Biliverdin Protects against Liver Ischemia Reperfusion Injury in Swine

Ischemia reperfusion injury (IRI) in organ transplantation remains a serious and unsolved problem. Organs that undergo significant damage during IRI, function less well immediately after reperfusion and tend to have more problems at later times when rejection can occur. Biliverdin has emerged as an agent that potently suppress IRI in rodent models. Since the use of biliverdin is being developed as a potential therapeutic modality for humans, we tested the efficacy for its effects on IRI of the liver in swine, an accepted and relevant pre-clinical animal model. Administration of biliverdin resulted in rapid appearance of bilirubin in the serum and significantly suppressed IRI-induced liver dysfunction as measured by multiple parameters including urea and ammonia clearance, neutrophil infiltration and tissue histopathology including hepatocyte cell death. Taken together, our findings, in a large animal model, provide strong support for the continued evaluation of biliverdin as a potential therapeutic in the clinical setting of transplantation of the liver and perhaps other organs

Microvascular blood flow improvement in hyperglycemic obese adult patients by hypocaloric diet

The present study was aimed to assess the changes in skin microvascular blood flow (SBF) in newly diagnosed hyperglycemic obese subjects, administered with hypocaloric diet. Adult patients were recruited and divided in three groups: NW group (n=54), NG (n=54) and HG (n=54) groups were constituted by normal weight, normoglycemic and hyperglycemic obese subjects, respectively. SBF was measured by laser Doppler perfusion monitoring technique and oscillations in blood flow were analyzed by spectral methods under baseline conditions, at 3 and 6 months of dietary treatment. Under resting conditions, SBF was lower in HG group than in NG and NW ones. Moreover, all subjects showed blood flow oscillations with several frequency components. In particular, hyperglycemic obese patients revealed lower spectral density in myogenic-related component than normoglycemic obese and normal weight ones. Moreover, postocclusive reactive hyperemia (PORH) was impaired in hyperglycemic obese compared to normoglycemic and normal weigh subjects. After hypocaloric diet, in hyperglycemic obese patients there was an improvement in SBF accompanied by recovery in myogenic-related oscillations and arteriolar responses during PORH. In conclusion, hyperglycemia markedly affected peripheral microvascular function; hypocaloric diet ameliorated tissue blood flow

Impact of endobiliary radiofrequency ablation on survival of patients with unresectable cholangiocarcinoma: a narrative review

Cholangiocarcinoma (CCA) is a rare cancer originating from the biliary epithelium and accounts for about 3% of all gastrointestinal malignancies. Unfortunately, the majority of patients are not eligible for surgical resection at the time of diagnosis, because of the locally advanced stage or metastatic disease. The overall survival time of unresectable CCA is generally less than 1 year, despite current chemotherapy regimens. Biliary drainage is often required as a palliative treatment for patients with unresectable CCA. Recurrent jaundice and cholangitis tend to occur because of reobstruction of the biliary stents. This not only jeopardizes the efficacy of chemotherapy, but also causes significant morbidity and mortality. Effective control of tumor growth is crucial for prolonging stent patency and consequently patient survival. Recently, endobiliary radiofrequency ablation (ERFA) has been experimented as a treatment modality to reduce tumor mass, and delay tumor growth, extending stent patency. Ablation is accomplished by means of high-frequency alternating current which is released from the active electrode of an endobiliary probe placed in a biliary stricture. It has been shown that tumor necrosis releases intracellular particles which are highly immunogenic and activate antigen-presenting cells, enhancing local immunity directed against the tumor. This immunogenic response could potentially enhance tumor suppression and be responsible for improved survival of patients with unresectable CCA who undergo ERFA. Several studies have demonstrated that ERFA is associated with an increased median survival of approximately 6 months in patients with unresectable CCA. Furthermore, recent data support the hypothesis that ERFA could ameliorate the efficacy of chemotherapy administered to patients with unresectable CCA, without increasing the risk of complications. This narrative review discusses the results of the studies published in recent years and focuses on the impact that ERFA could have on overall survival of patients with unresectable cholangiocarcinoma

A randomized phase 3 study on the optimization of the combination of bevacizumab with FOLFOX/OXXEL in the treatment of patients with metastatic colorectal cancer-OBELICS (Optimization of BEvacizumab scheduLIng within Chemotherapy Scheme).

