Role of ghrelin isoforms in the mitigation of hepatic inflammation, mitochondrial dysfunction, and endoplasmic reticulum stress after bariatric surgery in rats.

BACKGROUND/OBJECTIVES: Bariatric surgery improves nonalcoholic fatty liver disease (NAFLD) and nonalcoholic steatohepatitis (NASH), but the underlying mechanisms remain elusive. We evaluated the potential role of ghrelin isoforms in the amelioration of hepatic inflammation after sleeve gastrectomy and Roux-en-Y gastric bypass (RYGB). SUBJECTS/METHODS: Plasma ghrelin isoforms were measured in male Wistar rats (n = 129) subjected to surgical (sham operation, sleeve gastrectomy, or RYGB) or dietary interventions [fed ad libitum a normal (ND) or a high-fat diet (HFD) or pair-fed diet]. The effect of acylated and desacyl ghrelin on markers of inflammation, mitochondrial dysfunction, and endoplasmic reticulum (ER) stress in primary rat hepatocytes under palmitate-induced lipotoxic conditions was assessed. RESULTS: Plasma desacyl ghrelin was decreased after sleeve gastrectomy and RYGB, whereas the acylated/desacyl ghrelin ratio was augmented. Both surgeries diminished obesity-associated hepatic steatosis, CD68+- and apoptotic cells, proinflammatory JNK activation, and Crp, Tnf, and Il6 transcripts. Moreover, a postsurgical amelioration in the mitochondrial DNA content, oxidative phosphorylation (OXPHOS) complexes I and II, and ER stress markers was observed. Specifically, following bariatric surgery GRP78, spliced XBP-1, ATF4, and CHOP levels were reduced, as were phosphorylated eIF2α. Interestingly, acylated and desacyl ghrelin inhibited steatosis and inflammation of palmitate-treated hepatocytes in parallel to an upregulation of OXPHOS complexes II, III, and V, and a downregulation of ER stress transducers IRE1α, PERK, ATF6, their downstream effectors, ATF4 and CHOP, as well as chaperone GRP78. CONCLUSIONS: Our data suggest that the increased relative acylated ghrelin levels after bariatric surgery might contribute to mitigate obesity-associated hepatic inflammation, mitochondrial dysfunction, and ER stress.

Perineural Invasion is a Major Prognostic and Predictive Factor of Response to Adjuvant Chemotherapy in Stage I-II Colon Cancer.

BACKGROUND: Perineural invasion (PNI) in colon cancer (CC) has been associated with poorer prognosis even in stage II disease (T3-4 N0 M0). The aim of this study is to analyze prognostic histopathologic factors in stage II colon cancer in patients treated with curative surgery as established in National Comprehensive Cancer Network guidelines. METHODS: From a prospective database of CC cases, 507 patients with stage I-II disease who had undergone curative resection from January 2000 and December 2012 were identified. Of these patients, 17 % received 5-flurouracil-based adjuvant chemotherapy. Together with demographic and anatomic variables, we also studied perineural and lymphovascular invasion, degree of differentiation, and their correlation with disease-free survival. RESULTS: Perineural invasion was identified in 57 patients (11.2 %) and lymphovascular invasion (LVI) in 82 (16.2 %) of the 507 patients. Perineural invasion was associated with LVI, the depth of invasion of the wall of the colon, and location of the tumor. Overall and disease-free survival of the complete series at 5 and 10 years was 89.5, 85.2, 83.2 and 81.6 %, respectively. In the PNI positive patients, disease-free survival at 5 years was significantly lower than in those without PNI (73.5 vs 88.6 %; p = 0.02). Multivariate analysis showed the presence of PNI to be a significant independent prognostic factor for disease-free survival (p = 0.025). Adjuvant chemotherapy reversed the impact of PNI on 5- to 10-year disease-free survival. CONCLUSIONS: PNI a major prognostic and predictive factor in stage II colon cancer, and our results support the use of adjuvant chemotherapy in patients with PNI.

Clinical significance of cellular and acellular mucin pools in rectal carcinoma following preoperative chemoradiotherapy.

