Inhibition of γδ-TcR or IL17a Reduces T-Cell and Neutrophil Infiltration after Ischemia/Reperfusion Injury in Mouse Liver.

Neutrophil and T-cell recruitment contribute to hepatic ischemia/reperfusion injury. The initial inflammatory response is orchestrated by Kupffer cells and liver sinusoid endothelial cells. However, other cell types, including γδ-Τ cells, seem to be key mediators in further inflammatory cell recruitment and proinflammatory cytokine release, including IL17a. In this study, we used an in vivo model of partial hepatic ischemia/reperfusion injury (IRI) to investigate the role of the γδ-Τ-cell receptor (γδTcR) and the role of IL17a in the pathogenesis of liver injury. Forty C57BL6 mice were subjected to 60 min of ischemia followed by 6 h of reperfusion (RN 6339/2/2016). Pretreatment with either anti-γδΤcR antibodies or anti-IL17a antibodies resulted in a reduction in histological and biochemical markers of liver injury as well as neutrophil and T-cell infiltration, inflammatory cytokine production and the downregulation of c-Jun and NF-κΒ. Overall, neutralizing either γδTcR or IL17a seems to have a protective role in liver IRI.

Effects of an active lifestyle on the physical frailty of liver transplant candidates.

BACKGROUND: Liver transplantation is the most important therapeutic intervention for end-stage liver disease (ELD). The prioritization of these patients is based on the model for end-stage liver disease (MELD), which can successfully predict short-term mortality. However, despite its great validity and value, it cannot fully incor porate several comorbidities of liver disease, such as sarcopenia and physical frailty, variables that can sufficiently influence the survival of such patients. Subsequently, there is growing interest in the importance of physical frailty in regard to mortality in liver transplant candidates and recipients, as well as its role in improving their survival rates. AIM: To evaluate the effects of an active lifestyle on physical frailty on liver transplant candidates. METHODS: An observational study was performed within the facilities of the Department of Transplant Surgery of Aristotle University of Thessaloniki. Twenty liver tran splant candidate patients from the waiting list of the department were included in the study. Patients that were bedridden, had recent cardiovascular incidents, or had required inpatient treatment for more than 5 d in the last 6 mo were excluded from the study. The following variables were evaluated: Activity level via the International Physical Activity Questionnaire (IPAQ); functional capacity via the 6-min walking test (6MWT) and cardiopulmonary exercise testing; and physical frailty via the Liver Frailty Index (LFI). RESULTS: According to their responses in the IPAQ, patients were divided into the following two groups based on their activity level: Active group (A, 10 patients); and sedentary group (S, 10 patients). Comparing mean values of the recorded variables showed the following results: MELD (A: 12.05 ± 5.63 vs S: 13.99 ± 3.60; P > 0.05); peak oxygen uptake (A: 29.78 ± 6.07 mL/kg/min vs S: 18.11 ± 3.39 mL/kg/min; P < 0.001); anaerobic threshold (A: 16.71 ± 2.17 mL/kg/min vs S: 13.96 ± 1.45 mL/kg/min; P < 0.01); 6MWT (A: 458.2 ± 57.5 m vs S: 324.7 ± 55.8 m; P < 0.001); and LFI (A: 3.75 ± 0.31 vs S: 4.42 ± 0.32; P < 0.001). CONCLUSION: An active lifestyle can be associated with better musculoskeletal and functional capacity, while simultaneously preventing the evolution of physical frailty in liver transplant candidates. This effect appears to be independent of the liver disease severity.

Enhanced recovery after surgery in liver transplantation: Challenges and feasibility.

BACKGROUND: Enhanced recovery after surgery (ERAS) started a revolution that changed age-old surgical stereotypical practices regarding the overall management of the surgical patient. In the last decade, ERAS has gained significant acceptance in the community of general surgery, in addition to several other surgical specialties, as the evidence of its advantages continues to grow. One of the last remaining fields, given its significant complexity and intricate nature, is liver transplantation (LT). AIM: To investigate the existing efforts at implementing ERAS in LT. METHODS: We conducted a systematic review of the existing studies that evaluate ERAS in orthotopic LT, with a multimodal approach and focusing on measurable clinical primary endpoints, namely length of hospital stay. RESULTS: All studies demonstrated a considerable decrease in length of hospital stay, with no readmission or negative impact of the ERAS protocol applied to the postoperative course. CONCLUSIONS: ERAS is a well-validated multimodal approach for almost all types of surgical procedures, and its future in selected LT patients seems promising, as the preliminary results advocate for the safety and efficacy of ERAS in the field of LT.

