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Activation of WNT/β-catenin signaling has been associated with a non-T-cell-inflamed tumor microenvironment (TME) in several cancers. The aim of this work was to investigate the relationship between β-catenin signaling and TME inflammation in head and neck squamous cell carcinomas (HNSCCs). Membrane and nuclear β-catenin expression, PD-L1 expression, and CD8+ tumor-infiltrating lymphocyte (TIL) density were jointly evaluated by immunohistochemistry in a series of 372 HPV-negative HNSCCs. Membrane β-catenin levels decreased in carcinomas compared to the normal epithelium. Positive nuclear β-catenin was detected in 50 tumors (14.3%) and was significantly associated with a low CD8+ TIL density (168 cells/mm2 versus 293 cells/mm2 in nuclear-β-catenin-negative cases; p = 0.01) and a tendency for a lower expression of PD-L1, resulting in association with a noninflamed TME (i.e., type II, immunological ignorance). Multivariate Cox analysis further demonstrated that low infiltration by CD8+ TILs (HR = 1.6, 95% CI = 1.19–2.14, p = 0.002) and nuclear β-catenin expression (HR = 1.47, 95% CI = 1.01–2.16, p = 0.04) were both independently associated with a poorer disease-specific survival. In conclusion, tumor-intrinsic nuclear β-catenin activation is associated with a non-inflamed TME phenotype and a poorer prognosis, thereby suggesting a possible implication as an immune exclusion mechanism for a subset of HNSCC patients.

SummaryBackground In the last few decades, patient satisfaction has become a critical component of quality assessment and is being incorporated into payment for performance plans. However, assessment of satisfaction with anesthesia services is problematic and few validated satisfaction tools have been published. Assessing parent satisfaction with pediatric anesthesia services is even more challenging. Objective Our aim was to develop, implement, and start validating a set of survey questions that evaluate parental satisfaction with the pediatric anesthesia services in order to identify strengths and potential areas for improvement. Methods The Pediatric Anesthesia Parent Satisfaction (PAPS) survey contained 17 questions adapted from the American Society of Anesthesiologists Committee on Outcomes and Performance Measures. With consent of the hospital quality improvement committee, the PAPS survey was randomly administered on iPads to 250 English-speaking parents in the main operating room and procedure center postanesthesia care units prior to discharge. Statistical analyses including descriptive statistics, exploratory factor analysis, Cronbach's alpha and Raykov's rho coefficients, composite scale creation, correlations between items, composite scores, and overall satisfaction measures were used to provide evidence for a subset of validity and reliability types. Results and Conclusions The PAPS survey is a short and simple tool for evaluation of parent satisfaction with pediatric anesthesia services and provides some evidence for validity and reliability. The majority (greater than 95%) of parents reported were satisfied or very satisfied with the care provided by the pediatric anesthesia department.

Background: Congenital leptin deficiency is a recessive genetic disorder associated with severe early-onset obesity. It is caused by mutations in the leptin (LEP) gene, which encodes the protein product leptin. These mutations may cause nonsense-mediated mRNA decay, defective secretion or the phenomenon of biologically inactive leptin, but typically lead to an absence of circulating leptin, resulting in a rare type of monogenic extreme obesity with intense hyperphagia, and serious metabolic abnormalities. Methods: We present two severely obese sisters from Colombia, members of the same lineal consanguinity. Their serum leptin was measured by MicroELISA. DNA sequencing was performed on MiSeq equipment (Illumina) of a next-generation sequencing (NGS) panel involving genes related to severe obesity, including LEP. Results: Direct sequencing of the coding region of LEP gene in the sisters revealed a novel homozygous missense mutation in exon 3 [NM_002303.3], C350G&gt, T [p.C117F]. Detailed information and clinical measurements of these sisters were also collected. Their serum leptin levels were undetectable despite their markedly elevated fat mass. Conclusions: The mutation of LEP, absence of detectable leptin, and the severe obesity found in these sisters provide the first evidence of monogenic leptin deficiency reported in the continents of North and South America.

