First-line therapy with palbociclib in patients with advanced HR+/HER2- breast cancer: The real-life study PALBOSPAIN.

PURPOSE: To evaluate the efficacy and safety of first-line therapy with palbociclib in a Spanish cohort treated after palbociclib approval. METHODS: PALBOSPAIN is an observational, retrospective, multicenter study evaluating real-world patterns and outcomes with 1 L palbociclib in men and women (any menopausal status) with advanced HR+/HER2- BC diagnosed between November 2017 and November 2019. The primary endpoint was real-world progression-free survival (rw-PFS). Secondary endpoints included overall survival (OS), the real-world response rate (rw-RR), the clinical benefit rate, palbociclib dose reduction, and safety. RESULTS: A total of 762 patients were included. The median rw-PFS and OS were 24 months (95% CI 21-27) and 42 months (40-not estimable [NE]) in the whole population, respectively. By cohort, the median rw-PFS and OS were as follows: 28 (95% CI 23-39) and 44 (95% CI 38-NE) months in patients with de novo metastatic disease, 13 (95% CI 11-17) and 36 months (95% CI 31-41) in patients who experienced relapse < 12 months after the end of ET, and 31 months (95% CI 26-37) and not reached (NR) in patients who experienced relapse > 12 months after the end of ET. rw-PFS and OS were longer in patients with oligometastasis and only one metastatic site and those with non-visceral disease. The most frequent hematologic toxicity was neutropenia (72%; grade ≥ 3: 52.5%), and the most common non-hematologic adverse event was asthenia (38%). CONCLUSION: These findings, consistent with those from clinical trials, support use of palbociclib plus ET as 1 L for advanced BC in the real-world setting, including pre-menopausal women and men. TRIAL REGISTRATION NUMBER: NCT04874025 (PALBOSPAIN). Date of registration: 04/30/2021 retrospectively registered.

Efecto del plomo y del arsénico en condiciones de laboratorio sobre la rana africana de uñas (Xenopus laevis) y la rana leopardo (Lithobates berlandieri) / Effect of lead and arsenic under laboratory conditions on African clawed frog (Xenopus laevis) and leopard frog (Lithobates berlandieri)

Actualmente, existe una creciente preocupación ya que algunas especies de anfibios han mostrado un declive en sus poblaciones por causa de diversos factores, entre ellos los metales pesados; por esta razón, es importante realizar estudios sobre esta problemática ambiental. El objetivo de este estudio fue determinar la cantidad del plomo y arsénico que se concentra en los tejidos de la rana Africana de uñas (Xenopus laevis) en etapa juvenil y de la rana Leopardo (Lithobates berlandieri) en etapa larvaria y en el agua después de 16 semanas expuestas a placas de plomo y arseniato de sodio, con la finalidad de determinar si esta acumulación de metales provoca eventualmente anomalías morfológicas en su desarrollo. Los individuos fueron puestos en contacto con placas de plomo, arseniato de sodio, agua de la red de abastecimiento de agua de consumo público (grupos experimentales) y con agua potable (grupo control). Los organismos fueron inspeccionados de manera externa para identificar anomalías macroscópicas, además de realizarles análisis morfométricos. Los análisis espectroquímicos (espectrofotometría de absorción atómica, con la técnica de horno de grafito) mostraron que hay un proceso de bioconcentración y bioacumulación de metales cuando los organismos están en contacto con estos metales y con agua de la red de abastecimiento público, la cual está contaminada también, pues se detectaron cantidades altas de metales en los tejidos de las larvas. Respecto a la morfometría hubo diferencias significativas en algunas estructuras entre el grupo control y los grupos experimentales en X. laevis. En L. berlandieri fueron detectadas anomalías macroscópicas como curvatura de la cola, problemas de pigmentación, protuberancias en el abdomen e inadecuada posición de los intestinos en aquellos individuos que estuvieron en contacto con estos metales pesados. (AU)

