The role of clinically relevant intra-abdominal collections after pancreaticoduodenectomy : Clinical impact and predictors. A retrospective analysis from a European tertiary centre.

BACKGROUND: There is controversial evidence regarding the impact of clinically relevant postoperative intra-abdominal collections (CR-IC) on the clinical course after pancreaticoduodenectomy. C-reactive Protein (CRP) has been validated as a predictor of postoperative pancreatic fistula (POPF). Still, its role in predicting CR-IC has not been studied. METHODS: A retrospective analysis was conducted on patients who underwent PD at a tertiary hospital between October 2012 and October 2017. The incidence of CR-IC, clinically relevant POPF and other complications, as well as mortality and length of hospitalisation, was retrieved. The impact of CR-IR on mortality and major complications was analysed. The serum CRP levels were retrieved on the third and fifth postoperative days (POD3 and POD5), followed by an analysis of sensitivity, specificity, and area under the curve to predict CR-IC using CRP. RESULTS: One hundred forty patients were enrolled following inclusion and exclusion criteria. The mean age was 66.5 years (15-83). The incidence of CR-IC was 33.7% (47), and CR-POPF was 24.3%. Pancreatic duct diameter ≤ 4 mm was identified as a risk factor related to CR-IC occurrence. The group of patients who developed CR-IC after PD exhibited a higher rate of complications Clavien-Dindo ≥ III compared to patients without CR-IC (40.4% vs 7.5%, p < 0.001), as well as other events such as admission to the intensive care unit (25.5% vs 4.3%, p < 0.001), the incidence of CR-POPF (66% vs 3.2%, p < 0.001), prolonged hospital stay (32 vs 13 days, p < 0.001), postoperative haemorrhage (23.4 vs 5.4%, p = 0.002), and delayed gastric empty (38.8% vs 11.8%, p < 0.001) respectively. Logistic regression analysis identified CR-IC related to POPF as a risk factor for Clavien-Dindo > III: OR = 10.6 (95% CI: 3.90-28.7). No differences in mortality were reported between the CR-IC group and non-CR-IC group. CRP at postoperative day 3 (POD3) > 17.55 mg/dl and CRP at postoperative day 5 (POD5) > 13.46 mg/dl were predictors of CR-IC (AUC: 0.731 and AUC:0.821, respectively). CONCLUSIONS: CR-IC has a significant impact after pancreaticoduodenectomy and is associated with a higher incidence of Clavien-Dindo ≥ III complications. Additionally, CRP levels at POD3 and POD5 play a role in predicting CR-IC. Prospective studies are essential to explore strategies for mitigating the occurrence of CR-IC after PD.

Adipose Tissue Protects against Hepatic Steatosis in Male Rats Fed a High-Fat Diet plus Liquid Fructose: Sex-Related Differences.

Non-alcoholic fatty liver disease is a sexual dimorphic disease, with adipose tissue playing an essential role. Our previous work showed that female rats fed a high-fat high-fructose diet devoid of cholesterol (HFHFr) developed simple hepatic steatosis dissociated from obesity. This study assessed the impact of the HFHFr diet on the male rat metabolism compared with data obtained for female rats. A total of 16 Sprague Dawley (SD) male rats were fed either a control (standard rodent chow and water) or HFHFr (high-fat diet devoid of cholesterol, plus 10% fructose in drinking water) diet for 3 months. Unlike female rats, and despite similar increases in energy consumption, HFHFr males showed increased adiposity and hyperleptinemia. The expression of hormone-sensitive lipase in the subcutaneous white adipose tissue was enhanced, leading to high free fatty acid and glycerol serum levels. HFHFr males presented hypertriglyceridemia, but not hepatic steatosis, partially due to enhanced liver PPARα-related fatty acid ß-oxidation and the VLDL-promoting effect of leptin. In conclusion, the SD rats showed a sex-related dimorphic response to the HFHFr diet. Contrary to previous results for HFHFr female rats, the male rats were able to expand the adipose tissue, increase fatty acid catabolism, or export it as VLDL, avoiding liver lipid deposition.

Liquid biopsy after resection of pancreatic adenocarcinoma and its relation to oncological outcomes. Systematic review and meta-analysis.

BACKGROUND: It has been hypothesised that manipulation during surgery releases tumoral components into circulation. We investigate the effect of surgery on plasma-borne DNA biomarkers and the oncological outcomes in resectable pancreatic ductal adenocarcinoma (PDAC). We also compare non-touch isolation techniques (NTIT) with standard techniques. MATERIALS AND METHODS: We performed a systematic review and a meta-analysis of studies analysing liquid biopsy as circulating tumour DNA (ctDNA), circulating tumour cells (CTCs), and messenger RNA (mRNA) in resectable PDAC patients who underwent surgery and its association with overall survival (OS) and disease-free survival (DFS). Research in EMBASE, Web of Science and PubMed was performed. The ctDNA shift negative-to-positive (ctDNA -/+) or ctDNA shift positive-to-negative (ctDNA +/-) before and after surgery was evaluated. RESULTS: Twelve studies comprising 413 patients were included. Shorter OS and DFS were identified in patients with positive ctDNA status before (HR = 2.28, p = 0.005 and HR = 2.16, p = 0.006) or after surgery (HR = 3.88, p < 0.0001 and HR = 3.81, p = 0.03), respectively. Surgical resection increased the rate of ctDNA +/-. There were no differences in OS or DFS in the ctDNA +/- group compared with ctDNA +/+ or ctDNA -/+. However, there was a trend to shorter OS in the ctDNA -/+ group (HR = 5.00, p = 0.09). No differences between NTIT and standard techniques on liquid biopsy status were found. CONCLUSION: Positive ctDNA in the perioperative period is associated with a worse prognosis. Surgical resection has a role in the negativisation of liquid biopsy status. More studies are needed to assess the potential of minimally invasive techniques on ctDNA dynamics.