Histology and Immunohistochemistry of Radial Arteries Are Suggestive of an Interaction between Calcification and Early Atherosclerotic Lesions in Chronic Kidney Disease.

Background and Objectives: recent studies suggest an implication of immune mechanisms in atherosclerotic disease. In this paper, the interaction between inflammation, calcification, and atherosclerosis on the vessel walls of patients with chronic kidney disease (CKD) is described and evaluated. Materials and Methods: patients with stage V CKD, either on pre-dialysis (group A) or on hemodialysis (HD) for at least 2 years (group B), in whom a radiocephalic arteriovenous fistula (RCAVF) was created, were included in the study. The control group included healthy volunteers who received radial artery surgery after an accident. The expressions of inflammatory cells, myofibroblasts, and vascular calcification regulators on the vascular wall were estimated, and, moreover, morphometric analysis was performed. Results: the expressions of CD68(+) cells, matrix carboxyglutamic acid proteins (MGPs), the receptor activator of nuclear factor-kB (RANK) and RANK ligand (RANKL), and osteoprotegerin (OPG), were significantly increased in CKD patients compared to the controls p = 0.02; p = 0.006; p = 0.01; and p = 0.006, respectively. In morphometric analysis, the I/M and L/I ratios had significant differences between CKD patients and the controls 0.3534 ± 0.20 vs. 0.1520 ± 0.865, p = 0.003, and 2.1709 ± 1.568 vs. 4.9958 ± 3.2975, p = 0.03, respectively. The independent variables correlated with the degree of vascular calcification were the intensity of CD34(+), aSMA(+) cells, and OPG, R2 = 0.76, p < 0.0001, and, with intima-media thickness (IMT), the severity of RANKL expression R2 = 0.3, p < 0.0001. Conclusion: atherosclerosis and vascular calcification in CKD seem to be strongly regulated by an immunological and inflammatory activation on the vascular wall.

Everolimus with or without mycophenolate mofetil in a liver transplantation setting: a single-center experience.

BACKGROUND: This study evaluated the efficacy, safety, and impact on renal function of everolimus in patients after liver transplantation (LT) with or without mycophenolate mofetil (MMF). METHODS: We evaluated LT recipients with calcineurin inhibitor (CNI)-related renal dysfunction after everolimus initiation. Laboratory data, including evaluation of renal function based on glomerular filtration rate (GFR) at baseline (i.e., everolimus initiation) and at the end of follow up, were analyzed. RESULTS: Fifty consecutive patients started taking everolimus at 30 months post-LT (range: 1-240), 6 as monotherapy and 44 in combination with MMF. After 30.5 months (range: 6-112), all patients were alive, without any biochemical evidence of a rejection episode or recurrence of hepatocellular carcinoma. The mean GFR, based on the Modification of Diet in Renal Disease equation, was 53±13 mL/min at baseline and 59±12 mL/min at the end of follow up (P=0.031). Eleven (22%) of the patients had GFR <60 mL/min at baseline but returned to GFR >60 mL/min by the end of follow up. In multivariate analysis, the time between the development of renal dysfunction and everolimus initiation was the only factor independently associated with GFR improvement (odds ratio [OR] 0.85, 95% confidence interval [95%CI] 0.76-0.96; P=0.007). Everolimus was stopped in 11 patients (22%) at the end of follow up because of adverse events. CONCLUSION: A CNI-free everolimus-based regimen was effective in LT recipients with renal dysfunction and was associated with an improvement in GFR.

Targeting hepatocarcinogenesis model in C56BL6 mice with pan-aurora kinase inhibitor Danusertib.