Currently, there is growing concern as some amphibian species have shown a decline in their populations due to various factors, including heavy metals; for this reason, it is important to carry out studies on this environmental problem. The objective of this study was to determine the amount of lead and arsenic concentrated in the tissues of the African clawed frog (Xenopus laevis) in the juvenile stage and the Leopard frog (Lithobates berlandieri) in the larval stage and in the water after 16 weeks exposed to lead plates and sodium arsenate, in order to determine if this accumulation of metals eventually causes morphological abnormalities in their development. The individuals were placed in contact with lead plates, sodium arsenate, water from the public water supply network (experimental groups) and with drinking water (control group). The organisms were externally inspected to identify macroscopic anomalies, in addition to performing morphometric analysis. The spectrochemical analyzes (atomic absorption spectrophotometry, with the graphite furnace technique) showed that there is a process of bioconcentration and bioaccumulation of metals when the organisms are in contact with these metals and with water from the public supply network, which is also contaminated, since high amounts of metals were detected in the tissues of the larvae. Regarding morphometry, there were significant differences in some structures between the control group and the experimental groups in X. laevis. In L. berlandieri, macroscopic abnormalities such as curvature of the tail, pigmentation problems, protuberances in the abdomen and inappropriate position of the intestines were detected in those individuals that were in contact with these heavy metals. (AU)

SEOM clinical guidelines in advanced and recurrent breast cancer (2018).

Although the metastasic breast cancer is still an incurable disease, recent advances have increased significantly the time to progression and the overall survival. However, too much information has been produced in the last 2 years, so a well-based guideline is a valuable document in treatment decision making. The SEOM guidelines are intended to make evidence-based recommendations on how to manage patients with advanced and recurrent breast cancer to achieve the best patient outcomes based on a rational use of the currently available therapies. To assign a level of certainty and a grade of recommendation the United States Preventive Services Task Force guidelines methodology was selected as reference.

SEOM clinical guidelines in advanced and recurrent breast cancer (2018)

Although the metastasic breast cancer is still an incurable disease, recent advances have increased significantly the time to progression and the overall survival. However, too much information has been produced in the last 2 years, so a well-based guideline is a valuable document in treatment decision making. The SEOM guidelines are intended to make evidence-based recommendations on how to manage patients with advanced and recurrent breast cancer to achieve the best patient outcomes based on a rational use of the currently available therapies. To assign a level of certainty and a grade of recommendation the United States Preventive Services Task Force guidelines methodology was selected as reference

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Parkin loss of function contributes to RTP801 elevation and neurodegeneration in Parkinson's disease.

Mutations in the PARK2 gene are associated with an autosomal recessive form of juvenile parkinsonism (AR-JP). These mutations affect parkin solubility and impair its E3 ligase activity, leading to a toxic accumulation of proteins within susceptible neurons that results in a slow but progressive neuronal degeneration and cell death. Here, we report that RTP801/REDD1, a pro-apoptotic negative regulator of survival kinases mTOR and Akt, is one of such parkin substrates. We observed that parkin knockdown elevated RTP801 in sympathetic neurons and neuronal PC12 cells, whereas ectopic parkin enhanced RTP801 poly-ubiquitination and proteasomal degradation. In parkin knockout mouse brains and in human fibroblasts from AR-JP patients with parkin mutations, RTP801 levels were elevated. Moreover, in human postmortem PD brains with mutated parkin, nigral neurons were highly positive for RTP801. Further consistent with the idea that RTP801 is a substrate for parkin, the two endogenous proteins interacted in reciprocal co-immunoprecipitates of cell lysates. A potential physiological role for parkin-mediated RTP801 degradation is indicated by observations that parkin protects neuronal cells from death caused by RTP801 overexpression by mediating its degradation, whereas parkin knockdown exacerbates such death. Similarly, parkin knockdown enhanced RTP801 induction in neuronal cells exposed to the Parkinson's disease mimetic 6-hydroxydopamine and increased sensitivity to this toxin. This response to parkin loss of function appeared to be mediated by RTP801 as it was abolished by RTP801 knockdown. Taken together these results indicate that RTP801 is a novel parkin substrate that may contribute to neurodegeneration caused by loss of parkin expression or activity.

