A systems approach identifies time-dependent associations of multimorbidities with pancreatic cancer risk.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is usually diagnosed in late adulthood; therefore, many patients suffer or have suffered from other diseases. Identifying disease patterns associated with PDAC risk may enable a better characterization of high-risk patients. METHODS: Multimorbidity patterns (MPs) were assessed from 17 self-reported conditions using hierarchical clustering, principal component, and factor analyses in 1705 PDAC cases and 1084 controls from a European population. Their association with PDAC was evaluated using adjusted logistic regression models. Time since diagnosis of morbidities to PDAC diagnosis/recruitment was stratified into recent (<3 years) and long term (≥3 years). The MPs and PDAC genetic networks were explored with DisGeNET bioinformatics-tool which focuses on gene-diseases associations available in curated databases. RESULTS: Three MPs were observed: gastric (heartburn, acid regurgitation, Helicobacter pylori infection, and ulcer), metabolic syndrome (obesity, type-2 diabetes, hypercholesterolemia, and hypertension), and atopic (nasal allergies, skin allergies, and asthma). Strong associations with PDAC were observed for ≥2 recently diagnosed gastric conditions [odds ratio (OR), 6.13; 95% confidence interval CI 3.01-12.5)] and for ≥3 recently diagnosed metabolic syndrome conditions (OR, 1.61; 95% CI 1.11-2.35). Atopic conditions were negatively associated with PDAC (high adherence score OR for tertile III, 0.45; 95% CI, 0.36-0.55). Combining type-2 diabetes with gastric MP resulted in higher PDAC risk for recent (OR, 7.89; 95% CI 3.9-16.1) and long-term diagnosed conditions (OR, 1.86; 95% CI 1.29-2.67). A common genetic basis between MPs and PDAC was observed in the bioinformatics analysis. CONCLUSIONS: Specific multimorbidities aggregate and associate with PDAC in a time-dependent manner. A better characterization of a high-risk population for PDAC may help in the early diagnosis of this cancer. The common genetic basis between MP and PDAC points to a mechanistic link between these conditions.

Gallbladder disease and pancreatic cancer risk: a multicentric case-control European study.

BACKGROUND AND AIMS: The overall evidence on the association between gallbladder conditions (GBC: gallstones and cholecystectomy) and pancreatic cancer (PC) is inconsistent. To our knowledge, no previous investigations considered the role of tumour characteristics on this association. Thus, we aimed to assess the association between self-reported GBC and PC risk, by focussing on timing to PC diagnosis and tumour features (stage, location, and resection). METHODS: Data derived from a European case-control study conducted between 2009 and 2014 including 1431 PC cases and 1090 controls. We used unconditional logistic regression models to estimate odds ratios (ORs) and corresponding 95% confidence intervals (CIs) adjusted for recognized confounders. RESULTS: Overall, 298 (20.8%) cases and 127 (11.6%) controls reported to have had GBC, corresponding to an OR of 1.70 (95% CI 1.33-2.16). The ORs were 4.84 (95% CI 2.96-7.89) for GBC diagnosed <3 years before PC and 1.06 (95% CI 0.79-1.41) for ≥3 years. The risk was slightly higher for stage I/II (OR = 1.71, 95% CI 1.15-2.55) vs. stage III/IV tumours (OR = 1.23, 95% CI 0.87-1.76); for tumours sited in the head of the pancreas (OR = 1.59, 95% CI 1.13-2.24) vs. tumours located at the body/tail (OR = 1.02, 95% CI 0.62-1.68); and for tumours surgically resected (OR = 1.69, 95% CI 1.14-2.51) vs. non-resected tumours (OR = 1.25, 95% CI 0.88-1.78). The corresponding ORs for GBC diagnosed ≥3 years prior PC were close to unity. CONCLUSION: Our study supports the association between GBC and PC. Given the time-risk pattern observed, however, this relationship may be non-causal and, partly or largely, due to diagnostic attention and/or reverse causation.

Risk of pancreatic cancer associated with family history of cancer and other medical conditions by accounting for smoking among relatives.

