Systematic review and meta-analysis of open versus laparoscopy-assisted versus pure laparoscopic versus robotic living donor hepatectomy.

The value of minimally invasive approaches for living donor hepatectomy remains unclear. Our aim was to compare the donor outcomes after open versus laparoscopy-assisted versus pure laparoscopic versus robotic living donor hepatectomy (OLDH vs. LALDH vs. PLLDH vs. RLDH). A systematic literature review of the MEDLINE, Cochrane Library, Embase, and Scopus databases was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (up to December 8, 2021). Random-effects meta-analyses were performed separately for minor and major living donor hepatectomy. The risk of bias in nonrandomized studies was assessed using the Newcastle-Ottawa Scale. A total of 31 studies were included. There was no difference in donor outcomes after OLDH versus LALDH for major hepatectomy. However, PLLDH was associated with decreased estimated blood loss, length of stay (LOS), and overall complications versus OLDH for minor and major hepatectomy, but also with increased operative time for major hepatectomy. PLLDH was associated with decreased LOS versus LALDH for major hepatectomy. RLDH was associated with decreased LOS but with increased operative time versus OLDH for major hepatectomy. The scarcity of studies comparing RLDH versus LALDH/PLLDH did not allow us to meta-analyze donor outcomes for that comparison. There seems to be a marginal benefit in estimated blood loss and/or LOS in favor of PLLDH and RLDH. The complexity of these procedures limits them to transplant centers with high volume and experience. Future studies should investigate self-reported donor experience and the associated economic costs of these approaches.

The process of estimating the cost of surgery: Providing a practical framework for surgeons.

Over the last decades, health care costs have been increasing at an alarming, exponential rate which is considered unsustainable. Surgical care utilizes one-third of health care costs. Estimating, evaluating, and understanding the cost of surgery is a vital step towards cost management and reduction. Current cost estimation studies and cost-effectiveness studies have vast disparities in their methodology, with published costs of Operating Room varying from as low as $7 and as high as $113 per minute. Costs in surgery are distinguished as direct and indirect. Allocation of direct costs involves identification, measurement, and valuation processes. Allocation of indirect costs involves the allocation of capital and overhead costs and of indirect department costs. Annualised capital costs and overhead hospital costs are then allocated to surgery by either the cost-centre allocation or the activity-based allocation frameworks. Indirect department costs are allocated to a specific surgery by weighted service allocation or hourly rate allocation or inpatient day allocation, or marginal markup allocation. The growing societal, financial and political pressure for cost reduction has brought cost analysis to the forefront of healthcare discussions. Thus, we believe that almost every single surgeon will eventually enter the field of healthcare economics by necessity. This review aims to provide surgeons with a practical framework for engaging in cost estimation studies.

The Role of Immunotherapy in Hepatocellular Carcinoma: A Systematic Review and Pooled Analysis of 2,402 Patients.

BACKGROUND: Immune checkpoints inhibitors (ICIs) have emerged as a treatment option for several malignancies. Nivolumab, pembrolizumab, nivolumab plus ipilimumab, and atezolizumab plus bevacizumab have been approved for the management of advanced-stage hepatocellular carcinoma (HCC). We aimed to systematically review the literature and summarize the characteristics and outcomes of patients with HCC treated with ICIs. METHODS: A systematic literature search of PubMed, the Cochrane Library, and ClinicalTrials.gov was performed according to the PRISMA statement (end of search date: November 7, 2020). Quality of evidence assessment was also performed. RESULTS: Sixty-three articles including 2,402 patients were analyzed, 2,376 of whom received ICIs for unresectable HCC. Response to ICIs could be evaluated in 2,116 patients; the overall objective response rate (ORR) and disease control rate (DCR) were 22.7% and 60.7%, respectively, and the mean overall survival (OS) was 15.8 months. The ORR, DCR, and OS for nivolumab (n = 846) were 19.7%, 51.1%, and 18.7 months, respectively; for pembrolizumab (n = 435) they were 20.7%, 64.6% and 13.3 months, respectively. The combination of atezolizumab/bevacizumab (n = 460) demonstrated an ORR and DCR of 30% and 77%, respectively. The overall rate of treatment discontinuation because of adverse events was 14.9%. Fifteen patients received ICIs in the liver transplant (LT) setting (one pre-LT for bridging, 14 for post-LT recurrence); fatal graft rejection was reported in 40.0% (n = 6/15) and mortality in 80.0% (n = 12/15). CONCLUSION: ICIs are safe and effective against unresectable HCC, but caution is warranted regarding their use in the LT setting because of the high graft rejection rate. IMPLICATIONS FOR PRACTICE: This systematic review pooled the outcomes from studies reporting on the use of immune checkpoint inhibitors (ICIs) for the management of 2,402 patients with advanced-stage hepatocellular carcinoma (HCC), 2,376 of whom had unresectable HCC. The objective response rate and disease control rate were 22.7% and 60.7%, respectively, and the mean overall survival was 15.8 months. The overall rate of treatment discontinuation because of adverse events was 14.9%. Fifteen patients received ICIs in the liver transplant (LT) setting (one pre-LT for bridging, 14 for post-LT recurrence). Six of these patients experienced graft rejection (40.0%).

