Stratification of pregnancy care based on risk of pre-eclampsia derived from biophysical and biochemical markers at 19-24 weeks' gestation.

OBJECTIVE: We have proposed previously that all pregnant women should have assessment of risk for pre-eclampsia (PE) at 20 and 36 weeks' gestation and that the 20-week assessment should be used to define subgroups requiring additional monitoring and reassessment at 28 and 32 weeks. The objective of this study was to examine the potential improvement in screening at 19-24 weeks' gestation for PE with delivery at < 28, < 32, < 36 and ≥ 36 weeks' gestation by the addition of serum placental growth factor (PlGF) and soluble fms-like tyrosine kinase-1 (sFlt-1) to the combination of maternal demographic characteristics and medical history, uterine artery pulsatility index (UtA-PI) and mean arterial pressure (MAP). METHODS: This was a prospective, non-intervention study in women attending for an ultrasound scan at 19-24 weeks as part of routine pregnancy care. Patient-specific risks of delivery with PE at < 36 weeks' gestation were calculated using the competing-risks model to combine the prior distribution of gestational age at delivery with PE, obtained from maternal characteristics and medical history, with multiples of the median values of UtA-PI, MAP, PlGF and sFlt-1. Different risk cut-offs were used to vary the proportion of the population stratified into each of four risk categories (very high risk, high risk, intermediate risk and low risk) with the intention of detecting about 80%, 85%, 90% and 95% of cases of delivery with PE at < 28, < 32 and < 36 weeks' gestation. The performance of screening was assessed by plotting the detection rate against the screen-positive rate and calculating the areas under these curves, and by the proportion stratified into a given group for fixed detection rates. Model-based estimates of screening performance for these various combinations of markers were also produced. RESULTS: In the study population of 37 886 singleton pregnancies, there were 1130 (3.0%) that subsequently developed PE, including 160 (0.4%) that delivered at < 36 weeks' gestation. In both the modeled and empirical results, there was incremental improvement in the performance of screening with the addition of PlGF and sFlt-1 to the combination of maternal factors, UtA-PI and MAP. If the objective of screening was to identify about 90% of cases of PE with delivery at < 28, < 32 and < 36 weeks and the method of screening was a combination of maternal factors, UtA-PI and MAP, the respective screen-positive rates would be 3.1%, 8.5% and 19.1%. The respective values for screening by maternal factors, UtA-PI, MAP and PlGF were 0.2%, 0.7% and 10.6%, and for screening by maternal factors, UtA-PI, MAP, PlGF and sFlt-1 they were 0.1%, 0.4% and 9.5%. The empirical results were consistent with the modeled results. There was good agreement between the predicted risk and the observed incidence of PE at < 36 weeks' gestation for all three strategies of screening. Prediction of PE at ≥ 36 weeks was poor for all three screening methods, with the detection rate, at a 10% screen-positive rate, ranging from 33.2% to 38.4%. CONCLUSIONS: The performance of screening at 19-24 weeks' gestation for PE with delivery at < 28, < 32 and < 36 weeks' gestation achieved by a combination of maternal demographic characteristics and medical history, UtA-PI and MAP is improved by the addition of serum PlGF and sFlt-1. The performance of screening for PE at ≥ 36 weeks' gestation is poor irrespective of the method of screening at 19-24 weeks. © 2021 International Society of Ultrasound in Obstetrics and Gynecology.

[Program offer for the integral development of early childhood in Chile: Scoping review]. / Oferta de programas para el desarrollo integral de la primera infancia en Chile: Revisión exploratoria.

OBJECTIVE: To describe the program offering designed to promote comprehensive early childhood de velopment in Chile. METHOD: A scoping review was carried out following the Joanna Briggs Institute's methodological framework. A researcher conducted the review considering as inclusion criteria go vernment programs aimed at the comprehensive development of children under 5 years of age in Chile. The data were organized and synthesized to describe the characteristics of the program and the service(s) it provides. RESULTS: The search identified 2.060 documents and 72 met the inclusion crite ria. 59 current programs are covering early childhood, which are mainly managed by the Ministries of Justice, Education, Health, and Social Development. Most of the programs are aimed at promotion and intervention, focusing on vulnerable populations, are cross-sectoral, and use different strategies for their implementation. CONCLUSION: The program offering in Chile for early childhood has charac teristics suggested as effective to promote child development.

