Correlation between response to neoadjuvant chemotherapy and survival in locally advanced breast cancer patients.

BACKGROUND: Measurement of residual disease following neoadjuvant chemotherapy that accurately predicts long-term survival in locally advanced breast cancer (LABC) is an essential requirement for clinical trials development. Several methods to assess tumor response have been described. However, the agreement between methods and correlation with survival in independent cohorts has not been reported. PATIENTS AND METHODS: We report survival and tumor response according to the measurement of residual breast cancer burden (RCB), the Miller and Payne classification and the Response Evaluation Criteria in Solid Tumors (RECIST) criteria, in 151 LABC patients. Kappa Cohen's coefficient (К) was used to test the agreement between methods. We assessed the correlation between the treatment outcome and overall survival (OS) and relapse-free survival (RFS) by calculating Harrell's C-statistic (c). RESULTS: The agreement between Miller and Payne classification and RCB classes was very high (К = 0.82). In contrast, we found a moderate-to-fair agreement between the Miller and Payne classification and RECIST criteria (К = 0.52) and RCB classes and RECIST criteria (К = 0.38). The adjusted C-statistic to predict OS for RCB index (0.77) and RCB classes (0.75) was superior to that of RECIST criteria (0.69) (P = 0.007 and P = 0.035, respectively). Also, RCB index (c = 0.71), RCB classes (c = 0.71) and Miller and Payne classification (c = 0.67) predicted better RFS than RECIST criteria (c = 0.61) (P = 0.005, P = 0.006 and P = 0.028, respectively). CONCLUSIONS: The pathological assessment of tumor response might provide stronger prognostic information in LABC patients.

Healthcare workers' perception of the usefulness of a healthcare ethics consultation service.

BACKGROUND AND OBJECTIVE: Clinical ethics consultation services (CEC) have arisen from Healthcare Ethics Committees (HEC) to address ethical conflicts in real-time. Our aim was to determine the perception of usefulness of a CEC service among healthcare workers one year after its creation as well as to assess changes in trends in the use of the CEC and HEC between 2015 and 2021. MATERIALS AND METHODS: This observational, cross-sectional study was based on a standardized survey of healthcare workers at an urban tertiary care hospital. The results were also compared to those from an identical survey conducted in the same population in 2015. RESULTS: A total of 213 professionals participated (mean age 44 ± 11 years, 69% women). The professionals were more familiar with the HEC than the CEC service (94% vs 61%; p < 0.001). Forty-five individuals (21%) had consulted the CEC since its implementation; 95% of them found the consultation useful. Physicians knew about and used the CEC more than other groups of professionals. The degree of knowledge of the HEC increased significantly by 2021 compared to 2015 (94% v. 76%; p < 0.001). Some areas for improvement identified were the need for greater dissemination of the service, guaranteeing institutional resources to maintain the service, and encouraging greater participation from different professional groups. CONCLUSIONS: Knowledge of the institutional HEC and CEC services has increased in recent years among healthcare workers, who considered the CEC service to be useful for addressing ethical conflicts in daily practice.

Glutathione S-transferase P1 c.313A > G polymorphism could be useful in the prediction of doxorubicin response in breast cancer patients.

BACKGROUND: Identification of predicting factors for anthracyclines-based chemotherapy remains a clinical challenge. Glutathione S-transferase (GSTs) enzymes detoxify chemotherapy drugs and their metabolites. Several polymorphisms in GST genes result in reduced or no activity of the enzymes. Specifically, GSTM1 and GSTT1 genes are polymorphically deleted, the polymorphism GSTP1 c.313A>G (rs1695) determines the amino acid substitution Ile105Val, where the Val-containing enzyme has reduced activity. Also, GSTA1*B allele has reduced levels of GSTA1 enzyme. Several polymorphisms in GSTs have been associated with differences in survival for cancer patients treated with chemotherapy. PATIENTS AND METHODS: We genotyped a total of five polymorphisms in GSTM1, GSTT1, GSTP1 and GSTA1 genes in 159 patients with locally advanced breast cancer, treated with single-agent doxorubicin or docetaxel (Taxotere). Gene expression microarrays were performed in 67 breast tumor samples. We correlate this data with treatment outcome. RESULTS: In multivariate analysis, patients homozygous GG for GSTP1 c.313A>G SNP had a lower risk of chemoresistance when treated with doxorubicin (odds ratio 0.106; confidence interval 0.012-0.898; P=0.040). No association was found in the docetaxel arm. Also, we found that GSTP1 expression varied significantly among breast cancer molecular subtypes. CONCLUSIONS: GSTP1 may constitute another tool contributing to individualized anthracycline-based therapy.

