Multigene germline testing usefulness instead of BRCA1/2 single screening in triple negative breast cancer cases.

Triple negative breast cancer is considered as the worst aggressive subtype with poor prognosis. Recent studies suggest a hereditary component is involved in TNBC development, especially in young patients. However, genetic spectrum remains unclear. Our purpose was to evaluate the usefulness of multigene panel testing in triple negative patients compared to overall breast cancer cases as well as contributing to elucidate which genes are most implicated in triple negative subtype development. Two breast cancer cohorts, comprising 100 triple negative breast cancer patients and 100 patients with other breast cancer subtypes, were analyzed by Next-Generation Sequencing using an On-Demand panel which included 35 predisposition cancer genes associated with inherited cancer susceptibility. The percentage of germline pathogenic variant carriers was higher in the triple negative cohort. ATM, PALB2, BRIP1 and TP53 were the most non-BRCA mutated genes. Moreover, triple negative breast cancer patients without family history related who were identified as carriers were diagnosed at significantly earlier age. As conclusion, our study reinforces the usefulness of multigene panel testing in breast cancer cases but specifically in those with triple negative subtype regardless family history.

SEOM clinical guideline on hereditary colorectal cancer (2019).

In the last 2 decades, clinical genetics on hereditary colorectal syndromes has shifted from just a molecular characterization of the different syndromes to the estimation of the individual risk of cancer and appropriate risk reduction strategies. In the last years, new specific therapies for some subgroups of patients have emerged as very effective alternatives. At the same time, germline multigene panel testing by next-generation sequencing (NGS) technology has become the new gold standard for molecular genetics.

Characterization of Fusarium solani Populations Associated with Spanish Strawberry Crops.

Fusarium solani is an emerging pathogen reported on Spanish strawberry crops both in nurseries and in fruit production fields, causing wilt and root rot. Pathogenicity, morphocultural characteristics, and sensitivity to biocides of 103 F. solani isolates recovered from symptomatic strawberry plants and soils from both Spanish strawberry areas were determined. The differences of isolates within and between nurseries and field crops in relation to these parameters were analyzed. Considerable variability in morphological and pathogenic characteristics was observed among the isolates in both areas. The majority of isolates were not pathogenic (62%), and only 38 F. solani isolates (37.62%) caused disease on strawberry plants under controlled conditions; 52.63% of pathogenic isolates induced low severity symptoms. Almost 70% of pathogenic isolates caused stunting on plants. The morphological characters that best explain the F. solani variability (86.85%) were colony color and the presence of macroconidia on culture medium. The sensitivity to the fumigants tested was similar between the isolates from nurseries and fruit production fields, showing greater sensitivity to the field doses of dazomet and chloropicrin. However, the isolates were less sensitive to metam sodium and poorly sensitive to 1,3-dichloropropene. This work can contribute to the advancement of sustainable production of strawberry.

SEOM clinical guidelines in Hereditary Breast and ovarian cancer.

Approximately, 7 % of all breast cancers (BC) and 11-15 % of ovarian cancers (OC) are associated with inherited predisposition, mainly related to germline mutations in high penetrance BRCA1/2 genes. Clinical criteria for genetic testing are based on personal and family history to estimate a minimum 10 % detection rate. Selection criteria are evolving according to new advances in this field and the clinical utility of genetic testing. Multiplex panel testing carries its own challenges and we recommend inclusion of genes with clinical utility. We recommend screening with annual mammography from age 30 and breast MRI from age 25 for BRCA1 and BRCA2 mutation carriers. Bilateral salpingo-oophorectomy should be offered to women with a BRCA1 or BRCA2 mutation, between 35 and 40 years and after completion of childbearing, or individualise based on the earliest age of ovarian cancer diagnosed in the family. Bilateral risk-reducing mastectomy is an option for healthy BRCA1 and BRCA2 mutation carriers, as well as contralateral mastectomy for young patients with a prior BC diagnosis. BRCA genetic testing in patients with BC and OC may influence their locoregional and systemic treatment.

