Risk of delayed bleeding after colorectal endoscopic submucosal dissection: the Limoges Bleeding Score.

BACKGROUND: Clinically significant delayed bleeding (CSDB) is a frequent, and sometimes severe, adverse event after colorectal endoscopic submucosal dissection (ESD). We evaluated risk factors of CSDB after colorectal ESD. METHODS: We analyzed a prospective registry of 940 colorectal ESDs performed from 2013 to 2022. The incidence of bleeding was evaluated up to 30 days. Risk factors for delayed bleeding were evaluated by multivariate logistic regression. A Korean scoring model was tested, and a new risk-scoring model was developed and internally validated. RESULTS: CSDB occurred in 75 patients (8.0%). The Korean score performed poorly in our cohort, with a receiver operating characteristic (ROC) curve of 0.567. In the multivariate analysis, risk factors were age ≥75 years (odds ratio [OR] 1.63; 95%CI 0.97-2.73; 1 point), use of antithrombotics (OR 1.72; 95%CI 1.01-2.94; 1 point), rectal location (OR 1.51; 95%CI 0.92-2.48; 1 point), size >50 mm (OR 3.67; 95%CI 2.02-7.14; 3 points), and American Society of Anesthesiologists (ASA) score of III or IV (OR 2.26; 95%CI 1.32-3.92; 2 points). The model showed fair calibration and good discrimination, with an area under the ROC curve of 0.751 (95%CI 0.690-0.812). The score was used to define two groups of patients, those with low-medium risk (0 to 4 points) and high risk (5 to 8 points) for CSDB (respective bleeding rates 4.1% and 17.5%). CONCLUSION: A score based on five simple and meaningful variables was predictive of CSDB.

Sex-dependent effect of socioeconomic status on cardiovascular event risk in a population-based cohort of patients with type 2 diabetes.

BACKGROUND: Socioeconomic status (SES) factors often result in profound health inequalities among populations, and their impact may differ between sexes. The aim of this study was to estimate and compare the effect of socioeconomic status indicators on incident cardiovascular disease (CVD)-related events among males and females with type 2 diabetes (T2D). METHODS: A population-based cohort from a southern European region including 24,650 patients with T2D was followed for five years. The sex-specific associations between SES indicators and the first occurring CVD event were modeled using multivariate Fine-Gray competing risk models. Coronary Heart Disease (CHD) and stroke were considered secondary outcomes. RESULTS: Patients without a formal education had a significantly higher risk of CVD than those with a high school or university education, with adjusted hazard ratios (HRs) equal to 1.24 (95%CI: 1.09-1.41) for males and 1.50 (95%CI: 1.09-2.06) for females. Patients with <18 000€ income had also higher CVD risk than those with ≥18 000€, with HRs equal to 1.44 (95%CI: 1.29-1.59) for males and 1.42 (95%CI: 1.26-1.60) for females. Being immigrant showed a HR equal to 0.81 (95%CI: 0.66-0.99) for males and 1.13 (95%CI: 0.68-1.87) for females. Similar results were observed for stroke, but differed for CHD when income is used, which had higher effect in females. CONCLUSION: Socioeconomic inequalities in CVD outcomes are present among T2D patients, and their magnitude for educational attainment is sex-dependent, being higher in females, suggesting the need to consider them when designing tailored primary prevention and management strategies.

Does Lidocaine Shorten Seizure Duration in Electroconvulsive Therapy?

