Controversies regarding transplantation of mesenchymal stem cells

Mesenchymal stem cells(MSCs)have tantalized regenerative medicine with their therapeutic potential,yet a cloud of controversies looms over their clinical tran-splantation.This comprehensive review navigates the intricate landscape of MSC controversies,drawing upon 15 years of clinical experience and research.We delve into the fundamental properties of MSCs,exploring their unique immuno-modulatory capabilities and surface markers.The heart of our inquiry lies in the controversial applications of MSC transplantation,including the perennial debate between autologous and allogeneic sources,concerns about efficacy,and lingering safety apprehensions.Moreover,we unravel the enigmatic mechanisms surro-unding MSC transplantation,such as homing,integration,and the delicate balance between differentiation and paracrine effects.We also assess the current status of clinical trials and the ever-evolving regulatory landscape.As we peer into the future,we examine emerging trends,envisioning personalized medicine and innovative delivery methods.Our review provides a balanced and informed perspective on the controversies,offering readers a clear understanding of the complexities,challenges,and potential solutions in MSC transplantation.

Donor defects after lymph vessel transplantation and free vascularized lymph node transfer:A comparison and evaluation of complications

BACKGROUND Secondary lymphedema after surgical interventions is a progressive,chronic disease that is still not completely curable.Over the past years,a multitude of surgical therapy options have been described.AIM To summarize the single-center complications in lymph vessel(LVTx)and free vascularized lymph node transfer(VLNT).METHODS In total,the patient collective consisted of 87 patients who were undergoing treatment for secondary leg lymphedema during the study period from March 2010 to April 2020.The data collection was performed preoperatively during consultations,as well as three weeks,six months and twelve months after surgical treatment.In the event of complications,more detailed follow-up checks were carried out.In total n=18 robot-assisted omental lymph node transplantations,n=33 supraclavicular lymph node transplantations and n=36 Lymph vessel transplantations were analyzed.An exemplary drawing is shown in Figure 1.A graphical representation of patient selection is shown in Figure 2.Robotic harvest was performed with the Da Vinci Xi Robot Systems(Intuitive Surgical,CA,United States).RESULTS In total,11 male and 76 female patients were operated on.The mean age of the patients at study entry was:omental VLNT:57.45±8.02 years;supraclavicular VLNT:49.76±4.16 years and LVTx:49.75±4.95 years.The average observation time postoperative was:omental VLNT:18±3.48 mo;supraclavicular VLNT:14.15±4.9 and LVTx:14.84±4.46 mo.In our omental VLNT,three patients showed a slight abdominal sensation of tension within the first 12 postoperative days.No other donor side morbidities occurred.No intraoperative conversion to open technique was needed.Our supraclavicular VLNT collective showed 10 lift defect morbidities with one necessary surgical intervention.In our LVTx collective,12 cases of donor side morbidity were registered.In one case,surgical intervention was necessary.CONCLUSION Concerning donor side morbidity,robot-assisted omental VLNT is clearly superior to supraclavicular lymph node transplantation and LVTx.

Cardiovascular risk factors following renal transplant

Kidney transplantation is the gold-standard treatment for many patients with end-stage renal disease. Renal transplant recipients(RTRs) remain at an increased risk of fatal and non-fatal cardiovascular(CV) events compared to the general population, although rates are lower than those patients on maintenance haemodialysis. Death with a functioning graft is most commonly due to cardiovascular disease(CVD) and therefore this remains an important therapeutic target to prevent graft failure. Conventional CV risk factors such as diabetes, hypertension and renal dysfunction remain a major influence on CVD in RTRs. However it is now recognised that the morbidity and mortality from CVD are not entirely accounted for by these traditional risk-factors. Immunosuppression medications exert a deleterious effect on many of these well-recognised contributors to CVD and are known to exacerbate the probability of developing diabetes, graft dysfunction and hypertension which can all lead on to CVD. Nontraditional CV risk factors such as inflammation and anaemia have been strongly linked to increased CV events in RTRs and should be considered alongside those which are classified as conventional. This review summarises what is known about risk-factors for CVD in RTRs and how, through identification of those which are modifiable, outcomes can be improved. The overall CV risk in RTRs is likely to be multifactorial and a complex interaction between the multiple traditional and non-traditional factors; further studies are required to determine how these may be modified to enhance survival and quality of life in this unique population.