SEOM clinical guidelines in Hereditary Breast and ovarian cancer

Approximately, 7 % of all breast cancers (BC) and 11-15 % of ovarian cancers (OC) are associated with inherited predisposition, mainly related to germline mutations in high penetrance BRCA1/2 genes. Clinical criteria for genetic testing are based on personal and family history to estimate a minimum 10 % detection rate. Selection criteria are evolving according to new advances in this field and the clinical utility of genetic testing. Multiplex panel testing carries its own challenges and we recommend inclusion of genes with clinical utility. We recommend screening with annual mammography from age 30 and breast MRI from age 25 for BRCA1 and BRCA2 mutation carriers. Bilateral salpingo-oophorectomy should be offered to women with a BRCA1 or BRCA2 mutation, between 35 and 40 years and after completion of childbearing, or individualise based on the earliest age of ovarian cancer diagnosed in the family. Bilateral risk-reducing mastectomy is an option for healthy BRCA1 and BRCA2 mutation carriers, as well as contralateral mastectomy for young patients with a prior BC diagnosis. BRCA genetic testing in patients with BC and OC may influence their locoregional and systemic treatment

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Association of BRCA1 germline mutations in young onset triple-negative breast cancer (TNBC)

BACKGROUND: BRCA1-associated breast cancers have been associated to a triple-negative phenotype. The prevalence of BRCA1 germline mutations in young onset TNBC based on informativeness of family history has not been reported. PATIENTS AND METHODS: From January 2008 to May 2009 were collected blood and tumor samples from patients with TNBC younger than 50 years and without a family history of breast and ovarian cancer in first- and second-degree relatives. Analysis of BRCA1 germline mutations was made. Age at diagnosis and informativeness of family history (presence of female in first- and second-degree relatives alive until age 45) was collected in all cases. Immunohistochemistry of basal-like features was performed centrally in all available tumors. RESULTS: Seven pathogenic mutations were detected in 92 patients (7.6 %), two of them in patients younger than 35 years (28.6 %) (Fisher's exact test, p = 0.631). Three non-classified variants were detected (3.2 %). Family history was informative in two patients with a pathogenic mutation (28.6 %) and not informative in five (71.4 %) (Fisher's exact test, p = 0.121). Of the seven patients with a pathogenic mutation, four had a basal-like phenotype. CONCLUSION: Patients with apparently sporadic TNBC younger than 50 years and a non-informative family history are candidates for germline genetic testing of BRCA1 (AU)

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Association of BRCA1 germline mutations in young onset triple-negative breast cancer (TNBC).

BACKGROUND: BRCA1-associated breast cancers have been associated to a triple-negative phenotype. The prevalence of BRCA1 germline mutations in young onset TNBC based on informativeness of family history has not been reported. PATIENTS AND METHODS: From January 2008 to May 2009 were collected blood and tumor samples from patients with TNBC younger than 50 years and without a family history of breast and ovarian cancer in first- and second-degree relatives. Analysis of BRCA1 germline mutations was made. Age at diagnosis and informativeness of family history (presence of female in first- and second-degree relatives alive until age 45) was collected in all cases. Immunohistochemistry of basal-like features was performed centrally in all available tumors. RESULTS: Seven pathogenic mutations were detected in 92 patients (7.6 %), two of them in patients younger than 35 years (28.6 %) (Fisher's exact test, p = 0.631). Three non-classified variants were detected (3.2 %). Family history was informative in two patients with a pathogenic mutation (28.6 %) and not informative in five (71.4 %) (Fisher's exact test, p = 0.121). Of the seven patients with a pathogenic mutation, four had a basal-like phenotype. CONCLUSION: Patients with apparently sporadic TNBC younger than 50 years and a non-informative family history are candidates for germline genetic testing of BRCA1.

Asymmetric transfer hydrogenation of ketones catalyzed by enantiopure osmium(II) pybox complexes.

