REGISTRI: Regorafenib in first-line of KIT/PDGFRA wild type metastatic GIST: a collaborative Spanish (GEIS), Italian (ISG) and French Sarcoma Group (FSG) phase II trial.

BACKGROUND: Approximately 15% of adult GIST patients harbor tumors that are wild-type for KIT and PDGFRα genes (KP-wtGIST). These tumors usually have SDH deficiencies, exhibit a more indolent behavior and are resistant to imatinib. Underlying oncogenic mechanisms in KP-wtGIST include overexpression of HIF1α high IGFR signaling through the MAPK pathway or BRAF activating mutation, among others. As regorafenib inhibits these signaling pathways, it was hypothesized that it could be more active as upfront therapy in advanced KP-wtGIST. METHODS: Adult patients with advanced KP-wtGIST after central confirmation by NGS, naïve of systemic treatment for advanced disease, were included in this international phase II trial. Eligible patients received regorafenib 160 mg per day for 21 days every 28 days. The primary endpoint was disease control rate (DCR), according to RECIST 1.1 at 12 weeks by central radiological assessment. RESULTS: From May 2016 to October 2020, 30 patients were identified as KP-wtGIST by Sanger sequencing and 16 were confirmed by central molecular screening with NGS. Finally, 15 were enrolled and received regorafenib. The study was prematurely closed due to the low accrual worsened by COVID outbreak. The DCR at 12 weeks was 86.7% by central assessment. A subset of 60% experienced some tumor shrinkage, with partial responses and stabilization observed in 13% and 87% respectively, by central assessment. SDH-deficient GIST showed better clinical outcome than other KP-wtGIST. CONCLUSIONS: Regorafenib activity in KP-wtGIST compares favorably with other tyrosine kinase inhibitors, especially in the SDH-deficient GIST subset and it should be taken into consideration as upfront therapy of advanced KP-wtGIST. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT02638766.

Perianal Paget's disease.

The incidence of extramammary Paget's disease (EMPD) is very low. It is very important to distinguish between primary Paget's disease and secondary to another process. An 85-year-old man consulted for the presence of an erythematous plaque located in the anal and gluteal area, confirming Paget cells in the biopsy.

Epithelioid Sarcoma in the Median Nerve of the Hand: A Case Report.

Epithelioid sarcoma of the peripheral nerves is extremely rare. We present a case concerning the median nerve of the right hand in a 35-year-old woman who was treated with radical resection, reconstructive surgery, and chemotherapy. After 2 years of follow-up, there is no evidence of local recurrence or metastatic dissemination.

Frequency of low-level and high-level mosaicism in sporadic retinoblastoma: genotype-phenotype relationships.

Somatic mutational mosaicism is a common feature of monogenic genetic disorders, particularly in diseases such as retinoblastoma, with high rates of de novo mutations. The detection and quantification of mosaicism is particularly relevant in these diseases, since it has important implications for genetic counseling, patient management, and probably also on disease onset and progression. In order to assess the rate of somatic mosaicism (high- and low-level mosaicism) in sporadic retinoblastoma patients, we analyzed a cohort of 153 patients with sporadic retinoblastoma using ultra deep next-generation sequencing. High-level mosaicism was detected in 14 out of 100 (14%) bilateral patients and in 11 out of 29 (38%) unilateral patients in whom conventional Sanger sequencing identified a pathogenic mutation in blood DNA. In addition, low-level mosaicism was detected in 3 out of 16 (19%) unilateral patients in whom conventional screening was negative in blood DNA. Our results also reveal that mosaicism was associated to delayed retinoblastoma onset particularly in unilateral patients. Finally we compared the level of mosaicism in different tissues to identify the best DNA source to identify mosaicism in retinoblastoma patients. In light of these results we recommended analyzing the mosaic status in all retinoblastoma patients using accurate techniques such as next-generation sequencing, even in those cases in which conventional Sanger sequencing identified a pathogenic mutation in blood DNA. Our results suggest that a significant proportion of those cases are truly mosaics that could have been overlooked. This information should be taking into consideration in the management and genetic counseling of retinoblastoma patients and families.

Expression of dog1 in low-grade fibromyxoid sarcoma: A study of 19 cases and review of the literature.