Psychopathological aspects of kidney transplantation: Efficacy of a multidisciplinary team

Renal transplantation is a well established treatment for end-stage renal disease, allowing most patients to return to a satisfactory quality of life. Studies have identified many problems that may affect adaptation to the transplanted condition and postoperative compliance. The psychological implications of transplantation have important consequences even on strictly physical aspects. Organ transplantation is very challenging for the patient and acts as an intense stressor stimulus to which the patient reacts with neurotransmitter and endocrine-metabolic changes. Transplantation can result in a psychosomatic crisis that requires the patient to mobilize all bio-psychosocial resources during the process of adaptation to the new foreign organ which may result in an alteration in self-representation and identity, with possible psychopathologic repercussions. These reactions are feasible in mental disorders, e.g., post-traumatic stress disorder, adjustment disorder, and psychosomatic disorders. In organ transplantation, the fruitful collaboration between professionals with diverse scientific expertise, calls for both a guarantee for mental health and greater effectiveness in challenging treatments for a viable association between patients, family members and doctors. Integrated and multidisciplinary care should include uniform criteria and procedures for standard assessments, for patient autonomy, adherence to therapy, new coping strategies and the adoption of more appropriate lifestyles.

m TOR signaling in liver regeneration: Rapamycin combined with growth factor treatment

AIM: To investigate the effects of mammalian target of rapamycin(mT OR) inhibition on liver regeneration and autophagy in a surgical resection model.METHODS: C57BL/6 mice were subjected to a 70% partial hepatectomy(PH) and treated intraperitoneally every 24 h with a combination of the m TOR inhibitor rapamycin(2.5 mg/kg per day) and the steroid dexamethasone(2.0 mg/kg per day) in phosphate bufferedsaline(PBS) or with PBS alone as vehicle control. In the immunosuppressant group, part of the group was treated subcutaneously 4 h prior to and 24 h after PH with a combination of human recombinant interleukin 6(IL-6; 500 μg/kg per day) and hepatocyte growth factor(HGF; 100 μg/kg per day) in PBS. Animals were sacrificed 2, 3 or 5 d after PH and liver tissue and blood were collected for further analysis. Immunohistochemical staining for 5-Bromo-2'-deoxyuridine(Brd U) was used to quantify hepatocyte proliferation. Western blotting was used to detect hepatic microtubule-associated protein 1 light chain 3(LC3)-Ⅱ protein expression as a marker for autophagy. Hepatic gene expression levels of proliferation-, inflammation- and angiogenesisrelated genes were examined by real-time reverse transcription-polymerase chain reaction and serum bilirubin and transaminase levels were analyzed at the clinical chemical core facility of the Erasmus MC-University Medical Center.RESULTS: m TOR inhibition significantly suppressed regeneration, shown by decreased hepatocyte proliferation(2% vs 12% Brd U positive hepatocyte nuclei at day 2, P < 0.01; 0.8% vs 1.4% at day 5, P = 0.02) and liver weight reconstitution(63% vs 76% of initial total liver weight at day 3, P = 0.04), and furthermore increased serum transaminase levels(aspartate aminotransferase 641 U/L vs 185 U/L at day 2, P = 0.02). Expression of the autophagy marker LC3-Ⅱ, which was reduced during normal liver regeneration, increased after mT OR inhibition(46% increase at day 2, P = 0.04). Hepatic gene expression showed an increased inflammation-related response [tumor necrosis factor(TNF)-α 3.2-fold upregulation at day 2, P = 0.03; IL-1Ra 6.0-fold upregulation at day 2 and 42.3-fold upregulation at day 5, P < 0.01] and a reduced expression of cell cycle progression and angiogenesis-related factors(HGF 40% reduction at day 2; vascular endothelial growth factor receptor 2 50% reduction at days 2 and 5; angiopoietin 1 60% reduction at day 2, all P ≤ 0.01). Treatmentwith the regeneration stimulating cytokine IL-6 and growth factor HGF could overcome the inhibitory effect on liver weight(75% of initial total liver weight at day 3, P = 0.02 vs immunosuppression alone and P = 0.90 vs controls) and partially reversed gene expression changes caused by rapamycin(TNF-α and IL-1Ra levels at day 2 were restored to control levels). However, no significant changes in hepatocyte proliferation, serum injury markers or autophagy were found.CONCLUSION: mT OR inhibition severely impairs liver regeneration and increases autophagy after PH. These effects are partly reversed by stimulation of the IL-6 and HGF pathways.