BACKGROUND AND OBJECTIVES: The standard treatment for locally advanced rectal cancer (LARC) is neoadjuvant chemoradiotherapy (CRT) followed by surgery. Pathological findings remain the most significant prognostic factor. The presence of mucin pools and their prognostic significance is a controversial issue. The aim of this study was to analyze the incidence of cellular and acellular mucin pools and their clinical significance. METHODS: Four-hundred and forty-six consecutive prospectively collected specimens from patients with LARC treated with long-course preoperative CRT and surgery were analyzed. Kaplan-Meier analysis was performed. RESULTS: Mucin pools were present in 182 specimens (40.8 %); 66 (14.7 %) were acellular, and viable tumor cells were identified in 116 (26 %). The complete pathological response rate was 13.5 % (60 of 446). With a median follow-up of 79.0 months, the 5- and 10-year disease-free survivals for patients with acellular and cellular mucin pools were 81.5, 78.1, 63.7 and 61.2 %, respectively (p ≤ 0.026). The presence of cells in the colloid response to treatment was associated with a 17.8 and 16.9 % decrease in 5- and 10-year disease survival vs. acellular colloid response. CONCLUSIONS: Our results suggest that cellular mucin pools are an indicator of an aggressive phenotype and harbingers of a worse prognosis.

Patterns and management of distant failure in locally advanced rectal cancer: a cohort study.

PURPOSE: To determine the long-term outcomes of locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiation (CRT) and surgery, and to analyze the management and survival once distant failure has developed. METHODS: Data from LARC patients treated from 2000 to 2010 were retrospectively reviewed. CRT protocols were based on fluoropirimidines ± oxaliplatin. Follow-up consisted of physical examination, carcinoembryonic antigen levels, and chest-abdominal-pelvic CT scan. RESULTS: The study included 228 patients with a mean age of 59 years. Forty-eight (21.1 %) patients had distant recurrence and 6 patients (2.6 %) had local recurrence. Median follow-up was 49 months. The 5- and 10-year actuarial disease free survival was 75.3 and 65.0 %, respectively. The 5- and 10-year actuarial overall survival (OS) was 89.6 and 71.2 %, respectively. Patients were classified as having liver (14 patients) or lung (27 patients) relapse according to the organ firstly metastasized. The variables significantly associated by univariate Cox analysis to survival were the achievement of an R0 metastases resection and the Köhne risk index, while the metastatic site showed a statistical trend. By multivariate Cox analysis, the only variable associated with survival was a R0 resection (HR = 16.3, p < 0.001). Median OS for patients undergoing a R0 resection was 73 months (95 % CI 67.8-78.2) compared to 25 months (95 % CI 5.47-44.5) in those non-operated patients (p < 0.001). CONCLUSIONS: Combined treatment for LARC obtains a 5-year OS rounding 90 %. Follow-up based on thoracic-abdominal CT scan allows an early diagnosis of metastatic lesions. Surgical resection of metastases, regardless of their location, greatly increases the patient's survival rate.

Impact of perineural and lymphovascular invasion on oncological outcomes in rectal cancer treated with neoadjuvant chemoradiotherapy and surgery.

BACKGROUND: The prognostic significance of perineural and/or lymphovascular invasion (PLVI) and its relationship with tumor regression grade (TRG) in patients with locally advanced rectal cancer (LARC) treated with neoadjuvant chemoradiotherapy (CRT) and surgery. METHODS: A total of 324 patients with LARC were treated with CRT and operated on between January 1992 and June 2007. Tumors were graded using a quantitative 5-grade TRG classification and the presence of PLVI was histologically studied. RESULTS: At a median follow-up of 79.0 months (range 3-250 months), a total of 80 patients (24.7%) relapsed. The observed 5- and 10-year overall survival (OS) was 83.2 and 74.9 %, respectively. The 5- and 10-year disease-free survival (DFS) was 75.1 and 71.4%, respectively. A significant correlation was found between the TRG and survival (log rank, p < 0.001). The 10-year OS was 32.7% for grade 1, 63.8% for grade 2, 75.0% for grade 3, 90.4% for grade 3+, and 96.0%,for grade 4. The 10-year DFS was 31.8% for grade 1, 58.6% for grade 2, 70.4% for grade 3, 88.4% for grade 3+, and 97.1% for grade 4. In patients with PLVI, the TRG had no impact on survival. When excluding patients with PLVI, the TRG was an independent prognostic factor for OS and DFS. CONCLUSIONS: The presence of PLVI is a more powerful prognostic factor than TRG in LARC patients treated with neoadjuvant CRT followed by surgery. PLVI denotes an aggressive phenotype, suggesting that these patients may benefit from adjuvant systemic therapy.

