Targeting oncogenic ALK: a promising strategy for cancer treatment

Recently, the anaplastic lymphoma kinase (ALK) has been found to be altered in several solid and hematologic tumors. Novel drugs targeting this tyrosine kinase receptor are under development, and early clinical trials are showing promising activity in non-small cell lung cancer patients with ALK+ tumors. Here, we review the structure and function of the ALK receptor, the mechanisms associated with its deregulation in cancer, methods for ALK detection in tumor samples, its potential as a new marker for candidate patient selection for tailored therapy, and novel drugs under development that target ALK.     

Embryonal sarcoma of the liver

Purpose

Embryonal sarcoma accounts for 6 % of liver tumors. This study reviews its features and the results of treatment in a referral center.

Methods

We retrospectively reviewed liver tumors treated between 1995 and 2011. PRETEXT staging and biopsy were used to tailor chemotherapy according to SIOP protocols. Radical surgery was performed when possible. Complications and cumulative survival were the outcome endpoints.

Results

Six out of 156 primary liver tumors (four males and two females) were sarcomas. The mean age at diagnosis was 81 ± 8.5 months. The most frequent finding was abdominal mass. Alfa-fetoprotein was normal. Imaging depicted heterogeneous tumors with septa, necrosis, and hemorrhagic areas. The diagnosis was ascertained by biopsy. Three tumors were located in the right lobe (PRETEXT II): two were bilobar (PRETEXT III) and one was in the left lobe (PRETEXT I). Two children had metastases at diagnosis and high-risk chemotherapy (vincristine, carboplatin, epirubicin) was administered with poor response. They died without operation 4 and 10 months later. Four patients with local disease underwent typical liver resections after chemotherapy (iphosphamide, vincristine, actinomycin D, and doxorrubicin). Overall actuarial survival at 70 months was 66.6 %.

Conclusions

Extended and metastatic embryonal sarcoma do poorly whereas localized tumors amenable to complete surgical removal after chemotherapy can cure.     

Endoscopic and anesthetic feasibility of EUS and ERCP combined in a single session versus two different sessions

AIM:To discuss the feasibility of single session endoscopic ultrasonography(EUS) to discuss and endoscopic retrograde cholangiopancreatography(ERCP) execution.METHODS:Retrospective endoscopic and anesthetic outcome comparison of performing both EUS and ERCP in a single endoscopic session(Group Ⅰ) versus performing each procedure in two different sessions(Group Ⅱ) was made.The following variables were evaluated:epidemiological variables,American Society of Anesthesiologists Physical Status Classification(ASA) level,procedural time,propofol dose,anesthetic complications,endoscopic complications and diagnostic yield,and therapeutic procedures on both groups.T-student,ChiSquare and Fisher test were used for comparison.RESULTS:We included 39 patients in Group Ⅰ(mean age:69.85 ± 9.25;27 men) and 46 in Group Ⅱ(mean age:67.46 ± 12.57;25 men).Procedural time did not differ significantly between both groups(Group Ⅰvs Group Ⅱ:93 ± 32.78 vs 98.98 ± 38.17;P >0.05) but the dose of propofol differed(Group Ⅰ vs Group Ⅱ:322.28 ± 250.54 mg vs 516.96 ± 289.06 mg;P = 0.001).Three patients had normal findings on both explorations.Three anesthetic complications [O2 desaturation(2),broncoaspiration(1)] and 9 endoscopic complications [pancreatitis(6),bleeding(1),perforation(1),cholangitis(1)] occurred without significant differences between both groups(P > 0.05).We did not find any significant difference regarding age,sex,ASA scale level,diagnostic yield or therapeutic maneuvers between both groups.CONCLUSION:The performance of EUS and ERCP in a single session offers a similar diagnostic and therapeutic yield,does not entail a higher complication risk and requires a significantly smaller dose of propofol for sedation compared with performing each exploration in a different session.     

Early-Onset Colorectal Cancer is an Easy and Effective Tool to Identify Retrospectively Lynch Syndrome

Background and Objectives

Early age of onset is a marker of a possible hereditary component in colorectal cancer (CRC). We evaluated whether early age of onset is a good marker to identify Lynch syndrome, especially retrospectively, and if there is any other feature that could improve this identification.

Methods

We selected patients with CRC aged 45 years or younger from the pathological reports of three different institutions and different periods of time. Clinical information, family history, and tumor samples were obtained. Cases were classified according to mismatch repair (MMR) proficiency.

Results

Of 133 tumors, 22 showed microsatellite instability (MSI). In 15 MSI cases, a germline mutation in 1 of the MMR genes was identified, 7 of which were not identified before. The positive predictive value (PPV) of right colon CRC for a positive genetic MMR test is 30.6%, whereas “signet ring” cells and fulfillment Amsterdam II criteria have PPVs of 42.9% and 47.8%, respectively. Combining right-sided CRC with mucin production, with fulfilling Amsterdam II criteria, or with “signet ring” cells, PPVs are 54.5, 64.3, and 100%. The probability of the absence of a mutation when CRC is located in the left colon is 94.7%, whereas absence of aggregation for Lynch-related neoplasm has a 100% probability.

Conclusions

Early age of onset is an effective method to identify retrospectively Lynch syndrome. Taking into account the location and histology features of the tumor, and the familial history of the cases, we notably increase the a priori probability of detecting a germline MMR mutation.     