To determine the variety of chemotherapy drugs administrable for malignant pancreatic neoplasm as a result of typification with endoscopic ultrasonography-fine needle aspiration (EUS-FNA). A retrospective assessment, in one center, over a period of 1 year. Only malignant pancreatic neoplasm diagnosed by EUS-FNA was recorded. Benign (serous cystic neoplasm) and potentially malignant lesions (mucinous cystic neoplasm and intraductal papillary-mucinous neoplasm) were excluded. Medical data were recorded and Oncological Pharmacy records were studied. Ductal adenocarcinoma were detected in 17 patients (N = 17/22), 2 of them with adenocarcinoma in signet ring and 1 with mucinous adenocarcinoma. The primary therapies used were as follows: Whipple pancreaticoduodenectomy (3), biliary stent by endoscopic retrograde cholangiopancreatography (3), radiological transhepatic percutaneous stent (2), intestinal bypass (2), and a gastric stent (1). The adjuvant drugs used were gemcitabine (10), erlotinib (3), and cetuximab (1), and also radiotherapy was used (1). An unresectable squamous cell carcinoma (N = 1) of the tail was detected, and gemcitabine + vinorelbine + fluorouracil + cisplatin used. Nonfunctioning neuroendocrine tumors were seen in 3 (N = 3) cases and long-acting somatostatin analogues were used (1); the remaining 2 patients showed resectable tumors and were resected accordingly. A metastasis to the pancreatic head in a hepatocellular carcinoma was found in 1 patient (N = 1), allowing specific treatment with sorafenib. Histopathologic analysis with EUS-FNA implies a variety of different treatments. Optimal management was achieved as a result of improved diagnosis, with the advent of new molecular genetic diagnostic methods facilitating the design of specific new therapy and neoadjuvant targeting strategies.

The endometrium is one of a number of factors involved in achieving optimal outcomes after assisted reproductive treatment. Owing to its "passive" growth following adequate ovarian stimulation, it has received virtually no attention. Only when either endometrial thickness or ultrasonographic pattern seem inadequate have different strategies been assessed to try to improve it, especially in those cases where it seems difficult or impossible to make it grow. The objective of this review is to summarize the different strategies that have been investigated in patients with inadequate endometrium, to attempt to provide solid evidence of therapies that may be beneficial and to move away from empirism. A review of the existing literature was performed by searching MEDLINE, EMBASE, Cochrane library and Web of Science for publications in English related to refractory endometrium. Most current treatments are based on anecdotal cases and not on solid data, although worldwide many doctors and patients use them. In conclusion, this review found that it is not easy to provide a pragmatic, evidence-based approach to help physicians and patients confused by the available data on how to improve a poor endometrium. Honest balanced information provided to our patients is the best that we can do.

The folate availability seems to be critical for the DNA integrity since it is required for the transfer of methyl groups in the biosynthesis of thymidilate. Although the excessive incorporation of uracils to the DNA can be efficiently removed, this mechanism of reparation produces many double-strand breaks from two opposing nicks. Several chromosomal abnormalities (mainly translocations and deletions perhaps not well understood) are involved in the origin of lymphoproliferative disorders. The TT homozygosity at nucleotide 677 in the gene of methylene tetrahydrofolatereductase (MTHFR), a key enzyme in folate metabolism, was recently linked to a significant protection against colon carcinoma and acute lymphoblastic leukaemia in adults. We analysed the genotype frequencies of C677T-MTHFR in a group of 143 patients with lymphoproliferative disorders (REAL classification) and 200 controls. Overally, the frequencies of the polymorphic allele were similar (35.3% and 32.0% respectively)(P=0.6). We did not find differences between patients and controls except for myeloma/plasmacytoma group (n=26) which showed a CC genotype less than expected (19% vs 46%) (p=0.01) with a frequency ratio of 0.28 (0.10-0.77). Even among the IgG myeloma cases only one patient showed a common genotype (CC) (1/15, 7%) (P=0.003). If these preliminary data are validated with prospective studies, the 677C allele of MTHFR gene could be confirmed as an effective multiple myeloma protective factor (specially for the IgG cases).