The complexes trans-[OsCl2(L){(S,S)-(i)Pr-pybox}] ((S,S)-(i)Pr-pybox = 2,6-bis[4'-(S)-isopropyloxazolin-2'-yl]pyridine, L = P(OMe)3 (1a), P(OEt)3 (2a), P(O(i)Pr)3 (3a), P(OPh)3 (4a), and cis-[OsCl2(L){(S,S)-(i)Pr-pybox}] (L = PPh3 (5a), P(i)Pr3 (6a), and PCy3 (7a)) have been synthesized from the complex trans-[OsCl2(η(2)-C2H4){(S,S)-(i)Pr-pybox}] via substitution of ethylene by phosphites and phosphines, respectively, under toluene reflux conditions. On the other hand, the synthesis of the complexes trans-[OsCl2(L){(R,R)-Ph-pybox}] (L = P(OMe)3 (1b) and cis-[OsCl2(L){(R,R)-Ph-pybox}] (L = PPh3 (5b), P(i)Pr3 (6b), and PCy3 (7b)) has been achieved from the complex trans-[OsCl2(η(2)-C2H4){(R,R)-Ph-pybox}] ((R,R)-Ph-pybox = 2,6-bis[4'-(R)-phenyloxazolin-2'-yl]pyridine under microwave irradiation. Complexes 1a-6a, 1b, 5b, and 6b have been assayed as catalysts for the asymmetric transfer hydrogenation (ATH) of ketones. Among the catalysts tested, the (i)Pr-pybox complexes trans-[OsCl2(L){(S,S)-(i)Pr-pybox}] (L = P(OMe)3 (1a), P(OEt)3 (2a), P(O(i)Pr)3 (3a), P(OPh)3 (4a)) have proven to be the most active catalysts for the reduction of a variety of aromatic ketones as nearly complete conversion and high enantioselectivity (up to 94%) are reached.

1,3-Dipolar cycloadditions of ruthenium(II) azido complexes with alkynes and nitriles.

The diazido complex [Na][Ru(N3)2{κ(3)(N,N,N)-Tpms}(PPh3)] (1) (Tpms = tris(pyrazolyl)methanesulfonate) has been synthesized, and its reactivity toward dipolarophiles has been investigated. Thus, the reaction of 1 with alkynes leads to complexes with one or two triazolate ligands depending on the alkyne and the reaction conditions. Complex 1 also reacts with nitriles. Thus, the reaction with RCN (R = Me, Ph) leads to the substitution products [Ru(N3)(NCR){κ(3)(N,N,N)-Tpms}(PPh3)]. However, when fumaronitrile is used, a complex containing a new κ(2)(N(1),N(3))-5-(1,2,3-triazol-4-yl)-1,2,3,4-tetrazolate ligand is obtained as the result of two consecutive cycloaddition reactions. The mechanism for this unusual reaction has been unambiguously established through the isolation of the intermediate complex resulting from a first cycloaddition between a coordinated azide and the C═C double bond.

Incidence of -93 MLH1 promoter polymorphism in familial and sporadic colorectal cancer.

AIM: The MLH1 promoter contains a common single nucleotide polymorphism (-93 guanine > adenine) located in an essential region for maximum transcriptional activity. This has been associated with an increased risk of microsatellite instability (MSI) colorectal cancer. The aim of the study was to compare the distribution of MLH1 -93G>A genotypes between patients with familial colon cancer, sporadic colon cancer and healthy subjects. METHOD: We genotyped 200 familial colon samples, 183 cases of sporadic colon cancer and 236 control subjects. MSI was analysed. RESULTS: The GA genotype was under-represented in patients with familial colon cancer, whereas the AA genotype was over-represented in cases of sporadic colon cancer. A greater frequency of the MLH1 GA genotype was found in the cancer cases with MLH1 focal immunohistochemistry (IHC) for anti-MLH1 antibody. When we compared genotype distribution in the familial colorectal cancer cases with and without MSI, we failed to detect any correlation, although the GA genotype is more frequent in cases with MSI. CONCLUSION: There is a relationship between the MLH1 -93G>A polymorphism in the homozygous state and the risk of sporadic colorectal cancer. The variant MLH1 -93G>A appears to be related to cases with focal IHC activity more than to complete absence of the MLH1 protein in the tumour tissue.

Long-term evaluation of phrenic nerve pacing for respiratory failure due to high cervical spinal cord injury.