Links between donor macrosteatosis,interleukin-33 and complement after liver transplantation

BACKGROUND As prevalence of nonalcoholic fatty liver disease increases in the population,livers with steatosis will continue to infiltrate the donor pool.Safe utilization of these extended criteria grafts is paramount given the increased risk associated with their use in transplantation.Prognostic factors that can predict liver dysfunction immediately after transplantation with macrosteatotic grafts are lacking.AIM To understand the relationship between interleukin-33(IL-33)and complement in recipients immediately following liver reperfusion as a marker of liver dysfunction.METHODS Cohort consisted of patients who received a liver transplant from September 2016–September 2019 at our institution.Clinical variables were retrospectively extracted from the electronic medical record.Back-table donor biopsies were obtained with donor steatosis percentage retrospectively determined by a boardcertified pathologist.Blood samples were available immediately following liver transplantation.Quantification of plasma IL-33 and complement proteins,C3a and C5a,were determined by enzyme-linked immunosorbent assay.For mRNA expression,RNA was extracted from donor biopsies and used against a 780 gene panel.RESULTS Cohort consisted of 99 donor and recipients.Donor median age was 45 years and 55%male.Recipients had a median age of 59 years with 62%male.The main etiologies were alcoholic hepatitis,nonalcoholic steatohepatitis,and hepatocellular carcinoma.Median MELD-Na at transplant was 21.Donors were grouped based on moderate macrosteatosis(≥30%).Recipients implanted with moderate macrosteatotic grafts had significantly higher peak alanine aminotransferase/aspartate aminotransferase(P<0.001 and P<0.004),and increased incidence of early allograft dysfunction(60%compared to 18%).Circulating IL-33 levels were significantly elevated in recipients of≥30%macrosteatotic grafts(P<0.05).Recipients with detectable levels of circulating IL-33 immediately following reperfusion had significantly higher alanine aminotransferase/aspartate aminotransferase(P<0.05 and P<0.01).Activated complement(C3a and C5a)were elevated in recipients implanted with moderate macrosteatotic grafts.RNA expression analysis of donor biopsies revealed moderate steatotic grafts upregulated genes inflammatory processes while downregulated hepatocyte-produced complement factors.CONCLUSION Circulating IL-33 and activated complement levels immediately following liver reperfusion in recipients of moderate macrosteatotic grafts may identify which patients are at risk of early allograft dysfunction.