BACKGROUND: Electroconvulsive therapy (ECT) is an effective short-term treatment for schizophrenia and depression, amongst other disorders. Lidocaine is typically added to reduce pain from intravenous propofol injection. However, depending on the dose used in the ECT setting, it can shorten seizure duration. The aim of this study was to investigate the effect of lidocaine dose on seizure duration. METHODS: This retrospective, naturalistic cohort study included 169 patients treated with ECT. We examined 4714 ECT sessions with propofol or propofol plus lidocaine. Ictal quality was manually rated by visual inspection. The main outcome of this study was the relation of lidocaine with seizure duration after controlling for socio-demographic, ECT, and other anesthetic variables. RESULTS: There was a significant negative association between lidocaine usage and seizure duration. Multivariate analyses showed that seizure duration was shortened by an average of 3.21 s in sessions with lidocaine. Moreover, in this subgroup, there was a significant negative dose-dependent association between lidocaine dose and seizure length. Complementarily, a significant positive association between preictal BIS and seizure length was found in the subgroup of sessions where preictal was used. CONCLUSIONS: We provide additional evidence highlighting the importance of caution regarding lidocaine dosing due to the effect on seizure length in the ECT setting. It is advisable for clinicians to exercise caution when administering lidocaine regarding its dosing and seizure length in ECT settings. Future investigation is needed to assess causal relationships by studying certain vulnerable groups or employing other charge calculation techniques, such as the titration method.

COVID-19 infection and complications according to ABO blood group in the elderly: A population-based subcohort and meta-analysis.

BACKGROUND AND OBJECTIVES: It is reported that ABO antibodies have a role in COVID-19 infection and severity; however, ABO antibody titres vary with advanced age. The aim was to analyse the association between ABO blood group and risk of COVID-19 infection and complications in elderly patients, and to contrast this data with findings in the overall adult population. MATERIALS AND METHODS: A prospective cohort study of the Navarre (Spain) population aged ≥60 years and a meta-analysis of published studies including participants of ≥60 years were carried out. RESULTS: In the Navarre elderly population, a higher risk of COVID-19 infection was identified in the A versus non-A and O group and lower risk in O versus non-O, with no significant association between hospitalization, intensive care unit admission or mortality and any of the blood groups, results that coincide with those of the overall Navarre adult population. The meta-analyses using studies that included participants of ≥60 years demonstrated a higher risk of hospitalization and mortality in A versus non-A and a lower mortality risk with B versus non-B. Similar mortality results were found in the meta-analyses of the overall adult population. CONCLUSION: There are no relevant differences between the overall adult population and population aged ≥60 years in the risk of COVID-19 infection and severity according to ABO blood groups, suggesting that age-related changes in ABO would be of limited clinical significance.

Role of the AB0 blood group in COVID-19 infection and complications: A population-based study.

Since the beginning of the COVID-19 pandemic, the ABO blood group has been described as a possible biological marker of susceptibility for the disease. This study evaluates the role of ABO group on the risk of SARS-CoV-2 infection and related complications in a population-based cohort including 87,090 subjects from the Navarre population (Northern Spain) with no history of SARS-CoV-2 infection and with known ABO blood group, after one year of the pandemic (May 2020 - May 2021). The risk of infection, hospitalization, Intensive Care Unit (ICU) admission and death was analyzed using multivariate logistic regression, adjusting for possible confounding variables. A lower risk of infection was observed in group 0 vs non-0 groups [OR 0.94 (95 %CI 0.90-0.99)], a higher risk of infection in group A vs non-A groups [OR 1.09 (95 %CI 1.04-1.15)] and a higher risk of infection in group A vs group 0 [OR 1.08 (95CI 1.03-1.14)] (when the 4 groups are analyzed separately). No association was observed between blood groups and hospitalization, ICU admission, or death in SARS-CoV-2 infected subjects. Regarding the risk of SARS-CoV-2 infection, we observed a protective role of group O and a greater risk in the A group.

Mass Switch From Intravenous to Subcutaneous Tocilizumab in Rheumatic Diseases During the SARS-COV-2 Pandemic.