Background: Family history (FH) of pancreatic cancer (PC) has been associated with an increased risk of PC, but little is known regarding the role of inherited/environmental factors or that of FH of other comorbidities in PC risk. We aimed to address these issues using multiple methodological approaches. Methods: Case-control study including 1431 PC cases and 1090 controls and a reconstructed-cohort study (N = 16 747) made up of their first-degree relatives (FDR). Logistic regression was used to evaluate PC risk associated with FH of cancer, diabetes, allergies, asthma, cystic fibrosis and chronic pancreatitis by relative type and number of affected relatives, by smoking status and other potential effect modifiers, and by tumour stage and location. Familial aggregation of cancer was assessed within the cohort using Cox proportional hazard regression. Results: FH of PC was associated with an increased PC risk [odds ratio (OR) = 2.68; 95% confidence interval (CI): 2.27-4.06] when compared with cancer-free FH, the risk being greater when ≥ 2 FDRs suffered PC (OR = 3.88; 95% CI: 2.96-9.73) and among current smokers (OR = 3.16; 95% CI: 2.56-5.78, interaction FHPC*smoking P-value = 0.04). PC cumulative risk by age 75 was 2.2% among FDRs of cases and 0.7% in those of controls [hazard ratio (HR) = 2.42; 95% CI: 2.16-2.71]. PC risk was significantly associated with FH of cancer (OR = 1.30; 95% CI: 1.13-1.54) and diabetes (OR = 1.24; 95% CI: 1.01-1.52), but not with FH of other diseases. Conclusions: The concordant findings using both approaches strengthen the notion that FH of cancer, PC or diabetes confers a higher PC risk. Smoking notably increases PC risk associated with FH of PC. Further evaluation of these associations should be undertaken to guide PC prevention strategies.

Intraoperative flow measurement of native liver and allograft during orthotopic liver transplantation in children.

Hepatic hemodynamic changes during liver transplantation (OLT) in children have not yet been studied. We measured intraoperative portal vein flow (PVF) and hepatic arterial flow (HAF) (mL/min) in 53 children and 58 grafts during OLT. Flows were measured in the native organ and in the allograft. In the native liver, PVF and HAF are similar; after transplantation they return to the physiological situation. No flow differences were seen between whole and partial grafts. Among the 8 (14%) portal vein thromboses, PVF was lower in both the native liver and the graft than in the no thrombosis group (P < .05). PVF <5 mL/min/kg was a risk factor to develop PV thrombosis. No graft loss occurred in 3 cases without PVF at the time of OLTs despite the observation that repermeabilization was not possible. In 4 patients with PVF <5 mL/min/kg, after tying a spontaneous spleno-renal shunt (n = 3) or performing a porto-renal vein anastomosis (n = 1), PVF reached >20 mL/min/kg, avoiding thrombosis. In conclusion, PVF and HAF measurements during pediatric OLT may predict patients at high risk for development of PV thrombosis.

Portocaval shunt throughout anhepatic phase in orthotopic liver transplantation for cirrhotic patients.

The aim of this study was to assess whether the use of a temporary portocaval shunt (PCS) with inferior vena caval (IVC) preservation during orthotopic liver transplant procedures (OLT) in cirrhotic patients had any advantage. This work evaluated a group of cirrhotic patients who underwent liver-transplant between 1999 and 2006 with a temporary portocaval anastomosis and IVC preservation (PC group, n = 356) versus an historical group (no-PC group, n = 45) with only IVC preservation. We excluded cases of fulminant hepatitis, retransplants, portal vein thrombosis, or prior surgical portosystemic shunts. In both groups, graft reperfusion was achieved by simultaneous arterial and venous revascularization. Donor, recipient, and surgical characteristics were similar in both groups. The PCS group displayed significantly higher portovenous flow (PVF) than the no-PCS group (773 +/- 402 mL/min vs 555 +/- 379 mL/min, P = .004). We studied two subgroups: high PVF subgroup A (>800 mL/min; mean 1099 +/- 261 mL/min) and a low PVF subgroup B (<800 mL/min; mean 433 +/- 423 mL/min). In the high flow group (subgroup A) with PCS, a smaller number of blood units were required and better renal function was exhibited at the third postoperatory day. In contrast, no differences were observed among subgroup B between patients with or without PCS. The use of PCS with IVC preservation during the OLT enhanced the hemodynamic recipient status requiring a smaller number of blood units and displaying better renal function.