OBJECTIVES: Phrenic nerve pacing is a method of respiratory support that can replace mechanical ventilation in high-level cervical spinal cord injury patients with diaphragmatic paralysis. Our objective was to evaluate survival and long-term quality of life in patients with external respiratory support by PNP vs volumetric respirator in patients with severe respiratory insufficiency due to a high-level spinal cord injury. DESIGN: This is a retrospective review study of a prospectively collected database for evaluate the survival and a questionnaire for quality of life has been collected face-to-face or by telephone at present. PATIENTS: Cervical SCI patients with permanent respiratory support (PNP or MV). METHODS: Long-term evaluation of a cohort of PNP-supported patients. We performed a comparison between these patients and volumetric respirator-supported patients. For survival analysis, we used the Kaplan-Meier method and Cox proportional hazards model. The health-related quality of life was assessed with SF-36 questionnaire, a general HRQL evaluation. RESULTS: One hundred twenty six patients on permanent respiratory support were evaluated during the study period. Of these, 38 were on PNP and 88 were mechanically ventilated. Paced patients were younger and had a longer survival, but in a multivariate analysis adjusted for age using a multiple logistic correlation we found that length of survival was greater for PNP patients. In terms of HRQL, the PNP-supported patients showed better results in terms of social functioning. CONCLUSIONS: PNP is a stable and effective method of long-term respiratory support in this type of patients (SCI patients dependent on external respiratory support). In these patients it improves the length of survival and some social issues by quality of life when compared with patients under MV.

Lynch syndrome diagnostics: decision-making process for germ-line testing.

Cancer risks and medical management of Lynch syndrome (LS) differ from other hereditary or familial clustering of colorectal cancer. Differential diagnosis has improved as a result of the growing clinical and molecular knowledge about LS. Appropriate application of these advances in several scenarios constitutes a decision-making process to further decide germ-line testing with accuracy and efficiency. However, an only molecular-screening algorithm, with a limited number of steps and choices, may be difficult to devise. How, when, where and at what expense to use the different diagnostic tools remain dynamic and changeable under different circumstances. From a clinical point of view, it is advisable to discuss conflicting aspects to guide LS diagnosis.

Lynch syndrome diagnostics: decision-making process for germ-line testing

Cancer risks and medical management of Lynch syndrome (LS) differ from other hereditary or familial clustering of colorectal cancer. Differential diagnosis has improved as a result of the growing clinical and molecular knowledge about LS. Appropriate application of these advances in several scenarios constitutes a decision-making process to further decide germ-line testing with accuracy and efficiency. However, an only molecular-screening algorithm, with a limited number of steps and choices, may be difficult to devise. How, when, where and at what expense to use the different diagnostic tools remain dynamic and changeable under different circumstances. From a clinical point of view, it is advisable to discuss conflicting aspects to guide LS diagnosis (AU)

SEOM clinical guidelines for hereditary cancer

Research in genetics has facilitated the identification of highly penetrant genes responsible for a large number of diseases. In the oncology field, genetic counselling and gene testing are focused on the two most common syndromes in familial cancer: hereditary breast and ovarian cancer syndrome (HBOC) and hereditary non-polyposis colorectal cancer or Lynch syndrome (LS). The objective of this guideline in hereditary cancer is to summarise the current state of knowledge and make recommendations in the areas of diagnosis, prevention and treatment of hereditary cancer (AU)

Leucoencefalopatía posterior reversible en un paciente con lesión medular / Reversible posterior leucoencephalopathy in a patient with spinal cord injury

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BRCA1 5272-1G>A and BRCA2 5374delTATG are founder mutations of high relevance for genetic counselling in breast/ovarian cancer families of Spanish origin.

The distribution of BRCA1 and BRCA2 germ line mutations in breast/ovarian cancer families varies among different populations, which typically present a wide spectrum of unique mutations. Splicing mutation 5272-1G>A of BRCA1 and frameshift mutation 5374delTATG of BRCA2 are highly prevalent mutations in Castilla-León (Spain), accounting for 18.4% and 13.6% of BRCA1 and BRCA2 positive families, respectively. To test the presence of founder effects, 9 Spanish 5272-1G>A and 13 5374delTATG families were genotyped with polymorphic markers linked to BRCA1 or BRCA2. All the 5272-1G>A families shared a common haplotype in eight markers (1.1 Mb region) and the mutation age was estimated in 15 generations (approximately 380 years). A conserved haplotype associated to 5374delTATG was observed in four markers (0.82 Mb). The mutation occurred approximately 48 generations ago (approximately 1200 years). Each mutation likely arose from a common ancestor that could be traced to a small area of Castilla-León and expanded to other Spanish regions. They can have a significant impact on the clinical management of asymptomatic carriers as well as on the genetic screening strategy to be followed in populations with Spanish ancestries.

