CDH1 methylation analysis in invasive lobular breast carcinomas with and without gene mutation.

The proposed role of CDH1 (E-cadherin gene) methylation as a mechanism of gene inactivation in invasive lobular carcinoma (ILC) remains inconclusive. For many years, CDH1 promoter hypermethylation has been regarded as a mechanism for gene inactivation in ILC. However, this assumption has primarily relied on non-quantitative assays, which have reported CDH1 methylation frequencies ranging from 26 to 93% at CpG sites within the island region. Few studies employing quantitative methods and covering CpG island shores, regions of relatively low CpG density situated proximal to conventional promoter CpGs, have been conducted, revealing lower percentages of methylation ranging from 0 to 51%. Therefore, using the quantitative pyrosequencing method, we examined CDH1 methylation in the island region and shores in E-cadherin deficient ILC cases (15 with CDH1 mutation and 22 non-mutated), 19 cases of invasive breast carcinomas non-special type (IBC-NSTs), and five cases of usual ductal hyperplasia (UDH). Our analysis revealed CDH1 methylation frequencies ranging from 3 to 64%, with no significant increase in methylation levels in any group of ILCs (median = 12%) compared to IBC-NST (median = 15%). In addition, considering the poorly studied association between the number of tumor-infiltrating lymphocytes (TILs) and CDH1 methylation in breast cancer, we undertook a thorough analysis within our dataset. Our findings revealed a positive correlation between CDH1 methylation and the presence of TILs (r = 0.5; p-value < 0.05), shedding light on an aspect of breast cancer biology warranting further investigation. These findings challenge CDH1 methylation as a CDH1 inactivation mechanism in ILC and highlight TILs as a potential confounding factor in gene methylation.

Fístula gastrocólica como causa infrecuente de diarrea persistente en un paciente portador de gastrostomía radiológica percutánea / Gastrocolic fistula as infrequent cause of chronic diarrhea in a patient with percutaneous radiological gastrostomy

Introducción: la fístula gastrocólica supone una complicación infrecuente pero potencialmente grave de las sondas de gastrostomía. La sospecha clínica ante una diarrea de origen incierto que comienza tras el recambio de la sonda es clave para la detección y el tratamiento precoces. Caso clínico: se presenta el caso de un paciente portador de gastrostomía radiológica percutánea (PRG) que comienza con diarrea persistente tras el primer recambio de la sonda y desnutrición grave secundaria. Tras el fracaso de las medidas terapéuticas iniciales se amplían los estudios, con hallazgo de esta complicación en la imagen de TC. Se suspende el uso de esta sonda con resolución de la diarrea y evolución nutricional favorable. Discusión: este caso pone de manifiesto la importancia de incluir la fístula gastrocólica en el diagnóstico diferencial de la diarrea persistente en un paciente portador de sonda de gastrostomía.(AU)

Introduction: gastrocolic fistula is an infrequent but severe complication of percutaneous gastrostomy. Clinical suspicion in the presence of chronic diarrhea of unknown etiology manifesting after percutaneous radiological gastrostomy (PRG) tube replacement is key to early detection and treatment. Case report: we report the case of a patient with PRG that began with chronic diarrhea after tube replacement and developed severe malnutrition. Initial treatment was not effective, studies were extended with the finding of this complication in a CT image. The use of this tube was discontinued with resolution of diarrhea and a favorable nutritional outcome. Discussion: this case report shows the importance of considering gastrocolic fistula in the differential diagnosis of persistent diarrhea in a patient with a gastrostomy tube.(AU)

[Gastrocolic fistula as infrequent cause of chronic diarrhea in a patient with percutaneous radiological gastrostomy]. / Fístula gastrocólica como causa infrecuente de diarrea persistente en un paciente portador de gastrostomía radiológica percutánea.

Introduction: Introduction: gastrocolic fistula is an infrequent but severe complication of percutaneous gastrostomy. Clinical suspicion in the presence of chronic diarrhea of unknown etiology manifesting after percutaneous radiological gastrostomy (PRG) tube replacement is key to early detection and treatment. Case report: we report the case of a patient with PRG that began with chronic diarrhea after tube replacement and developed severe malnutrition. Initial treatment was not effective, studies were extended with the finding of this complication in a CT image. The use of this tube was discontinued with resolution of diarrhea and a favorable nutritional outcome. Discussion: this case report shows the importance of considering gastrocolic fistula in the differential diagnosis of persistent diarrhea in a patient with a gastrostomy tube.