DOG1 is a highly-sensitive marker often included in the immunohistochemical panel for the diagnosis of gastrointestinal stromal tumors (GISTs). Recent research has shown that DOG1 may also be expressed by low-grade fibromyxoid sarcomas (LGFMSs); this may give rise to diagnostic error when the sarcoma is located in the abdominal cavity. This paper reports on immnohistochemical expression of DOG1 in 19 LGFMSs using two different monoclonal antibodies: K9 (Leica, Novocastra Laboratories, Newcastle upon Tyne, UK) and SP31 (Thermo Scientific, Freemont, USA). All LGFMSs displayed the standard histological pattern of alternating myxoid and fibrous areas, low cellularity and bland spindle-cell morphology. Positive staining for MUC4 was observed in 18/19 cases (94.7%), while there was rearrangement of the FUS gene in 14/19 (73.7%) cases and of the EWR1 gene in 2/19 (10.5%). The sarcoma staining negative for MUC4 displayed FUS gene rearrangement. Whole-section immunohistochemistry revealed positive staining for DOG1 in 8/19 cases (42.1%), though only with clone K9. Cytoplasmic as well as membrane staining was observed in all cases; staining was focal (10-30%) and of varying intensity (1+ to 2+). In conclusion, DOG1 clone K9 exhibited low sensitivity (42.1%) for the diagnosis of LGFMS, although higher than clone SP31. Since the two clones display similar sensitivity and specificity for GIST diagnosis, SP31 would appear to be more specific for this purpose, since no reaction was observed here with LGFMS, a GIST-mimicking lesion.

A study of the suitability of autoencoders for preprocessing data in breast cancer experimentation.

Breast cancer is the most common cause of cancer death in women. Today, post-transcriptional protein products of the genes involved in breast cancer can be identified by immunohistochemistry. However, this method has problems arising from the intra-observer and inter-observer variability in the assessment of pathologic variables, which may result in misleading conclusions. Using an optimal selection of preprocessing techniques may help to reduce observer variability. Deep learning has emerged as a powerful technique for any tasks related to machine learning such as classification and regression. The aim of this work is to use autoencoders (neural networks commonly used to feed deep learning architectures) to improve the quality of the data for developing immunohistochemistry signatures with prognostic value in breast cancer. Our testing on data from 222 patients with invasive non-special type breast carcinoma shows that an automatic binarization of experimental data after autoencoding could outperform other classical preprocessing techniques (such as human-dependent or automatic binarization only) when applied to the prognosis of breast cancer by immunohistochemical signatures.

Tumores del estroma gastrointestinal: breve actualización y consenso de la SEAP-SEOM sobre diagnóstico patológico y molecular / A brief up-date and consensus about the pathological and molecular diagnosis of gastrointestinal stromal tumours from the SEAP-SEOM

Los tumores del estroma gastrointestinal (GIST) son las neoplasias mesenquimales más frecuentes del tubo digestivo con una incidencia de 1,1 casos/100.000 habitantes/año. Un grupo de expertos de la Sociedad Española de Anatomía Patológica y la Sociedad Española de Oncología se reunieron para realizar una breve actualización de los GIST y consensuar los aspectos relacionados con su diagnóstico patológico y molecular. Los GIST generalmente son lesiones solitarias, bien circunscritas, de dimensiones variables (< 10 mm-35cm), que pueden presentar crecimiento parietal intra o extraluminal o mixto (en reloj de arena). Histológicamente, son neoplasias no encapsuladas, con crecimiento expansivo y celularidad fusiforme (70%), epitelioide (20%) o mixta (10%). La actividad mitótica generalmente es moderada o baja y debe evaluarse exclusivamente en los territorios con mayor celularidad o con mayor número de mitosis. La gran mayoría de los GIST presentan mutaciones activadoras, mutuamente excluyentes, en los genes que codifican para los receptores tirosina quinasa de tipo iii KIT y PDGFRA; con mucha menor frecuencia también se han descrito mutaciones en otros genes, tales como BRAF, NF1, y genes del complejo SDH. El método de detección de mutaciones de KIT y PDGFRA más ampliamente utilizado es la amplificación mediante reacción en cadena de la polimerasa de los exones de interés y la secuenciación directa (método Sanger) de estos productos de amplificación. Los informes moleculares siempre deben especificar el tipo de análisis llevado a cabo y la región o mutaciones que se han evaluado, así como indicar la sensibilidad del método de detección empleado (AU)