Lobar lung transplantation from deceased donors: A systematic review

AIM To systematically review reports on deceased-donor-lobar lung transplantation(dd LLTx) and uniformly describe sizematching using the donor-to-recipient predicted-total lung-capacity(pT LC) ratio. METHODS We set out to systematically review reports on ddL LTx and uniformly describe size matching using the donorto-recipient pT LC ratio and to summarize reported oneyear survival data of ddL LTx and conventional-LTx. We searched in Pub Med, CINAHL via EBSCO, Cochrane Database of Systematic Reviews via Wiley(CDSR),Database of Abstracts of Reviews of Effects via Wiley(DARE), Cochrane Central Register of Controlled Trials via Wiley(CENTRAL), Scopus(which includes EMBASE abstracts), and Web of Science for original reports on ddL LTx. RESULTS Nine observational cohort studies reporting on 301 ddL LTx met our inclusion criteria for systematic review of size matching, and eight for describing one-year-survival. The dd LLTx-group was often characterized by high acuity;however there was heterogeneity in transplant indications and pre-operative characteristics between studies. Data to calculate the pT LC ratio was available for 242 ddL LTx(80%). The mean pT LCratio before lobar resection was1.25 ± 0.3 and the transplanted pT LCratio after lobar resection was 0.76 ± 0.2. One-year survival in the ddL LTxgroup ranged from 50%-100%, compared to 72%-88%in the conventional-LTx group. In the largest study ddL LTx(n = 138) was associated with a lower one-year-survival compared to conventional-LTx(n = 539)(65.1% vs84.1%, P < 0.001). CONCLUSION Further investigations of optimal donor-to-recipient size matching parameters for ddL LTx could improve outcomes of this important surgical option.

Mucocele mimicking a gallbladder in a transplanted liver:A case report and review of the literature

Biliary mucoceles after deceased donor liver transplantation are a rarity,and mucoceles mimicking a gallbladder from the recipient remnant cystic duct have not been described until this case.We describe a 48-year-old male who presented with right upper quadrant pain and was found to have a recipient cystic duct mucocele 3 mo after receiving a deceased donor liver transplant.We describe the clinical presentation,laboratory and imaging findings(including the appearance of a gallbladder),multidisciplinary approach and surgical resolution of this mucocele originating from the recipient cystic duct,and a review of the literature.

Cavitary lung lesion 6 years after renal transplantation

The differential diagnoses of a cavitary lung lesion in renal transplant recipients would include infection, malignancy and less commonly inflammatory diseases. Bacterial infection, Tuberculosis, Nocardiosis, fungal infections like Aspergillosis and Cryptococcosis need to be considered in these patients. Pulmonary cryptococcosis usually presents 16-21 mo after transplantation, more frequently in patients who have a high level of cumulative immunosuppression. Here we discuss an interesting patient who never received any induction/anti-rejection therapy but developed both BK virus nephropathy as well as severe pulmonary Cryptococcal infection after remaining stable for 6 years after transplantation. This case highlights the risk of serious opportunistic infections even in apparently low immunologic risk transplant recipients many years after transplantation.

Current status of clinical islet transplantation

Islet transplantation(IT) is today a well-established treatment modality for selected patients with type 1 diabetes mellitus(T1DM). After the success of the University of Alberta group with a modified approach to the immune protection of islets, the international experience grew along with the numbers of transplants in highly specialized centers. Yet, long-term analysis of those initial results from the Edmonton group indicated that insulin-independence was not durable and most patients return to modest amounts of insulin around the fifth year, without recurrent hypoglycemia events. Many phenomena have been identified as limiting factor for the islet engraftment and survival, and today all efforts are aimed to improve the quality of islets and their engrafting process, as well as more optimized immunosuppression to facilitate tolerance and ultimately, better long term survival. This brief overview presents recent progress in IT. A concise historical perspective is provided, along with the latest efforts to improve islet engraftment, immune protection and ultimately, prolonged graft survival. It is apparent that as the community continues to work together further optimizing IT, it is hopeful a cure for T1 DM will soon be achievable.

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?