Fused in Sarcoma (FUS) gene mutations are not a frequent cause of essential tremor in Europeans.

FUS/TLS (denoting fused in sarcoma/translocated in liposarcoma [MIM 137070]) codifies an RNA binding protein. Mutations in this gene cause amyotrophic lateral sclerosis (ALS; MIM 608030). Essential tremor (ET [MIM 190300]) is the most frequent movement disorder. Despite its strong familiar aggregation, recently a whole exome sequencing study has identified FUS mutations as a cause of familial ET. To determine whether mutations in FUS are also common in other populations, we sequenced FUS gene in 178 unrelated Spanish subjects with ET. We detected only an intronic single-pair nucleotide deletion (c.1293-37delC), which was predicted to affect mRNA splicing. However, leukocyte mRNA analysis showed no changes in FUS expression. In conclusion, coding or splicing FUS mutations are not a frequent cause of ET in the Spanish population.

SEOM clinical guidelines for the treatment of metastatic breast cancer

Patients with metastatic breast cancer have a wide number of treatment options, including medical, surgical, and supportive care measures. Treatment decisions are based in predictive and prognostic factors and the informed choice of the patients. SEOM has elaborated these guidelines with evidence-based recommendations for the diagnostic work-up, treatment (chemotherapy, endocrine therapy and targeted therapies) and supportive care for the management of these patient (AU)

Nuevos retos en la formación especializada. I. Perfil y evaluación del Jefe de Estudios. II. Plan de calidad de la docencia en los centros sanitarios. III. Evaluación del residente. Propuesta de evaluación de las rotaciones / New challenges in specialised training. I. Profile and appraisal of the Head of Studies. II. Plan for improving teaching quality in health centres. III. Evaluation of house officers. Proposal for the evaluation of rotations

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A novel mutation in the PSEN1 gene (L286P) associated with familial early-onset dementia of Alzheimer type and lobar haematomas.

The aim of this study was to describe a novel mutation in exon 8 of the presenilin gene (L286P) associated with early-onset autosomal dominant Alzheimer's disease (AD) and lobar haematomas. The proband was a woman who developed cognitive decline with predominant memory loss at the age of 35 years. The patient died at the age of 54 years and the neuropathological examination confirmed the diagnosis of AD. Three of her four siblings, one parent and one sibling of her parent had suffered from cognitive decline at ages between 35 and 42 years. Three of them also presented lobar haematomas. The neuropathological examination, available in one of them, disclosed the presence of severe amyloid angiopathy as the cause of the haematoma. The study of PSEN1 gene with single strand conformation polymorphism technique failed to show abnormalities suggestive of mutations. Direct sequencing disclosed the presence of a missense mutation in codon 286 (L286P) in the proband and her already affected descendent, which was absent in the healthy sibling. L286P is a novel mutation in PSEN1 that causes familial early-onset AD and brain haematomas related to amyloid angiopathy.

Brain tau expression and correlation with the H1/H1 tau genotype in frontotemporal lobar degeneration patients.

Alterations in tau mRNA splicing and association with H1/H1 tau genotype have been described in some sporadic tauopathies. We evaluated the 4R/3R tau mRNA ratio in 18 patients with frontotemporal lobar degeneration (FTLD), and the effect of the H1/H1 genotype on this ratio. The 4R/3R mRNA ratio in frontal cortex was similar in FTLD patients and controls. The H1/H1 genotype carriers showed a significant increase in 4R/3R mRNA ratio, suggesting that this genotype could modulate the tau mRNA splicing.

Late-onset frontotemporal dementia associated with a novel PGRN mutation.

We describe a new mutation in the PGRN gene (A303AfsX57) associated with late-onset frontotemporal dementia and with "cat's eye" shaped intranuclear and cytoplasmatic ubiquitin immunoreactive inclusions in the neuropathological exam. The A303AfsX57 mutation is consistent with a nucleotide deletion in exon 8 (c908delC). This deletion causes a frameshift at codon 303 that introduces a premature termination codon (A303AfsX57).