BACKGROUND: With the arrival of the SARS-CoV-2 pandemic in 2020, it was proposed to make the change from intravenous (IV) tocilizumab (TCZ) to its subcutaneous formulation, in order to avoid rheumatological patients having to go to the day hospital and guarantee enough IV TCZ for those critical patients with COVID who needed it. The aim of this study was to describe the rate and reasons for switching back to IV TCZ from subcutaneous TCZ. METHODS: We included patients from the rheumatology service that were on treatment with IV TCZ in February 2020 and were followed up until March 2021. Patients that remained on subcutaneous TCZ were compared with those who switched back to IV TCZ (switch-back group). A subgroup analysis according to rheumatic disease was performed. RESULTS: Fifty-five patients switched to subcutaneous TCZ: 28 rheumatoid arthritis, 19 giant cell arteritis, 4 polymyalgia rheumatica, 2 juvenile idiopathic arthritis, and 2 systemic sclerosis. Seventeen patients switched back to IV TCZ due to ineffectiveness (n = 8), patient preference (n = 4), adverse events (n = 4), and difficulty with the SC administration route (n = 1). In the analysis by disease, 4 of 23 patients switched back to IV TCZ in giant cell arteritis/polymyalgia rheumatica group due to ineffectiveness (n = 2), injection site reaction (n = 1), or patient preference (n = 1). In rheumatoid arthritis group, 11 of 28 patients switched back to IV TCZ: ineffectiveness (n = 5), patient preference (n = 3), headache (n = 1), injection site reaction (n = 1), and due to difficulty with the SC administration route (n = 1). CONCLUSIONS: Mass switch from IV to subcutaneous TCZ during the SARS-CoV-2 pandemic has been safe, effective, and well tolerated after 1 year of follow-up.

Prophylactic Clipping After Colorectal Endoscopic Resection Prevents Bleeding of Large, Proximal Polyps: Meta-analysis of Randomized Trials.

BACKGROUND & AIMS: The benefits of prophylactic clipping to prevent bleeding after polypectomy are unclear. We conducted an updated meta-analysis of randomized trials to assess the efficacy of clipping in preventing bleeding after polypectomy, overall and according to polyp size and location. METHODS: We searched the MEDLINE/PubMed, Embase, and Scopus databases for randomized trials that compared the effects of clipping vs not clipping to prevent bleeding after polypectomy. We performed a random-effects meta-analysis to generate pooled relative risks (RRs) with 95% CIs. Multilevel random-effects metaregression analysis was used to combine data on bleeding after polypectomy and estimate associations between rates of bleeding and polyp characteristics. RESULTS: We analyzed data from 9 trials, comprising 71897 colorectal lesions (22.5% 20 mm or larger; 49.2% with proximal location). Clipping, compared with no clipping, did not significantly reduce the overall risk of postpolypectomy bleeding (2.2% with clipping vs 3.3% with no clipping; RR, 0.69; 95% confidence interval [CI], 0.45-1.08; P = .072). Clipping significantly reduced risk of bleeding after removal of polyps that were 20 mm or larger (4.3% had bleeding after clipping vs 7.6% had bleeding with no clipping; RR, 0.51; 95% CI, 0.33-0.78; P = .020) or that were in a proximal location (3.0% had bleeding after clipping vs 6.2% had bleeding with no clipping; RR, 0.53; 95% CI, 0.35-0.81; P < .001). In multilevel metaregression analysis that adjusted for polyp size and location, prophylactic clipping was significantly associated with reduced risk of bleeding after removal of large proximal polyps (RR, 0.37; 95% CI, 0.22-0.61; P = .021) but not small proximal lesions (RR, 0.88; 95% CI, 0.48-1.62; P = .581). CONCLUSIONS: In a meta-analysis of randomized trials, we found that routine use of prophylactic clipping does not reduce risk of postpolypectomy bleeding overall. However, clipping appeared to reduce bleeding after removal of large (more than 20 mm) proximal lesions.

The Answer to "When to Clip" After Colorectal Endoscopic Mucosal Resection Based on a Cost-Effectiveness Analysis.