New Aluminum Syntactic Foam: Synthesis and Mechanical Characterization.

Metal matrix syntactic foams (MMSF) are advanced cellular materials constituted by a system of a minimum of two phases, in which a dispersion of hollow particles is embedded by a continuous metal matrix. The incorporation of porous fillers favors the development of low-density materials with exceptional behavior for damping vibrations, impacts, and blast effects, shielding acoustic, thermal, and electromagnetic energies. There are three main techniques to produce them: infiltration casting technique (ICT), stir casting technique (SCT), and powder metallurgy technique (P/M). The first two techniques are used for embedding filler into lower melting point metallic matrices than fillers, in contrast to P/M. The present study demonstrates the feasibility of producing MMSF with components of similar melting points by ICT. The fillers were synthesized in-situ with aluminum and a natural foaming agent from wastes of Spanish white marble quarries. These novel aluminum syntactic foams (ASF) were mechanically characterized following the ISO-13314 and exhibited a porosity, plateau stress, and energy absorption capacity of 41%, 37.65 MPa, 8.62 MJ/m3 (at 35% of densification), respectively. These properties are slightly superior to equal porosity LECA ASF, making these novel ASF suitable for the same applications as LECA-ASF.

Description of the experience of a clinical ethics consultation service from 2019 to 2021.

INTRODUCTION: Clinical ethics consultation services (CEC) are useful model for ethical counselling, albeit with scarce implementation in European countries. This article shares the experience of one of the first ethics consultation services in Spain. MATERIALS AND METHODS: This work is a retrospective, observational study of all consultations received by the CEC service at La Princesa University Hospital (Madrid, Spain) from September 1, 2019 to August 31, 2021. The demographic, logistic, and ethical variables of the cases were analyzed. RESULTS: A total of 63 cases were analyzed in which a total of 124 ethical conflicts were identified. Forty-one percent of the cases (n = 26) were emergency consultations and 38% (n = 24) were preferential inquiries. An initial evaluation was performed with 24 h in 50 cases (79%). The department that consulted most often was the Intensive Care Unit (9; 14%). The preferred contact methods were via pager (36; 57%), the electronic medical record system (13; 21%), or direct conversations with consulting team (7; 11%). The most common ethical conflicts were those related to the adequacy of treatment measures (24; 19%), refusal of treatment (19; 15%), communication with the patient or his/her family (29; 23%), or the patient's capacity (13; 11%). CONCLUSION: CEC services provide quick, efficient assistance for resolving ethical problems in daily practice. Their implementation in Spain is feasible.

Genomic predictors of response to doxorubicin versus docetaxel in primary breast cancer.

UNLABELLED: Taxanes and anthracyclines improve the outcome of early breast cancer, although the benefit is limited to a small proportion of patients and are toxic. We prospectively looked for predictors of response to these drugs. EXPERIMENTAL DESIGN: Four cycles of doxorubicin (75 mg/m²) or docetaxel (100 mg/m²) were compared as presurgical chemotherapy for breast cancer. Biomarkers were determined by immunohistochemistry and fluorescent in situ hybridization using prechemotherapy core biopsies. Tumors were also classified into one of the molecular intrinsic subtypes using an immunohistochemical panel of five biomarkers and genomic profiles. Single genes and intrinsic subtypes were correlated with response to doxorubicin versus docetaxel. Among the 204 evaluable patients, significant predictors of sensitivity in multivariate analysis were low topo2a expression and ER-negative status for doxorubicin and small tumor size and ER-negative status for docetaxel. Predictors of resistance in multivariate analysis were triple-negative status (ER/PgR/HER2 negative by IHC/FISH) for doxorubicin, and high TNM stage for docetaxel. Triple-negative tumors were associated with topo2a overexpression more than the other subtypes. In 94 patients with gene expression profiles, docetaxel was superior to doxorubicin in the basal-like subtype (good pathological response rate - PCR + class I of 56 vs. 0%; P = 0.034); no significant differences were observed in the other subtypes when comparing these two drugs. Low topo2a expression and ER-negative status were predictors of response to doxorubicin, while small tumor size and ER-negative status predicted response to docetaxel. Docetaxel was superior to doxorubicin in triple-negative/basal-like tumors, while no significant differences were seen in the remaining intrinsic subtypes.