Background: To elucidate the expression of Aurora kinases (AURK) and the anticancer effects of pan-aurora kinase inhibitor Danusertib in hepatocarcinogenesis model in C56Bl6 mice. Methods: Thirty mice C56Bl6 were randomly divided into Group A or control, Group B animals who underwent experimental hepatocarcinogenesis with diethylnitrosamine (DEN), and Group C animals with DEN-induced hepatocarcinogenenesis that treated with pan-aurora kinase inhibitor Danusertib. Primary antibodies for immunochistochemistry (IHC) included rabbit antibodies against Ki-67, DKK1, INCENP, cleaved caspase-3, NF-κB p65, c-Jun, ß-catenin. Hepatocyte growth factor receptor (C-MET/HGFR) and Bcl-2 antagonist of cell death (BAD) serum levels were determined using a quantitative sandwich enzyme immunoassay technique. Results: Inhibition of AURK reduced the number of DEN-induced liver tumours. Apoptosis and proliferation was very low in both DEN-induced and anti- AURK groups respectively. The hepatocellular adenoma cells of DEN-treated mice uniformly had ample nuclear INCENP whereas in anti- AURK markedly decreased. Expression of ß-catenin, NF-kB and c-Jun did not differ in liver tumors of both AURK -depleted and non-depleted mice. Conclusions: Depletion of AURK reduced the number of DEN-induced hepatic tumours. However, their size did not differ significantly between the groups.

Preconditioning of primary human renal proximal tubular epithelial cells without tryptophan increases survival under hypoxia by inducing autophagy.

PURPOSE: Hypoxia plays a significant role in the pathogenesis of acute kidney injury (AKI). Autophagy protects from AKI. Amino acid deprivation induces autophagy. The effect of L-tryptophan depletion on survival and autophagy in cultures of renal proximal tubular epithelial cells (RPTECs) under hypoxia was evaluated. METHODS: RPTECs were preconditioned in a medium containing or not tryptophan, following culture under hypoxia and treatment with or without the autophagy inhibitor chloroquine. Cell survival was assessed by cell imaging, the level of certain proteins by western blotting and cellular ATP fluorometrically. RESULTS: Preconditioning of RPTECs in a medium without tryptophan activated general control nonderepressible 2 kinase and induced changes that favored autophagy and cell survival under hypoxic conditions. Additionally, it increased cellular ATP, while it inhibited apoptosis. Inhibition of autophagy nullified the induced increase in cellular ATP and cell survival by the absence of tryptophan. The absence of tryptophan increased p53, although its effect on p53's transcriptional targets was heterogeneous. In accordance with the decreased apoptosis, expression of p21 increased, while expression of Bax decreased. The expression of BNIP3L, which may be pro-apoptotic or pro-autophagic, increased. Considering the decreased apoptosis, it is likely that tryptophan depletion enhances autophagy through a p53-mediated increase of BNIP3L. CONCLUSION: Preconditioning of primary human RPTECs in a medium without tryptophan increases their survival under hypoxia by inducing autophagy. Identifying new molecular mechanisms that protect renal tissue from hypoxia could be proved clinically important in the prevention of AKI.

Undifferentiated embryonal sarcoma of the liver in a young female: treatment with portal vein embolization and liver trisectonectomy.

Undifferentiated Embryonal Sarcoma of the Liver (UESL) is a tumor highly malignant, of mesenchymal origin. It is a rare finding in adults, though less rare in children. The strategy to be followed and the therapeutic targets to be reached for this tumor, in adult cases, remain ambiguous and controversial. Herein we report the case of a 29 year old female patient with a massive UESL and we describe our therapeutic approach. A 29 year-old female patient was referred to our center with severe intermittent epigastric pain and fever due to a voluminous liver tumor: Needle biopsy was of no specific findings and surgical excision was decided. Right portal vein embolization and selective embolization of the segment's IV branch was performed in order to achieve adequate future liver remnant (FLR). Right trisectonectomy was then performed, with uneventful post operative period and the patient was discharged at the 11(th) post operative day. UESL is a rare tumor that needs aggressive surgical approach and multidisciplinary team management is of paramount importance.

Everolimus-based immunosuppression in liver transplant recipients: a single-centre experience.