Impact of comorbidities on hospital mortality in patients with acute pancreatitis: a population-based study of 110,021 patients.

BACKGROUND: The impact of pre-existing comorbidities on acute pancreatitis (AP) mortality is not clearly defined. Our study aims to determine the trend in AP hospital mortality and the role of comorbidities as a predictor of hospital mortality. METHODS: We analyzed patients aged ≥ 18 years hospitalized with AP diagnosis between 2016 and 2019. The data have been extracted from the Spanish National Hospital Discharge Database of the Spanish Ministry of Health. We performed a univariate and multivariable analysis of the association of age, sex, and comorbidities with hospital mortality in patients with AP. The role of the Charlson and Elixhauser comorbidity indices as predictors of mortality was evaluated. RESULTS: A total of 110,021 patients diagnosed with AP were hospitalized during the analyzed period. Hospital mortality was 3.8%, with a progressive decrease observed in the years evaluated. In multivariable analysis, age ≥ 65 years (OR: 4.11, p < 0.001), heart disease (OR: 1.73, p < 0.001), renal disease (OR: 1.99, p < 0.001), moderate-severe liver disease (OR: 2.86, p < 0.001), peripheral vascular disease (OR: 1.43, p < 0.001), and cerebrovascular disease (OR: 1.63, p < 0.001) were independent risk factors for mortality. The Charlson > 1.5 (OR: 2.03, p < 0.001) and Elixhauser > 1.5 (OR: 2.71, p < 0.001) comorbidity indices were also independently associated with mortality, and ROC curve analysis showed that they are useful for predicting hospital mortality. CONCLUSIONS: Advanced age, heart disease, renal disease, moderate-severe liver disease, peripheral vascular disease, and cerebrovascular disease before admission were independently associated with hospital mortality. The Charlson and Elixhauser comorbidity indices are useful for predicting hospital mortality in AP patients.

The role of high serum triglyceride levels on pancreatic necrosis development and related complications.

BACKGROUND: The relevance of elevated serum triglyceride (TG) levels in the early stages of acute pancreatitis (AP) not induced by hypertriglyceridemia (HTG) remains unclear. Our study aims to determine the role of elevated serum TG levels at admission in developing pancreatic necrosis. METHODS: We analyzed the clinical data collected prospectively from patients with AP. According to TG levels measured in the first 24 h after admission, we stratified patients into four groups: Normal TG (< 150 mg/dL), Borderline-high TG (150-199 mg/dL), High TG (200-499 mg/dL) and Very high TG (≥ 500 mg/dL). We analyzed the association of TG levels and other risk factors with the development of pancreatic necrosis. RESULTS: A total of 211 patients were included. In the Normal TG group: 122, in Borderline-high TG group: 38, in High TG group: 44, and in Very high TG group: 7. Pancreatic necrosis developed in 29.5% of the patients in the Normal TG group, 26.3% in the Borderline-high TG group, 52.3% in the High TG group, and 85.7% in the Very high TG group. The trend analysis observed a significant association between higher TG levels and pancreatic necrosis (p = 0.001). A multivariable analysis using logistic regression showed that elevated TG levels ≥ 200 mg/dL (High TG and Very high TG groups) were independently associated with pancreatic necrosis (OR: 3.27, 95% CI - 6.27, p < 0.001). CONCLUSIONS: An elevated TG level at admission ≥ 200 mg/dl is independently associated with the development of pancreatic necrosis. The incidence of pancreatic necrosis increases proportionally with the severity of HTG.

Elevated Serum Triglyceride Levels in Acute Pancreatitis: A Parameter to be Measured and Considered Early.