Epidermal growth factor receptor and epididymis invasion as prognostic biomarkers in clinical stage I testicular germ cell tumours.

BACKGROUND: Inguinal orchiectomy is curative in 70-80% of clinical stage I testicular germ cell tumours (CS I TGCT). The identification of patients who are at low risk of relapse is critical to avoid unnecessary treatment. The aim of this study is to explore EGFR, hMLH-1/hMSH-2 and microsatellite instability (MSI) as potential prognostic factors of recurrence in CS I TGCT. METHODS: Fifty-six CS I TGCT patients who underwent inguinal orchiectomy were included in this study. We analysed the relationship between clinicopathological and molecular factors with survival. Analysis of hMLH1, hMSH2 and EGFR expression was carried out by immunohistochemistry. Methylation status of the hMLH1 promoter was determined by pyrosequencing analysis in selected cases. EGFR exons 19, 20, 21 were analysed by PCR labeled-fragments and MSI status was determined using standard Multiplex MSI assays. RESULTS: Classical pathological factors such as lymphovascular invasion, high percentage of embryonal carcinoma, rete testis invasion or tumour size ≥4 cm showed a significant relationship with a higher risk of relapse. Additionally, it was found that an epididymis invasion proved to be a significant independent poor prognostic factor of recurrence (p = 0.001). hMLH1 or hMSH2 expression showed no significant association with risk of relapse and no MSI was found. EGFR expression was observed in 30.4% of samples and its expression was associated with higher risk of relapse (HR 3.5; 95% CI 1.3-9.8; p = 0.016). None of the cases presented EGFR kinase domain mutations. CONCLUSIONS: Epididymis invasion and EGFR expression, but not hMLH-1/hMSH-2 or MSI, could be potentially useful as new prognostic factors of recurrence for CS I TGCT.

Molecular biology of neuroendocrine tumors: from pathways to biomarkers and targets.

Neuroendocrine tumors (NETs) represent a heterogeneous group of diseases with varied natural history and prognosis depending upon the organ of origin and grade of aggressiveness. The most widely used biomarker to determine disease burden and monitor response to treatment is chromogranin A (CgA), but it is far from being the optimal predictive and prognostic biomarker in NETs. Biological understanding and derived treatment options for NETs have changed markedly in recent years. Over the last decade, the genomic landscape of these tumors has been extensively investigated. This has resulted in the discovery of mutations and expression anomalies in genes and pathways such as the PI3K/Akt/mTOR, DAXX/ATRX, and MEN1, which are promising predictive and prognostic biomarkers and future candidates for targeted therapies. Additionally, the study of tumor stroma and environment are one of the most promising fields for discovery of potential new targets and biomarkers.

Merkel cell carcinoma and Merkel cell polyomavirus: a systematic review and meta-analysis.

Several observational studies have assessed the correlation between Merkel cell carcinoma and Merkel cell polyomavirus with variable results. The objective of this systematic review was to determine whether there is a correlation between Merkel cell carcinoma and Merkel cell polyomavirus. Studies assessing the relationship between Merkel cell carcinoma and Merkel cell polyomavirus from January 2008 to August 2014 were pooled from Medline, Embase, PubMed, Cochrane Database of Systemic Reviews and Google Scholar. From each study we collected the first author's last name, publication year, country of origin, type of study design, characteristics of participants, possible variables incorporated into the multivariable analyses and the risk ratio (RR) for Merkel cell carcinoma associated with Merkel cell polyomavirus combined with the corresponding 95% confidence interval (CI). Methodological assessment of the study was evaluated using the Newcastle-Ottawa scale. Crude RR was calculated from the data provided in each article. Meta-analyses for the global RR and for the proportion of positives in both case and control samples were performed. In addition, in order to explore the sources of heterogeneity among the studies, meta-regression and sensitivity analyses are also provided. A total of 22 studies were identified for the analysis. The pooled RR from random-effects analysis was determined to be 6.32 (95% CI, 4.02-9.93). Global proportions of positive samples were 0.79 (95% CI, 0.72-0.84) and 0.12 (95% CI, 0.08-0.19) in the case and control groups, respectively. The findings support the association between Merkel cell carcinoma and Merkel cell polyomavirus. However, a non-negligible percentage of positive results have been identified in controls. Some caution must be taken in the interpretation of these results because heterogeneity between studies was found.