Artificial Intelligence, Machine Learning, and Surgical Science: Reality Versus Hype.

Artificial intelligence (AI) has made increasing inroads in clinical medicine. In surgery, machine learning-based algorithms are being studied for use as decision aids in risk prediction and even for intraoperative applications, including image recognition and video analysis. While AI has great promise in surgery, these algorithms come with a series of potential pitfalls that cannot be ignored as hospital systems and surgeons consider implementing these technologies. The aim of this review is to discuss the progress, promise, and pitfalls of AI in surgery.

Liver transplantation for hepatocellular carcinoma: Management after the transplant.

Hepatocellular carcinoma (HCC) is an increasingly common indication for liver transplantation (LT) in the United States and in many parts of the world. In the last decade, significant work has been done to better understand how to risk stratify LT candidates for recurrence of HCC following transplant using a combination of biomarker and imaging findings. However, despite the high frequency of HCC in the LT population, guidance regarding posttransplant management is lacking. In particular, there is no current evidence to support specific post-LT surveillance strategies, leading to significant heterogeneity in practices. In addition, there are no current recommendations regarding recurrence prevention, including immunosuppression regimen or secondary prevention with adjuvant chemotherapy. Finally, guidance on treatment of disease recurrence is also lacking and there is significant controversy about the use of immunotherapy in transplant recipients due to the risk of rejection. Thus, outcomes for patients with recurrence are poor. This paper therefore provides a comprehensive review of the current literature on post-LT management of patients with HCC and identifies gaps in our current knowledge that are in urgent need of further investigation.

Frailty assessment and postoperative outcomes among patients undergoing general surgery.

BACKGROUND: Frailty is an emerging concept in modern general surgery because of its correlation with adverse outcomes. More frail older patients are undergoing general surgery due to the rapid aging of the population and the effect of the "baby boom" generation. However, there is no consensus on the definition of frailty and on ways to assess its severity and effect. PURPOSE: To describe the definition and epidemiology, measurement tools, and the effect of frailty on postoperative outcomes after general surgery. METHODS: PubMed and Google Scholar databases were comprehensively searched. RESULTS: Frailty is a syndrome defined as increased vulnerability to stressors due to a decline in physiological function and reserve among organ systems, resulting in adverse outcomes. Numerous tools have been described and tested for frailty measurement, but the ideal clinical tool has not been found yet. The evidence from cohort studies and meta-analyses shows associations between preoperative frailty and adverse perioperative outcomes after general surgery. CONCLUSION: Frailty is an essential concept in general surgery. However, further studies have to identify the optimal way to preoperatively assess frailty and risk-stratify older patients.

Developing a novel international undergraduate surgical masterclass during a financial crisis: our 4-year experience.