Introducción: Introducción: la fístula gastrocólica supone una complicación infrecuente pero potencialmente grave de las sondas de gastrostomía. La sospecha clínica ante una diarrea de origen incierto que comienza tras el recambio de la sonda es clave para la detección y el tratamiento precoces. Caso clínico: se presenta el caso de un paciente portador de gastrostomía radiológica percutánea (PRG) que comienza con diarrea persistente tras el primer recambio de la sonda y desnutrición grave secundaria. Tras el fracaso de las medidas terapéuticas iniciales se amplían los estudios, con hallazgo de esta complicación en la imagen de TC. Se suspende el uso de esta sonda con resolución de la diarrea y evolución nutricional favorable. Discusión: este caso pone de manifiesto la importancia de incluir la fístula gastrocólica en el diagnóstico diferencial de la diarrea persistente en un paciente portador de sonda de gastrostomía.

Cannabidiol as an adjuvant treatment in adults with drug-resistant focal epilepsy.

Cannabidiol oil (CBD) has been approved as an anti-seizure medication for the treatment of uncommon types of epilepsy, occurring in children: Dravet syndrome, Lennox-Gastaut syndrome, and Tuberous Sclerosis Complex. There are few publications in relation to use the CBD in adult patients with focal drug-resistant epilepsy. The objective of this study was to evaluate the efficacy, tolerability, safety, and quality of life, of adjuvant treatment with CBD, in adult patients with drug-resistant focal epilepsy for at least 6 months. An open, observational, prospective cohort study was conducted using a before-after design (time series) in adult patients undergoing outpatient follow-up in a public hospital in Buenos Aires, Argentina. From a total of 44 patients, 5% of patients were seizure-free, 32% of patients reduced more than 80% of their seizures and 87% of patients reduced 50% of their monthly seizures. Eleven percent presented a decrease of less than 50% in seizure frequency. The average final dose was 335 mg/d orally administered. Thirty-four percent of patients reported mild adverse events and no patient reported severe adverse effects. At the end of the study, we found in most patients a significant improvement in the quality of life, in all the items evaluated. Adjuvant treatment with CBD in adult patients with drug-resistant focal epilepsy was effective, safe, well tolerated, and associated with a significant improvement in their quality of life.

Iodine status in pregnant women in northern Spain. Effect of iodised salt and iodine supplements on thyroid function.

INTRODUCTION: Iodine deficiency is linked to thyroid dysfunction, particularly in pregnant women. The objective of this study was to ascertain the iodine levels of women in the second trimester of pregnancy, analysing the influence of iodine ingestion on urinary iodine concentration (UIC) and maternal thyroid function. METHODS: A prospective observational study of pregnant women from Health Area IV of Asturias (northern Spain) recruited before 13 weeks of gestation between May and June 2017. A questionnaire on iodine intake was completed at the first visit, and urine and serum samples were collected at baseline and again during the second trimester. UIC, thyroid stimulating hormone (TSH) and free thyroxine (FT4) obtained in the second trimester of gestation were analysed and related to iodine intake. Thyroid autoimmunity was also analysed in half of the pregnant women at baseline. RESULTS: A total of 241 pregnant women were studied. Of these, 56.7% used iodised salt, 46.7% consumed ≥2 servings of dairy products daily and 88.1% took iodine supplements. Median UIC was 191µg/l (135.3-294µg/l), with 68.1% of the women having UIC ≥150µg/l. Only iodised salt consumption provided protection against iodine deficiency (odds ratio 0.35 [0.20-0.63], p=0.001). In women with no autoimmune thyroid disease (n=88), mean levels of TSH were lower in those that consumed iodised salt than in those that did not (respectively, 2.08±0.89mIU/l vs. 2.56±1.02mIU/l, p=0.025). In women with autoimmune thyroid disease (n=30), mean levels of TSH were higher in those that took iodine supplements than in those that did not (respectively, 2.97±1.25mIU/l vs. 1.16±0.41mIU/l, p=0.002). CONCLUSIONS: The pregnant women studied from Health Area IV in Asturias maintain adequate nutritional iodine status in the second trimester of gestation. In our sample, only the consumption of iodised salt was associated with adequate iodine nutrition, without affecting maternal thyroid function. Most of the women used iodine supplements, which was linked to higher levels of TSH in pregnant women with autoimmune thyroid disease.