The relation between hypoxia-inducible factor (HIF)-1alpha expression with p53 expression and outcome in surgically treated supraglottic laryngeal cancer.

OBJECTIVE: The purpose of this study was to examine whether a relationship exists between HIF-1alpha expression and the pro-apoptotic protein p53 in supraglottic laryngeal squamous cell carcinomas (SCCs), which could provide information concerning patient prognosis. METHODS: The study population was composed of 106 previously untreated men with SCC of the supraglottic larynx. All the patients underwent surgical resection of the tumor and bilateral neck dissection. Immunohistochemical analysis of HIF-1alpha and p53 protein expression was performed in relation with clinicopathological parameters and prognosis. RESULTS: HIF-1alpha nuclear expression was detected in 71% of primary carcinomas and 55% of the paired lymph node metastases. There was a significant positive correlation between HIF-1alpha and T-classification but no associations were observed with other clinicopathological variables and with prognosis. There was no correlation between the expression of HIF-1alpha and p53. HIF-1alpha overexpression in combination with p53 immunostaining was not associated with disease recurrence or survival. CONCLUSION: The data suggest that HIF-1alpha expression does not have a prognostic value in surgically treated supraglottic laryngeal SCC, and that immunohistochemical determination of p53 does not allow improving the clinical significance of HIF-1alpha.

Analysis of Olig2 and YKL-40 expression: a clinicopathological/immunohistochemical study for the distinction between subventricular zone II and III glioblastomas.

Glioblastomas (GBs) are the most common and lethal primary brain tumors in the adults. Glioblastomas originates either from astrocytes that have accumulated mutations and de-differentiated or from neural stem cells within the subventricular zone (SVZ) in close contact with the vasculature. Recently, several studies have hypothesized that gliomagenesis occurs in perivascular niches with highly invasive peripheral proliferating zones. The purpose of our study was to investigate the pathological and clinical significance of Olig2 and YKL40 immunoexpression in 152 GBs in relationship to the SVZ II and III. Olig2 expressions were successfully detected in 12 (15.58%) of 77 SVZ type II GBs and 16 (21.3%) of 75 SVZ type III GBs, respectively. YKL-40 expression was observed in 45 (58.4%) of 77 SVZ type II GBs and in 17 (22.6%) of 75 SVZ type III GBs, respectively. Stepwise multivariate Cox proportional hazards models were used, and the prognostic factors to significantly impact OS were: PFS < 54 weeks (HR: 5.86; CI: 3.02-11.33; p = 0.00); radiotherapy (HR: 0.34; CI: 0.18-0.60; p = 0.00); radio- and chemotherapy (HR: 0.05; CI: 0.03-0.10; p = 0.0), and YKL-40+ GBs (HR: 1.61; CI: 1.28-2.31; p = 0.01).

Expression and prognostic value of EGFR in invasive breast cancer.

Epidermal growth factor receptor (EGFR) is a membrane receptor expressed in a variety of solid human cancers and directly related with poor prognosis. The objective of this work was to evaluate the EGFR content in breast carcinomas, its possible relationship with different clinical-pathological parameters, and its potential prognostic significance and predictive value. EGFR levels were examined by radioligand binding assays in 846 patients with invasive breast cancer. The median follow-up period was 50 months. There was a wide variability of EGFR levels among the studied tumors (0.01-403 fmol/mg protein). Statistical analysis showed that EGFR levels were significantly higher in younger patients (p=0.0001). EGFR were also notably higher in ER-negative or PgR-negative tumors than in ER-positive (p=0.0001) or PgR-positive tumors (p=0.001). In addition, the presence of high intratumoral EGFR levels (cut-off: 6 fmol/mg protein) was associated with both shorter relapse-free survival (p=0.04) and overall survival (p=0.01) in the group of patients as a whole, as well as with overall survival in the subgroup of patients without any type of systemic adjuvant treatment (p=0.02). However, EGFR levels did not achieve significance as independent prognostic factor in the multivariate analysis. There is a wide variability of intratumoral EGFR levels in breast carcinomas, and these protein levels correlated positively with a poor prognosis in the t univariate analysis. However, further studies are necessary in order to assess the possible clinical value of EGFR in combination with other essential components of the EGFR family network.

