procurement and during EVLP. Pulmonary function and perfusate concentration of gases, electrolytes, metabolites, nitric-oxide, mediators, and cells were assessed throughout EVLP. ATP content and specific MCR expression were investigated in perfused lungs and in biopsies collected from rats in resting conditions (Native, N = 5).
NDP-MSH reduced the release of inflammatory mediators in perfusates of both the IR and the CD groups. Treatment was likewise associated with a lesser amount of leukocytes (IR: p = 0.034; CD: p = 0.002) and reduced lactate production (IR: p = 0.010; CD: p = 0.008). In lungs exposed to IR injury, the NDP-MSH group showed increased ATP content (p = 0.040) compared to controls. In CD lungs, a significant improvement of vascular (p = 0.002) and airway (Ppeak: p < 0.001, compliance: p < 0.050, pO2: p < 0.001) parameters was observed. Finally, the expression of MC1R and MC5R was detected in both native and ex vivo-perfused lungs.
The results indicate that NDP-MSH administration preserves lung function through broad positive effects on multiple pathways and suggest that exploitation of the melanocortin system during EVLP could improve reconditioning of marginal lungs before transplantation.
The partial understanding of the biological events that occur during normothermic machine perfusion (NMP) and particularly during prolonged perfusion might hinder its deployment in clinical ...transplantation. The aim of our study was to implement a rat model of prolonged NMP to characterize the bio-molecular phenotype and metabolism of the perfused organs. Livers (n = 5/group) were procured and underwent 4 h (NMP4h) or 12 h (NMP12h) NMP, respectively, using a perfusion fluid supplemented with an acellular oxygen carrier. Organs that were not exposed to any procedure served as controls (Native). All perfused organs met clinically derived viability criteria at the end of NMP. Factors related to stress-response and survival were increased after prolonged perfusion. No signs of oxidative damage were detected in both NMP groups. Evaluation of metabolite profiles showed preserved mitochondrial function, activation of Cori cycle, induction of lipolysis, acetogenesis and ketogenesis in livers exposed to 12 h-NMP. Increased concentrations of metabolites involved in glycogen synthesis, glucuronidation, bile acid conjugation, and antioxidant response were likewise observed. In conclusion, our NMP12h model was able to sustain liver viability and function, thereby deeply changing cell homeostasis to maintain a newly developed equilibrium. Our findings provide valuable information for the implementation of optimized protocols for prolonged NMP.
BACKGROUND:During mechanical ventilation, stress and strain may be locally multiplied in an inhomogeneous lung. The authors investigated whether, in healthy lungs, during high pressure/volume ...ventilation, injury begins at the interface of naturally inhomogeneous structures as visceral pleura, bronchi, vessels, and alveoli. The authors wished also to characterize the nature of the lesions (collapse vs. consolidation).
METHODS:Twelve piglets were ventilated with strain greater than 2.5 (tidal volume/end-expiratory lung volume) until whole lung edema developed. At least every 3 h, the authors acquired end-expiratory/end-inspiratory computed tomography scans to identify the site and the number of new lesions. Lung inhomogeneities and recruitability were quantified.
RESULTS:The first new densities developed after 8.4 ± 6.3 h (mean ± SD), and their number increased exponentially up to 15 ± 12 h. Afterward, they merged into full lung edema. A median of 61% (interquartile range, 57 to 76) of the lesions appeared in subpleural regions, 19% (interquartile range, 11 to 23) were peribronchial, and 19% (interquartile range, 6 to 25) were parenchymal (P < 0.0001). All the new densities were fully recruitable. Lung elastance and gas exchange deteriorated significantly after 18 ± 11 h, whereas lung edema developed after 20 ± 11 h.
CONCLUSIONS:Most of the computed tomography scan new densities developed in nonhomogeneous lung regions. The damage in this model was primarily located in the interstitial space, causing alveolar collapse and consequent high recruitability.
Pancreatic Cancer (PC) has a poor prognosis, with a 5-year survival rate of only 9%. Even after radical surgical procedures, PC patients have poor survival rates, with a high chance of relapse ...(70-80%). Imaging is involved in all aspects of the clinical management of PC, including detection and characterization of primary tumors and their resectability, assessment of vascular, perineural and lymphatic invasion and detection of distant metastases. The role of Positron Emission Tomography/Computed Tomography (PET/CT) in detecting PC is still controversial, with the international guidelines not recommending its routine use. However, in resectable PC, PET/CT may play a role in assessing PC stage and grade and potential resectability after neoadjuvant treatment. Quantitative image analysis (radiomics) and new PET/CT radiotracers account for future developments in metabolic imaging and may further improve the relevance of this technique in several aspects of PC. In the present review, the current state of the art and future directions of PET/CT in resectable PC are presented.