INTRODUCTION: Delayed bleeding (DB) is the most common major complication of endoscopic mucosal resection (EMR). Two randomized clinical trials recently demonstrated that clip closure after EMR of large nonpedunculated colorectal polyps (LNPCPs) reduces the risk of DB. We analyzed the cost-effectiveness of this prophylactic measure. METHODS: EMRs of LNCPCPs were consecutively registered in the ongoing prospective multicenter database of the Spanish EMR Group from May 2013 until July 2017. Patients were classified according to the Spanish Endoscopy Society EMR group (GSEED-RE2) DB risk score. Cost-effectiveness analysis was performed for both Spanish and US economic contexts. The average incremental cost-effectiveness ratio (ICER) thresholds were set at 54,000 € or $100,000 per quality-adjusted life year, respectively. RESULTS: We registered 2,263 EMRs in 2,130 patients. Applying their respective DB relative risk reductions after clip closure (51% and 59%), the DB rate decreased from 4.5% to 2.2% in the total cohort and from 13.7% to 5.7% in the high risk of the DB GSEED-RE2 subgroup. The ICERs for the universal clipping strategy in Spain and the United States, 469,706 € and $1,258,641, respectively, were not cost effective. By contrast, selective clipping in the high-risk of DB GSEED-RE2 subgroup was cost saving, with a negative ICER of -2,194 € in the Spanish context and cost effective with an ICER of $87,796 in the United States. DISCUSSION: Clip closure after EMR of large colorectal lesions is cost effective in patients with a high risk of bleeding. The GSEED-RE2 DB risk score may be a useful tool to identify that high-risk population.

Clip Closure After Resection of Large Colorectal Lesions With Substantial Risk of Bleeding.

BACKGROUND & AIMS: It is not clear whether closure of mucosal defects with clips after colonic endoscopic mucosal resection (EMR) prevents delayed bleeding, although it seems to have no protective effects when risk is low. We performed a randomized trial to evaluate the efficacy of complete clip closure of large (≥2 cm) nonpedunculated colorectal lesions after EMR in patients with an estimated average or high risk of delayed bleeding. METHODS: We performed a single-blind trial at 11 hospitals in Spain from May 2016 through June 2018, including 235 consecutive patients who underwent EMR for large nonpedunculated colorectal lesions with an average or high risk of delayed bleeding (based on Spanish Endoscopy Society Endoscopic Resection Group score). Participants were randomly assigned to groups that received closure of the scar with 11-mm through-the-scope clips (treated, n = 119) or no clip (control, n = 116). The primary outcome was proportion of patients in each group with delayed bleeding, defined as evident hematochezia that required medical intervention within 15 days after colonoscopy. RESULTS: In the clip group, complete closure was achieved in 68 (57%) cases, with partial closure in 33 (28%) cases and failure to close in 18 (15%) cases. Delayed bleeding occurred in 14 (12.1%) patients in the control group and in 6 (5%) patients in the clip group (absolute risk difference, reduction of 7% in the clip group; 95% confidence interval, -14.7% to 0.3%). After completion of the clip closure, there was only 1 (1.5%) case of delayed bleeding (absolute risk difference, reduction of 10.6%; 95% confidence interval, -4.3% to 17.9%). CONCLUSIONS: In a randomized trial of patients with large nonpedunculated colorectal lesions undergoing EMR, we found that clip closure of mucosal defects in patients with a risk of bleeding can be a challenge, but also reduces delayed bleeding. Prevention of delayed bleeding required complete clip closure. ClinicalTrials.gov ID: NCT02765022.

Colorectal endoscopic submucosal dissection is here to stay.

Endoscopic mucosal resection (EMR) or mucosectomy and endoscopic submucosal dissection (ESD) are both techniques that have modified the therapeutic outlook of superficial gastrointestinal tract lesions and neoplasms. EMR is used for the en-bloc excision of lesions smaller than 2-3 cm or the piecemeal resection of larger ones. In theory, ESD achieves higher rates of en-bloc resections as compared to EMR with a lower rate of recurrence; however, it shows a higher percentage of complications, particularly in inexperienced centers or in centers at the start of their learning curve.