TSH neonatal como marcador del estado de nutrición de yodo. Influencia de la yoduria y la función tiroidea maternas sobre la TSH neonatal / Neonatal TSH as a marker of iodine nutrition status. Effect of maternal ioduria and thyroid function on neonatal TSH

Introducción: La TSH neonatal (TSHn) es un marcador de nutrición de yodo en la población. La OMS relaciona una prevalencia<3% de TSHn>5mUI/L, obtenida a partir de las 72h del nacimiento, con un adecuado estado nutricional de yodo. El objetivo de este estudio es conocer la prevalencia de TSHn>5mUI/L en una población yodosuficiente y su relación con factores maternos, neonatales y obstétricos. Materiales y métodos: Se reclutaron 243 gestantes entre mayo-junio de 2017 en nuestra área sanitaria. Se realizó un cuestionario sobre consumo de yodo y determinación de yoduria, función y autoinmunidad tiroideas en el primer trimestre de gestación. Se analizó la TSHn entre 48-72h del nacimiento, así como otros factores obstétricos y neonatales. Resultados: La TSHn media fue 2,43±1,68mUI/L, con un 7,8% de neonatos con TSHn>5mUI/L. La TSHn más elevada pertenecía a los neonatos de madres con yodurias insuficientes (p=0,021) o con TSH>2,5mUI/L, tanto en autoinmunidad tiroidea negativa (p=0,049) como positiva (p=0,006). La yoduria materna<150μg/L fue un factor de riesgo de TSHn>5mUI/L (3,70 [1,06-14,60], p=0,046), mientras que el peso neonatal ≥2500g fue un factor protector (0,14 [0,02-1,00], p=0,038). Conclusiones: La prevalencia de TSHn>5mUI/L en nuestra área sanitaria fue elevada, según las recomendaciones de la OMS. Se asoció el déficit de yodo materno con mayor riesgo de TSHn>5mUI/L. Dado que en la actualidad la determinación de la TSHn se realiza antes de las 72h del nacimiento, precisamos de nuevos puntos de corte para continuar empleando la TSHn como marcador de nutrición de yodo. (AU)

Introduction: Neonatal thyroid stimulating hormone (nTSH) is a marker of iodine nutrition status in the population. The WHO considers a prevalence of less than 3% of nTSH levels greater than 5mIU/L in samples obtained within 72h from birth indicative of iodine sufficiency. The aim of this study was to determine the prevalence of nTSH levels greater than 5mIU/L in an iodine-sufficient population and its association with maternal, neonatal and obstetric factors. Materials and methods: A total of 243 pregnant women were recruited between May and June 2017 in our health area. A questionnaire of iodine intake was administered, in addition to determination of ioduria, thyroid function and autoimmunity in the first trimester of gestation. We analysed nTSH levels in samples collected between 48 and 72h post birth and other obstetric and neonatal factors. Results: The mean nTSH level (standard deviation) was 2.43 (1.68mIU/L), with 7.8% of neonates having levels greater than 5mIU/L. The highest nTSH levels corresponded to neonates of mothers with insufficient ioduria (p=.021) or TSH levels greater than 2.5mIU/L, in both the case of negative (p=0.049) and positive (p=0.006) thyroid autoimmunity results. Maternal ioduria greater than 150μg/L was a risk factor for nTSH levels greater than 5mIU/L (3.70 [1.06–14.60]; p=0.046), while a neonatal weight of 2500g or greater was a protective factor (0.14 [0.02–1.00]; p=0.038). Conclusions: The prevalence of nTSH levels greater than 5mIU/L in our health area was high based on the WHO recommendations. Maternal iodine deficiency was associated with a higher risk of nTSH levels less than 5mIU/L. Given that nTSH is currently measured before 72h post birth, we need new cut-off points to keep on using nTSH as a marker of iodine nutritional status. (AU)

Neonatal TSH as a marker of iodine nutrition status. Effect of maternal ioduria and thyroid function on neonatal TSH.