[Orthotopic murine model of head and neck squamous cell carcinoma]. / Modelo murino ortotópico de carcinoma epidermoide de cabeza y cuello.

PURPOSE: To develop a reliable animal model able to reproduce the behavior of head and neck squamous cell carcinomas (HNSCC). This model should facilitate our understanding of the molecular mechanisms of tumorigenicity and progression of these tumors, as well as the evaluation of novel therapies. MATERIAL AND METHODS: 20 nude mice nu/nu were injected intraorally and submucosally with a cell line derived from a human squamous cell carcinoma of the glottis. RESULTS: 90% of the mice developed locally agressive squamous cell carcinomas, invading the surrounding muscle fibers and into loose connective tissue structures. All the tumors showed perineural growth. Four (22%) of the 18 mice showed bone destruction, and 22% vascular invasion. Tumor cells invaded lymphatic vessels in all the specimens, and 100% of the mice developed regional lymph node metastases. None of the animals developed haematogenous metastases. CONCLUSIONS: We present a metastasing model of HNSCC that resembles its human counterpart in many aspects.

Oferta de programas para el desarrollo integral de la primera infancia en Chile: revisión exploratoria / Program offer for the integral development of early childhood in Chile: scoping review

OBJETIVO: Describir la oferta programática en primera infancia destinada a favorecer el desarrollo infantil integral en Chile. MÉTODO: Se realizó una revisión exploratoria siguiendo el marco método lógico del Joanna Briggs Institute. La búsqueda fue realizada por un investigador y los criterios de inclusión fueron: programas gubernamentales destinados al desarrollo integral en menores de 5 años en Chile. Los datos fueron organizados y sintetizados para describir características del programa y de la o las prestaciones que entrega. RESULTADOS: La búsqueda identificó 2060 documentos y 72 cumplieron los criterios de inclusión. Se describen 59 programas vigentes que abarcan la primera infancia, es tando principalmente a cargo de los Ministerio de Justicia, Educación, Salud y Desarrollo Social. Los programas están destinados en su mayoría a la promoción e intervención, se encuentran focalizados en población vulnerable, son intersectoriales y utilizan diversas estrategias para su implementación. CONCLUSIÓN: La oferta programática en Chile para la primera infancia presenta características sugeridas como efectivas para favorecer el desarrollo infantil.

OBJECTIVE: To describe the program offering designed to promote comprehensive early childhood de velopment in Chile. METHOD: A scoping review was carried out following the Joanna Briggs Institute's methodological framework. A researcher conducted the review considering as inclusion criteria go vernment programs aimed at the comprehensive development of children under 5 years of age in Chile. The data were organized and synthesized to describe the characteristics of the program and the service(s) it provides. RESULTS: The search identified 2.060 documents and 72 met the inclusion crite ria. 59 current programs are covering early childhood, which are mainly managed by the Ministries of Justice, Education, Health, and Social Development. Most of the programs are aimed at promotion and intervention, focusing on vulnerable populations, are cross-sectoral, and use different strategies for their implementation. CONCLUSION: The program offering in Chile for early childhood has charac teristics suggested as effective to promote child development.

Prognostic significance of the markers IDH1 and YKL40 related to the subventricular zone.

Glioblastoma multiforme (GBM), a highly aggressive brain cancer characterized by uncontrolled proliferation, resistance to cell death, angiogenesis, and vascular edema, remains one of the deadliest types of cancer. The subventricular zone (SVZ) harbors cells with great proliferative potential, and the microenvironment within the SVZ is permissive to growth and proliferation. This neurogenic niche is suspected to be a vulnerable site for the origin of subtypes of GBM. The aim of our study was to determine the immunohistochemical expression of mIDH1 and YKL40 in relationship to the SVZ of GBMs. YKL40, also known as chitinase-like protein 1, is included as a mesenchymal marker and associated with a poor prognosis. The protein is a secreted inflammatory molecule with no chitinolytic activity. However, the mutation of IDH1 (mIDH1) has been found in the cytoplasm and peroxisomes of 70-80% of secondary GBMs. In our study we found that YKL40-positive GBM is significantly linked to SVZ types IV and V (p < 0.0001). Our results show the diversity among GBMs related to the SVZ, which should be considered in the design of future targeted therapies. There was a significant impact of patient age, mIDH1 positivity, SVZ type III, and chemoradiotherapy on overall survival.