BACKGROUND: Essential Skills in the Management of Surgical Cases (ESMSC) is a novel 3-day international undergraduate surgical masterclass. Its current curriculum (Cores integrated for Research-Ci4R) is built on a tetracore, multiclustered architecture combining high-fidelity and low-fidelity simulation-based learning (SBL), with applied and basic science case-based workshops, and non-technical skills modules. We aimed to report our experience in setting up ESMSC during the global financial crisis. METHODS: We report the evolution of our curriculum's methodology and summarised the research outcomes related to the objective performance improvement of delegates, the educational environment of the course and the use of mixed-fidelity SBL. Feedback from the last three series of the course was prospectively collected and analysed using univariate statistics on IBM SPSS V.23. RESULTS: 311 medical students across the European Union (EU) were selected from a competitive pool of 1280 applicants during seven series of the course between 2014 and 2017. During this period, curriculum 14 s evolved to the final Ci4R version, which integrates a tetracore structure combining 32 stations of in vivo, ex vivo and dry lab SBL with small group teaching workshops. Ci4R was positively perceived across different educational background students (p>0.05 for any comparison). CONCLUSIONS: ESMSC is considered an innovative and effective multidisciplinary teaching model by delegates, where it improves delegates objective performance in basic surgical skills. Our experience demonstrates provision of high-quality and free surgical education during a financial crisis, which evolved through a dynamic feedback mechanism. The prospective recording and subsequent analysis of curriculum evolution provides a blueprint to direct development of effective surgical education courses that can be adapted to local needs.

Modulation of neural activity by reward in medial intraparietal cortex is sensitive to temporal sequence of reward.

To restore movements to paralyzed patients, neural prosthetic systems must accurately decode patients' intentions from neural signals. Despite significant advancements, current systems are unable to restore complex movements. Decoding reward-related signals from the medial intraparietal area (MIP) could enhance prosthetic performance. However, the dynamics of reward sensitivity in MIP is not known. Furthermore, reward-related modulation in premotor areas has been attributed to behavioral confounds. Here we investigated the stability of reward encoding in MIP by assessing the effect of reward history on reward sensitivity. We recorded from neurons in MIP while monkeys performed a delayed-reach task under two reward schedules. In the variable schedule, an equal number of small- and large-rewards trials were randomly interleaved. In the constant schedule, one reward size was delivered for a block of trials. The memory period firing rate of most neurons in response to identical rewards varied according to schedule. Using systems identification tools, we attributed the schedule sensitivity to the dependence of neural activity on the history of reward. We did not find schedule-dependent behavioral changes, suggesting that reward modulates neural activity in MIP. Neural discrimination between rewards was less in the variable than in the constant schedule, degrading our ability to decode reach target and reward simultaneously. The effect of schedule was mitigated by adding Haar wavelet coefficients to the decoding model. This raises the possibility of multiple encoding schemes at different timescales and reinforces the potential utility of reward information for prosthetic performance.

Diagnostic and Prognostic Value of Machine Perfusion Biomarkers in Kidney Graft Evaluation.

BACKGROUND: With the rising prevalence of end-stage kidney disease, the use of expanded criteria donor allografts, seen as essential for meeting organ demand, still proves challenging due to their higher risk of graft loss, delayed function, and rejection. Machine perfusion, a technique in preserving allografts, offers improved allograft outcomes compared to static cold storage while allowing for the noninvasive measurement of kidney injury biomarkers in the perfusate solution. This offers an objective method to assess graft function at various preservation stages. MATERIALS AND METHODS: We conducted a narrative review of the databases PubMed and Scopus, including studies written in the English language and published after 2010. RESULTS: In this narrative review, we identified biomarkers, like 4-hydroxyproline, taurine, and glutathione transferase, as predictive markers of delayed graft function. Additionally, biomarkers, like extracellular histone h3, vascular cell adhesion protein, and matrix metalloprotease protein, have shown correlation with decreased graft function, although their predictive ability remains inconclusive. DISCUSSION: The review outlines various suggestions for potential areas of research focus to enhance future expanded criteria donor allograft utilization. However, limitations exist, including the absence of a singular reliable biomarker and the challenges of validating biomarker effectiveness across diverse outcomes.

Critical considerations for the management of acute abdomen in transplant patients.

