Next-generation sequencing of uveal melanoma with clinical and histological correlations: Prognostic value of new mutations in the PI3K/AKT/mTOR pathway.

BACKGROUND: Uveal melanoma (UM) is the eye's most common primary malignancy and there are no effective therapies for disseminated disease. It is important to try to know the patient's prognosis. The aim of this study was to reflect genetic variants, studied using NGS, of a series of 69 cases of UM and its correlation with histopathology and clinical progression. METHODS: We performed targeted NGS using a 519-gene panel. RESULTS: There were selected 28 different mutated genes, showing a total of 231 genetic variants that affected the function of the protein. The most common secondary mutations occurred in SF3B1 (in 26%), followed by BAP1 (in 23%), LRP1B (22%) and FGFR4 (20%). BAP1 mutation was associated with a greater likelihood of metastases and with greater presence of epithelioid cells. LRP1B was also associated with presence of epithelioid cells SF3B1 mutation was significantly associated with a spindle morphology. We found variants in the RAD51B, TOP2A, PTPRD, TSC2, DHX9, PDK1 and MTOR that have not been previously reported in consulted databases. The presence of a mutation in: CHEK2, DHX9 and PDK1 was associated with metastases. CONCLUSIONS: BAP1 is the most solid biomarker of a poor prognosis in UM and mutations can be detected using NGS. SF3B1 is associated with the spindle cell subtype of UM, which gives it probably a favourable prognostic value. Our study suggests that mutations in DHX9 and PDK1 can have prognostic value. These potential biomarkers are related to the PI3K/AKT/mTOR pathway and makes them candidates for developing new directed therapies.

Behaviour of the Peri-Implant Soft Tissue with Different Rehabilitation Materials on Implants.

(1) Background: Mucointegration seems to gain interest when talking about success in the maintenance of dental implants. As we well know, collagen fibres cannot be inserted due to the lack of root structure on the implant surface, so the structural integration of peri-implant tissues that provide a firm seal around implants seems to be of interest when it comes to ensuring the survival of dental implants. To achieve a good epithelial barrier, the physicochemical characteristics of the surfaces of the restorative materials are of vital importance; therefore, the objective of this study is to analyse the histological behaviour of the peri-implant soft tissues in three different restorative materials. (2) Methods: Histological analysis of biopsied peri-implant keratinised mucosa, inflammatory epithelium and connective tissue in contact with a reinforced composite (BRILLIANT Crios), a cross-linked polymethylmethacrylate (TELIO CAD), and a hybrid ceramic (Vita Enamic), restored on a customised Atlantis-type abutment (Dentsply Sirona) between 60 and 180 days after restoration. (3) Results: A greater number of cells per mm2 of keratinised epithelium is observed in the reinforced composite, which could indicate greater surface roughness with greater inflammatory response. In this way, the greater number of lymphocytes and the lateral cellular composition of the inflammatory cells confirm the greater inflammatory activity towards that material. The best material to rehabilitate was hybrid ceramic, as it shows a better cellular response. (4) Conclusions: Knowing the limitations of the proposed study, despite the fact that greater inflammation is observed in the reinforced composite relative to the other materials studied, no statistically significant differences were found.

Effects of polyphenolic maqui (Aristotelia chilensis) extract on the inhibition of NLRP3 inflammasome and activation of mast cells in a mouse model of Crohn's disease-like colitis.