Liver transplantation in childhood with more than 10 years of follow-up: analysis of a single-center experience.

UNLABELLED: We pioneered pediatric liver transplantation (OLT) in Spain (June 1985). The aim of this study was to evaluate the current status of our OLT recipients with more than 10 years follow-up. MATERIALS AND METHODS: The 50 patients with >10 years follow-up had a mean age at OLT of 5.6 years with 60% showing a main indication of biliary atresia. All but one (tacrolimus) received cyclosporine. RESULTS: No patient loss occurred among these patients. Eighteen patients had follow-up >15 years and 12 >20 years. The incidence of acute rejection was 56%; chronic rejection, 16%; and lymphoproliferative disorders, 12%. Seven (14%) required retransplantation at a mean of 4.2 years after the first OLT due in four instances to chronic rejection. After 10 years of follow-up, one patient developed portal vein thrombosis and three biliary strictures. All patients remain on immunosuppression. In 64% cyclosporine was switched to tacrolimus or another agent. One patient developed acute rejection at 19.2 years. In 14% of patients the liver function test is abnormal with serum creatinine is >1.5 mg/dL in 10%; one requires insulin and three, antihypertensive drugs. Noncompliance with medications was detected in 10%. Three recipients had offspring. CONCLUSIONS: OLT was an effective treatment with a good quality of life also on long-term follow-up.

Recurrence of hepatocellular carcinoma after liver transplantation.

Outcome after liver transplantation (OLT) clearly depends on recurrence of hepatocellular carcinoma (HCC). After recurrence, patient outcome will depend on the time and site of appearance. The aim of this study was to analyze the therapeutic implications of tumor recurrence behavior. From October 1988 to December 2005, 685 patients received OLT, including 202 due to HCC (32%). We analyzed 28 recurrences (15.2%) among 184 patients who survived at least 3 months (minimum follow-up 1 year). According to the time of recurrence, we divided the patients into early recurrence (ER < 12 months; n = 9; 32.1%) and late recurrence (LR > 12 months n = 19; 67.9%). Actuarial survivals at 1, 5, and 10 years were 82%, 65%, and 50% and disease-free survival, 80%, 58%, and 46%, respectively. Risk factors for recurrence were: vascular invasion (P < .01), bad differentiation (P < .01), and previous hepatectomy (P < .05). After OLT, ER presented at: 5.7 +/- 2.3 months (range 3-10) vs 33.5 +/- 24.3 months (range 12-103) for LR P < .001). Survival postrecurrence (SPR) was shorter: 3.1 +/- 2.4 (range 1-8) months vs 16.4 +/- 14.2 (range 1-5) months (P < .001). Treatment was offered to one ER (11%) and to eight LR (47.1%; P < .05), achieving in these cases longer SPR: 20.1 +/- 14 vs 6.9 +/- 9 months (P < .05). The most common sites of recurrence were liver (n = 7), lung (n = 7), bone (n = 5), adrenal gland (n = 2), peritoneum (n = 2), lymph node (n = 2), skin (n = 2) or cerebral (n = 1). Early recurrences showed short survivals; no treatment could be offered to these patients. Liver recurrence appeared early. In contrast, most lung recurrences appeared later with the possibility of treatment and longer SPR. Bone recurrence appeared later, usually associated with other locations. Treatment was palliative and prognosis was worse. Skin and lymph node recurrences can be treated curatively with prolonged survival. In conclusion, HCC recurrence was difficult to treat curatively and was only prevented by employing restricted criteria.

Pancreatic cancer heterogeneity and response to Mek inhibition.