Increased cerebral activity in Parkinson's disease patients carrying the DRD2 TaqIA A1 allele during a demanding motor task: a compensatory mechanism?

Previous studies suggest that neuroimaging techniques are useful for detecting the effects of functional genetic polymorphisms on brain function in healthy subjects or in patients presenting with psychiatric or neurodegenerative conditions. Former evidence showed that individuals carrying risk alleles displayed broader patterns of brain activity during behavioural and cognitive tasks, despite being clinically comparable to non-carriers. This suggests the presence of compensatory brain mechanisms. In the present study, we investigated this effect in Parkinson's disease (PD) patients carrying the DRD2 TaqIA A1 allelic variant. This variant may confer an increased risk of developing the disease and/or influence the clinical presentation. During a complex sequential motor task, we evidenced by functional magnetic resonance imaging that A1 allele carriers activated a larger network of bilateral cerebral areas than non-carriers, including cerebellar and premotor regions. Both groups had similar clinical and demographic measures. In addition, their motor performance during the functional magnetic resonance experiment was comparable. Therefore, our conclusions, pending replication in a larger sample, seem to reflect the recruitment of compensatory cerebral resources during motor processing in PD patients carrying the A1 allele.

Anti-TNF-alpha treatment and bile duct drainage restore cellular immunity and prevent tissue injury in experimental obstructive jaundice.

Several experimental studies of obstructive jaundice (OJ) have shown the presence of immunosuppressive state associated with the rise of tumor necrosis factor-alpha (TNF-alpha) concentration in plasma. The present study evaluates the impact of anti-TNF- alpha administration or bile duct drainage on the inflammatory response, liver injury and renal insufficiency in obstructed rats. OJ was induced by the ligation of bile duct in Wistar rats. The parameters were determined at 14 and 21 days after OJ. Two additional groups of animals were treated with anti-TNF-alpha antibodies or submitted to bile duct drainage at 14 days, and sacrificed 21 days after OJ. Cholestasis decreased glucose, and enhanced urea, creatinin, bilirubin and transaminases. Cholestasis increased the number of different inflammatory cells (T and B lymphocytes, and monocytes-macrophages) but reduced the expression of the corresponding cellular activation markers. This low responsiveness of the inflammatory cells was related to a decreased free radical production and phagocytic activity of cells. Anti-TNF-alpha and bile duct drainage reduced tissue injury, and prevented the reduction of the number and activity of T lymphocytes and phagocytic cells observed at the advanced stages of cholestasis. In conclusion, anti-TNF- alpha and bile duct drainage improved cell immunodeficiency, and reduced liver injury, cholestasis and renal insufficiency in experimental OJ.

Sequence analysis of tau 3'untranslated region and saitohin gene in sporadic progressive supranuclear palsy.

BACKGROUND: The extended tau H1 haplotype has previously been described in association with progressive supranuclear palsy (PSP). Recently, a new gene called saitohin (STH), nested within an intron of tau, has been discovered. The Q7R polymorphism of STH appears to be related to late onset Alzheimer's disease. OBJECTIVES: To search for genetic changes in the 3'untranslated region (3'UTR) of tau and adjacent sequence LOC147077, and in the coding region of STH in PSP patients. METHODS: The study included 57 PSP patients and 83 healthy controls. The genetic analysis of each region was performed through sequencing. The Q7R polymorphism was studied through restriction enzyme and electrophoresis analysis. RESULTS: No mutations were found in the regions analysed. The QQ genotype of the STH polymorphism was over-represented in participants with PSP (91.5%) compared with control subjects (47%) (p< or =0.00001). This genotype co-segregated with the H1/H1 haplotype in our PSP cases. CONCLUSIONS: Our results do not support a major role for the tau 3'UTR in PSP genetics. The QQ genotype of STH confers susceptibility for PSP and is in linkage disequilibrium with the H1/H1 haplotype.