PURPOSE: Everolimus, a mammalian target of rapamycin inhibitor, has been shown to reduce growth factor-mediated cell proliferation, but data regarding its effectiveness and impact on renal function and recurrence of hepatocellular carcinoma (HCC) in liver transplant (LT) recipients are limited. METHODS: We evaluated LT recipients with a calcineurin inhibitor (CNI)-based immunosuppression regimen in whom everolimus treatment was initiated. The changes in laboratory data, including glomerular filtration rate (GFR), compared to the baseline (i.e. the day of everolimus conversion), were assessed. RESULTS: Totally, 44 consecutive patients (32 men, age 55 ± 7 years) were commenced on everolimus [indications: renal dysfunction post-LT (16 patients, group 1); prevention of HCC recurrence (21 patients) or others (7 patients), group 2] at 6 months (range 1-206) post-LT. After 48 (range 12-76) months, all patients were alive without any rejection episodes. Compared to group 2 patients, group 1 patients had significantly greater improvement in renal function (DGFR: 12 ± 5 vs. -0.4 ± 0.2 ml/min, p = 0.02). GFR at baseline (OR 0.08, p = 0.002) and the combination of everolimus + MMF (OR 0.14, p = 0.024) were the factors independently associated with improvement in renal function. Finally, HCC recurrence was observed less frequently in the everolimus group of patients (n = 21) compared to the CNI-historical control group (n = 22) with HCC before LT [0/21 (0 %) vs. 4/22 (18.5 %), log rank p = 0.055), although the two groups of recipients had similar baseline characteristics and follow-up. CONCLUSIONS: Everolimus is effective and is associated with low rates of HCC recurrence and improvement of renal function in LT recipients.

Dichloroacetate at therapeutic concentration alters glucose metabolism and induces regulatory T-cell differentiation in alloreactive human lymphocytes.

BACKGROUND: Most cancer cells rely on aerobic glycolysis. Dichloroacetate (DCA) inhibits aerobic glycolysis and is a promising relatively nontoxic anticancer compound. However, rapidly proliferating effector T-cells also rely on aerobic glycolysis, whereas regulatory T-cells (Treg) do not. The effect of DCA on glucose metabolism and Treg differentiation was evaluated in alloreactive lymphocytes. METHODS: Peripheral blood mononuclear cells from healthy volunteers were used in a two-way mixed lymphocyte reaction. Lymphocyte proliferation was assessed by cell counting; DCA cytotoxicity, by lactate dehydrogenase release assay; and glucose uptake and aerobic glycolysis, by measuring in the supernatants the correspondent glucose and lactate concentrations. Interleukin-10 (IL-10) was measured in the supernatants, whereas the Treg signature transcription factor forkhead box P3 (FOXP3) was measured in cell lysates by means of enzyme-linked immunosorbent assay. RESULTS: DCA had a minor effect on lymphocyte proliferation and cytotoxicity. However, DCA decreased glucose uptake and inhibited aerobic glycolysis. Finally, DCA markedly increased the production of IL-10 and the expression of FOXP3. CONCLUSIONS: DCA inhibits aerobic glycolysis and induces Treg differentiation in human alloreactive lymphocytes. This could result in decreased immunosurveillance in case of its use as an anticancer drug. However, DCA could play a role as an immunosuppressant in the fields of transplantation and autoimmunity.

Combined cardiac surgery and liver transplantation: three decades of worldwide results.

BACKGROUND: Patients with end-stage-liver-disease (ESLD) require orthotopic liver transplantation (OLT) as treatment. However, cirrhotic cardiomyopathy can be clinically revealed during OLT, with the possible development of a transient overt congestive heart failure. A number of patients require a combined procedure of liver transplantation and heart surgery, which includes heart transplantation, aortic valve replacement or coronary artery bypass grafting. Indications for combined liver-heart transplantation include heart failure with associated cardiac cirrhosis, familial amyloidosis, familial hypercholesterolemia and hemochromatosis, and homozygous ß-thalassemia. METHODS/RESULTS. We performed a thorough research of Pubmed/ Medline, gathering and discussing data concerning this clinical condition and its treatment. CONCLUSION: In patients with end-stage liver disease, who are unable to tolerate an OLT post-operatively due to cardiac dysfunction, combined cardiac surgery and OLT appears to have certain advantages.

HCC influence on patient survival after liver transplantation for HDV cirrhosis.