BACKGROUND: Despite the improvements in diagnosis and treatment, colorectal cancer (CRC) is the second cause of cancer deaths in both sexes. Therefore, research in this field remains of great interest. The approval of bevacizumab, a humanized anti-vascular endothelial growth factor (VEGF) monoclonal antibody, in combination with a fluoropyrimidine-based chemotherapy in the treatment of metastatic CRC has changed the oncology practice in this disease. However, the efficacy of bevacizumab-based treatment, has thus far been rather modest. Efforts are ongoing to understand the better way to combine bevacizumab and chemotherapy, and to identify valid predictive biomarkers of benefit to avoid unnecessary and costly therapy to nonresponder patients. The BRANCH study in high-risk locally advanced rectal cancer patients showed that varying bevacizumab schedule may impact on the feasibility and efficacy of chemo-radiotherapy. METHODS/DESIGN: OBELICS is a multicentre, open-label, randomised phase 3 trial comparing in mCRC patients two treatment arms (1:1): standard concomitant administration of bevacizumab with chemotherapy (mFOLFOX/OXXEL regimen) vs experimental sequential bevacizumab given 4 days before chemotherapy, as first or second treatment line. Primary end point is the objective response rate (ORR) measured according to RECIST criteria. A sample size of 230 patients was calculated allowing reliable assessment in all plausible first-second line case-mix conditions, with a 80% statistical power and 2-sided alpha error of 0.05. Secondary endpoints are progression free-survival (PFS), overall survival (OS), toxicity and quality of life. The evaluation of the potential predictive role of several circulating biomarkers (circulating endothelial cells and progenitors, VEGF and VEGF-R SNPs, cytokines, microRNAs, free circulating DNA) as well as the value of the early [(18)F]-Fluorodeoxyglucose positron emission tomography (FDG-PET) response, are the objectives of the traslational project. DISCUSSION: Overall this study could optimize bevacizumab scheduling in combination with chemotherapy in mCRC patients. Moreover, correlative studies could improve the knowledge of the mechanisms by which bevacizumab enhance chemotherapy effect and could identify early predictors of response. EudraCT Number: 2011-004997-27 TRIAL REGISTRATION: ClinicalTrials.gove number, NCT01718873

Cetuximab continuation after first progression in metastatic colorectal cancer (CAPRI-GOIM): A randomized phase II trial of FOLFOX plus cetuximab versus FOLFOX

Background: Cetuximab plus chemotherapy is a first-line treatment option in metastatic KRAS and NRAS wild-type colorectal cancer (CRC) patients. No data are currently available on continuing anti-epidermal growth factor receptor (EGFR) therapy beyond progression. Patients and methods: We did this open-label, 1:1 randomized phase II trial at 25 hospitals in Italy to evaluate the efficacy of cetuximab plus 5-fluorouracil, folinic acid and oxaliplatin (FOLFOX) as second-line treatment of KRAS exon 2 wild-type metastatic CRC patients treated in first line with 5-fluorouracil, folinic acid and irinotecan (FOLFIRI) plus cetuximab. Patients received FOLFOX plus cetuximab (arm A) or FOLFOX (arm B). Primary end point was progressionfree survival (PFS). Tumour tissues were assessed by next-generation sequencing (NGS). This report is the final analysis. Results: Between 1 February 2010 and 28 September 2014, 153 patients were randomized (74 in arm A and 79 in arm B). Median PFS was 6.4 [95% confidence interval (CI) 4.7-8.0] versus 4.5 months (95% CI 3.3-5.7); [hazard ratio (HR), 0.81; 95% CI 0.58-1.12; P = 0.19], respectively. NGS was performed in 117/153 (76.5%) cases; 66/117 patients (34 in arm A and 32 in arm B) had KRAS, NRAS, BRAF and PIK3CA wild-type tumours. For these patients, PFS was longer in the FOLFOX plus cetuximab arm [median 6.9 (95% CI 5.5-8.2) versus 5.3 months (95% CI 3.7-6.9); HR, 0.56 (95% CI 0.33-0.94); P = 0.025]. There was a trend in better overall survival: median 23.7 [(95% CI 19.4-28.0) versus 19.8 months (95% CI 14.9-24.7); HR, 0.57 (95% CI 0.32-1.02); P = 0.056]. Conclusions: Continuing cetuximab treatment in combination with chemotherapy is of potential therapeutic efficacy in molecularly selected patients and should be validated in randomized phase III trials

Los Batanes: A trap for the Pyrenean wild goat during the Late Pleistocene (Spain)

Los Batanes cave (1025 m.a.s.l.) is a karstic system formed by pressure ducts, near the locality of Biescas in the Upper Gallego Valley (Huesca, Spain). Many fossil remains were retrieved from the cave sediments. The minimum sediment calendar age was determined to be 12.770 ± 60 BP. This date indicates that the deposit was formed before the Late Pleistocene-Early Holocene transition at the Pyrenees. Here we analyze the faunal assemblage of the site that is only conformed by remains of Pyrenean wild goat (Capra pyrenaica pyrenaica), which is a recently extinct subspecies of Iberian wild goat (C. pyrenaica). In the site, 1079 remains of Iberian wild goat have been recovered being one of the most numerous both in minimum number of individuals (MNI) and number of identified specimens (NISP) recovered until now in a natural trap in the Spanish Pyrenees. The population of Los Batanes shows a wide range of ages between juvenile and senile individuals and the MNI estimated from the number of right metatarsus is nine. The taphonomic features indicate that the cave acted as a trap for the goats which inhabited the vicinity of the cave. These goats probably stumbled and fell to the bottom of the pit and they could not get out, dying inside. Due to the origin of the accumulation numerous complete bones have been recovered. These fossil allow us to perform a biometric analysis that indicates that population of Los Batanes is in the range size of other goats from Late Pleistocene of Iberian Peninsula