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.

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.

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)

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.

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.

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.

A novel presenilin 1 mutation (Leu166Arg) associated with early-onset Alzheimer disease.

BACKGROUND: Pathogenic mutations in the presenilin 1 (PS1) gene leading to early-onset Alzheimer disease have been described in various populations. The different mutations are not distributed randomly in the PS1 protein but are clustered in some PS1 exons. OBJECTIVE: To screen the PS1 gene in search of a potential mutation in a Spanish family with early-onset Alzheimer disease. METHODS: Single-stranded conformational polymorphism and heteroduplex analyses of all exons were used to search for a potential mutation. Subsequent sequencing of the DNA samples with an abnormal heteroduplex pattern was performed to identity the mutation in the sense strand and in the complementary strand. RESULTS: We found a novel mutation in exon 6 of the PS1 gene at a site that, so far, had not been described as a cluster of mutations. The mutation (an A to C change) causes a substitution of leucine for arginine at position 166 of the PS1 protein and is located adjacent to the transmembrane domain III, where few mutations have been found. In this family, the disease follows an autosomal inheritance pattern with early onset (range, 32-44 years). CONCLUSION: A novel missense mutation (Leu166Arg) at an atypical site associated with early-onset Alzheimer disease has been identified in a Spanish family.

Significant changes in the tau A0 and A3 alleles in progressive supranuclear palsy and improved genotyping by silver detection.

BACKGROUND: Progressive supranuclear palsy (PSP) is characterized by intraneuronal inclusions of neurofibrillary tangles formed by aggregated tau protein. A significant association between the tau gene A0/A0 genotype and PSP recently has been reported. OBJECTIVES: To determine if a significant association between the tau gene A0/A0 genotype and PSP could be found in an independent population with a genetic background different from that in which the initial association was reported, and to standardize a nonradioactive method for tau gene genotyping. SETTING: Hospital and university research laboratories. SUBJECTS AND METHODS: To facilitate genotyping of the tau gene, we standardized the conditions for silver-based detection of the tau gene dinucleotide polymorphism. Thirty patients from Spain clinically diagnosed as having probable PSP were included in the study and compared with different control groups. RESULTS: A highly significant overrepresentation of the A0/A0 genotype (P<.001) and a decrease in the frequency of the A0/A3 genotype were found in the Spanish patients with PSP compared with the control group. A method based on silver detection was standardized for the genotyping of the tau gene. CONCLUSIONS: The detection of a significant association between the tau gene A0/A0 genotype and PSP in 2 independent populations rules out genetic stratification as an explanation for the association and indicates that the presence of the tau A0/A0 genotype is a risk factor for developing PSP independent of genetic background. Alternatively, the results could be interpreted as a protective effect of the A3 allele.

A presenilin 1 mutation (Ser169Pro) associated with early-onset AD and myoclonic seizures.

OBJECTIVE: To characterize the mutation responsible for early-onset AD in a large Spanish kindred. BACKGROUND: Mutations in the presenilin 1 (PS1) gene have been identified and are known to be responsible for 18 to 50% of familial early-onset AD cases. METHODS: Patients were characterized clinically. The proband was further studied with EEG, CSF analysis, CT, brain biopsy, and histology. Other members were studied using EEG, CT, MRI, and SPECT. Genetic analysis of PS1 was performed using PCR amplification of PS1 exons and direct sequencing followed by PS1 modeling of the normal and mutant PS1 proteins. RESULTS: A novel mutation (Ser169Pro) in exon 6 of the PS1 gene was identified in different affected members. The Ser169Pro mutation is located at a site of the PS1 protein that is not a cluster of mutations. The mutation was not present in 100 general population controls and in 50 unrelated sporadic AD cases. The Ser169Pro mutation is associated with generalized myoclonic seizures several years after the initial symptoms of AD, a very early AD onset (< or =35 years), and a rapidly progressive cognitive decline. CONCLUSIONS: The absence of the PS1 Ser169Pro mutation in the general population and in sporadic AD cases together with its detection in the affected members of this kindred suggests that it is a pathogenic mutation. The serine to proline change predicts a kink in the alpha-helix of the transmembrane domain of the PS1 protein that could radically disrupt its normal structure. Further characterization of the effect of this mutation could help identify the function of the PS1 protein and the pathogenic mechanisms of AD.

Alpha1-antichymotrypsin gene polymorphism and susceptibility to Parkinson's disease.

OBJECTIVE: To determine whether the alpha1-antichymotrypsin AA genotype (ACT-AA) confers susceptibility for developing Parkinson's disease (PD) in the Spanish population. BACKGROUND: A correlation between the ACT-AA genotype and the risk of developing PD has been recently reported in the Japanese population. METHODS: The ACT genotypes of 71 patients diagnosed with clinically definite PD were compared with those of 109 age-matched healthy control subjects. RESULTS: The authors found that the ACT-AA polymorphism frequency was not increased significantly in the PD group (31%) compared with the control group (28.4%). The ACT allelic distribution was also similar for familial and sporadic PD, for female and male patients, and for the different clinical subtypes of PD. The age at onset of PD was significantly lower in the ACT-AA patients compared with non-ACT-AA patients. When the actual age was considered, the ACT-AA frequency was higher in PD patients < or =50 years old (50%) compared with that present in patients >50 years old (26.8%), but the same effect was found in control subjects. CONCLUSIONS: The ACT-AA polymorphism is not related to an increased risk of developing PD in the Spanish population. The ACT-AA overrepresentation in PD and control subjects < or =50 years old suggests that this polymorphism could be associated with life-threatening conditions other than PD.

Alzheimer disease is not associated with polymorphisms in the angiotensinogen and renin genes.