Short- and long-term changes in gastric morphology and histopathology following sleeve gastrectomy in diet-induced obese rats.

BACKGROUND: Sleeve gastrectomy (SG) has been used as a multipurpose surgical procedure for the treatment of morbid obesity. The aim of the study was to analyze gastric morphology and histology at two different time points after SG in rats. METHODS: Thirty-five male Wistar rats were fed ad libitum during 3 months on a high-fat diet to induce obesity. Subsequently, 25 diet-induced obese rats underwent either SG (n = 12) or a sham operation (n = 13). The remaining ten obese animals encompassed the nonoperated control group (Co). Four weeks postoperatively, 15 rats (n = 5 rats/experimental group) were sacrificed, while the remaining 20 rats were sacrificed after 16 weeks (animals/group; Co = 5, sham = 8, SG = 7) to compare the gastric morphological and histopathological changes over time. Body weight and food intake were regularly recorded. RESULTS: For both time periods, the Co groups exhibited the highest body weight, while the rats undergoing the SG showed the lowest weight gain (P < 0.05). Initially, significant differences (P < 0.005) in food intake relative to body weight were observed between the Co rats and animals undergoing surgery, which disappeared thereafter. The actual total stomach size after both experimental periods in the SG group was similar to that of non- and sham-operated rats mainly due to a forestomach enlargement, which was more pronounced after 16 weeks. Traits of gastritis cystica profunda characterized by gastric foveolae elongation with hyperplasia and cystic dilatation of the glands were observed in the residual stomachs of the sleeve-gastrectomized rats. These findings were mostly observed after 16 weeks of performing the SG, although they were also detected occasionally following 4 weeks postoperatively. No intestinal metaplasia was observed. CONCLUSION: After SG gastric macro- and microscopic changes with functional implications in both the short and long term take place.

Morbidity, mortality, and pathological response in patients with gastric cancer preoperatively treated with chemotherapy or chemoradiotherapy.

BACKGROUND: Significant tumor downstaging has been achieved in patients with localized gastric adenocarcinoma by preoperative chemoradiotherapy (ChRT) or induction chemotherapy (Ch). However the influence of ChRT and Ch on postoperative outcomes has not yet been clarified, with very few studies examining this issue. We retrospectively analyzed the efficacy in terms of pathological response and early postoperative complications of two protocols of preoperative ChRT and Ch for locally advanced gastric cancer. METHODS: Between 2000 and 2008, 72 patients with operable locally advanced gastric cancer (cT3-4/N+) were treated with preoperative treatment: 1-patients receiving induction Ch or 2-neoadjuvant Ch followed by concurrent ChRT. Postoperative histopathological regression and surgical complications were investigated including variables related to patients, surgical variables, preoperative treatment, and tumor. RESULTS: There were no differences in the incidence of complications between the ChRT and Ch groups (30.9% vs. 33.3%). The most frequent complications were nonspecific surgical complications (pneumonia [12.5%] and infection from intravenous catheters [9.7%]). Risk factors for complications were high-body mass index (BMI > 25 kg/m(2) ) and extension of surgery to the pancreas and spleen. A major pathological response was observed in 33.3% of patients, being more frequent in the ChRT group (47.6% vs. 13.3%; χ(2) , P = 0.0024). CONCLUSIONS: Preoperative treatment with Ch or ChRT for locally advanced gastric cancer can be performed safely with an acceptable operative morbidity and low operative mortality rate with careful consideration of the added risk associated with BMI and surgical resection of the pancreas and spleen. Ch and ChRT is feasible and effective in terms of pathological response and R0 resection.