BACKGROUND: The value of serum triglycerides (TGs) related to complications and the severity of acute pancreatitis (AP) has not been clearly defined. Our study aimed to analyze the association of elevated levels of TG with complications and the severity of AP. METHODS: The demographic and clinical data of patients with AP were prospectively analyzed. TG levels were measured in the first 24 h of admission. Patients were divided into two groups: one with TG values of<200 mg/dL and another with TG≥200 mg/dL. Data on the outcomes of AP were collected. RESULTS: From January 2016 to December 2019, 247 cases were included: 200 with TG<200 mg/dL and 47 with TG≥200 mg/dL. Triglyceride levels≥200 mg/dL were associated with respiratory failure (21.3 vs. 10%, p=0.033), renal failure (23.4 vs. 12%, p=0.044), cardiovascular failure (19.1 vs. 7.5%, p=0.025), organ failure (34 vs. 18.5%, p=0.02), persistent organ failure (27.7 vs. 9.5%, p=0.001), multiple organ failure (19.1 vs. 8%, p=0.031), moderately severe and severe AP (68.1 vs. 40.5%, p=0.001), pancreatic necrosis (63.8 vs. 34%, p<0.001), and admission to the intensive care unit (27.7 vs. 9.5%, p=0.003). In the multivariable analysis, a TG level of≥200 mg/dL was independently associated with respiratory, renal, and cardiovascular failure, organ failure, persistent organ failure, multiple organ failure, pancreatic necrosis, severe pancreatitis, and admission to the intensive care unit (p<0.05). CONCLUSIONS: In our cohort, TG≥200 mg/dL was related to local and systemic complications. Early determinations of TG levels in AP could help identify patients at risk of complications.

The role of procalcitonin as a prognostic factor for acute cholangitis and infections in acute pancreatitis: a prospective cohort study from a European single center.

BACKGROUND: Infection in acute pancreatitis will worsen the disease prognosis. The aim of our study was to analyze the role of procalcitonin as a prognostic biomarker for infections and clinical severity. METHOD: A prospective single-cohort observational study of patients diagnosed of acute pancreatitis (n = 152) was designed. PCT determination was tested on admission (first 72 h). Infections (biliary, extrapancreatic and infected pancreatic necrosis), need for antibiotics, urgent ERCP and severity scores for acute pancreatitis was assessed. ROC curves were designed and the area under the curve was calculated. Logistic regression for multivariate analysis was performed to evaluate the association between procalcitonin optimal cut-off level and major complications. RESULTS: PCT >0.68 mg/dL had higher incidence of global infection, acute cholangitis, bacteraemia, infected pancreatic necrosis, use of antibiotics in general, and need for urgent ERCP. In the multivariate regressions analysis, PCT >0.68 mg/dL at admission demonstrated to be a strong risk factor for complications in acute pancreatitis. DISCUSSION: PCT levels can be used as a reliable laboratory test to predict infections and the clinical severity of acute pancreatitis. High levels of PCT predict antibiotics prescription as well as the need for urgent ERCP in patients with concomitant clinically severe cholangitis.

Acquired hepatocerebral degeneration in a metastatic neuroendocrine tumor long-term survivor - an update on neuroendocrine neoplasm's treatment: A case report.

BACKGROUND: Metastatic small bowel low-grade neuroendocrine tumors (NETs) have a good prognosis. Surgery is the only curative treatment; however, this may induce advanced liver disease, particularly in long-term survivor patients. Acquired hepatocerebral degeneration or Parkinsonism in cirrhosis is characterized by rapidly progressive extrapyramidal symptoms in patients with advanced liver disease. CASE SUMMARY: A 70-year-old man presented to the emergency department with diminished consciousness and disorientation, and was diagnosed with hepatic encephalopathy. The patient was diagnosed in 1993 with a metastatic small bowel NET, for which he twice underwent hepatic surgery, with metastatic resection in 1993 and a right hepatectomy in 2002 to remove two hepatic metastases. In 2003, the patient started first-line chemotherapy and in 2004 started the first of three consecutive biological treatments, followed by radio-molecular therapy, achieving stable disease for 14 years. Disease progression was identified and he underwent an endoscopic retrograde cholangiopancreatography. However, in 2019 advanced liver disease was identified. We diagnosed the development of acquired hepatocerebral degeneration, an unusual long-term side effect after multiple hepatic procedures. CONCLUSION: The importance of regular and ongoing surveillance in long-term NET survivors who undergo hepatic procedures should be integrated into the therapeutic management plan, as some of these negative outcomes could be prevented.

Early Changes in Blood Urea Nitrogen (BUN) Can Predict Mortality in Acute Pancreatitis: Comparative Study between BISAP Score, APACHE-II, and Other Laboratory Markers-A Prospective Observational Study.

Background: Changes in BUN have been proposed as a risk factor for complications in acute pancreatitis (AP). Our study aimed to compare changes in BUN versus the Bedside Index for Severity in Acute Pancreatitis (BISAP) score and the Acute Physiology and Chronic Health Evaluation-II score (APACHE-II), as well as other laboratory tests such as haematocrit and its variations over 24 h and C-reactive protein, in order to determine the most accurate test for predicting mortality and severity outcomes in AP. Methods: Clinical data of 410 AP patients, prospectively enrolled for study at our institution, were analyzed. We define AP according to Atlanta classification (AC) 2012. The laboratory test's predictive accuracy was measured using area-under-the-curve receiver-operating characteristics (AUC) analysis and sensitivity and specificity tests. Results: Rise in BUN was the only score related to mortality on the multivariate analysis (p=0.000, OR: 12.7; CI 95%: 4.2-16.6). On the comparative analysis of AUC, the rise in BUN was an accurate test in predicting mortality (AUC: 0.842) and persisting multiorgan failure (AUC: 0.828), similar to the BISAP score (AUC: 0.836 and 0.850) and APACHE-II (AUC: 0.756 and 0.741). The BISAP score outperformed both APACHE-II and rise in BUN at 24 hours in predicting severe AP (AUC: 0.873 vs. 0.761 and 0.756, respectively). Conclusion: Rise in BUN at 24 hours is a quick and reliable test in predicting mortality and persisting multiorgan failure in AP patients.