Innovative immunosuppression in kidney transplantation:A challenge for unmet needs

Due to the optimal results obtained in kidney transplantation and to the lack of interest of the industries,new innovative drugs in kidney transplantation are difficult to be encountered.The best strategy to find the new drugs recently developed or under development is to search in the sections of kidney transplantation still not completely covered by the drugs on the market.These unmet needs are the prevention of delayed graft function(DGF),the protection of the graft over the long time and the desensitization of preformed anti human leukocyte antigen antibodies and the treatment of the acute antibody-mediated rejection.These needs are particularly relevant due to the expansion of some kind of kidney transplantation as transplantation from non-heart beating donor and in the case of antibody-incompatible grafts.The first are particularly exposed to DGF,the latter need a safe desensitization and a safe treatments of the antibody mediated rejections that often occur.Particular caution is needed in treating these drugs.First,they are described in very recent studies and the follow-up of their effect is of course rather short.Second,some of these drugs are still in an early phase of study,even if in well-conducted randomized controlled trials.Particular caution and a careful check need to be used in trials launched 2 or 3 years ago.Indeed,is always necessary to verify whether the study is still going on or whether and why the study itself was abandoned.

Psychological perspective of medication adherence in transplantation

AIM To identify the risk factors and the post-transplant psychological symptoms that affect adherence to therapy in a population of kidney transplant recipients. METHODS The study examined the psychological variables likely responsible for the non-adherent behavior using a psychological-psychiatric assessment, evaluation of the perception of patients' health status, and an interview regarding the anti-rejection drug therapy assumption. The study included 74 kidney transplant recipients. RESULTS Individuals with a higher level of education and more years since transplantation showed better mental balance. Regarding gender, women appeared to be less adherent to therapy. Further, the years since transplantation adversely affected the proper pharmacological assumption. Adherence to therapy did not significantly change with the mental health index. CONCLUSION The biopsychosocial illness model provides a conceptualframe of reference in which biological, psychological, and social aspects take on the same importance in the adherence to treatment protocols. For effective management, it is necessary to understand the patients' personal experiences, their assumptions about the disease, health status perception, and mood, and to identify any "barriers" that could cause them to become noncompliant.

Cryptosporidium infection in solid organ transplantation

Diarrhea is a common complication in solid organ transplant(SOT) recipients and may be attributed to immunosuppressive drugs or infectious organisms such as bacteria, viruses or parasites. Cryptosporidium usually causes self-limited diarrhea in immunocompetent hosts. Although it is estimated that cryptosporidium is involved in about 12% of cases of infectious diarrhea in developing countries and causes approximately 748000 cases each year in the United States, it is still an under recognized and important cause of infectious diarrhea in SOT recipients. It may run a protracted course with severe diarrhea, fluid and electrolyte depletion and potential for organ failure. Although diagnostic methodologies have improved significantly, allowing for fast and accurate identification of the parasite, treatment of the disease is difficult because antiparasitic drugs have modest activity at best. Current management includes fluid and electrolyte replacement, reduction of immunosuppression and single therapy with Nitazoxanide or combination therapy with Nitazoxanide and other drugs. Future drug and vaccine development may add to the currently poor armamentarium to manage the disease. The current review highlights key epidemiological, diagnostic and management issues in the SOT population.

Multiple indications for everolimus after liver transplantation in current clinical practice

AIM: To assess our experience with the use and management of everolimus-based regimens post-liver transplantation and to redefine the potential role of this drug in current clinical practice.METHODS: From October 1988 to December 2012, 1023 liver transplantations were performed in 955 patients in our Unit. Seventy-four patients(7.74%) received immunosuppression with everolimus at some time post-transplantation. Demographic characteristics, everolimus indication, time elapsed from transplantation to the introduction of everolimus, doses and levels administered, efficacy, side effects, discontinuation andpost-conversion survival were analyzed. RESULTS: Mean age at the time of conversion to everolimus was 57.7 ± 10 years. Indications for conversion were: refractory rejection 31.1%, extended hepatocellular carcinoma in explanted liver 19%, post-transplant hepatocellular carcinoma recurrence 8.1%, de novo tumour 17.6%, renal insufficiency 8.1%, severe neurotoxicity 10.8%, and others 5.4%. Median time from transplantation to introduction of everolimus was 6 mo(range: 0.10-192). Mean follow-up post-conversion was 22 ± 19 mo(range: 0.50-74). The event for which the drug was indicated was resolved in 60.8% of patients, with the best results in cases of refractory rejection, renal insufficiency and neurotoxicity. Results in patients with cancer were similar to those of a historical cohort treated with other immunosuppressants. The main side effects were dyslipidemia and infections. Post-conversion acute rejection occurred in 14.9% of cases. The drug was discontinued in 28.4% of patients.CONCLUSION: Everolimus at low doses in combination with tacrolimus is a safe immunosuppressant with multiple early and late indications post-liver transplantation.