The number of solid organ transplantations performed annually is increasing and are increasing in the following order: Kidney, liver, heart, lung, pancreas, small bowel, and uterine transplants. However, the outcomes of transplants are improving (organ survival > 90% after the 1st year). Therefore, there is a high probability that a general surgeon will be faced with the management of a transplant patient with acute abdomen. Surgical problems in immunocompromised patients may not only include graft-related problems but also nongraft-related problems. The perioperative regulation of immunosuppression, the treatment of accompanying problems of immunosuppression, the administration of cortisol and, above all, the realization of a rapidly deteriorating situation and the accurate evaluation and interpretation of clinical manifestations are particularly important in these patients. The perioperative assessment and preparation includes evaluation of the patient's cardiovascular system and determining if the patient has hypertension or suppression of the hypothalamic-pituitary-adrenal axis, or if the patient has had any coagulation mechanism abnormalities or thromboembolic episodes. Immunosuppression in transplant patients is associated with the use of calcineurin inhibitors, corticosteroids, and antiproliferation agents. Many times, the clinical picture is atypical, resulting in delays in diagnosis and treatment and leading to increased morbidity and mortality. Multidetector computed tomography is of utmost importance for early diagnosis and management. Transplant recipients are prone to infections, especially specific infections caused by cytomegalovirus and Clostridium difficile, and they are predisposed to intraoperative or postoperative complications that require great care and vigilance. It is necessary to follow evidence-based therapeutic protocols. Thus, it is required that the clinician choose the correct therapeutic plan for the patient (conservative, emergency open surgery or minimally invasive surgery, including laparoscopic or even robotic surgery).

Clinical Prediction Models for Prognosis of Colorectal Liver Metastases: A Comprehensive Review of Regression-Based and Machine Learning Models.

Colorectal liver metastasis (CRLM) is a disease entity that warrants special attention due to its high frequency and potential curability. Identification of "high-risk" patients is increasingly popular for risk stratification and personalization of the management pathway. Traditional regression-based methods have been used to derive prediction models for these patients, and lately, focus has shifted to artificial intelligence-based models, with employment of variable supervised and unsupervised techniques. Multiple endpoints, like overall survival (OS), disease-free survival (DFS) and development or recurrence of postoperative complications have all been used as outcomes in these studies. This review provides an extensive overview of available clinical prediction models focusing on the prognosis of CRLM and highlights the different predictor types incorporated in each model. An overview of the modelling strategies and the outcomes chosen is provided. Specific patient and treatment characteristics included in the models are discussed in detail. Model development and validation methods are presented and critically appraised, and model performance is assessed within a proposed framework.

Artificial kidney: Challenges and opportunities.

This review aims to present the developments occurring in the field of artificial organs and particularly focuses on the presentation of developments in artificial kidneys. The challenges for biomedical engineering involved in overcoming the potential difficulties are showcased, as well as the importance of interdisciplinary collaboration in this marriage of medicine and technology. In this review, modern artificial kidneys and the research efforts trying to provide and promise artificial kidneys are presented. But what are the problems faced by each technology and to what extent is the effort enough to date?

Kidney Transplantation and Cellular Immunity Dynamics: Immune Cell Alterations and Association with Clinical and Laboratory Parameters.

Background/Objectives: The purpose of this study was to evaluate numerical changes in immune cells after successful kidney transplantation and associate their recovery with clinical and laboratory factors. Methods: In 112 kidney transplant recipients, we performed flow cytometry to evaluate counts of CD4+, CD8+, and regulatory T cells (Tregs), as well as natural killer (NK) cells, before kidney transplantation (T0) and three (T3), six (T6), and twelve (T12) months later. The results were associated with the recipient's age, cold ischemia time (CIT), the type of donor, dialysis method and vintage, and graft function in one year. Results: Total and CD8+ T cell counts increased gradually one year post transplantation in comparison with pre-transplantation levels, whereas the number of CD4+ T cells and Tregs increased, and the number of NK cells decreased in the first three months and remained stable thereafter. The recipient's age was negatively correlated with total, CD4+, and Treg counts at T12, whereas CIT affected only total and CD4+ T cell count. Moreover, recipients receiving kidneys from living donors presented better recovery of all T cell subsets at T12 in comparison with recipients receiving kidneys from cadaveric donors. Patients on peritoneal dialysis had increased numbers of total and CD8+ T cells, as well as NK cells. Finally, estimated glomerular filtration rate was positively correlated with Treg level and potentially CD4+ T cells one-year post transplantation. Conclusions: Successful kidney transplantation results in the recovery of most T cell subsets. Lower recipient age and better graft function contribute to increased T cell counts, whereas donor type and dialysis modality are the most important modifiable factors for optimal immune recovery.