Cohort Profile: CArdiovascular Risk in patients with DIAbetes in NAvarra (CARDIANA cohort).

PURPOSE: The CArdiovascular Risk in patients with DIAbetes in Navarra (CARDIANA cohort) cohort was established to assess the effects of sociodemographic and clinical variables on the risk of cardiovascular events in patients with type 1 (T1D) or type 2 (T2D) diabetes, with a special focus on socioeconomic factors, and to validate and develop cardiovascular risk models for these patients. PARTICIPANTS: The CARDIANA cohort included all patients with T1D and T2D diabetes registered in the Public Health Service of Navarra with prevalent disease on 1 January 2012. It consisted of 1067 patients with T1D (ages 2-88 years) and 33842 patients with T2D (ages 20-105 years), whose data were retrospectively extracted from the Health and Administrative System Databases. FINDINGS TO DATE: The follow-up period for wave 1 was from 1 January 2012 to 31 December 2016. During these 5 years, 9 patients (0.8%; 95% CI (0.4% to 1.6%)) in the T1D cohort developed a cardiovascular disease event, whereas for the T2D cohort, 2602 (7.7%; 95% CI (7.4% to 8.0%)) had an event. For the T2D cohort, physical activity was associated with a reduced risk of cardiovascular events, with adjusted estimated ORs equal to 0.84 (95% CI 0.66 to 1.07) for the partially active group and 0.71 (95% CI 0.56 to 0.91) for the active group, compared with patients in the non-active group. FUTURE PLANS: The CARDIANA cohort is currently being used to assess the effect of sociodemographic risk factors on CV risk at 5 years and to externally validate cardiovascular predictive models. A second wave is being conducted in late 2022 and early 2023, to extend the follow-up other 5 years, from 1 January 2016 to 31 December 2021. Periodic data extractions are planned every 5 years.

Relapse, cognitive reserve, and their relationship with cognition in first episode schizophrenia: a 3-year follow-up study.

Schizophrenia is frequently characterized by the presence of multiple relapses. Cognitive impairments are core features of schizophrenia. Cognitive reserve (CR) is the ability of the brain to compensate for damage caused by pathologies such as psychotic illness. As cognition is related to CR, the study of the relationship between relapse, cognition and CR may broaden our understanding of the course of the disease. We aimed to determine whether relapse was associated with cognitive impairment, controlling for the effects of CR. Ninety-nine patients with a remitted first episode of schizophrenia or schizophreniform disorder were administered a set of neuropsychological tests to assess premorbid IQ, attention, processing speed, working memory, verbal and visual memory, executive functions and social cognition. They were followed up for 3 years (n=53) or until they relapsed (n=46). Personal and familial CR was estimated from a principal component analysis of the premorbid information gathered. Linear mixed-effects models were applied to analyse the effect of time and relapse on cognitive function, with CR as covariate. Patients who relapsed and had higher personal CR showed less deterioration in attention, whereas those with higher CR (personal and familial CR) who did not relapse showed better performance in processing speed and visual memory. Taken together, CR seems to ameliorate the negative effects of relapse on attention performance and shows a positive effect on processing speed and visual memory in those patients who did not relapse. Our results add evidence for the protective effect of CR over the course of the illness.

Cardiovascular risk in patients with type 2 diabetes: A systematic review of prediction models.

AIMS: To identify all cardiovascular disease risk prediction models developed in patients with type 2 diabetes or in the general population with diabetes as a covariate updating previous studies, describing model performance and analysing both their risk of bias and their applicability METHODS: A systematic search for predictive models of cardiovascular risk was performed in PubMed. The CHARMS and PROBAST guidelines for data extraction and for the assessment of risk of bias and applicability were followed. Google Scholar citations of the selected articles were reviewed to identify studies that conducted external validations. RESULTS: The titles of 10,556 references were extracted to ultimately identify 19 studies with models developed in a population with diabetes and 46 studies in the general population. Within models developed in a population with diabetes, only six were classified as having a low risk of bias, 17 had a favourable assessment of applicability, 11 reported complete model information, and also 11 were externally validated. CONCLUSIONS: There exists an overabundance of cardiovascular risk prediction models applicable to patients with diabetes, but many have a high risk of bias due to methodological shortcomings and independent validations are scarce. We recommend following the existing guidelines to facilitate their applicability.