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms of the digestive tract, with an incidence of 1.1 cases/100,000 inhabitants/year. A group of experts from the Spanish Societies of Pathology and Oncology met to discuss a brief update on GISTs and agree on aspects relating to the pathological and molecular diagnosis of these tumors. GISTs are generally solitary, well-circumscribed lesions of variable size (<10 mm-35cm) that may present with intra- or extra-luminal parietal growth or a mixed-type (hourglass) growth pattern. Histologically, they are unencapsulated neoplasms displaying expansive growth and spindle-shaped (70%), epithelioid (20%) or mixed cellularity (10%). Mitotic activity is generally moderate or low and should be evaluated only in areas with high cellularity or higher mitotic frequency. The great majority of GISTs harbour mutually-exclusive activating mutations in genes coding for the type iii receptor tyrosine kinases KIT and PDGFRA; less commonly, GISTs have also been reported to display mutations elsewhere, including BRAF and NF1 and SDH-complex genes. The method most widely used to detect KIT and PDGFRA mutations is amplification of the exons involved by polymerase chain reaction followed by direct sequencing (Sanger method) of these amplification products. Molecular analyses should always specify the type of analysis performed, the region or mutations evaluated and the sensitivity of the detection method employed (AU)

Planos conjugados y sistema de iluminación de Köhler en microscopía óptica / Conjugate planes and Köhler illumination in optical microscopy

Un adecuado conocimiento y comprensión del concepto de planos conjugados es de capital importancia en la utilización del microscopio por cuanto que desde hace ya bastante tiempo el diseño de los microscopios se basa en la correcta situación de sus dos conjuntos de planos conjugados. En 1893 August Köhler publicó el trabajo «Un nuevo sistema de iluminación en microfotografía» donde dio a conocer los fundamentos básicos de una técnica de iluminación que actualmente lleva su nombre. El conocimiento y aplicación de los principios del sistema de iluminación de Köhler constituye el elemento de mayor importancia en el correcto manejo de un microscopio. Dichos principios no siempre son bien conocidos y comprendidos por los usuarios del microscopio constituyendo una fuente frecuente de errores en microscopía, particularmente en microfotografía. En este artículo revisamos los principios básicos del concepto de planos conjugados y del sistema de iluminación de Köhler (AU)

Adequate knowledge and understanding of the concept of conjugate planes is of paramount importance in the use of the microscope and for a long time microscope design was based on the correct location of the two sets of conjugate planes. In 1893 August Köhler published the article «A new illumination system in microphotography» in which he introduced the basics of an illumination technique that now bears his name. The knowledge and application of the principles of the Köhler illumination system is the most important element in the proper handling of a microscope. These principles are not always well known or understood by the users of microscopes, frequently leading to errors in microscopy, particularly in photomicrography. This article reviews the basic principles of the concept of conjugate planes and Köhler illumination system (AU)

Hiperplasia difusa idiopática de células neuroendocrinas de pulmón (DIPNECH): una entidad preneoplásica, infradiagnosticada y poco conocida / Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia (DIPNECH): a little-known, underdiagnosed preneoplastic lesion

La hiperplasia difusa idiopática de células neuroendocrinas de pulmón aparece recogida en la clasificación de la OMS de tumores torácicos desde el año 1999 como una lesión epitelial preinvasiva caracterizada por una proliferación generalizada de células dispersas y aisladas, nódulos pequeños (cuerpos neuroendocrinos) o proliferaciones lineales de células neuroendocrinas pulmonares, confinadas al epitelio bronquial o bronquiolar, e incluye proliferaciones locales extraluminales (tumorlets o carcinoides). En la presente revisión se actualizan los criterios morfológicos cuantitativos establecidos recientemente y se consideran nuevos aspectos cualitativos que pueden contribuir a una mejor caracterización de la entidad (AU)

Diffuse idiopathic pulmonary neuroendocrine cell hyperplasia appears in the WHO classification of thoracic tumours since 1999 as a preinvasive epithelial lesion characterized by a proliferation of scattered and isolated cells, small nodules (neuroendocrine bodies) or linear pulmonary neuroendocrine cell proliferations, confined to the bronchial or bronchiolar epithelium, including extraluminal local proliferations (tumorlets or carcinoids). In this review we update the recently established quantitative morphological criteria and new qualitative aspects are considered to contribute to a better characterization of the entity (AU)

Epidemiología del esófago de Barrett y adenocarcinoma esofágico en España. Estudio unicéntrico / Epidemiology of Barrett's esophagus and esophageal adenocarcinoma in Spain. A unicentric study