Evaluation of Regulatory B Cell Subpopulations CD24++CD38++, CD24++CD27+, Plasmablasts and Their Correlation with T Regs CD3+CD4+CD25+FOXP3+ in Dialysis Patients and Early Post-Transplant Rejection-Free Kidney Recipients.

Background: B and T regulatory cells, also known as Bregs and Tregs, are involved in kidney transplantation. The purpose of this study is to monitor changes in the frequency and absolute numbers of Tregs (CD3+CD4+CD25+FoxP3+), transitional Bregs (tBregs) (CD24++CD38++), memory Bregs (mBregs) (CD24++CD27+), and plasmablasts before (T0) and six months (T6) after transplantation. Additionally, we aim to investigate any correlation between Tregs and tBregs, mBregs, or plasmablasts and their relationship with graft function. Methods: Flow cytometry was used to immunophenotype cells from 50 kidney recipients who did not experience rejection. Renal function was assessed using the estimated glomerular filtration rate (eGFR). Results: At T6, there was a significant decrease in the frequency of Tregs, plasmablasts, and tBregs, as well as in the absolute number of tBregs. The frequency of mBregs, however, remained unchanged. Graft function was found to have a positive correlation with the frequency of tBregs and plasmablasts. A significant correlation was observed between the frequency and absolute number of tBregs only when the eGFR was greater than 60 but not at lower values. At an eGFR greater than 60, there was a positive correlation between the absolute numbers of Tregs and mBregs but not between Tregs and tBregs. No correlation was observed for any cell population in dialysis patients. Conclusions: The data show a correlation between the frequency and absolute number of tBregs and the absolute number of Tregs and mBregs with good renal function in the early post-transplant period.

Vaccination with Tozimameran Induces T-Cell Activation, but Not Senescent or Exhaustive Alterations, in Kidney Transplant Recipients.

BACKGROUND: Multiple vaccinations have potential inimical effects on the immune system aging process. We examined whether response to SARS-CoV-2 vaccination with Tozinameran is associated with immunosenescence and immunoexhaustion in kidney transplant recipients (KTRs). METHODS: In this prospective observational study, we observed 39 adult kidney transplant recipients (KTRs) who had no pre-existing anti-SARS-CoV-2 antibodies and were on stable immunosuppression. CD4+ and CD8+ T-cell subpopulations [comprising CD45RA+CCR7+ (naïve), CD45RA-CCR7+ (T-central memory, TCM), CD45RA-CCR7- (T-effector memory, TEM) and CD45RA+CCR7- (T-effector memory re-expressing CD45RA, TEMRA, senescent), CD28- (senescent) and PD1+ (exhausted)] were evaluated at 2 time points: T1 (48 h prior to the 3rd), and T2 (3 weeks following the 3rd Tozinameran dose administration). At each time point, patients were separated into Humoral and/or Cellular Responders and Non-Responders. RESULTS: From T1 to T2, CD4+TCM and CD8+TEM were increased, while naïve CD4+ and CD8+ proportions were reduced in the whole cohort of patients, more prominently among responders. At T2, responders compared to non-responders had higher CD8+CD28+ [227.15 (166) vs. 131.44 (121) cells/µL, p: 0.036], lower CD4+CD28- T-lymphocyte numbers [59.65 (66) cells/µL vs. 161.19 (92) cells/µL, p: 0.026] and percentages [6.1 (5.5)% vs. 20.7 (25)%, p: 0.04]. CONCLUSION: In KTRs, response to vaccination is not associated with an expansion of senescent and exhausted T-cell concentrations, but rather with a switch from naïve to differentiated-activated T-cell forms.