INTRODUCTION: Neonatal thyroid stimulating hormone (nTSH) is a marker of iodine nutrition status in the population. The WHO considers a prevalence of less than 3% of nTSH levels greater than 5 mIU/L in samples obtained within 72h from birth indicative of iodine sufficiency. The aim of this study was to determine the prevalence of nTSH levels greater than 5 mIU/L in an iodine-sufficient population and its association with maternal, neonatal and obstetric factors. MATERIALS AND METHODS: A total of 243 pregnant women were recruited between May and June 2017 in our health area. A questionnaire of iodine intake was administered, in addition to determination of ioduria, thyroid function and autoimmunity in the first trimester of gestation. We analysed nTSH levels in samples collected between 48 and 72h post birth and other obstetric and neonatal factors. RESULTS: The mean nTSH level (standard deviation) was 2.43 (1.68 mIU/L), with 7.8% of neonates having levels greater than 5 mIU/L. The highest nTSH levels corresponded to neonates of mothers with insufficient ioduria (P = 0.021) or TSH levels greater than 2.5 mIU/L, in both the case of negative (P = 0.049) and positive (P = 0.006) thyroid autoimmunity results. Maternal ioduria less than 150 µg/L was a risk factor for nTSH levels greater than 5 mIU/L (3.70 [1.06-14.60]; P = 0.046), while a neonatal weight of 2500 g or greater was a protective factor (0.14 [0.02-1.00]; P = 0.038). CONCLUSIONS: The prevalence of nTSH levels greater than 5 mIU/L in our health area was high based on the WHO recommendations. Maternal iodine deficiency was associated with a higher risk of nTSH levels greater than 5 mIU/L. Given that nTSH is currently measured before 72h post birth, we need new cut-off points to keep on using nTSH as a marker of iodine nutritional status.

Differences in the Molecular Profile between Primary Breast Carcinomas and Their Cutaneous Metastases.

BACKGROUND: The characterization of molecular alterations of primary breast carcinomas (BC) and their cutaneous metastases (CM) to identify genes involved in the metastatic process have not yet been completely accomplished. METHODS: To investigate the molecular alterations of BC and their CM, a total of 66 samples (33 BC and 33 CM) from 33 patients were analyzed by immunohistochemical and massive parallel sequencing analyses. In addition, the clinicopathological characteristics of patients and tumors were analyzed. RESULTS: Triple negative (TN) BCs were overrepresented (36.4%) among tumors that developed CM. A change of tumor surrogate molecular type in metastases was found in 15% of patients and 48.5% of the CM presented some additional molecular alteration with respect to the primary tumor, the most frequent were amplification of MYC and MDM4, and mutations in TP53 and PIK3CA. Survival was related to histological grade, tumor surrogate molecular type and TP53 mutations in the univariate analysis but only the tumor surrogate molecular type remained as a prognostic factor in the multivariate analysis. CONCLUSIONS: The TN molecular type has a greater risk of developing skin metastases. There are phenotypic changes and additional molecular alterations in skin metastases compared to the corresponding primary breast tumors in nearly half of the patients. Although these changes do not follow a specific pattern and varied from patient to patient, they could impact on the treatment. More studies with larger patient and sample cohorts are needed.

The Leptin Axis and Its Association With the Adaptive Immune System in Breast Cancer.

Adipose tissue secretes various peptides, including leptin. This hormone acts through the leptin receptor (Ob-R), which is expressed ubiquitously on the surface of various cells, including breast cancer cells and immune cells. Increasing evidence points to an interaction between the tumor microenvironment, tumor cells, and the immune system. Leptin plays an important role in breast cancer tumorigenesis and may be implicated in activation of the immune system. While breast cancer cannot be considered an immunogenic cancer, the triple-negative subtype is an exception. Specific immune cells - tumor infiltrating lymphocytes - are involved in the immune response and act as predictive and prognostic factors in certain breast cancer subtypes. The aim of this article is to review the interaction between adipose tissue, through the expression of leptin and its receptor, and the adaptive immune system in breast cancer.

Clinical, Pathological, and Molecular Features of Breast Carcinoma Cutaneous Metastasis.