Primary progressive aphasia as the initial manifestation of corticobasal degeneration and unusual tauopathies.

The clinical, neuroradiological, neuropathological and biochemical findings in four patients with primary progressive aphasia and tauopathy are described. The aphasic syndrome preceded by several years the appearance of other symptoms in every case. Asymmetrical apraxia with alien hand phenomenon occurred in one case. Frontotemporal symptoms occurred in three cases, but progressed to dramatic cognitive devastation in only one of these. Generalized dementia consistent with probable Alzheimer's disease (AD) developed with time in another. Cerebral computer tomography scans, magnetic resonance imaging and SPECT studies revealed marked asymmetries in one case, and showed nonspecific cerebral atrophy in the remaining ones. The neuropathological examination revealed typical corticobasal degeneration (CBD) in one case; CBD and AD in another; and atypical CBD, argyrophilic grain disease (AGD) and alpha-synucleinopathy consistent with Parkinson's disease in a third. Unique neuropathological findings were found in the remaining case. This was characterized by severe cerebral atrophy, marked neuronal loss in the cerebral cortex and abnormal tau deposition in neurons of the cerebral cortex, diencephalon and brain stem. Ballooned neurons, Pick bodies, generalized cortical neurofibrillary tangles and astrocytic plaques were absent. However, massive globular inclusions, containing phospho-tau, occurred in glial cells, mainly oligodendrocytes, in the white matter. Biochemical studies of frontal homogenates revealed four bands of 73/74, 68, 64 and 60 kDa of phosphorylated tau (using antibodies recognizing phospho-tau Thr181, Ser262 and Ser422) in the patient with AD and CBD, suggesting a predominant AD pattern in this case. Two bands of 68 and 64 kDa of phospho-tau were recovered in the sarkosyl-insoluble fraction in the other three cases. This pattern is similar to that found in CBD, progressive supranuclear palsy and AGD. Taken together, the present series further supports pure and combined CBD as causes of primary progressive aphasia, and they extend the hypothesis that primary progressive aphasia may be the initial symptom of distinct tauopathies.

A novel mutation (V89L) in the presenilin 1 gene in a family with early onset Alzheimer's disease and marked behavioural disturbances.

A novel mutation (V89L) in the presenilin 1 (PSEN1) gene is described in a family with pathologically confirmed Alzheimer's disease. The mutation was identified in two affected members with early onset Alzheimer's disease characterised by early and marked behavioural disturbances. The mutation is located on the same side of the helix as other described mutations in the first transmembrane domain and its relation to other mutations in this helix suggests that they share a common pathogenic mechanism.

Analysis of the coding and the 5' flanking regions of the alpha-synuclein gene in patients with Parkinson's disease.

Missense mutations of the alpha-synuclein gene have been reported to explain a few kindreds with autosomal dominant Parkinson's disease (PD). In order to identify mutations in our PD patients, we have screened the coding region and 5'flanking region of the gene. DNA samples from 50 patients with familial PD were screened via single-strand conformation polymorphism (SSCP) for mutations in the alpha-synuclein gene. The 5' flanking region was examined in 117 additional PD patients (27 patients with unclear family history for PD, and 90 patients without family history) and in 169 control subjects. We found one change (G199A) in exon 4 in one family with a pattern of autosomal dominant PD. However, this mutation did not result in an amino acid substitution (valine) and did not segregate completely with PD. The analysis of the 5' flanking region also showed a new polymorphism, a nucleotide insertion (- 164insA) linked to a nucleotide substitution (C-116G), in patients and in controls. The -164insA/C-116G allele was present in 52.3% of the patients and in 47.6% of the controls. We did not find significant differences regarding the allelic and genotype frequencies between PD and control groups. These results suggest that mutations in the alpha-synuclein gene are a very rare cause of familial PD and that the novel -164insA/C-116G polymorphism in the 5' flanking region does not confer susceptibility to develop PD.