Evaluation of the modified computed tomography severity index (MCTSI) and computed tomography severity index (CTSI) in predicting severity and clinical outcomes in acute pancreatitis.

OBJECTIVE: Our main purpose was to compare the modified computed tomography severity index (MCTSI), computed tomography severity index (CTSI), and acute physiological and chronic health evaluation (APACHE)-II predictions regarding severity according to the revised Atlanta classification 2012 and local complications in acute pancreatitis in a consecutive prospective cohort. METHODS: One hundred and forty-nine patients diagnosed with acute pancreatitis were prospectively enrolled. APACHE-II, MCTSI, and CTSI were calculated for all cases. Severity parameters included persistent organ or multiorgan failure, length of hospitalization, the need for intensive care, death, and local complications (intervention against necrosis and infected necrosis). Area under the receiver operating characteristic curve (AUROC) was calculated and the value of scoring systems was compared. RESULTS: Both CTSI and MCTSI were associated significantly with all the evaluated severity parameters and showed a correlation between imaging severity and the worst clinical outcomes. Persistent organ failure, persistent multiorgan failure, and death were found in 30 (20.1%), 20 (13.4%), and 13 (8.7%) patients, respectively. The most common extrapancreatic finding was pleural effusion in 76 (51.0%) patients. The AUROC for CTSI was higher for predicting persistent organ failure (0.749, 95% confidence interval [CI] 0.640-0.857), death (AUROC 0.793, 95% CI 0.650-0.936), intervention against necrosis (AUROC 0.862, 95% CI 0.779-0.945), and infected necrosis (AUROC 0.883, 95% CI 0.882-0.930). CONCLUSIONS: CT indexes outperformed the classic APACHE-II score for evaluating severity parameters in acute pancreatitis, with a slight advantage of CTSI over MCTSI. CTSI accurately predicted pancreatic infections and the need for intervention.

¿Es realmente la afectación del ganglio de la arteria hepática un factor de mal pronóstico en el adenocarcinoma de páncreas? / Is the involvement of the hepatic artery lymph node a poor prognostic factor in pancreatic adenocarcinoma?

INTRODUCCIÓN: El objetivo del presente estudio es analizar el impacto de la afectación del ganglio de la arteria hepática (GAH) en la supervivencia de los pacientes intervenidos de duodenopancreatectomía cefálica (DPC) por adenocarcinoma (ADK) de cabeza de páncreas. MÉTODOS: Estudio retrospectivo unicéntrico de pacientes intervenidos de DPC por ADK de cabeza de páncreas, con estudio anatomopatológico independiente del GAH. Los pacientes se agruparon en: 1) pacientes sin afectación del GAH ni ganglios peripancreáticos (GGP) (GPP-/GAH-); 2) pacientes con afectación ganglionar peripancreática (GPP+/GAH-), y 3)pacientes con afectación ganglionar peripancreática y de la arteria hepática (GGP+/GAH+). Para el análisis de supervivencia se utilizaron las curvas Kaplan-Meier. Los factores pronósticos de supervivencia global (SG) y libre de enfermedad (SLE) fueron identificados mediante el análisis de regresión de Cox. RESULTADOS: Entre enero de 2005 y diciembre de 2014 se intervinieron 118 pacientes, y el GAH fue analizado en 64 de ellos. La mediana de seguimiento fue de 20 meses (r: 1-159 meses). La distribución por grupos fue la siguiente: GPP-/GAH- en 12 (19%), GPP+/GAH- en 40 (62%), GGP+/GAH+ en 12 (19%) y CGP-/CGH+ en 0 (0%), La SG a 1, 3 y 5años fue estadísticamente mejor en el grupo GPP-/GAH- (82, 72 y 54%) comparado con GPP+/GAH- (68, 29 y 21%) y GGP+/GAH+ (72, 9 y 9%) (p = 0,001 vs p = 0,007). La probabilidad acumulada de recidiva a 1, 3 y 5 años fue estadísticamente inferior en el grupo GPP-/GAH- (18, 46 y 55%) comparado con el grupo GPP+/GAH- (57, 80 y 89%) y grupo GGP+/GAH+ (46, 91 y 100%) (p = 0,006 vs p = 0,021). En el análisis multivariante el principal factor de riesgo tanto de SG como de SLE fue la invasión linfática independientemente del estado del GAH. CONCLUSIONES: Nuestros resultados sugieren que la afectación adenopática impacta en la supervivencia del ADK de páncreas sin poder identificar la afectación del GAH como marcador pronóstico