Leukemia in AKR mice. I. Effects of leukemic cells on antibody-forming potential of syngeneic and allogeneic normal cells.

Cells from the spleen, thymus, lymph node, and liver of leukemic AKR mice suppress in vitro antibody responses of normal syngeneic and semiallogeneic cells. This suppression can be mediated by irradiated leukemic cells, requires cell contact between leukemic and normal cells, and may occur at any time during the in vitro culture period. Leukemic AKR cells do not suppress antibody responses of allogeneic cells, even when allogeneic cells have H-2 or background genes homologous with AKR. Leukemic cells do, however, suppress cells that are unable to respond allogeneically to leukemic AKR cells, such as cells of the F1s of AKR. Suppression of normal AKR antibody responses by leukemic AKR cells may be overcome by addition of irradiated allogeneic cells. The fact that leukemic AKR cells are able to suppress normal lymphocyte responses may be of significance in pathogenesis of leukemia in these mice.

Haemodynamic profile of Spanish adults with Down syndrome. / Perfil hemodinámico de los adultos españoles con síndrome de Down.

OBJECTIVES: Although the reasons are unknown, the prevalence of arterial hypertension and atherosclerotic cardiovascular events in the adult population with Down syndrome (SD) is anecdotal. To better understand this finding, we evaluated the haemodynamic characteristics of a cohort of adults with SD. METHODS: We conducted a cross-sectional study of adults with SD recruited consecutively from the outpatient clinics of an internal medicine department between June and November 2018. We collected demographic, clinical and laboratory variables and employed a thoracic bioimpedance device (HOTMAN® System) for the haemodynamic measures. Outpatient blood pressure monitoring (OBPM) was conducted on a subgroup of participants. RESULTS: Twenty-six participants (mean age, 45±11years) participated in the study (50% men). The sample's mean blood pressure (BP) was 109/69±11/9mmHg, with a mean heart rate of 60±12bpm. None of the participants had hypertension. The predominant haemodynamic profile consisted of normal dynamism (65%), normal BP (96%), hypochronotropism (46%), normal inotropism (50%) and hypervolaemia (54%), with normal peripheral vascular resistance values (58%). Twelve participants underwent OBPM (46%). The mean 24-h systolic BP, diastolic BP, mean BP and mean heart rate were 105±11mmHg, 67±11mmHg, 80±11mmHg and 61±6bpm, respectively. CONCLUSIONS: The most common haemodynamic profile observed in adults with SD consisted of hypochronotropism and hypervolaemia, with normal values for peripheral vascular resistance and optimal mean BP values. There were no participants with hypertension in our sample.

The popularity of neurology in Spain: An analysis of specialty selection. / Popularidad de Neurología en España: análisis de la elección de la especialidad.

INTRODUCTION: Neurology is one of the medical specialties offered each year to residency training candidates. This project analyses the data associated with candidates choosing neurology residency programmes in recent years. METHODS: Data related to specialty selection were obtained from official reports by the Spanish Ministry of Health, Social Services, and Equality. Information was collected on several characteristics of teaching centres: availability of stroke units, endovascular intervention, national reference clinics for neurology, specific on-call shifts for neurology residents, and links with medical schools or national research networks. RESULTS: The median selection list position of candidates selecting neurology training has been higher year on year; neurology was among the 4 most popular residency programmes in 2016. Potential residents were mainly female, Spanish, and had good academic results. The median number of hospitals with higher numbers of beds, endovascular intervention, stroke units, and national reference clinics for neurology is significantly lower. This is also true when centers are analysed by presence of specific on-call shifts for neurology residents and association with medical schools or national research networks. The centres selected by candidates with the highest median selection list position in 2012-2016 were the Clínico San Carlos, 12 de Octubre, and Vall d'Hebron university hospitals. CONCLUSIONS: Neurology has gradually improved in residency selection choices and is now one of the 4 most popular options. Potential residents prefer larger centres which are more demanding in terms of patient care and which perform more research activity.