Association of increased visfatin/PBEF/NAMPT circulating concentrations and gene expression levels in peripheral blood cells with lipid metabolism and fatty liver in human morbid obesity.

BACKGROUND AND AIMS: Nicotinamide phosphoribosyltransferase (NAMPT) is an adipokine with physiological effects on the control of glucose homeostasis as well as potentially involved in inflammation. The association of circulating NAMPT concentrations with obesity has not been clearly established. The aim of the present work was to evaluate the effect of obesity on circulating concentrations and gene expression levels of NAMPT in human peripheral blood cells (PBCs) as well as its involvement in inflammation, glucose and lipid metabolism. METHODS AND RESULTS: Forty-four serum samples obtained from 14 lean and 30 obese volunteers were used to analyse the circulating concentrations of NAMPT. In addition, PBC, omental adipose tissue (OM) and liver biopsy samples obtained from a subgroup of subjects were used to determine transcript levels of NAMPT by Real-time PCR. Glucose and lipid profile as well as several inflammatory factors and hepatic enzymes were analysed. NAMPT circulating concentrations (P<0.01) and gene expression levels in PBC (P<0.05) were significantly increased in obese patients as compared to lean subjects. Total-cholesterol (P=0.016), HDL-cholesterol (P=0.036) and triglycerides (P=0.050) were significant and independent determinants of circulating concentrations of NAMPT (P<0.01). Moreover, a positive correlation (P<0.01) was found with the hepatic enzymes alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase after BMI adjustment. CONCLUSION: Our work shows that NAMPT circulating concentrations and mRNA expression levels in PBC are increased in obese patients and that plasma NAMPT levels are related to inflammation, lipid metabolism and hepatic enzymes suggesting a potential involvement in fatty liver disease and in the obesity-associated inflammatory state.

Portal revascularization in the setting of cavernous transformation through a paracholedocal vein: a case report.

Diffuse thrombosis of the entire portal system (PVT) and cavernomatous transformation of the portal vein (CTPV) represents a demanding challenge in liver transplantation. We present the case of a patient with nodular regenerative hyperplasia and recurrent episodes of type B hepatic encephalopathy concomitant with PVT as well as CTPV, successfully treated with orthotopic liver transplantation. The portal inflow to the graft was carried out through the confluence of 2 thin paracholedochal varicose veins, obtaining good early graft function and recovery of the encephalopatic episodes. This alternative should be kept in mind as an option to assure hepatopetal splanchnic flow in those cases of diffuse thrombosis and cavernomatous transformation of portal vein.

Neoplasia papilar mucinosa intraductal del páncreas: resultados clínico-patológicos / No disponible

Introducción: la neoplasia papilar mucinosa intraductal(NPMI) del páncreas comprende una serie de lesiones que evolucionandesde lesiones benignas (adenoma) hasta carcinoma ductalinvasivo.Objetivo: analizar los resultados clínicos y patológicos de 15pacientes diagnosticados de NPMI e intervenidos según las recomendacionesde conferencia de consenso.Material y métodos: análisis retrospectivo de 15 pacientescon NPMI, intervenidos entre marzo de 1993 y septiembre de2009; según pautas de conferencias de consenso internacionales.Se recogieron datos demográficos, pruebas diagnósticas, tipo deintervención, histopatología y supervivencia actuarial con un seguimientoentre mes y medio y nueve años.Resultados: se realizaron 6 duodenopancreatectomías cefálicas,4 pancreatectomías totales, 2 pancreatectomías centrales,2 pancreatectomías parciales y una pancreatectomía distal. Se registróuna morbilidad del 40%, sin mortalidad operatoria, con unaestancia media de 10 días. En 5 casos la NPMI fue de tipo mixto,en 4 afectaba al conducto pancreático y en los 6 restantes a ramasaccesorias. Dos pacientes presentaron carcinoma in situ y 3carcinoma invasivo con ganglios negativos. Un paciente, sin carcinomainvasivo, falleció a los 66 meses por adenocarcinoma depáncreas. La supervivencia actuarial hasta recidiva o muerte fuede 105,133 meses; con un rango de seguimiento entre mes y medioy 9 años.Conclusiones: la NPMI tipo ductal y mixto exige la reseccióncompleta debido a la elevada incidencia de carcinoma invasivo ode lesiones precursoras de malignidad. Por su carácter multifocallos enfermos deben ser revisados a largo plazo. Existen controversiasen las NPMI tipo accesorio asintomáticas y menores de 3 cm(AU)