INTRODUCTION: The aim of this study is to analyze the impact of hepatic artery lymph node (HALN) involvement on the survival of patients undergoing pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PA). METHODS: A single-center retrospective study analyzing patients who underwent PD for PA. Patients were included if, during PD, the HALN was submitted for pathologic evaluation. Patients were stratified by node status: PPLN- (peripancreatic lymph node)/HALN-, PPLN+/HALN- and PPLN+/HALN+. Survival analysis was estimated by the Kaplan-Meier method, and Cox regression was used for risk factors analyses. RESULTS: Out of the 118 patients who underwent PD for PA, HALN status was analyzed in 64 patients. The median follow-up was 20months (r: 1-159months). HALN and PPLN were negative in 12 patients (PPLN-/HALN-, 19%), PPLN was positive and HALN negative in 40 patients (PPLN+/HALN-, 62%), PPLN and HALN were positive in 12 patients (PPLN+/HALN+, 19%) and PPLN was negative and HALN positive in 0 patients (PPLN-/HALN+, 0%). The overall 1, 3 and 5-year survival rates were statistically better in the PPLN-/HALN- group (82%, 72%, 54%) than in the PPLN+/HALN- group (68%, 29%, 21%) and the PPLN+/HALN+ group (72%, 9%, 9%, respectively) (P = .001 vs P = .007). The 1, 3 and 5-year probabilities of cumulative recurrence were also statistically better in the PPLN-/HALN- group (18%, 46%, 55%) than in the PPLN+/HALN- group (57%, 80%, 89%) and the PPLN+/HALN+ group (46%, 91%, 100%, respectively) (P = .006 vs P = .021). In the multivariate model, the main risk factor for overall survival and recurrence was lymphatic invasion, regardless of HALN status. CONCLUSIONS: In pancreatic adenocarcinoma patients with lymph node disease, survival after PD is comparable regardless of HALN status

Is the involvement of the hepatic artery lymph node a poor prognostic factor in pancreatic adenocarcinoma? / ¿Es realmente la afectación del ganglio de la arteria hepática un factor de mal pronóstico en el adenocarcinoma de páncreas?

INTRODUCTION: The aim of this study is to analyze the impact of hepatic artery lymph node (HALN) involvement on the survival of patients undergoing pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PA). METHODS: A single-center retrospective study analyzing patients who underwent PD for PA. Patients were included if, during PD, the HALN was submitted for pathologic evaluation. Patients were stratified by node status: PPLN- (peripancreatic lymph node)/HALN-, PPLN+/HALN- and PPLN+/HALN+. Survival analysis was estimated by the Kaplan-Meier method, and Cox regression was used for risk factors analyses. RESULTS: Out of the 118 patients who underwent PD for PA, HALN status was analyzed in 64 patients. The median follow-up was 20months (r: 1-159months). HALN and PPLN were negative in 12patients (PPLN-/HALN-, 19%), PPLN was positive and HALN negative in 40patients (PPLN+/HALN-, 62%), PPLN and HALN were positive in 12 patients (PPLN+/HALN+, 19%) and PPLN was negative and HALN positive in 0 patients (PPLN-/HALN+, 0%). The overall 1, 3 and 5-year survival rates were statistically better in the PPLN-/HALN- group (82%, 72%, 54%) than in the PPLN+/HALN- group (68%, 29%, 21%) and the PPLN+/HALN+ group (72%, 9%, 9%, respectively) (P=.001 vs P=.007). The 1, 3 and 5-year probabilities of cumulative recurrence were also statistically better in the PPLN-/HALN- group (18%, 46%, 55%) than in the PPLN+/HALN- group (57%, 80%, 89%) and the PPLN+/HALN+ group (46%, 91%, 100%, respectively) (P=.006 vs P=.021). In the multivariate model, the main risk factor for overall survival and recurrence was lymphatic invasion, regardless of HALN status. CONCLUSIONS: In pancreatic adenocarcinoma patients with lymph node disease, survival after PD is comparable regardless of HALN status.

Pharmacological modulation of CXCR4 cooperates with BET bromodomain inhibition in diffuse large B-cell lymphoma.

Constitutive activation of the chemokine receptor CXCR4 has been associated with tumor progression, invasion, and chemotherapy resistance in different cancer subtypes. Although the CXCR4 pathway has recently been suggested as an adverse prognostic marker in diffuse large B-cell lymphoma, its biological relevance in this disease remains underexplored. In a homogeneous set of 52 biopsies from patients, an antibody-based cytokine array showed that tissue levels of CXCL12 correlated with high microvessel density and bone marrow involvement at diagnosis, supporting a role for the CXCL12-CXCR4 axis in disease progression. We then identified the tetra-amine IQS-01.01RS as a potent inverse agonist of the receptor, preventing CXCL12-mediated chemotaxis and triggering apoptosis in a panel of 18 cell lines and primary cultures, with superior mobilizing properties in vivo than those of the standard agent. IQS-01.01RS activity was associated with downregulation of p-AKT, p-ERK1/2 and destabilization of MYC, allowing a synergistic interaction with the bromodomain and extra-terminal domain inhibitor, CPI203. In a xenotransplant model of diffuse large B-cell lymphoma, the combination of IQS-01.01RS and CPI203 decreased tumor burden through MYC and p-AKT downregulation, and enhanced the induction of apoptosis. Thus, our results point out an emerging role of CXCL12-CXCR4 in the pathogenesis of diffuse large B-cell lymphoma and support the simultaneous targeting of CXCR4 and bromodomain proteins as a promising, rationale-based strategy for the treatment of this disease.