Translational research and innovation in modern transplant practice: Paradigms from Greece and around the world.

The continuous clinical and technological advances, together with the social, health and economic challenges that the global population faces, have created an environment where the evolution of the field of transplantation is essentially necessary. The goal of this special issue is to provide a picture of the current status of transplantation in Greece as well as in many other countries in Europe and around the world. Authors from Greece and several other countries provide us with valuable insight into their respective areas of transplant expertise, with a main focus on the field of translational research and innovation. The papers that are part of this Special Issue "Translational Research and Innovation and the current status of Transplantation in Greece" have presented innovative and meaningful approaches in modern transplant research and practice. They provide us with a clear overview of the current landscape in transplantation, including liver transplantation in the context of a major pandemic, the evolution of living donor kidney transplantation or the evolution of the effect of hepatitis C virus infection in transplantation, while at the same time explore more recent challen ges, such as the issue of frailty in the transplant candidate and the changes brought by newer treatments, such as immunotherapy, in transplant oncology. Additionally, they offer us a glimpse of the effect that technological innovations, such as virtual reality, can have on transplantation, both in terms of clinical and educational aspects. Just as critical is the fact that this Special Issue emphasizes the multidisciplinary, collaborative efforts currently taking place that link transplant research and innovation with other cutting-edge disciplines such as bioengineering, advanced information technology and artificial intelligence. In this Special Issue, in addition to the clinical and research evolution of the field of transplantation, we are witnessing the importance of interdisciplinary collaboration in medicine.

Challenges involved in the application of artificial intelligence in gastroenterology: The race is on!

Gastroenterology is a particularly data-rich field, generating vast repositories of data that are a fruitful ground for artificial intelligence (AI) and machine learning (ML) applications. In this opinion review, we initially elaborate on the current status of the application of AI/ML-based software in gastroenterology. Currently, AI/ML-based models have been developed in the following applications: Models integrated into the clinical setting following real-time patient data flagging patients at high risk for developing a gastrointestinal disease, models employing non-invasive parameters that provide accurate diagnoses aiming to either replace, minimize, or refine the indications of endoscopy, models utilizing genomic data to diagnose various gastrointestinal diseases, computer-aided diagnosis systems facilitating the interpretation of endoscopy images, models to facilitate treatment allocation and predict the response to treatment, and finally, models in prognosis predicting complications, recurrence following treatment, and overall survival. Then, we elaborate on several challenges and how they may negatively impact the widespread application of AI in healthcare and gastroenterology. Specifically, we elaborate on concerns regarding accuracy, cost-effectiveness, cybersecurity, interpretability, oversight, and liability. While AI is unlikely to replace physicians, it will transform the skillset demanded by future physicians to practice. Thus, physicians are expected to engage with AI to avoid becoming obsolete.

Three-Dimensional Printing and Bioprinting in Renal Transplantation and Regenerative Medicine: Current Perspectives.

For patients with end-stage kidney disease (ESKD), renal transplantation is the treatment of choice, constituting the most common solid organ transplantation. This study aims to provide a comprehensive review regarding the application of three-dimensional (3D) printing and bioprinting in renal transplantation and regenerative medicine. Specifically, we present studies where 3D-printed models were used in the training of surgeons through renal transplantation simulations, in patient education where patients acquire a higher understanding of their disease and the proposed operation, in the preoperative planning to facilitate decision-making, and in fabricating customized, tools and devices. Three-dimensional-printed models could transform how surgeons train by providing surgical rehearsal platforms across all surgical specialties, enabling training with tissue realism and anatomic precision. The use of 3D-printed models in renal transplantations has shown a positive impact on surgical outcomes, including the duration of the operation and the intraoperative blood loss. Regarding 3D bioprinting, the technique has shown promising results, especially in the field of microfluidic devices, with the development of tissue demonstrating proximal tubules, glomerulus, and tubuloinerstitium function, and in renal organoid development. Such models can be applied for renal disease modeling, drug development, and renal regenerative medicine.