Chemometric methods in antimalarial drug design from 1,2,4,5-tetraoxanes analogues.

A set of 23 steroidal 1,2,4,5-tetraoxane analogues were studied using quantum-chemical method (B3LYP/6-31 G*) and multivariate analyses (PCA, HCA, KNN and SIMCA) in order to calculate the properties and correlate them with antimalarial activity (log RA) against Plasmodium falciparum clone D-6 from Sierra Leone. PCA results indicated 99.94% of the total variance and it was possible to divide the compounds into two classes: less and more active. Descriptors responsible for separating were: highest occupied molecular orbital energy (HOMO), bond length (O1-O2), Mulliken electronegativity (χ) and Bond information content (BIC0). We use HCA, KNN and SIMCA to explain relationships between molecular properties and biological activity of a training set and to predict antimalarial activity (log RA) of 13 compounds (#24-36) with unknown biological activity. We apply molecular docking simulations to identify intermolecular interactions with a selected biological target. The results obtained in multivariate analysis aided in the understanding of the activity of the new compound's design (#24-36). Thus, through chemometric analyses and docking molecular study, we propose theoretical synthetic routes for the most promising compounds 28, 30, 32 and 36 that can proceed to synthesis steps and in vitro and in vivo assays.

Neogenin, an avian cell surface protein expressed during terminal neuronal differentiation, is closely related to the human tumor suppressor molecule deleted in colorectal cancer.

Using a monoclonal antibody, we have identified and characterized a previously unknown cell surface protein in chicken that we call neogenin and have determined its primary sequence. The deduced amino acid sequence and structure of neogenin characterize it as a member of the immunoglobulin (Ig) superfamily. Based on amino acid sequence similarities, neogenin is closely related to the human tumor suppressor molecule DCC (deleted in colorectal cancer). Neogenin and DCC define a subgroup of Ig superfamily proteins structurally distinct from other Ig molecules such as N-CAM, Ng-CAM, and Bravo/Nr-CAM. As revealed by antibody staining of tissue sections and Western blots, neogenin expression correlates with the onset of neuronal differentiation. Neogenin is also found on cells in the lower gastrointestinal tract of embryonic chickens. DCC has been observed in human neural tissues and has been shown to be essential for terminal differentiation of specific cell types in the adult human colon. These parallels suggest that neogenin, like DCC, is functionally involved in the transition from cell proliferation to terminal differentiation of specific cell types. Since neogenin is expressed on growing neurites and downregulated at termination of neurite growth, it may also play an important role in many of the complex functional aspects of neurite extension and intercellular signaling.

Bravo/Nr-CAM is closely related to the cell adhesion molecules L1 and Ng-CAM and has a similar heterodimer structure.

Diverse cell-surface molecules of the nervous system play an important role in specifying cell interactions during development. Using a method designed to generate mAbs against neural surface molecules of defined molecular weight, we have previously reported on the surface protein, Bravo, found in the developing avian retinotectal system. Bravo is immunologically detected on developing optic fibers in the retina, but absent from distal regions of the same fibers in the tectum. We have isolated cDNA clones encompassing the entire coding region of Bravo, including clones containing five alternative sequences of cDNA. These putative alternatively spliced sequences encode stretches of polypeptide ranging in length from 10-93 amino acids and are predicted to be both extra- and intracellular. The deduced primary structure of Bravo reveals that, like the cell adhesion molecules (CAMs) chicken Ng-CAM and mouse L1, Bravo is composed of six Ig-like domains, five fibronectin type III repeats, a transmembrane domain, and a short cytoplasmic region. Recently, the cDNA sequence of a related molecule, Nr-CAM, was reported and its possible identity with Bravo discussed (Grumet, M., V. Mauro, M. P. Burgoon, G. E. Edelman, and B. A. Cunningham. 1991. J. Cell Biol. 113:1399-1412). Here we confirm this identity and moreover show that Bravo is found on Müller glial processes and end-feet in the developing retina. In contrast to the single polypeptide chain structure of Nr-CAM reported previously, we show that Bravo has a heterodimer structure composed of an alpha chain of M(r) 140/130 and a beta chain of 60-80 kD. As with L1 and Ng-CAM, the two chains of Bravo are generated from an intact polypeptide by cleavage at identical locations and conserved sites within all three molecules (Ser-Arg/Lys-Arg). The similar domain composition and heterodimer structure, as well as the 40% amino acid sequence identity of these molecules, defines them as an evolutionarily related subgroup of CAMs. The relationship of Bravo to molecules known to be involved in cell adhesion and process outgrowth, combined with its pattern of expression and numerous potential isoforms, suggests a complex role for this molecule in cell interactions during neural development.