BACKGROUND/AIMS: The effect of hepatocellular cancer (HCC) in patients transplanted for hepatitis B and D virus (HB/DV) cirrhosis is not well studied. Our aim was to study the long-term survival outcomes of patients who underwent liver transplantation for HB/DV cirrhosis with and without HCC. METHODOLOGY: A total of 231 primary, adult, single- organ liver transplants were performed from 1990 to 2007. HB/DV was the cause of cirrhosis in 36 patients. Nine patients died during the first 3 postoperative months from surgical complications. The study group comprised the remaining 27 patients. The median follow-up was 1515 days. RESULTS: The mean patient survival was 3760 days (95% CI: 3013-4507). Six patients were diagnosed with HCC. The mean patient survival was 3011 days (95% CI: 2344-3679) and 4036 days (95% CI: 3002-5070) for recipients without and with HCC, respectively. For the same groups, the incidence of microbial infections was 61.9% and 33.3%, respectively (p=0.219). HCC has not recurred in any of the six patients. CONCLUSIONS: The mean long-term survival after liver transplantation for HB/DV and HCC surpassed 11 years. The superior survival of HCC patients is difficult to explain. The increased number (almost double) of microbial infections in the non- HCC population might be held accountable.

Attenuation of liver ischemia/reperfusion induced apoptosis by epigallocatechin-3-gallate via down-regulation of NF-kappaB and c-Jun expression.

INTRODUCTION: Hepatic ischemia/reperfusion (I/R) activates Kupffer cells and initiates severe oxidative stress with enhanced production of reactive oxygen species (ROS) and tumor necrosis factor-alpha (TNF-alpha). ROS and TNF-alpha mediate the expression of nuclear factors and kinases, activating the signal transduction pathway, and triggering apoptosis. The aim of our study was to evaluate the potential protective effect of (-)-epigallocatechin-3-gallate (EGCG) administration in inhibition of apoptosis by attenuating the expression of NF-kappaB, c-Jun, and caspase-3 in a model of severe hepatic I/R. MATERIALS AND METHODS: Thirty Wistar rats were allocated into three groups. Sham operation, I/R, and I/R-EGCG 50mg/kg. Hepatic ischemia was induced for 60min by Pringle's maneuver. Malondialdehyde (MDA), myeloperoxidase (MPO), light histology, scanning electron microscopy, terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL), and immunocytochemistry for NF-kappaB, c-Jun, caspase-3, analysis on liver specimens and aspartate (AST), and alanine (ALT) transferases analysis in serum, were performed 120min after reperfusion. RESULTS: Apoptosis as indicated by TUNEL and caspase-3 was widely expressed in the I/R group but very limited in the EGCG treated group. Liver was stained positive for NF-kappaB and c-Jun in the I/R group but failed to be stained positive in the EGCG treated group. MDA, MPO, AST, and ALT showed marked increase in the I/R group and significant decrease in EGCG treated group. Significant alterations of liver specimens were observed by light histology and transmission electron microscopy whilst pretreatment with EGCG resulted in parenchymal preservation. CONCLUSIONS: Administration of EGCG is likely to inhibit I/R-induced apoptosis and protect liver by down-regulating NF-kappaB and c-Jun signal transduction pathways.

Ganglio centinela en carcinoma de células escamosas de piel: reporte de un caso / Sentinel node in skin squamous cell carcinoma: a case report

El cáncer de piel presenta un incremento en su incidencia en los últimos años. La sobrevida general a 5 años pasa de 90 por ciento si no hay metástasis a ganglios, 28 por ciento a 60 por ciento si hay compromiso ganglionar. El tratamiento es la resección quirúrgica, resección local amplia, disección ganglionar sólo en caso de ganglios linfáticos palpables. Presentamos un paciente masculino 37 años de edad, con diagnóstico de carcinoma epidermoide bien diferenciado de piel de rodilla derecha, presenta factores de riesgo como son tamaño mayor de 2 cm, espesor mayor de 4 mm e invasión angiolinfática: sin ganglios inguinales aumentados de tamaño; se decide realizar ganglio centinela. El ganglio centinela fue reportado en el corte congelado como positivo para metástasis procediendo a realizarse la disección inguinal. Planteamos el uso del ganglio centinela como alternativa factible para el estudio de pacientes con carcinoma epidermoide, factores de riesgo y sin ganglios palpables.

The skin cancers present increment in his incidence in the last years. The general super life to 5 years is 90 % if is not present ganglion metastases, 28 %-60 % is it ganglion compromise. The treatment is surgical resection, local enough resection and ganglion dissection only in case of palpable linfatics nodule. A male patient 37 years old with diagnostic epidermoide carcinoma of skin of right knee, with presentation risk factors how mayor size 2 cm, depth mayor of 4 mm and angio lymphatic invasion; without inguinal increase size ganglions; we decide realize a sentinel ganglion. The ganglion sentinel was reported in the frozen study how positive to metastases we proceeded to realize and inguinal dissection. In these work we propose the use of sentinel ganglion biopsy how and fictile alternative to the study of patients with epidermoide carcinoma with risk factors and without palpable ganglions.