Impact of clinical ultrasound in patients with heart failure treated in home. / Impacto de la ecografía clínica en pacientes con insuficiencia cardíaca atendidos en hospitalización a domicilio.

BACKGROUND AND OBJECTIVE: In Spain, more than 10% of patients discharged with acute heart failure (AHF) are readmitted in the first 30 days. This study is designed to assess whether the treatment of AHF guided by clinical ultrasound (CU) in the setting of hospitalization at home (HAH) reduces the incidence of readmission and mortality compared to the standard care (SC). PATIENTS AND METHODS: A randomized, open, parallel, single-center and controlled clinical trial (RCT) was designed (NT05042752). Patients >18 years of age admitted for AHF to HAD from January 2021 to April 2021 at the Reina Sofía Hospital in Tudela were consecutively included. The patients were randomized to the UG-ultrasound group (SC and CU performed) and the CG-control group (SC). The diuretic treatment was tailored according to the findings of the SC together with the CU or according to the findings of the SC respectively. The main variables were the relative risk of readmission and mortality from AHF. RESULTS: A total of 79 patients were randomized, 39 to UG and 40 to CG. Of these, only 35 of the UG and 35 of the CG completed the intervention. The risk of readmission due to AHF was reduced by 60% in UG compared to CG (RR 0.4; 95% CI: 0.1-1) and mortality by 30% (RR 0.7; 95% CI: 0.2-2.2). Despite the relevant magnitude of the effect found, the results did not reach statistical significance due to lack of power. CONCLUSION: Our results suggest that in HAH, a CE guided strategy for AHF could reduce the risk of readmission and mortality compared to SC alone. However, studies with greater statistical power are needed to confirm these results.

KIT expression and methylation in medulloblastoma and PNET cell lines and tumors.

The stem cell factor/kit tyrosine kinase receptor pathway is related to tumor growth and progression in several cancers including Ewing sarcoma, a peripheral PNET (pPNET). Identifying additional groups of tumors that may use the pathway is important as they might be responsive to imatinib mesylate treatment. MB and central PNET (cPNET) are embryonal tumors of the CNS that share similar undifferentiated morphology with Ewing sarcomas and display aggressive clinical behavior. cPNET outcome is significantly lower than MB outcome, even for localized tumors treated with high-risk MB therapy. The elucidation of signaling pathways involved in MB and cPNET pathogenesis, and the discovery of new therapeutic targets is necessary to improve the treatment of these neoplasms. We analyzed KIT expression in 2 MB, one pPNET, one cPNET and 2 rhabdomyosarcoma (RMS) cell lines. Also, in 13 tumor samples (12 MB and one cPNET), we found KIT overexpression in the most aggressive cell lines (metastatic MB and pPNET). Hypermethylation of KIT was clear in the RMS non-expressing cell lines. Among MB tumors, we could see variable levels of KIT expression; a subset of them (25%) might be related in its growth pattern to KIT up-regulation. No methylated KIT was detected in the tumors expressing the lowest levels of KIT. Our results point to methylation as an epigenetic regulatory mechanism for KIT inhibition only in the KIT non-expressing RMS cell lines, and neither in the rest of the cell lines nor in the tumor samples.

Effect of Physical Activity on Cardiovascular Event Risk in a Population-Based Cohort of Patients with Type 2 Diabetes.