Topologically restricted appearance in the developing chick retinotectal system of Bravo, a neural surface protein: experimental modulation by environmental cues.

A novel neural surface protein, Bravo, shows a pattern of topological restriction in the embryonic chick retinotectal system. Bravo is present on the developing optic fibers in the retina; however, retinal axons in the tectum do not display Bravo. The appearance of Bravo in vitro is modulated by environmental cues. Axons growing out from retinal explants on retinal basal lamina, their natural substrate, express Bravo, whereas such axons growing on collagen do not. Retinal explants provide a valuable system to characterize the mechanism of Bravo restriction, as well as the cellular signals controlling it. Bravo was identified with monoclonal antibodies from a collection generated against exposed molecules isolated by using a selective cell surface biotinylation procedure. The NH2-terminal sequence of Bravo shows similarity with L1, a neural surface molecule which is a member of the immunoglobulin superfamily. This possible relationship to L1, together with its restricted appearance, suggests an involvement of Bravo in axonal growth and guidance.

Deuterium isotope effect on denitrosation and demethylation of N-nitrosodimethylamine by rat liver microsomes.

In an attempt to elucidate the molecular basis for the decrease in rat liver carcinogenicity and DNA-alkylating ability that accompanies deuteration of N-nitrosodimethylamine (NDMA), NDMA and its fully deuterated analogue ([2H6]NDMA) were incubated with acetone-induced rat liver microsomes. Rates for the competing metabolic routes, denitrosation and demethylation, were determined from colorimetric data on nitrite and formaldehyde generation, respectively. The Vmax calculated for demethylation of NDMA was 7.9 nmol/min/mg, while that for denitrosation was 0.83 nmol/min/mg. Deuteration of NDMA did not significantly change the Vmax for either pathway, but it did increase the Km for demethylation from 0.06 to 0.3 mM. The Km for denitrosation was also increased from 0.06 to 0.3 mM on deuteration, as determined by incubating an equimolar mixture of amino-15N-labeled NDMA with [2H6]NDMA and measuring the methyl[15N]amine:[2H3]methylamine ratio by derivatization-gas chromatography-mass spectrometry. The fact that the Km values for denitrosation were so similar to those for demethylation suggested that the two pathways were catalyzed by the same enzyme. The isotope effects calculated from these data [VmaxH/VmaxD approximately 1 and (Vmax/Km)H/(Vmax/Km)D approximately 5] show that microsomal metabolism of NDMA is not significantly shifted from demethylation to denitrosation on deuteration of substrate and may indicate a low commitment to catalysis for the enzyme. The results are consistent with the view that the metabolism of NDMA is initiated by formation of an alpha-nitrosamino radical which either combines with a hydroxyl radical to form the alpha-hydroxynitrosamine as the initial product of the demethylation pathway or fragments to nitric oxide and N-methylformaldimine as the first products of denitrosation.

Oxytocin enhances gaze-following responses to videos of natural social behavior in adult male rhesus monkeys.

Gaze following is a basic building block of social behavior that has been observed in multiple species, including primates. The absence of gaze following is associated with abnormal development of social cognition, such as in autism spectrum disorders (ASD). Some social deficits in ASD, including the failure to look at eyes and the inability to recognize facial expressions, are ameliorated by intranasal administration of oxytocin (IN-OT). Here we tested the hypothesis that IN-OT might enhance social processes that require active engagement with a social partner, such as gaze following. Alternatively, IN-OT may only enhance the perceptual salience of the eyes, and may not modify behavioral responses to social signals. To test this hypothesis, we presented four monkeys with videos of conspecifics displaying natural behaviors. Each video was viewed multiple times before and after the monkeys received intranasally either 50 IU of OT or saline. We found that despite a gradual decrease in attention to the repeated viewing of the same videos (habituation), IN-OT consistently increased the frequency of gaze following saccades. Further analysis confirmed that these behaviors did not occur randomly, but rather predictably in response to the same segments of the videos. These findings suggest that in response to more naturalistic social stimuli IN-OT enhances the propensity to interact with a social partner rather than merely elevating the perceptual salience of the eyes. In light of these findings, gaze following may serve as a metric for pro-social effects of oxytocin that target social action more than social perception.