Mielitis transversa aguda: revisión clínica y algoritmo de actuación diagnóstica / Acute transverse myelitis: a clinical review and algorithm for diagnostic intervention

Introducción. Bajo el término de mielitis transversa aguda (MTA) se engloba un grupo heterogéneo de enfermedades, con el nexo común de producir una lesión focal inflamatoria de la médula espinal, de forma aguda. Para intentar agrupar todas las etiologías que pueden cursar con dicha afectación, se intenta hoy en día definir varios grupos de patologías con un nexo común: aquellas MTA asociadas a algún proceso causante, o al menos predisponente de la MTA, como son ciertas infecciones, procesos sistémicos y/o multifocales inmunológicos, e incluso tumorales, y aquéllas en las que no llegamos a conocer dicho desencadenante, a las que llamamos entonces MTA idiopáticas. Objetivo. Conocer las distintas clases de MTA existentes, creando un algoritmo diagnóstico que ayude a dicha clasificación de forma ordenada, simplificando el trabajo al clínico que se enfrente a una MTA, y exponiendo su diagnóstico diferencial, pronóstico y posible tratamiento. Desarrollo. Se consultan las últimas guías y trabajos publicados relacionados con la MTA, sobre todo desde el punto de vista diagnóstico y terapéutico. Conclusiones. Nuestro conocimiento de la MTA se está viendo modificado constantemente con el advenimiento de nuevas técnicas diagnósticas y teorías que intentan explicar su origen, probablemente inmunológico. Desgraciadamente, el tratamiento y, por tanto, el pronóstico no han variado en la misma proporción al conocimiento que vamos adquiriendo en las otras áreas. Sin duda, queda un camino importante por recorrer, pero el futuro próximo nos puede enseñar más sobre esta enfermedad (AU)

Introduction. Under the term of acute transverse myelitis (ATM), there are included a heterogeneous group of diseases, with the nexus common to produce an inflammatory focal injury of the spinal cord, of acute form. In order to try to group all the etiologies that can provoke this affectation, it is nowadays tried to define several groups of pathologies with a common nexus: those ATM associated to some process, or at least predisposed of the ATM, like are certain infections, immunological systemic and/or multifocal processes, and inclusive tumors, but when we did not get to know this triggering factor, then calling them idiopathic ATM. Aim. To know the different classes from existing ATM, creating an algorithm diagnosis that helps to this classification of ordinate form, simplifying the work to the clinicians that faces a ATM, exposing its differential diagnosis, prognosis and possible treatment. Development. For it we consulted the last guides and works published related to the ATM, mainly from the diagnostic and therapeutic point of view. Conclusions. Our knowledge of the ATM is being constantly modified with the coming of new diagnostic techniques and theories that try to explain their origin, probably immunological. Unfortunately, the treatment, and therefore the prognosis, has not varied in the same proportion to the knowledge that we are acquiring in the other areas. Without a doubt, it is a way important to walk, but the next future can teach to us more on this disease (AU)

[Acute transverse myelitis: a clinical review and algorithm for diagnostic intervention]. / Mielitis transversa aguda: revisión clínica y algoritmo de actuación diagnóstica.

INTRODUCTION: Under the term of acute transverse myelitis (ATM), there are included a heterogeneous group of diseases, with the nexus common to produce an inflammatory focal injury of the spinal cord, of acute form. In order to try to group all the etiologies that can provoke this affectation, it is nowadays tried to define several groups of pathologies with a common nexus: those ATM associated to some process, or at least predisposed of the ATM, like are certain infections, immunological systemic and/or multifocal processes, and inclusive tumors, but when we did not get to know this triggering factor, then calling them idiopathic ATM. AIM: To know the different classes from existing ATM, creating an algorithm diagnosis that helps to this classification of ordinate form, simplifying the work to the clinicians that faces a ATM, exposing its differential diagnosis, prognosis and possible treatment. DEVELOPMENT: For it we consulted the last guides and works published related to the ATM, mainly from the diagnostic and therapeutic point of view. CONCLUSIONS: Our knowledge of the ATM is being constantly modified with the coming of new diagnostic techniques and theories that try to explain their origin, probably immunological. Unfortunately, the treatment, and therefore the prognosis, has not varied in the same proportion to the knowledge that we are acquiring in the other areas. Without a doubt, it is a way important to walk, but the next future can teach to us more on this disease.