After treatment intended to cure systemic neoplasms, a series of monitoring strategies are followed.To analyse our experience in confirming the cases of lymphatic or extraparietal relapse in areas accessible to endoscopic ultrasonography plus fine-needle aspiration (EUS-FNA) in long-term monitoring (1 year of treatment for the primary neoplasm) and define what implications have been derived with regards histopathological confirmation in relation to treatment.Retrospective analysis was made of all EUS-FNA carried out in our Endoscopy Unit during the period from 1/07/2007 to 28/02/2010 by means of searches in the Endobase (Olympus) database. Medical records of patients and drug therapy were reviewed in order to check the chemotherapy used in each case.From a total of 154 EUS-FNA carried out in our service, we have detected histopathological confirmation of malignancy in primary neoplasm treated with initial curative intention at least 1 year before. Locations were: esophageal extraparietal involvement of a squamous cell carcinoma (one patient), perirectal adenopathy of rectal adenocarcinoma (one patient), multiple lymphatic relapse of melanoma (two patients), perigastric adenopathy relapse of gastric adenocarcinoma (one patient), pancreatic head mass secondary to initial breast ductal carcinoma (one patient). In all cases, this fact has involved a directed treatment: surgery (one patient), radiotherapy (one patient), chemotherapy (four patients).Confirmation by means of EUS-FNA of late relapse in any section of the digestive tract allowed a treatment to be carried out by surgery, radiotherapy, or chemotherapy.

Background Epigenetic changes associated with promoter DNA methylation results in silencing of several tumor suppressor genes that lead to increased risk for tumor formation and for progression of the cancer. Methods Methylation specific PCR (MSP) and bisulfite sequencing were used for determination of proapoptotic gene Caspase 8 (CASP8) and the tumor suppressor gene maspin promoter methylation in four breast cancer and two non-tumorigenic breast cell lines. Involvement of histone H3 methylation in those cell lines were examined by CHIP assay. Results The CpG sites in the promoter region of CASP8 and maspin were methylated in all four breast cancer cell lines but not in two non-tumorigenic breast cell lines. Demethylation agent 5-aza-2'-deoxycytidine (5-aza-dc) selectively inhibits DNA methyltransferases, DNMT3a and DNMT3b, and restored CASP8 and maspin gene expression in breast cancer cells. 5-aza-dc also reduced histone H3k9me2 occupancy on CASP8 promoter in SKBR3cells, but not in MCF-7 cells. Combination of histone deacetylase inhibitor Trichostatin A (TSA) and 5-aza-dc significant decrease in nuclear expression of Di-methyl histone H3-Lys27 and slight increase in acetyl histone H3-Lys9 in MCF-7 cells. CASP8 mRNA and protein level in MCF-7 cells were increased by the 5-aza-dc in combination with TSA. Data from our study also demonstrated that treatment with 5-FU caused a significant increase in unmethylated CASP8 and in CASP8 mRNA in all 3 cancer lines. Conclusions CASP8 and maspin expression were reduced in breast cancer cells due to promoter methylation. Selective application of demethylating agents could offer novel therapeutic opportunities in breast cancer.

ORIGINAL ARTICLE Two Expressive Polymorphisms on the Endothelial Nitric Oxide Synthase Gene (intron4, 27 bp repeat and 2786 T/C) and the Venous Thromboembolism A.J. Gonzalez Ordonez1, J.M. Fernandez Carreira2, A. Gonzalez Franco3, L. Martin Sanchez1, M.V. Alvarez4 and E. Coto Garcia4 1Hematology Department, 2Research Unit, and 3Internal Medicine Department, Hospital S. Agustin Aviles, and 4Foundation for Nephrological Investigations and Molecular Genetic Department, Hospital Central de Asturias, Oviedo, Spain