The natural history of vascular access for hemodialysis: a single center study of 2,422 patients.

BACKGROUND: Our objective is to provide provision of primary and secondary patency rates data and incidence of complications. Despite the publication of some review articles and small prospective trials about vascular accesses, controversy still exists regarding the choice of the outflow conduit and especially the choice of the fistula to be formed in secondary and tertiary access procedures. METHODS: This is a retrospective study of 2,422 consecutive patients who underwent 3,685 vascular access procedures in a tertiary care hospital, including radial-cephalic (RCAVF), brachial-cephalic (BCAVF), brachial-basilic (BBAVF), and prosthetic graft (PTFE) fistulas. Maximum follow-up period was 20 years. Actuarial patency rates were obtained by Kaplan-Meier analysis. RESULTS: The median primary patency (days) of the most common 1st choices for vascular access were 712 (95% CI: 606, 818), 1,009 (95% CI: 823, 1,195), and 384 (95% CI: 273, 945) days for RCAVF, BCAVF, and PTFE, respectively. The median secondary patency was 1809 days (95% CI: 1,692, 1,926) for the RCAVF. The median primary patency of BBAVF (2nd or 3rd choice for vascular access) was 1,582 days (95% CI: 415, 2,749). The cumulative incidence of clinically important complications for the patients who received a RCAVF, BCAVF, BBAVF, and u-PTFE was 0.25, 0.57, 0.33, and 0.61 per patient-year, respectively. CONCLUSION: We advocate maximal use of autogenous conduits, except probably the case of the older diabetic patient, in whom access at the antecubital fossa should be the first choice. BBAVF is an excellent fistula and should probably be constructed before prosthetic graft placement.

Papillomatosis of intra- and extrahepatic biliary tree: Successful treatment with liver transplantation.

Approximately 60 cases of biliary papillomatosis have been reported in the world literature, while only 6 cases have been reported to be treated with liver transplantation. This rare disease, which is characterized by relapsing episodes of obstructive jaundice and cholangitis that lead to secondary cirrhosis and death from sepsis or liver failure, it is also considered premalignant because of its frequent malignant transformation (25-50%). We present a case of a 43-year-old white man with papillomatosis of intra- and extrahepatic biliary tree who sought care for repeated episodes of obstructive jaundice and cholangitis. The diagnosis was suspected after endoscopic retrograde cholangiopancreatography and confirmed by liver and common bile duct biopsies. The patient underwent orthotopic liver transplantation with Roux-en-Y hepatico-jejunostomy to treat end-stage liver cirrhosis. Fifteen months' follow-up revealed a patient with normal graft function and with no clinically or laboratory findings of disease recurrence or cancer development.

Living-related transplantation of an ectopic pelvic kidney.

Ectopic kidneys are usually contraindicated for transplantation as a result of anomalous vascular and drainage system. Graft shortage increases the need of expanding the donor pool and the use of ectopic pelvic kidneys might provide a small but useful source. Transplantation of an ectopic pelvic kidney is a technically demanding procedure and very few cases have been published. We present a case of a living-related kidney transplantation of an ectopic pelvic kidney. The donor was a healthy 65-year-old lady and preoperative work-up had showed a left ectopic pelvic kidney. The recipient was a 34-year-old male with a history of end-stage renal disease secondary to chronic glomerulonephritis. After the transplantation, there was an immediate function of the allograft and the donor's postoperative course was uneventful. The donor was discharged on the fifth postoperative day.

Tumor único de mensenterio como forma de presentación de linfoma: reporte de un caso / Unique mesenteric tumor lymphoma presented as lymphoma: report of one case

Se presenta un caso de tumor único de mesenterio. El diagnóstico histológico definitivo reveló que se trataba de un linfoma de células grandes. Se ofrece así mismo una revisión de la literatuta relacionada con tumores únicos de mesenterio, resaltando la importancia de los métodos diagnósticos disponibles, así como las opciones terapéuticas