The role of extra-pancreatic infections in the prediction of severity and local complications in acute pancreatitis.

BACKGROUND: The aim of our study was to determine the risk factors for extrapancreatic infection (EPI) occurrence and its predictive power for assessing severity and local complications in acute pancreatitis including infected pancreatic necrosis (IPN). METHODS: Clinical data of 176 AP patients prospectively enrolled were analysed. EPI analysed were bacteraemia, lung infection, urinary tract infection and catheter line infection. Risk factors analysed were: Leukocyte count, C-reactive protein, liver function test, serum calcium, serum glucose, Blood urea nitrogen, mean arterial pressure at admission, total parenteral nutrition (TPN), enteral nutrition, hypotension, respiratory, cardiovascular and renal failure at admission, persistent systemic inflammatory response (SIRS) and intrapancreatic necrosis. Severity outcomes assessed were defined according to the Atlanta Criteria definition for acute pancreatitis. The predictive accuracy of EPI for morbidity and mortality was measured using area-under-the-curve (AUC) receiver-operating characteristics. RESULTS: Forty-four cases of EPI were found (25%). TPN (OR:9.2 CI95%: 3.3-25.7), APACHE-II>8 (OR:6.2 CI95%:2.48-15.54) and persistent SIRS (OR:2.9 CI95%: 1.1-7.8), were risk factors related with EPI. Bacteraemia, when compared with others EPI, showed the best accuracy in predicting significantly persistent organ failure (AUC:0.76, IC95%:0.64-0.88), ICU admission (AUC:0.80 IC95%:0.65-0.94), and death (AUC:0.73 CI95%:0.54-0.91); and for local complications including IPN (AUC:0.72 CI95%:0.53-0.92) as well. Besides, it was also needed for an interventional procedure against necrosis (AUC:0.74 IC95%: 0.57-0.91). When bacteraemia and IPN occurs, bacteraemia preceded infected necrosis in all cases. On multivariate analysis, risk factor for IPN were lung infection (OR:6.25 CI95%1.1-35.7 p = 0.039) and TPN (OR:22.0CI95%:2.4-205.8, p = 0.007), and for mortality were persistent SIRS at first week (OR: 22.9 CI95%: 2.6-203.7, p = 0.005) and Lung infection (OR: 9.7 CI95%: 1.7-53.8). CONCLUSION: In our study, EPI, played a role in predicting the severity and local complications in acute pancreatitis.

Nitrogen positional scanning in tetramines active against HIV-1 as potential CXCR4 inhibitors.

The paradigm, derived from bicyclams and other cyclams, by which it is necessary to use the p-phenylene moiety as the central core in order to achieve high HIV-1 antiviral activities has been reexamined for the more flexible and less bulky structures 4, previously described by our group as potent HIV-1 inhibitors. The symmetrical compounds 7{x,x} and the non-symmetrical compounds 8{x,y} were designed, synthesized and biologically evaluated in order to explore the impact on the biological activity of the distance between the phenyl ring and the first nitrogen atom of the side chains. EC50 exactly followed the order 7{x,x} < 8{x,x} < 4{x,x} indicating that, for such flexible tetramines, the presence of two methylene units on each side of the central phenyl ring increases the biological activity contrary to AMD3100. A computational study of the interactions of 4{3,3}, 7{3,3} and 8{3,3} with CXCR4 revealed interactions in the same pocket region with similar binding modes for 4{3,3} and 7{3,3} but a different one for 8{3,3}.

Resultados a largo plazo de la duodenopancreatectomía cefálica con resección de la vena mesentérica superior y vena porta por adenocarcinoma de la cabeza de páncreas / Long-term results of pancreaticoduodenectomy with superior mesenteric and portal vein resection for ductal adenocarcinoma in the head of the pancreas