Introducción: el esófago de Barrett (EB) es una enfermedad adquirida definida por la presencia de metaplasia intestinal en el esófago distal. Su prevalencia se ha incrementado de forma alarmante en los últimos años. Objetivos: los objetivos primarios del presente trabajo fueron analizar el comportamiento del EB y del adenocarcinoma esofágico (ACE) en un área sanitaria española durante el seguimiento del periodo del estudio. Métodos: se analizaron características sociodemográficas y el consumo de alcohol y tabaco. También se valoró el comportamiento histológico así como las causas de defunción en cada uno de los grupos. Resultados: se incluyeron 430 pacientes, 338 con EB y 92 con ACE. La tasa de incidencia pasó de 2,25 y 1,25 por 100.000 habitantes en 1996 a 6,5 y 4,75 en 2011, en EB y ACE, respectivamente. Hubo más varones, mayor edad e ingesta etílica en el grupo adenocarcinoma respecto al grupo de Barrett. La supervivencia del ACE fue de 23 meses. Las principales causas de muerte en los pacientes con Barrett fueron el cáncer no esofágico y la enfermedad cardiovascular. Conclusiones: existe una mayor incidencia y prevalencia tanto del EB como del ACE en los últimos años. Como factores de riesgo encontramos el sexo masculino, mayor edad y consumo de alcohol. El EB largo (> 3 cm) está implicado en la progresión de la displasia. El diagnóstico de ACE se hace, la mayor parte de las veces, con el debut de la enfermedad neoplásica y, en el menor de los casos, sobre un EB previo. La enfermedad cardiovascular y neoplásica no esofágica han sido las principales causas de mortalidad en los pacientes con EB (AU)

Introduction: Barrett’s esophagus (BE) is an acquired disease defined by the presence of intestinal metaplasia with goblet cells in the distal esophagus. The prevalence of BE has increased dramatically over the last years. Aims: The primary aims of the study were to analyze the characteristics of BE and esophageal adenocarcinoma (EAC) in a Spanish health district during a follow-up period. Methodology: Sociodemographic factors, alcohol consumption and cigarette smoking were analyzed. We also studied the histological behavior and cause of death in each group. Results: In the present study 430 patients were included, 338 with BE and 92 with EAC. Incidence rates have risen from 2.25 and 1.25 per 100,000 inhabitants in 1996 to 6.5 and 4.75 per 100,000 in 2011, respectively. In the EAC group, male gender, age and alcohol consumption were higher in comparison to the BE group, and the overall survival was 23 months. In the BE group, the main causes of death were non-esophageal cancer and cardiovascular disease. Conclusions: The incidence and prevalence rates of AEC and BE have risen over the past years. Risk factors for these conditions were male gender, age and alcohol consumption. Long BE (> 3 cm) is involved in dysplasia progression. AEC diagnosis mainly occurs after neoplasia is detected and, in a few cases, due to a previous BE. Cardiovascular diseases and non-esophageal cancers have been found to be the main cause of death in BE patients (AU)

Epidemiology of Barrett's esophagus and esophageal adenocarcinoma in Spain. A unicentric study.

INTRODUCTION: Barrett's esophagus (BE) is an acquired disease defined by the presence of intestinal metaplasia with goblet cells in the distal esophagus. The prevalence of BE has increased dramatically over the last years. AIMS: The primary aims of the study were to analyze the characteristics of BE and esophageal adenocarcinoma (EAC) in a Spanish health district during a follow-up period. METHODOLOGY: Sociodemographic factors, alcohol consumption and cigarette smoking were analyzed. We also studied the histological behavior and cause of death in each group. RESULTS: In the present study 430 patients were included, 338 with BE and 92 with EAC. Incidence rates have risen from 2.25 and 1.25 per 100,000 inhabitants in 1996 to 6.5 and 4.75 per 100,000 in 2011, respectively. In the EAC group, male gender, age and alcohol consumption were higher in comparison to the BE group, and the overall survival was 23 months. In the BE group, the main causes of death were non-esophageal cancer and cardiovascular disease. CONCLUSIONS: The incidence and prevalence rates of AEC and BE have risen over the past years. Risk factors for these conditions were male gender, age and alcohol consumption. Long BE (> 3 cm) is involved in dysplasia progression. AEC diagnosis mainly occurs after neoplasia is detected and, in a few cases, due to a previous BE. Cardiovascular diseases and non-esophageal cancers have been found to be the main cause of death in BE patients.