Cutaneous metastases (CMs) account for 2% of all skin malignancies, and nearly 70% of CMs in women originate from breast cancer (BC). CMs are usually associated with poor prognosis, are difficult to treat, and can pose diagnostic problems, such as in histopathological diagnosis when occurring long after development of the primary tumor. In addition, the molecular differences between the primary tumors and their CMs, and between CMs and metastases in other organs, are not well defined. Here, we review the main clinical, pathological, and molecular characteristics of breast cancer CMs. Identifying molecular markers in primary BC that predict CM and can be used to determine the molecular differences between primary tumors and their metastases is of great interest for the design of new therapeutic approaches.

Epithelial Mesenchymal Transition and Immune Response in Metaplastic Breast Carcinoma.

Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent triple negative (TN) invasive carcinomas with poor prognosis. MBCs have a different clinical behavior from other types of triple negative breast cancer (TNBC), being more resistant to standard chemotherapy. MBCs are an example of tumors with activation of epithelial-mesenchymal transition (EMT). The mechanisms involved in EMT could be responsible for the increase in the infiltrative and metastatic capacity of MBCs and resistance to treatments. In addition, a relationship between EMT and the immune response has been seen in these tumors. In this sense, MBC differ from other TN tumors showing a lower number of tumor-infiltrating lymphocytes (TILS) and a higher percentage of tumor cells expressing programmed death-ligand 1 (PD-L1). A better understanding of the relationship between the immune system and EMT could provide new therapeutic approaches in MBC.

Nutritional Iodine Status in Pregnant Women from Health Area IV in Asturias (Spain): Iodised Salt Is Enough.

BACKGROUND: Iodine deficiency during pregnancy may have adverse effects on the neurodevelopment of the foetus. Recent studies of pregnant women in Asturias (Spain) indicate that nutritional iodine levels are sufficient. The objective of this study was to confirm the appropriate nutritional iodine status and to analyse the influence of the ingestion of iodine on maternal urinary iodine concentration (UIC) and thyroid function. METHODS: An observational study was carried out between May and June 2017 on women in the first trimester of pregnancy from Health Area IV in Asturias. The women completed a questionnaire related to their consumption of iodine and samples were taken to analyse UIC and thyroid function. RESULTS: Three hundred and eighteen pregnant women were involved. Of these, 51.10% used iodised salt, 48.90% consumed ≥ 2 servings of dairy products daily and 87.08% took iodine supplements. The median UIC was 171.5 µg/L (116-265 µg/L) and 60.41% of women had UIC ≥ 150 µg/L. Multivariate logistic regression analysis demonstrated that iodised salt had a protective effect on UIC < 150 µg/L (odds ratio (OR) 0.404 (0.237-0.683), p = 0.001), but not iodine supplements (OR 0.512 (0.240-1.085), p = 0.080). The average level of thyroid stimulating hormone (TSH) was 2.26 ± 0.94 mIU/L; 68.40% of pregnant women taking iodine supplements had TSH < 2.5 mIU/L compared to 30.00% of those who were not taking supplements (p = 0.031). CONCLUSIONS: The pregnant women in our health area are maintaining appropriate nutritional iodine levels. The consumption of iodised salt protects against iodine deficiency; thus, iodine supplements should be taken on an individualised basis.

Molecular Features of Metaplastic Breast Carcinoma: An Infrequent Subtype of Triple Negative Breast Carcinoma.

Metaplastic breast carcinoma (MBC) is a heterogeneous group of infrequent invasive carcinomas that display differentiation of the neoplastic epithelium towards squamous cells and/or mesenchymal-type elements. Most MBC have a triple negative phenotype and poor prognosis. Thus, MBC have worse survival rates than other invasive breast carcinomas, including other triple negative breast carcinomas (TNBC). In this study, we reviewed the molecular features of MBC, pointing out the differences among subtypes. The most frequently mutated genes in MBC were TP53 and PIK3CA. Additionally, mutations in the other genes of the PI3K/AKT pathway indicated its importance in the pathogenesis of MBC. Regarding copy number variations (CNVs), MYC was the most frequently amplified gene, and the most frequent gene loss affected the CDKN2A/CDKN2B locus. Furthermore, the pattern of mutations and CNVs of MBC differed from those reported in other TNBC. However, the molecular profile of MBC was not homogeneous among histological subtypes, being the alterations in the PI3K pathway most frequent in spindle cell carcinomas. Transcriptomic studies have demonstrated an epithelial to mesenchymal program activation and the enrichment of stemness genes in most MBC. In addition, current studies are attempting to define the immune microenvironment of these tumors. In conclusion, due to specific molecular features, MBC have a different clinical behavior from other types of TNBC, being more resistant to standard chemotherapy. For this reason, new therapeutic approaches based on tumor molecular characteristics are needed to treat MBC.