Update on the reciprocal interference between immunosuppressive therapy and gut microbiota after kidney transplantation

Gut microbiota is often modified after kidney transplantation.This principally happens in the first period after transplantation.Antibiotics and,most of all,immunosuppressive drugs are the main responsible.The relationship between immunosuppressive drugs and the gut microbiota is bilateral.From one side immunosuppressive drugs modify the gut microbiota,often generating dysbiosis;from the other side microbiota may interfere with the immunosuppressant pharmacokinetics,producing products more or less active with respect to the original drug.These phenomena have influence over the graft outcomes and clinical consequences as rejections,infections,diarrhea may be caused by the dysbiotic condition.Corticosteroids,calcineurin inhibitors such as tacrolimus and cyclosporine,mycophenolate mofetil and mTOR inhibitors are the immunosuppressive drugs whose effect on the gut microbiota is better known.In contrast is well known how the gut microbiota may interfere with glucocorticoids,which may be transformed into androgens.Tacrolimus may be transformed by microbiota into a product called M1 that is 15-fold less active with respect to tacrolimus.The pro-drug mycophenolate mofetil is normally transformed in mycophenolic acid that according the presence or not of microbes producing the enzyme glucuronidase,may be transformed into the inactive product.

Changing landscape in living kidney donation in Greece

Patients with end-stage renal disease in Greece are facing long waiting times to receive a kidney transplant from a deceased donor.Living kidney donation offers a valuable alternative that provides optimal outcomes and significantly expands the donor pool but still remains relatively underutilised.Developments around the world in the field of kidney transplantation mandate a change in current practice to include additional options for living donation through paired exchange,antibody-incompatible transplantation and other strategies,following careful consideration of the cultural and ethical factors involved in these complex clinical decisions.An increase in living donation rates may be achieved in several ways,including targeted campaigning to overcome potential barriers.Educating clinicians on transplantation will prove as equally important as informing patients and prospective donors but requires training and resources.Adoption of established practices and implementation of new strategies must be tailored to the needs of the Greek donor and recipient population.Local beliefs about donation,perception of associated risk and other social characteristics must be considered in the design of future strategies.Facilitating living donation in a safe environment with appropriate donor and recipient education will form the solid foundation of a new era of kidney transplantation in Greece.

Vitamin D deficiency may predispose patients to increased risk of kidney transplant rejection