Dopamine agonist cabergoline reduces hemoconcentration and ascites in hyperstimulated women undergoing assisted reproduction

CONTEXT: Ovarian hyperstimulation syndrome (OHSS) results from increased vascular permeability (VP) caused by ovarian hypersecretion of vascular endothelial growth factor (VEGF), which activates its receptor-2. In animals, the dopamine receptor 2 agonist cabergoline (Cb2) inactivates VEGF receptor-2 and prevents increased VP. OBJECTIVE: Our objective was to test whether Cb2 reduces VP and prevents OHSS in humans. DESIGN: We conducted a prospective, randomized, double-blind study on oocyte donors at risk of developing OHSS (>20 follicles, >12 mm developed, and >20 oocytes retrieved). INTERVENTIONS: Cb2 0.5 mg/d (n = 37) or a placebo (n = 32) was administered from the day of human chorionic gonadotropin (d 0) until d 8. Ascites (a pocket of peritoneal fluid > 9 cm(2) in lithotomy position), hemoconcentration, and serum prolactin were recorded. Pharmacokinetic studies with magnetic resonance employing the transfer constant rate (K(trans), measure of permeability) and the extravascular extracellular space (upsilon(e), marker of cellular leakage) were performed to measure VP objectively. RESULTS: Hematocrit (P < 0.01), hemoglobin (P = 0.003), and ascites (P = 0.005) were significantly lower on d 4 and 6 after treatment with Cb2 as compared with placebo. The incidence of moderate OHSS was 20.0 and 43.8%, respectively (P = 0.04). Magnetic resonance studies showed an increase in VP and extravascular leakage of fluid 5 d after human chorionic gonadotropin injection that was significantly prevented with Cb2 (K(trans) P = 0.04 and upsilon(e) P = 0.001, respectively). CONCLUSIONS: Given that Cb2 is a well-established and safe medication, this study provides proof of concept for the use of dopamine agonists in the prevention of OHSS in women undergoing assisted reproduction.     

Histochemical identification of sialylated glycans in Xenopus laevis testis

Carbohydrate chains of glycoprotein and glycosphingolipids are highly diverse molecules involved in many cell functions, including cell recognition, adhesion and signalling. Sialylated glycans are of special interest because the terminal position of sialic acid (NeuAc) in glycans linked by different ways to subterminal monosaccharides has been shown to be involved in several biological processes, as occurs with gangliosides, which have been reported as being essential in spermatogenesis in mammals. Some glycan-binding proteins, the lectins, which specifically recognize glycan sequences, have been extensively used to characterize tissue and cell carbohydrates by means of cytochemical techniques. The aim of the present work was to determine the presence of NeuAc by means of histochemical techniques in the testis of Xenopus laevis, an animal model widely used in cell and molecular biology research. However, considering that some NeuAc-binding lectins are capable of binding to N-acetylglucosamine (GlcNAc), other GlcNAc-binding lectins were also assayed. The results showed that NeuAc is mainly expressed in the interstitium, and only a weak labelling in the male germ cells was observed. Most NeuAc was located in O-linked oligosaccharides, but some masked NeuAc in N-glycans were identified in primary and secondary spermatogonia and spermatocytes. By contrast, GlcNAc was widely expressed in all germ cell types. Deglycosylative pre-treatments suggest that both N- and O-glycans and/or glycolipids could be responsible for this labelling. In addition, GlcNAc in O-linked oligosaccharides has been identified in spermatogonial cells. The acrosome of spermatids was always negative. Variations of glycan expression have been found in different cell types, suggesting that glycosylation is modified during spermatogenetic development.     

Communicable diseases in the immigrant population attended to in a tropical medicine unit: epidemiological aspects and public health issues

For geographical and historical reasons, Spain is receiving an increasing number of immigrants. The aim of this study was to evaluate some epidemiological aspects and the main public health issues of communicable diseases in Barcelona's immigrant population. From 2001 to 2004, a population of immigrants from tropical, subtropical regions and Eastern Europe was attended to in our centre. Each patient was offered a complete screening for tropical and common diseases. The prevalence and demographical characteristics of eight diseases with a potential risk of transmission in our setting were studied: latent and active tuberculosis, syphilis, human immunodeficiency virus (HIV), hepatitis B virus (HBV) and hepatitis C virus (HCV), Chagas disease, Giardia intestinalis and Entamoeba histolytica/Entamoeba dispar. In all, 2464 immigrants mainly from sub-Saharan Africa were seen. Among the patients who underwent the screening, 46.5% had a positive tuberculin skin test (>or=10 mm), incidence of active tuberculosis was 324.7/100,000 immigrants in the period of the study, 6.4% had a positive syphilis serology, 7.7% had a positive HBsAg, 3.1% had a positive serology for HCV and 2.8% were HIV positive, 41 patients from Latin America with risk factors for American Trypanosomiasis were screened for Chagas disease by immunofluorescence assay and 34% had a positive result; 5.4% of stools parasitological tests were positive for G. intestinalis; 4.2% for E. histolytica/E. dispar. Communicable diseases in immigrant population could lead to emerging and re-emerging infections in the European Union with important issues for public health. European countries may have to establish guidelines for screening of infectious diseases in immigrants from low-income countries.