Cardiovascular disease (CVD) is the most common cause of morbidity and mortality among patients with type 2 diabetes (T2D). Physical activity (PA) is one of the few modifiable factors that can reduce this risk. The aim of this study was to estimate to what extent PA can contribute to reducing CVD risk and all-cause mortality in patients with T2D. Information from a population-based cohort including 26,587 patients with T2D from the Navarre Health System who were followed for five years was gathered from electronic clinical records. Multivariate Cox regression models were fitted to estimate the effect of PA on CVD risk and all-cause mortality, and the approach was complemented using conditional logistic regression models within a matched nested case-control design. A total of 5111 (19.2%) patients died during follow-up, which corresponds to 37.8% of the inactive group, 23.9% of the partially active group and 12.4% of the active group. CVD events occurred in 2362 (8.9%) patients, which corresponds to 11.6%, 10.1% and 7.6% of these groups. Compared with patients in the inactive group, and after matching and adjusting for confounders, the OR of having a CVD event was 0.84 (95% CI: 0.66-1.07) for the partially active group and 0.71 (95% CI: 0.56-0.91) for the active group. A slightly more pronounced gradient was obtained when focused on all-cause mortality, with ORs equal to 0.72 (95% CI: 0.61-0.85) and 0.50 (95% CI: 0.42-0.59), respectively. This study provides further evidence that physically active patients with T2D may have a reduced risk of CVD-related complications and all-cause mortality.

CD133+ cells from medulloblastoma and PNET cell lines are more resistant to cyclopamine inhibition of the sonic hedgehog signaling pathway than CD133- cells.

CD133 has recently been used as a reliable marker for brain tumor stem cells isolation. Sonic hedgehog (SHH) is implicated in medulloblastoma and central primitive neuroectodermal tumor (cPNET) formation. It has recently been suggested a role for the EWS/FLI1 fusion protein--typical of pPNET--in the upregulation of GLI1 and PTCH1 genes. Cyclopamine inhibits the SHH pathway in medulloblastoma cell lines, but its effect on cPNET and pPNET cell lines has not been well established yet. Our purpose was to study the effect of cyclopamine on medulloblastoma and PNET cell lines and to analyze whether CD133 expression might be able to modify this effect. We analyzed gene expression, cell viability, apoptosis, and tumorigenic capability before and after cyclopamine treatment in CD133 high-expressing and CD133 low-expressing cell lines. All medulloblastoma and PNET cell lines displayed an inhibitory effect on the expression of SHH pathway genes, on viability, and on tumorigenic potential after treatment. Nevertheless, CD133 expression made the cells more resistant to cyclopamine inhibition. These results open new doors to the understanding of CD133+ cancer stem cells as residual cells that might be responsible for treatment resistance.

Targeting the insulin-like growth factor pathway in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is the third leading cause of cancer-related deaths worldwide. Only 30%-40% of the patients with HCC are eligible for curative treatments, which include surgical resection as the first option, liver transplantation and percutaneous ablation. Unfortunately, there is a high frequency of tumor recurrence after surgical resection and most HCC seem resistant to conventional chemotherapy and radiotherapy. Sorafenib, a multi-tyrosine kinase inhibitor, is the only chemotherapeutic option for patients with advanced hepatocellular carcinoma. Patients treated with Sorafenib have a significant increase in overall survival of about three months. Therefore, there is an urgent need to develop alternative treatments. Due to its role in cell growth and development, the insulin-like growth factor system is commonly deregulated in many cancers. Indeed, the insulin-like growth factor (IGF) axis has recently emerged as a potential target for hepatocellular carcinoma treatment. To this aim, several inhibitors of the pathway have been developed such as monoclonal antibodies, small molecules, antisense oligonucleotides or small interfering RNAs. However recent studies suggest that, unlike most tumors, HCC development requires increased signaling through insulin growth factor II rather than insulin growth factor I. This may have great implications in the future treatment of HCC. This review summarizes the role of the IGF axis in liver carcinogenesis and the current status of the strategies designed to target the IGF-I signaling pathway for hepatocellular carcinoma treatment.