A comprehensive analysis of candidate genes in familial pancreatic cancer families reveals a high frequency of potentially pathogenic germline variants.

BACKGROUND: The 5-year survival rate of patients with pancreatic ductal adenocarcinoma (PDAC) is around 5% due to the fact that the majority of patients present with advanced disease that is treatment resistant. Familial pancreatic cancer (FPC) is a rare disorder that is defined as a family with at least two affected first degree relatives, with an estimated incidence of 4%-10%. The genetic basis is unknown in the majority of families although around 10%-13% of families carry germline mutations in known genes associated with hereditary cancer and pancreatitis syndromes. METHODS: Panel sequencing was performed of 35 genes associated with hereditary cancer in 43 PDAC cases from families with an apparent hereditary pancreatic cancer syndrome. FINDINGS: Pathogenic variants were identified in 19% (5/26) of PDAC cases from pure FPC families in the genes MLH1, CDKN2A, POLQ and FANCM. Low frequency potentially pathogenic VUS were also identified in 35% (9/26) of PDAC cases from FPC families in the genes FANCC, MLH1, PMS2, CFTR, APC and MUTYH. Furthermore, an important proportion of PDAC cases harboured more than one pathogenic, likely pathogenic or potentially pathogenic VUS, highlighting the multigene phenotype of FPC. INTERPRETATION: The genetic basis of familial or hereditary pancreatic cancer can be explained in 21% of families by previously described hereditary cancer genes. Low frequency variants in other DNA repair genes are also present in 35% of families which may contribute to the risk of pancreatic cancer development. FUNDING: This study was funded by the Instituto de Salud Carlos III (Plan Estatal de I + D + i 2013-2016): ISCIII (PI09/02221, PI12/01635, PI15/02101 and PI18/1034) and co-financed by the European Development Regional Fund ''A way to achieve Europe'' (ERDF), the Biomedical Research Network in Cancer: CIBERONC (CB16/12/00446), Red Temática de investigación cooperativa en cáncer: RTICC (RD12/0036/0073) and La Asociación Española contra el Cáncer: AECC (Grupos Coordinados Estables 2016).

High Frequency of ERBB2 Activating Mutations in Invasive Lobular Breast Carcinoma with Pleomorphic Features.

Background: Characterisation of molecular alterations of pleomorphic lobular carcinoma (PLC), an aggressive subtype of invasive lobular carcinoma (ILC), have not been yet completely accomplished. Methods: To investigate the molecular alterations of invasive lobular carcinoma with pleomorphic features, a total of 39 tumour samples (in situ and invasive lesions and lymph node metastases) from 27 patients with nuclear grade 3 invasive lobular carcinomas were subjected to morphological, immunohistochemical and massive parallel sequencing analyses. Results: Our observations indicated that invasive lobular carcinomas with pleomorphic features were morphologically and molecularly heterogeneous. All cases showed absence or aberrant expression of E-cadherin and abnormal expression of ß-catenin and p120. CDH1 (89%), PIK3CA (33%) and ERRB2 (26%) were the most common mutated genes. ERBB2 mutations preferentially affected the tyrosine-kinase activity domain, being the most frequent the targetable mutation p.L755S (57%). We also observed higher frequency of mutations in ARID1B, KMT2C, MAP3K1, TP53 and ARID1A in PLC than previously reported in classic ILC. Alterations related to progression from in situ to invasive carcinoma and/or to lymph node metastases included TP53 mutation, amplification of PIK3CA and CCND1 and loss of ARID1A expression. Conclusions: The high frequency of ERBB2 mutations observed suggests that ERBB2 mutation testing should be considered in all invasive lobular carcinomas with nuclear grade 3.