Mutation analysis of the BRCA2 gene in breast/ovarian cancer Spanish families: identification of two new mutations.

The recently isolated gene BRCA2 is responsible for about 45% of familial breast cancer and the majority of male breast cancer families. We have screened 12 high risk breast/ovarian Spanish families for mutations in BRCA2, using SSCP followed by direct sequencing. We have found mutations in four of our 12 families (33.3%), including two with male breast cancer. Three of the mutations were frameshift and one was a missense. Two of the mutations have been previously published and two are new mutations.

CYP2D6 genotypes in Spanish women with breast cancer.

Wild type and three mutated alleles of the polymorphic CYP2D6 gene were studied in genomic DNA samples from 187 women with breast carcinoma and 151 healthy women by a mutation-specific polymerase chain reaction. The prevalence of the enzyme-inactivating CYP2D6(B) allele was higher among patients (18.2%) than in controls (11.6%; OR = 1.7; 95% c.i. = 1.14-3.13; P = 0.018). This excess was more marked in postmenopausal patients (19.8%, P = 0.0086) and in patients with non-ductal infiltrating carcinomas (25.8%, P = 0.003). The percentage of carriers of only one active gene (heterozygote extensive metabolizers) was higher in patients (31% vs. 19.9%; OR = 1.81; 95% c.i. = 1.06-3.11; P = 0.02). The CYP2D6(B)-carrier state may be related to a greater risk of breast cancer in women.

Myofibroblastoma of the breast with diverse histological features.

We report two cases of myofibroblastoma with unusual pathological features, in a 66-year-old woman and a 49-year-old man. Both tumours were unilateral, grossly nodular and well circumscribed, but not encapsulated. The lesions were made up of bipolar spindle cells arranged in fascicular clusters separated by bands of hialinized collagen; one included several islands of mature cartilage next to fat cells. The other contained atypical mononucleated and multinucleated giant cells. No mitotic figures were observed. Immunohistochemically, both tumours showed strong and diffuse cytoplasmic staining for vimentin and CD 34 and focal positivity for alpha-smooth muscle actin, and both were negative for cytokeratins, CD 68, Ham 5, 6, Mac 387, and S-100 protein. Desmin was positive in one case. Ultrastructural study revealed populations composed of fibroblastic cells without signs of myofibroblastic differentiation in one case; the second featured abundant undifferentiated mesenchymal cells with myofibroblastic differentiation. Both patients remain disease-free 38 and 36 months after lumpectomy.

Quantitative measurement of prostaglandins E2 and E2 by selected ion monitoring.

A method for the simultaneous quantitative analysis of prostaglandin E2 (PGE2) and PGE3 is described. The PG were analyzed by selected ion monitoring as the methyl ester-TMS ether derivatives of PGB2 and PGB3, respectively. The internal standard for the quantification of both species was [3,3,4,4-2H4]PGE2. A linear response over the range 0.6--50 ng (1.7--143 pmoles) was demonstrated for PGE3. The chromatographic conditions used (2% SP-2330 column) afforded nearly baseline separation of the prostaglandins. New standard curves for PGE3 must be developed each time the ion source parameters are changed. In a typical calibration run, the instrumental precision, expressed as coefficient of variation, ranged from 1.1 to 7.2% for PGE2 (3 to 100 ng injected) and from 1.6 to 11.1% for PGE3 (1.5--50 ng injected). The method was applied to the PG analysis of rat renomedullary tissues. The recovery of synthetic PGE2 added to medullary homogenates was 100.5 +/- 1.7% (mean +/- SEM, n = 9), and the recovery of PGE3 was 91.3 +/- 1.4% (n = 9).