BACKGROUND Vitamin D deficiency occurs in more than 80%of kidney transplant recipients.Its immunomodulatory effects can predispose transplant recipients to rejection and chronic allograft nephropathy(CAN).This study determined the association between serum 25(OH)vitamin D,biopsy-proven allograft rejection,and CAN rates.AIM To determine the relationship between serum 25(OH)vitamin D level and biopsy-proven allograft rejection and CAN rate in renal transplant recipients.METHODS Adult renal transplant recipients followed at the clinic between January 2013 and 2018 were included.Recipients requiring graft biopsy due to declined function,hematuria,and proteinuria were reviewed.The two groups were compared regarding collected data,including the biopsy results,immunologic parameters,vitamin D,parathyroid hormone(PTH),phosphorus,albumin levels,and graft function tests.RESULTS Fifty-two recipients who underwent graft biopsy met the inclusion criteria.In all,14 recipients had a vitamin D level>15 ng/mL(group 1)vs≤15 ng/mL(group 2)in 38.In total,27 patients had biopsy-proven rejection,and 19 had CAN.There was only 1 recipient with biopsyproven rejection in group 1,whereas there were 24 patients with rejection in group 2.The rejection rate was significantly higher in group 2 than in group 1(P<0.001).Four patients were diagnosed with CAN in group 1 vs fifteen in group 2.There was no significant difference in the CAN rate between the two groups.PTH was higher at the time of graft biopsy(P=0.009,P=0.022)in group 1 with a mean of 268 pg/mL.Donor-specific antibodies were detected in 14(56.0%)of the recipients with rejection.Vitamin D level was 9.7±3.4 ng/mL in the rejection group vs 14.7±7.2 in the non-rejection group;this difference was statistically significant(P=0.003).The albumin levels were significantly lower in patients with rejection than in those without rejection(P=0.001).In univariate regression analysis of risk factors affecting rejection,sex,serum vitamin D,phosphorus and albumin were found to have an impact(P=0.027,P=0.007,P=0.023,P=0.008).In multivariate regression analysis,the same factors did not affect rejection.CONCLUSION The serum 25(OH)vitamin D level in kidney transplant recipients remained low.Although low serum vitamin D level emerged as a risk factor for rejection in univariate analysis,this finding was not confirmed by multivariate analysis.Prospective studies are required to determine the effect of serum vitamin D levels on allograft rejection.

Loco-regional therapies for patients with hepatocellular carcinoma awaiting liver transplantation: Selecting an optimal therapy

Hepatocellular carcinoma(HCC) is a common, increasingly prevalent malignancy. For all but the smallest lesions, surgical removal of cancer via resection or liver transplantation(LT) is considered the most feasible pathway to cure. Resection- even with favorable survival- is associated with a fairly high rate of recurrence, perhaps since most HCCs occur in the setting of cirrhosis. LT offers the advantage of removing not only the cancer but the diseased liver from which the cancer has arisen, and LT outperforms resection for survival with selected patients. Since time waiting for LT is time during which HCC can progress, locoregional therapy(LRT) is widely employed by transplant centers. The purpose of LRT is either to bridge patients to LT by preventing progression and waitlist dropout, or to downstage patients who slightly exceed standard eligibility criteria initially but can fall within it after treatment. Transarterial chemoembolization and radiofrequency ablation have been the most widely utilized LRTs to date, with favorable efficacy and safety as a bridge to LT(and for the former, as a downstaging modality). The list of potentially effective LRTs has expanded in recent years, and includes transarterial chemoembolization with drug-eluting beads, radioembolization and novel forms of extracorporal therapy. Herein we appraise the various LRT modalities for HCC, and their potential roles in specific clinical scenarios in patients awaiting LT.

Preclinical stem cell therapy in Chagas Disease: Perspectives for future research

Chagas cardiomyopathy still remains a challenging problem that is responsible for high morbidity and mortality in Central and Latin America. Chagas disease disrupts blood microcirculation via various autoimmune mechanisms, causing loss of cardiomyocytes and severe impairment of heart function. Different cell types and delivery approaches in Chagas Disease have been studied in both preclinical models and clinical trials. The main objective of this article is to clarify the reasons why the benefits that have been seen with cell therapy in preclinical models fail to translate to the clinical setting. This can be explained by crucial differences between the cellular types and pathophysiological mechanisms of the disease, as well as the differences between human patients and animal models. We discuss examples that demonstrate how the results from preclinical trials might have overestimated the efficacy of myocardial regeneration therapies. Future research should focus, not only on studying the best cell type to use but, very importantly, understanding the levels of safety and cellular interaction that can elicit efficient therapeutic effects in human tissue. Addressing the challenges associated with future research may ensure the success of stem cell therapy in improving preclinical models and the treatment of Chagas disease.