Our increasing knowledge of the mechanisms behind the progression of pancreatic cancer (PC) has not yet translated into effective treatments. Many promising drugs have failed in the clinic, highlighting the need for better preclinical models to assess drug efficacy and characterize mechanisms of resistance. Using different experimental models, including patient-derived xenografts (PDXs), we gauged the efficacy of therapies aimed at two hallmark lesions of PCs: activation of signaling pathways by oncogenic KRAS and inactivation of tumor-suppressor genes. Although the drug targeting inactivation of tumor suppressors by DNA methylation had little effect, the inhibition of Mek, a K-Ras effector, in combination with the standard of care (chemotherapy consisting of gemcitabine/Nab-paclitaxel), reduced the growth of three out of five PC-PDXs and impaired metastasis. The two least responding PC-PDXs were composed of genetically diverse cells, which displayed sensitivities to the Mek inhibitor differing by >10-fold. Unexpectedly, our analysis of this genetic diversity unveiled different KRAS mutations. As mutation in KRAS occurs early during progression, this heterogeneity may reflect the simultaneous appearance of different malignant cellular clones or, alternatively, that cells containing two mutations of KRAS are selected during tumor evolution. In vitro and in vivo analyses indicated that the intratumoral heterogeneity, along with the selective pressure imposed by the Mek inhibitor, resulted in rapid selection of resistant cells. Together with the gemcitabine/Nab-paclitaxel backbone, Mek inhibition could be effective in treatment of PC. However, resistance because of intratumoral heterogeneity is likely to develop frequently, pointing to the necessity of identifying the factors and mechanisms of resistance to further develop this therapy.

Initial experience in sentinel lymph node detection in pancreatic cancer.

BACKGROUND: The local recurrence of pancreatic cancer is around 30% when complete resection can be achieved. Extended lymphatic resections may improve survival, but increases severe morbidity. As accurate patient selection should be mandatory, a new method is presented for pancreatic sentinel lymph node (SLN) detection with lymphoscintigraphy and gamma probe. MATERIALS AND METHODS: Seven patients with cT2N0M0 pancreatic head cancer were enrolled between 2009 and 2012 in this prospective study. One day prior to surgery, preoperative lymphoscintigraphy with echoendoscopic intratumoural administration of Tc(99m)-labelled nanocolloid was performed, with planar and SPECT-CT images obtained 2h later. Gamma probe detection of SLN was also carried out during surgery. RESULTS: Radiotracer administration was feasible in all patients. Scintigraphy images showed inter-aortocaval lymph nodes in 2 patients, hepatoduodenal ligament lymph nodes in 1, intravascular injection in 3, intestinal transit in 5, and main pancreatic duct visualisation in 1. Surgical resection could only be achieved in 4 patients owing to locally advanced disease. Intraoperative SLN detection was accomplished in 2 patients, both with negative results. Only in one patient could SLN be confirmed as truly negative by final histopathological analysis. CONCLUSIONS: This new method of pancreatic SLN detection is technically feasible, but challenging. Our preliminary results with 7 patients are not sufficient for clinical validation.

Snapshots of titanium BINOLate complexes with diverse solid state structures.

[structure: see text]. Many important asymmetric reactions are catalyzed by (BINOLate)Ti species with unknown structures. Reported here are three structures of BINOLate titanium complexes that show an interesting aggregation of (BINOLate)Ti(OiPr)2 with itself and with titanium tetraisopropoxide. These complexes are potential intermediates in the asymmetric addition of alkyl groups to aldehydes.

Optimization of asymmetric catalysts using achiral ligands: metal geometry-induced ligand asymmetry.

[reaction: see text] Traditionally, asymmetric catalysts have been optimized by modification of resolved chiral ligands. In this Letter, we optimize the asymmetric addition of diethylzinc to aldehydes by modification of achiral methylene bis(phenol) ligands. Upon coordination of the substrate, the achiral ligand becomes asymmetric, a concept termed Metal Geometry-Induced Ligand Asymmetry. The enantioselectivity of the catalyst formed from a single resolved ligand and several achiral ligands ranged from 9% (R) to 83% (S).