INTRODUCCIÓN: El beneficio de la duodenopancreatectomía cefálica (DPC) con resección de la vena mesentérica superior/vena porta (RVP) para el adenocarcinoma de páncreas (ADCP) es controvertido en cuanto a la morbilidad, mortalidad y supervivencia. Se analizan los resultados de la DPC con RVP en un centro terciario español. MÉTODOS: Entre 2002 y 2012, 10 pacientes fueron tratados mediante RVP (RVP+) y 68 con DPC estándar (RVP−). La morbilidad, mortalidad, supervivencia global (SG) y supervivencia libre de enfermedad (SLE) se compararon entre pacientes RVP+/RVP−. Los factores pronósticos fueron identificados con regresión de Cox. RESULTADOS: La mortalidad postoperatoria fue del 5% (4/78), todos los pacientes en el grupo RVP−. La morbilidad fue mayor en el grupo RVP− comparado con RVP+ (63 vs. 30%; p = 0,04). La SG a 3 y 5 años fue 43 y 43% en el grupo RVP+, 35 y 29% en RVP− (p = 0,7). La SLE a 3 y 5 años fue 28 y 15% en RVP+, 25 y 20% en RVP− (p = 0,84). La mediana de supervivencia fue de 23,1 meses en el grupo RVP− y de 22,8 meses en el grupo RVP+ (p = 0,73). Los factores relacionados con la SG fueron ausencia de tratamiento adyuvante (OR 2,9; IC95%: 1,39-6,14; p = 0,003), resección R1 (OR 2,3; IC95%: 1,2-4,43; p = 0,006), CA 19.9 ≥ 170 UI/mL (OR 2,3; IC95%: 1,22-4,32; p = 0,01). Los factores de riesgo para SLE fueron resección R1 (OR 2,6; IC95%: 1,41-4,95; p = 0,002); tumores pobremente diferenciados (OR 2,7; IC95%: 1,23-6,17; p = 0,01); tumores N1 (OR 1,8; IC95%: 1,02-3,19; p = 0,04); CA 19.9 ≥ 170 UI/mL (OR 2,4; IC95%: 1,30-4,54; p = 0,005). CONCLUSIONES: La RVP para ADCP puede realizarse con seguridad. Pacientes con RVP tienen una supervivencia comparable a los pacientes tratados mediante DPC estándar si se obtienen márgenes libres

INTRODUCTION: The benefit of pancreaticoduodenectomy (PD) with superior mesenteric-portal vein resection (PVR) for pancreatic adenocarcinoma (PA) is still controversial in terms of morbidity, mortality and survival. We conducted a retrospective study to analyze outcomes of PD with PVR in a Spanish tertiary centre. METHODS: Between 2002 and 2012, 10 patients underwent PVR (PVR+ group) and 68 standard PD (PVR− group). Morbidity, mortality, overall survival (OS) and disease-free survival (DFS) were compared between PVR+ and PVR− group. Prognostic factors were identified by a Cox regression model. RESULTS: Postoperative mortality was 5% (4/78), all patients in PVR− group. Morbidity was higher in the PVR− group compared to PVR+ (63 vs. 30%, P=.004). OS at 3 and 5 years was 43 and 43% in PVR+ group, 35 and 29% in PVR− group (P=.07). DFS at 3 and 5 years DFS were 28 and 15% in PVR+ group, 25 and 20% in PVR− group (P=.84). Median survival was 23.1 months in PVR− group, and 22.8 months in PVR+ group (P=.73). Factors related with OS were absence of adjuvant treatment (OR 2.9, 95%IC: 1.39-6.14, P=.003), R1 resection (OR 2.3, 95%IC: 1.2-4.43, P=.006), preoperative CA 19.9 level ≥ 170 UI/mL (OR 2.3, 95%IC: 1.22-4.32, P=.01). DFS risk factors were R1 resection (OR 2.6, 95%IC: 1.41-4.95, P=.002); moderate or poor tumor differentiation grade (OR 2.7, 95%IC: 1.23-6.17, P=.01); N1 lymph node status (OR 1.8, 95%IC: 1.02-3.19, P=.04); CA 19.9 level ≥ 170 UI/mL (OR 2.4, 95%IC: 1.30-4.54, P=.005). CONCLUSIONS: PVR for PA can be performed safely. Patients with PVR have a comparable survival to patients undergoing standard PD if disease-free margins can be obtained

Long-term results of pancreaticoduodenectomy with superior mesenteric and portal vein resection for ductal adenocarcinoma in the head of the pancreas.

INTRODUCTION: The benefit of pancreaticoduodenectomy (PD) with superior mesenteric-portal vein resection (PVR) for pancreatic adenocarcinoma (PA) is still controversial in terms of morbidity, mortality and survival. We conducted a retrospective study to analyze outcomes of PD with PVR in a Spanish tertiary centre. METHODS: Between 2002 and 2012, 10 patients underwent PVR (PVR+ group) and 68 standard PD (PVR- group). Morbidity, mortality, overall survival (OS) and disease-free survival (DFS) were compared between PVR+ and PVR- group. Prognostic factors were identified by a Cox regression model. RESULTS: Postoperative mortality was 5% (4/78), all patients in PVR- group. Morbidity was higher in the PVR- group compared to PVR+ (63 vs. 30%, P=.004). OS at 3 and 5 years was 43 and 43% in PVR+ group, 35 and 29% in PVR- group (P=.07). DFS at 3 and 5 years DFS were 28 and 15% in PVR+ group, 25 and 20% in PVR- group (P=.84). Median survival was 23.1 months in PVR- group, and 22.8 months in PVR+ group (P=.73). Factors related with OS were absence of adjuvant treatment (OR 2.9, 95%IC: 1.39-6.14, P=.003), R1 resection (OR 2.3, 95%IC: 1.2-4.43, P=.006), preoperative CA 19.9 level ≥ 170 UI/mL (OR 2.3, 95%IC: 1.22-4.32, P=.01). DFS risk factors were R1 resection (OR 2.6, 95%IC: 1.41-4.95, P=.002); moderate or poor tumor differentiation grade (OR 2.7, 95%IC: 1.23-6.17, P=.01); N1 lymph node status (OR 1.8, 95%IC: 1.02-3.19, P=.04); CA 19.9 level ≥ 170 UI/mL (OR 2.4, 95%IC: 1.30-4.54, P=.005). CONCLUSIONS: PVR for PA can be performed safely. Patients with PVR have a comparable survival to patients undergoing standard PD if disease-free margins can be obtained.