Ex vivo lung perfusion (EVLP) is an emerging procedure that allows organ preservation, assessment and reconditioning, increasing the number of marginal donor lungs for transplantation. However, ...physiological and airflow measurements are unable to unveil the molecular mechanisms responsible of EVLP beneficial effects on lung graft and monitor the proper course of the treatment. Thus, it is urgent to find specific biomarkers that possess these requirements but also accurate and reliable techniques that identify them. The purpose of this study is to give an overview on the potentiality of shotgun proteomic platforms in characterizing the status and the evolution of metabolic pathways during EVLP in order to find new potential EVLP-related biomarkers. A nanoLC-MS/MS system was applied to the proteome analysis of lung tissues from an optimized rat model in three experimental groups: native, pre- and post-EVLP. Technical and biological repeatability were evaluated and, together with clustering analysis, underlined the good quality of data produced. In-house software and bioinformatics tools allowed the label-free extraction of differentially expressed proteins among the three examined conditions and the network visualization of the pathways mainly involved. These promising findings encourage further proteomic investigations of the molecular mechanisms behind EVLP procedure.
The COVID-19 pandemic has inevitably caused those involved in cancer care to change clinical practice in order to minimize the risk of infection while maintaining cancer treatment as a priority. ...General advice during the pandemic suggests that most patients continue with ongoing therapies or planned surgeries, while follow-up visits may instead be delayed until the resolution of the outbreak. We conducted a literature search using PubMed to identify articles published in English language that reported on care recommendations for cancer patients during the COVID-19 pandemic from its inception up to 1st June 2020, using the terms "(cancer or tumor) AND (COVID 19)". Articles were selected for relevance and split into five categories: (1) personal recommendations of single or multiple authors, (2) recommendations of single authoritative centers, (3) recommendations of panels of experts or of multiple regional comprehensive centers, (4) recommendations of multicenter cooperative groups, (5) official guidelines or recommendations of health authorities. Of the 97 included studies, 10 were personal recommendations of single or multiple independent authors, 16 were practice recommendations of single authoritative cancer centers, 35 were recommendations provided by panel of experts or of multiple regional comprehensive centers, 19 were cooperative group position papers, and finally, 17 were official guidelines statements. The COVID-19 pandemic is a global emergency, and has rapidly modified our clinical practice. Delaying unnecessary treatment, minimizing toxicity, and identifying care priorities for surgery, radiotherapy, and systemic therapies must be viewed as basic priorities in the COVID-19 era.
Reducing the respiratory rate during extracorporeal membrane oxygenation (ECMO) decreases the mechanical power, but it might induce alveolar de-recruitment. Dissecting de-recruitment due to lung ...edema vs. the fraction due to hypoventilation may be challenging in injured lungs.
We characterized changes in lung physiology (primary endpoint: development of atelectasis) associated with progressive reduction of the respiratory rate in healthy animals on ECMO.
Six female pigs underwent general anesthesia and volume control ventilation (Baseline: PEEP 5 cmH
O, Vt 10 ml/kg, I:E = 1:2, FiO
0.5, rate 24 bpm). Veno-venous ECMO was started and respiratory rate was progressively reduced to 18, 12, and 6 breaths per minute (6-h steps), while all other settings remained unchanged. ECMO blood flow was kept constant while gas flow was increased to maintain stable PaCO
.
At Baseline (without ECMO) and toward the end of each step, data from quantitative CT scan, electrical impedance tomography, and gas exchange were collected. Increasing ECMO gas flow while lowering the respiratory rate was associated with an increase in the fraction of non-aerated tissue (i.e., atelectasis) and with a decrease of tidal ventilation reaching the gravitationally dependent lung regions (
= 0.009 and
= 0.018). Intrapulmonary shunt increased (
< 0.001) and arterial PaO
decreased (
< 0.001) at lower rates. The fraction of non-aerated lung was correlated with longer expiratory time spent at zero flow (
= 0.555,
= 0.011).
Progressive decrease of respiratory rate coupled with increasing CO
removal in mechanically ventilated healthy pigs is associated with development of lung atelectasis, higher shunt, and poorer oxygenation.
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