MicroRNA deregulation in triple negative breast cancer reveals a role of miR-498 in regulating BRCA1 expression.

Emerging evidence suggests that BRCA1 pathway contributes to the behavior of sporadic triple negative breast cancer (TNBC), but little is known about the mechanisms underlying this association. Considering the central role that microRNAs (miRNAs) play in gene expression regulation, the aim of this study was to identify miRNAs specifically deregulated in TNBC and investigate their involvement in BRCA1 regulation. Using locked nucleic acid (LNA)-based microarrays, expression levels of 1919 miRNAs were measured in paraffin-embedded tissues from 122 breast tumors and 11 healthy breast tissue samples. Differential miRNA expression was explored among the main subtypes of breast cancer, and 105 miRNAs were identified as specific for triple negative tumors. In silico prediction revealed that miR-498 and miR-187-5p target BRCA1, and these results were confirmed by luciferase reporter assay. While miR-187-5p was found overexpressed in a luminal B cell line, miR-498 was highly expressed in a triple negative cell line, Hs578T, and its expression was negatively correlated with the levels of BRCA1. We functionally demonstrated that miR-498 inhibits BRCA1 in breast cancer cell lines, and showed that inhibition of miR-498 led to reduced proliferation in the triple negative cell line Hs578T. Our results indicate that miR-498 regulates BRCA1 expression in breast cancer and its overexpression could contribute to the pathogenesis of sporadic TNBC via BRCA1 downregulation.

A propósito de un caso; paciente joven con tumor desmoide de mama diagnosticado tras tumorectomía / Desmoid breast tumor diagnosed after lumpectomy in a young patient a case report

Presentamos el caso de una paciente de 16 años, sin antecedentes ginecológicos de interés, con previo diagnóstico de tumor filoides en línea intercuadrántica de mama derecha. Tras ser tratada con tumorectomía, y tras el estudio anatomopatológico de la pieza, resultó estar afecta de tumor desmoide en mama. Dada la escasa prevalencia de esta afección, y la afectación de los bordes quirúrgicos tras el tratamiento quirúrgico, consideramos necesario elaborar una revisión bibliográfica sobre el tumor desmoide en mama; etiología, clínica y tratamiento (AU)

We report the case of a 16-year-old patient with no relevant gynecologic history, who was diagnosed with a phyllodes tumor in the border between the lower and upper outer quadrants of the right breast. The patient was treated with a tumorectomy/lumpectomy, and after pathological study of the specimen, was diagnosed with a desmoid breast tumor. Given the rarity of this entity, and the positive microscopic surgical margins, we consider that a literature review of desmoid breast tumor (etiology, clinical presentation and treatment) is timely (AU)

Tumor microRNA expression profiling identifies circulating microRNAs for early breast cancer detection.

BACKGROUND: The identification of novel biomarkers for early breast cancer detection would be a great advance. Because of their role in tumorigenesis and stability in body fluids, microRNAs (miRNAs) are emerging as a promising diagnostic tool. Our aim was to identify miRNAs deregulated in breast tumors and evaluate the potential of circulating miRNAs in breast cancer detection. METHODS: We conducted miRNA expression profiling of 1919 human miRNAs in paraffin-embedded tissue from 122 breast tumors and 11 healthy breast tissue samples. Differential expression analysis was performed, and a microarray classifier was generated. The most relevant miRNAs were analyzed in plasma from 26 healthy individuals and 83 patients with breast cancer (36 before and 47 after treatment) and validated in 116 healthy individuals and 114 patients before treatment. RESULTS: We identified a large number of miRNAs deregulated in breast cancer and generated a 25-miRNA microarray classifier that discriminated breast tumors with high diagnostic sensitivity and specificity. Ten miRNAs were selected for further investigation, of which 4 (miR-505-5p, miR-125b-5p, miR-21-5p, and miR-96-5p) were significantly overexpressed in pretreated patients with breast cancer compared with healthy individuals in 2 different series of plasma. MiR-505-5p and miR-96-5p were the most valuable biomarkers (area under the curve 0.72). Moreover, the expression levels of miR-3656, miR-505-5p, and miR-21-5p were decreased in a group of treated patients. CONCLUSIONS: Circulating miRNAs reflect the presence of breast tumors. The identification of deregulated miRNAs in plasma of patients with breast cancer supports the use of circulating miRNAs as a method for early breast cancer detection.