Noncyclam tetraamines inhibit CXC chemokine receptor type 4 and target glioma-initiating cells.

The three stereoisomers of the noncyclam compound 1 (1(R,R), 1(S,S), and the meso form 1(S,R)) and their corresponding tetrahydrochlorides 11 were prepared from (S)- and (R)-2-methylpiperidine. We have evaluated their inhibitory activity on the CXC chemokine receptor type 4 (CXCR4), toxicity properties, and assessment of their effect on glioma initiating cells (GICs) in comparison with the prototype compound AMD3100. The IC(50) values determined on human recombinant (CHO) cells showed very similar inhibitory activities albeit a lower K(B) for AMD3100, with the 1(R,R) isomer being second in potency. All the compounds showed low cardiac toxicity but, contrary to AMD3100, gave maximum nonlethal doses of around 2.0 mg/kg. The CXCR4 inhibitors had an effect on the state of differentiation of GICs, decreasing the percentage of CD44+ cells in glioblastoma multiform neurospheres in vitro. Moreover, these CXCR4 inhibitors blocked the capacity of cells to initiate orthotopic tumors in immunocompromised mice.

Evolution and management of de novo neoplasm post-liver transplantation: a 20-year experience from a single European centre.

PURPOSE: Survival post-liver transplantation (LT) has improved; however, patients are considered at the, risk of malignancy due to prolonged immunosuppression. The long-term outcome of patients developing de novo neoplasm (DN) at our centre was evaluated. METHODS: Between October 1988 and December 2007, 800 LT were performed in 742 patients. Patients were divided into two study periods according to the time of LT; first: October 1988-December 1995; second: January 1996-December 2007. RESULTS: After a mean follow-up of 5 ± 4.6 years, 71 DN (9.5%) were detected in 742 patients. The cumulative risk of DN development increased with the time from LT although no differences at 3, 5, and 10 years were found when first and second periods were compared (3, 7, 16% vs. 2, 4, 11%, respectively; p = 0.4). DN incidence was higher in the first compared with the second period (10.7 vs. 7.8%; p < 0.04); no significant differences were observed in mortality rate (50 vs. 27%; p = 0.052). Actuarial patient survival post-DN at 1, 3, and 5 years: 67, 48, 45% versus 82, 71, 65%, in the first versus second period, respectively, p < 0.04. CONCLUSIONS: DN incidence has decreased in recent years; however, as survival post-LT increases, so does the incidence of DN. Surveillance programmes are necessary to diagnose DN at early stages.

Pancreatogastrostomy with gastric partition after pylorus-preserving pancreatoduodenectomy versus conventional pancreatojejunostomy: a prospective randomized study.

OBJECTIVE: To compare the results of postoperative morbidity rate of a new pancreatogastrostomy technique, pylorus-preserving pancreaticoduodenectomy (PPPD) with gastric partition (PPPD-GP) with the conventional technique of pancreaticojejunostomy (PJ). SUMMARY AND BACKGROUND DATA: Pancreatojejunostomy and pancreatogastrostomy (PG) are the commonly preferred methods of anastomosis after pancreatoduodenectomy (PD). All randomized controlled trials failed to show advantage of a particular technique, suggesting that both PJ and PG provide equally results. However, postoperative morbidity remains high. The best technique in pancreatic anastomosis is still debated. METHOD: Described here is a new technique, PPPD-GP; in this technique the gastroepiploic arcade is preserved. Gastric partition was performed using 2 endo-Gia staplers along the greater curvature of the stomach, 3 cm from the border. This gastric segment, 10 to 12 cm in length is placed in close proximity to the cut edge of the pancreatic stump. An end-to-side, duct-to-mucosa anastomosis (with pancreatic duct stent) is constructed. One hundred eight patients undergoing PPPD for benign and malignant diseases of the pancreatic head and the periampullary region were randomized to receive PG (PPPD-GP) or end-to-side PJ (PPPD-PJ). RESULTS: The two treatment groups showed no differences in preoperative parameters and intraoperative factors. The overall postoperative complications were 23% after PPPD-GP and 44% after PPPD-PJ (P < 0.01). The incidence of pancreatic fistula was 4% after PPPD-GP and 18% after PPPD-PJ (P < 0.01). The mean + SD hospital stay was 12 +/- 2 days after PPPD-GP and 16 +/- 3 days after PPPD-PJ. CONCLUSIONS: This study shows that PPPD-GP can be performed safely and is associated with less complication than PPPD-PJ. The advantage of this technique over other PG techniques is that the anastomosis is outside the area of the stomach where the contents empty into the jejunum, but pancreatic juice drains directly into the stomach.