Toward the total synthesis of variecolin.

[reaction: see text] An annulative approach toward the total synthesis of the sesterterpenoid variecolin (1) is presented. Synthesis of the key hemiketal, containing the core ABC ring skeleton, has been achieved on a model system by an expeditious route utilizing samarium(II) iodide. Furthermore, enantioselective syntheses of component fragments for the total synthesis have been developed.

Low-energy pathway for pauson-khand reactions: synthesis and reactivity of dicobalt hexacarbonyl complexes of chiral ynamines

A family of dicobalt hexacarbonyl complexes of 1-(dialkylamino)-2-(trimethysilyl)acetylenes (3a-f) derived both from achiral and chiral amines [a, morpholine; b, (S)-2-methoxymethylpyrrolidine; c, (2R,5R)-2, 5-bis(methoxymethyl)pyrrolidine; d, (+/-)-trans-2, 5-bis(benzyloxymethyl)pyrrolidine; e, (2R,5R)-2, 5-dimethylpyrrolidine; f, (S)-(alpha-methylbenzyl)benzylamine] has been prepared by a one-stage process from dichloroacetylene. The methanolysis at room temperature of these complexes (MeOH/K(2)CO(3)) induces the selective cleavage of the carbon-silicon bond, leading to the thermally unstable terminal ynamine complexes 12a-f. The Pauson-Khand reaction of 12a-f with strained olefins (norbornadiene and norbornene) takes place at unprecedentedly low temperatures (-35 degrees C) in the absence of chemical promoters. Diastereoselectivities of up to 94:6 are recorded in these reactions with the ynamine complexes derived from C(2) symmetrical chiral auxiliaries (12c,d). The high reactivity depicted by terminal ynamines in the Pauson-Khand reaction has been analyzed by theoretical semiempirical procedures [PM3(tm)] and with density functional theory (VWN/B88), and appears to reflect an easy CO loss from the ynamine-dicobalt hexacarbonyl complexes.

[Resection of hepatocarcinomas in liver cirrhosis: the value of intraoperative echography]. / Resección de hepatocarcinomas en hígado cirrótico: valor de la ecografía intraoperatoria.

In the last 3 years 21 cirrhotic patients with hepatocellular carcinoma were operated. All patients fulfilled the criteria of localized tumor and good liver function and underwent a laparotomy with the aim of resecting the tumor. Intraoperative ultrasound examination was essential to localize a non visible and non palpable tumor in 2 cases and it was useful to detect other nodules in 3 of the 16 patients who underwent a hepatic resection of the tumor. In 5 patients resection was considered not indicated. Therefore, the initial therapeutic approach of tumoral resection was changed in 23.8% of patients. Also, intraoperative ultrasonography was essential for performing a guided resection of hepatocellular carcinomas in cirrhotic liver with the aim of preserving as much liver parenchyma as possible.

[Cerebrovascular accident as the form of presentation of a pancreatic cystadenocarcinoma: an unusual form of presentation in a rare tumor]. / Accidente cerebrovascular como forma de presentación de un cistoadenocarcinoma de páncreas: una forma de presentación inusual en un tumor infrecuente.

Pancreatic cystadenocarcinoma is an uncommon neoplasm of the pancreas. Mucinous cystadenocarcinoma is the most frequent pancreatic cystadenocarcinoma. Symptoms are often non-specific but abdominal pain and jaundice are common in tumors localized in the head of the pancreas. Thromboembolic manifestations of pancreatic neoplasm have been described but are infrequent. The commonest manifestations are migratory thrombophlebitis, mesenteric venous thrombosis and pulmonary embolism. Cerebral stroke as the first manifestation of pancreatic carcinoma is exceptional. The mechanism by which pancreatic carcinoma induces stroke is unclear, although Trousseau's syndrome, complications of mucinous cancer or blood disorders could play a role. We report the case of a young woman with transient stroke and paraneoplastic thrombocytosis in whom pancreatic cystadenocarcinoma was diagnosed.