Background: intraductal papillary mucinous neoplasm(IPMN) shows a series of lesions which evolve from benign lesions–adenoma– to invasive carcinoma.Aim: to analyze the clinical and pathological results of 15 patientsdiagnosed of IPMN, and surgically treated according to theguidelines of International Consensus Conference.Material and method: a retrospective analysis of 15 patientssurgically treated between March 1993 and September 2009, accordingto the International Consensus recommendation. Demographic,diagnostic tools, surgical report, pathologic database andactuarial survival were analyzed with a follow-up from one and ahalf month through nine years.Results: 6 patients underwent pancreaticoduodenectomies,4 total pancreatectomies, 2 body or central pancreatectomies, 2 partialpancreatectomies (enucleation) and 1 distal pancreatectomy.A morbidity of 46 and 0% hospital mortality were assessed, witha median length hospital stay of 10 days. In five cases, the IPMNwas combined type (both main and branch pancreatic ducts involved)in four main duct-type and branch duct-type in the anothersix as well. Several atypia (IPMN carcinoma in situ) wasobserved in 2 patients and invasive carcinoma with negativelymph nodes was identified in 3 patients. A patient without invasivecarcinoma died at 66 months of follow-up for pancreas adenocarcinoma.The actuarial survival up to recurrence or deathwas 105,133 months with a range of follow-up from 1 monthand a half until 9 years.Conclusions: IPMN main duct or mixed type warrants completeresection due to its incidence of invasive carcinoma or precursorlesions of malignancy as well. Due to its multifocal pattern,patients should be followed in long-term surveillance. The managementof asymptomatic IPMN type branch less than 3 cm iscontroversial(AU)

Síndrome de compresión del tronco celiaco. Revisión crítica en la era de la cirugía laparoscópica / The celiac axis compression syndrome (CACS): critical review in the laparoscopic era

El síndrome de compresión del tronco celiaco fue descrito porHarjola en 1963 como la compresión extrínseca del tronco celiacopor las fibras tendinosas del ligamento arcuato; causando uncuadro de dolor intenso post-pandrial en epigastrio, pérdida depeso, soplo epigástrico y estenosis mayor del 75% en la angiografíaselectiva. Desde entonces, dicho síndrome ha sido motivo demúltiples controversias relacionadas con su patogenia y la variabilidadde los resultados obtenidos con la cirugía.Debido a la proliferación y accesibilidad de técnicas de imagenmás precisas y menos invasivas (angio-TAC multicorte, angio-RMN, eco-doppler), el diagnóstico de dicho síndrome puede realizarsecon mayor precisión y sentar las bases de la indicación quirúrgicacon mayor seguridad y eficacia.La introducción, en el año 2000, de técnicas laparoscópicasen la liberación del tronco celiaco, junto con procedimientos endovascularescomplementarios, ha representado un notable avanceen el tratamiento del síndrome.Basados en nuestra experiencia personal, presentamos una revisióncrítica y propuesta terapéutica del síndrome(AU)

The celiac axis compression syndrome (CACS) due to medianarcuate ligament (MAL) was first described by Harjola in 1963;originating postpandrial abdominal pain, weight loss, epigastricbruit and celiac axis stenosis > 75% in angiographic studies. Thisclinical condition has been the origin of controversies about itspathogenesis, diagnosis and its long term clinical results.Advances in diagnostic imaging as 64 multidetector–row CT(MDCT), 3-D reconstruction, magnetic resonance (MR) and colorduplex ultrasonography, provide better understanding of the syndromeand allow to identify the best candidates for surgical divisionof MAL fibers.Since the introduction of laparoscopic approach, and also endovascularprocedures, in 2000, a new perspective has establishedin this challenging syndrome. With the occasion of our ownexperience, a critical review of the syndrome is presented(AU)