Two pathogenic mutations in the mitochondrial DNA tRNA Leu(UUR) gene (T3258C and A3280G) resulting in variable clinical phenotypes.

We studied two patients with ragged-red fibers and combined defects of the mitochondrial respiratory chain in their muscle biopsy. One had mitochondrial encephalomyopathy, lactic acidosis, and stroke-like episodes, and harbored a T3258C transition in the tRNA(Leu(UUR)) gene. The other showed myopathy plus cardiomyopathy and had an A3280G mutation in the same gene. Both mutations were heteroplasmic, abundant in muscle of the patients, less abundant in blood, and still less abundant in blood from their maternal relatives. In both patients, single muscle fiber analysis revealed greater abundance of mutant genomes in ragged-red fibers than in normal fibers, supporting the pathogenicity of both mutations.

Unbiased estimation of the total number of nervous cells and volume of medial mammillary nucleus in humans.

In this study, we demonstrate that aging does not provoke any changes in neuronal number or in the glial cells of the medial mammillary nucleus (MMN) in humans. Three age groups were used: young (age 17-35), adult (age 50-57), and aged (age 70-88). Furthermore, no age-dependent volumetric changes were observed in the MMN. All the estimations were performed with stereological methods: an optical fractionator and Cavalier's principle. The total number of neurons cells was estimated using an optical fractionator and amounted to 32x10(3) in the young group, 24x103 in the adult group, and 29x103 in the aged group. The number of glial cells was 164x10(3), 187x103, 185x103, respectively. Thus, all three age groups had a neuron/glial ratio of about 1:5, 1:8, and 1:6, respectively. The MMN volume was estimated using the Cavalier's principle. The total volume was 6.98 mm3 in the young group, 6.66 mm3 in the adult group, and 6.80 mm3 in the aged group. We have demonstrated that neither the total number of neurons and glial cells nor the volume of MMN are affected by age.

Cholecyst-thoracic fistula. A rare complication of lithiasic cholecystitis.

A 64-year-old male patient was studied for repeated right basal pneumonia of long duration. A computed tomography scan showed a cholecystitis of concealed evolution. Surgery revealed fistulization toward the thorax, with the passage of multiple calculi of a biliary origin to the chest cavity. We report the first described case to our knowledge of cholecyst-thoracic fistula secondary to cholecystitis of long evolution.

Organisation of basement membrane components in the human adult and fetal pituitary gland and in pituitary adenomas.

Cell-matrix interactions undoubtedly have a role in the development and maintenance of the complex nonrandom structure of the human pituitary gland. We have extended previous studies by documenting the patterns of immunoreactivity for type IV collagen, laminin and fibronectin in the fetal gland, comparing these with the adult patterns. In both we have examined the differences between the anterior lobe and intermediate zone in an attempt to elucidate the apparent differences in functional response between corticotrophs in the two areas. We have also examined expression of these proteins in a series of pituitary adenomas. Finally, we have immunolocalised beta 4 integrin, a component of the alpha 6 beta 4 laminin receptor, in the adult gland and in adenomas. In the anterior lobe of the adult gland, type IV collagen and laminin were present in both epithelial and vascular basement membrane. Fibronectin was related to the basement membrane but showed a less continuous distribution. beta 4 Integrin was expressed on the basal aspects of pituitary cells, in association with laminin, suggesting that this did identify the alpha 6 beta 4 laminin receptor. In addition, immunoreactivity was present on the lateral margins of some pituitary cells, which might indicate a role in cell-cell adhesion. None of the proteins showed specific association with any particular cell type, suggesting that these specific interactions do not regulate differentiation. This pattern of expression had developed in the fetal gland by the second trimester, with expression relating to vessels preceding that in epithelial basement membrane. Type IV collagen, laminin and fibronectin were also expressed in epithelial and vascular basement membrane in the intermediate zone of the adult gland, and around Rathke's cleft in the fetal gland. However, the organisation differed, with larger groups of cells enclosed within a single basement membrane. Possible vascular connections demonstrated between the posterior lobe and the intermediate zone would permit access of posterior lobe hormones to this zone. Our data confirmed disruption of expression in pituitary adenomas, type IV collagen, laminin and beta 4 integrin having a mainly perivascular distribution, with more variable immunoreactivity for fibronectin.