Hypertension has been implicated as a risk factor for Alzheimer disease (AD) and dementia in epidemiological studies of humans. It is thus possible that there are common genetic determinants for hypertension and AD. Epidemiological, clinical, and experimental data suggest that the renin-angiotensin-aldosterone system is a critical regulator of blood pressure. The presence of an MboI site in an RFLP in the renin gene and the Thr at the Met/Thr polymorphism at codon 235 (M235T) of the angiotensinogen gene have been reported to be associated with hypertension. These variants were studied in autopsy-confirmed AD cases and matched controls from the U.K. While no association was detected with the renin polymorphism, a weak deleterious effect was observed in cases homozygous for the angiotensinogen Thr allele. However, this association was not observed in a French cohort of clinically diagnosed AD cases and controls, suggesting that the initial observation was a type I error. Thus, these polymorphisms are unlikely to be associated with AD risk.

Alpha-antichymotrypsin gene polymorphism and risk for Alzheimer's disease in the Spanish population.

The alpha-antichymotrypsin (ACT) and the ApoE polymorphisms have been determined in 136 Alzheimer's disease (AD) patients and in 92 age-matched controls. Only a borderline significant difference is found when comparing the overall ACT/AA genotype frequency between AD patients and controls (chi2, P = 0.08). However this difference is attributable entirely and significantly to the ApoE epsilon4 non-carrier AD group (chi2, P = 0.004). No differences are found in the ACT/AA genotype frequency of the ApoE epsilon4 AD carrier group as compared controls (chi2, P = 0.98) in contrast with previous works. These findings support that the presence of the ACT/AA genotype is a genetic risk factor for developing AD in non-ApoE epsilon4 carriers subjects in our population.

Detection of the presenilin 1 gene mutation (M139T) in early-onset familial Alzheimer disease in Spain.

In a family with early-onset Alzheimer disease (EOAD) from Spain we found a mutation in the presenilin 1 (PS1) gene that predicts a methionine-to-threonine change at the PS1 residue 139 (M139T). This mutation was previously reported in a independent French family. The age of onset of the disease was similar in the affected members from both families, suggesting a specific age of expression (range 47-50 years). The detection of the M139T mutation in an independent EOAD family strongly supports the pathogenicity of this mutation in familial Alzheimer disease (AD).

Identification of a novel polymorphism in the promoter region of the tau gene highly associated to progressive supranuclear palsy in humans.

An intronic polymorphism and other changes in the transcribed region of the tau gene forming a haplotype have been previously described associated to progressive supranuclear palsy (PSP). These results raised the possibility that a change at or near the tau gene could be responsible for an increased risk to develop PSP. We initiated the present work in research for potential changes in the promoter region of the tau gene that could further extend the previously described haplotype. The tau promoter region was analyzed through single strand conformation polymorphism followed by direct sequencing in PSP patients (n = 35), in controls (n = 195) and in Alzheimer's disease (AD; n = 74) patients. We have been able to identify a G to C change at position -221 of the tau gene promoter region. The CC genotype has been detected to be present with a significantly higher frequency in PSP patients (91.4%; P < 0.00001; OR = 11.8), but not in AD patients, as compared with controls (49.74%). Subsequently we have detected that the CC -221 tau promoter genotype is significantly associated to the tau intronic A0/A0 genotype (P < 0.00001). The detected -221 tau G to C change occurs within a potential c-myb proto-oncogene element present in the promoter region. Thus, in addition to extending the previously described haplotype associated to PSP, this -221 G to C change is an interesting candidate that could provide a potential explanation for the association of the haplotype to increased risk for developing PSP.

The genotype 2/2 of the presenilin-1 polymorphism is decreased in Spanish early-onset Alzheimer's disease.

We have found a significantly lower frequency of the presenilin-1 (PS-1) intronic polymorphism 2/2 genotype in early-onset Alzheimer's disease (AD) patients without APOE epsilon4 alleles (2/2 = 0.054; P = 0.009) as compared to age matched non-epsilon4 controls (2/2 = 0.227). Moreover the average age of onset in AD patients with the PS-1 2/2 genotype is older than that in AD patients with a 1/2 genotype or with a 1/1 genotype. This data suggest a protective effect of the 2/2 genotype which would delay the age of onset in AD. Our results do not support an association between the 1/1 genotype and AD. However, a non-significant increase of the 1/1 genotype is found in non-epsilon4 AD patients (P = 0.20).

Apolipoprotein E epsilon 4 alleles and meiotic origin of non-disjunction in Down syndrome children and in their corresponding fathers and mothers.

An increased risk of Alzheimer disease (AD) has been reported in young mothers of Down syndrome (DS) probands. Subsequently, an increased frequency of the apolipoprotein E (apoE) allele epsilon 4 has been found in mothers (< or = 32 years) of DS children due to meiosis II (MII) errors providing a potential explanation for the increased risk of AD in DS mothers. In the present study we genotyped apoE and determined the origin of non-disjunction of 132 mothers and the corresponding fathers and DS children from Spain. Unexpectedly no epsilon 4 alleles have been detected in MII mothers of < or = 32 years of age (P = 0.02). Thus our study not only fails to find the effect previously reported, but it detects an opposite correlation. An increase in the epsilon 4 frequency (0.227) is detected in MI mothers <28 as compared to the epsilon 4 frequency present in MI mothers >28 years of age (0.089), although the differences are not significant if correction for multiple comparisons is applied. The simplest overall interpretation of the previously reported and present findings is that the detected associations are due to random statistical variation rather than to some real effect of the epsilon 4 allele. However the important potential implications of alternative explanations imply that this issue deserves further clarification in independent studies in other populations.

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.

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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