Creutzfeldt-Jakob disease and non-convulsive status epilepticus: a clinical and electroencephalographic follow-up study.

OBJECTIVE: To describe the clinical and electroencephalographic findings from a confused elderly woman with Creutzfeldt-Jakob disease (CJD) that initially were compatible with the diagnosis of non-convulsive status epilepticus (NCSE). METHODS AND RESULTS: A 75-year-old right-handed woman was admitted to our hospital because of confusion and alteration of mental status. The two first electroencephalograms (EEGs) showed continuous diffuse spikes, rhythmic sharp waves and sharp-and-slow wave complexes which were completely abolished after the administration of 10 mg of intravenous diazepam. Over the following days, the clinical state of the patient was unmodified despite aggressive antiepileptic therapy. A third EEG revealed pseudo-periodic negative or positive-negative slow waves localised in the right frontal region. Subsequently, two consecutive EEGs showed continuous periodic generalised bi-triphasic complexes at a rate of 1 Hz, compatible with the diagnosis of CJD. Finally, the patient died, and postmortem examination was diagnostic of the sporadic form of CJD. CONCLUSIONS: Clinical and electroencephalographic features in the early stages of CJD may resemble NCSE. The administration of intravenous benzodiazepines and its clinical and electroencephalographic correlation, response to the antiepileptic therapy, and monitoring with serial EEG recordings may be helpful considerations in the differential diagnosis.

Pattern of apolipoprotein D immunoreactivity in human brain.

Presence of intracytoplasmatic apolipoprotein D (apo D), a lipophilic ligand transporter, was investigated in normal human brains between 20 and 55 years, using an anti-human apolipoprotein D antibody and extravidin-biotin-enhanced immunohistochemistry. Apo D immunoreactivity was found in neuroglial cells of white matter in all sampled brain regions studied but also in pial cells and perivascular cells. Immunoreactive neurons do not present a uniform pattern throughout the gray matter. The pons and the brainstem show a high immunoreactivity for apo D in several nuclei (olivary, arciforme, cuneado, raphe). In the cerebellum the immunoreactivity appears in some neurons of the Purkinje layer. Finally in the cerebral cortex apo D positive neurons were not observed. These results suggest that apo D role may vary depending of cellular synthesis or location.

Expression and clinical significance of pepsinogen C in uveal melanomas.

PURPOSE: we investigated by immunohistochemistry the pepsinogen C (pepC) expression in uveal melanomas and analyzed the possible relationship to clinicopathological parameters and prognostic significance. METHODS: We studied 22 patients who had undergone enucleation of the eyeball or local tumor resection for uveal melanoma. The specimens were immunostained for pepC on formalin-fixed, paraffin-embedded sections. Sex, age, tumor location, histological type, local invasion, postoperative treatment and metastasis were evaluated. RESULTS: Eleven tumors (50%) were positive for pepsinogen C. The percentage of pepC-positive tumors was significantly higher in uveal melanomas with scleral invasion than in those without scleral invasion (p < 0.01). PepC expression was significantly associated with a shortened overall survival (p < 0.05). CONCLUSIONS: Our results show that pepsinogen C may be expressed by uveal melanoma and suggest that this protein could be considered as a new, unfavorable prognostic factor in these tumors.

Bilateral fronto-occipital polymicrogyria and epilepsy.

We present a clinico-pathological case report in which both cortical dysplasia and epilepsy coexisted: a 30 year old male who was dead on arrival at hospital. One and a half hours earlier he had developed complex partial status with peri-oral cyanosis. At post mortem examination his brain showed bilateral occipital frontal polymicrogyria with unlayered neuronal migration disorder; in other parts there were fourth layer migration disorders. The white matter exhibited multicystic encephalopathy. In the heart there was chronic interstitial and perivascular fibrosis, although he died of a cardiac arrest. Bilateral frontal-occipital polymicrogyria is highly epileptogenic. This was a sporadic case and we cannot define a clear aetiology. There was a pathological cardiac condition without previous vascular risk factors which might be related to repetition of seizures and possibly to his sudden death during status epilepticus.