Introduction: Crohn's disease (CD) involves activation of mast cells (MC) and NF-кB in parallel with the PPAR-α/NLRP3 inflammasome/IL-1ß pathway in the inflamed colon. Whether polyphenols from maqui (Aristotelia chilensis) represent a natural alternative treatment for CD is unclear. Therefore, we used an animal model of 2,4,6-trinitrobenzene sulfonic acid (TNBS)-induced CD-like colitis to investigate protective effects of maqui extract through monitoring NLRP3 inflammasome and MC activation in colon tissue. Methods: Maqui extract was administered via orogastric route to mice after (post-Treatment group) or prior (pre-Treatment group) to TNBS-induction. Colon pathology was characterized by histoarchitectural imaging, disease activity index (DAI), and assessing NF-кB, p-NF-кB, PPAR-α/NLRP3 expression and IL-1ß levels. Results: Compared to mice treated with TNBS alone administration of anthocyanin-rich maqui extract improved the DAI, colon histoarchitecture and reduced both colon wet-weight and transmural inflammation. Induction with TNBS significantly increased colonic NLPR3 inflammasome activation, while co-treatment with maqui extract (either post- or pre-Treatment) significantly downregulated NLRP3, ASC and caspase-1 levels, which manifested as reduced colonic IL-1ß levels. Supplemented maqui extract marginally diminished NF-кB activity in epithelial cells but reached statistical significance in immune cells (as judged by decreased NF-кB phosphorylation). PPAR-α signaling was largely unaffected by Maqui whereas MC infiltration into the colon mucosa and submucosa decreased and their level of degranulation was suppressed. Conclusion: These outcomes show the post- and pre- Treatment effect of a polyphenolic extract rich in anthocyanins from maqui the acute phase of TNBS- induced CD-like colitis is linked to suppression of the NLRP3 inflammasome and reduced MC responses. These data indicate that maqui extract represents a potential nutraceutical for the treatment of inflammatory bowel disease (IBD).

Metanephric adenoma: molecular study and review of the literature.

INTRODUCTION: Metanephric adenoma (MA) is an uncommon benign tumor accounting for 0.2-0.7% of adult renal epithelial neoplasms. The clinical course is often indolent, but diagnosis should not be delayed since clinical symptoms (hematuria, fever, palpable abdominal mass, and flank pain) may be non-specific and overlap with those of a malign renal neoplasm. We report on 4 cases of AM, for which morphological and mutational analysis were performed. MATERIAL AND METHODS: Immunohistochemical staining was performed on sections cut from paraffin blocks to assess expression of WT1, vimentin, racemase, CK7, CD10 and RCC. Testing for the BRAF gene mutation V600 was carried out using real-time PCR (Cobas® 4800). RESULTS: In all four cases, tumors were visible as well-circumscribed, non-encapsulated masses located in the renal cortex and extending towards the medulla. At immunohistochemical examination, tumor cells stained negative for CK7, CD10 and RCC and positive for both WT1 (nuclear, intense) and vimentin (cytoplasmic, intense, and diffuse). Molecular analysis revealed the BRAF gene mutation V600E in three cases and wild-type BRAF in the fourth. CONCLUSIONS: BRAF molecular mutation analysis may aid diagnosis in cases with atypical histological features, especially in small incisional biopsies when reassessment of surgical treatment may be considered.

Autoencoded DNA methylation data to predict breast cancer recurrence: Machine learning models and gene-weight significance.

Breast cancer is the most frequent cancer in women and the second most frequent overall after lung cancer. Although the 5-year survival rate of breast cancer is relatively high, recurrence is also common which often involves metastasis with its consequent threat for patients. DNA methylation-derived databases have become an interesting primary source for supervised knowledge extraction regarding breast cancer. Unfortunately, the study of DNA methylation involves the processing of hundreds of thousands of features for every patient. DNA methylation is featured by High Dimension Low Sample Size which has shown well-known issues regarding feature selection and generation. Autoencoders (AEs) appear as a specific technique for conducting nonlinear feature fusion. Our main objective in this work is to design a procedure to summarize DNA methylation by taking advantage of AEs. Our proposal is able to generate new features from the values of CpG sites of patients with and without recurrence. Then, a limited set of relevant genes to characterize breast cancer recurrence is proposed by the application of survival analysis and a pondered ranking of genes according to the distribution of their CpG sites. To test our proposal we have selected a dataset from The Cancer Genome Atlas data portal and an AE with a single-hidden layer. The literature and enrichment analysis (based on genomic context and functional annotation) conducted regarding the genes obtained with our experiment confirmed that all of these genes were related to breast cancer recurrence.

Polyphenolic Maqui Extract as a Potential Nutraceutical to Treat TNBS-Induced Crohn's Disease by the Regulation of Antioxidant and Anti-Inflammatory Pathways.

Nutraceuticals include a wide variety of bioactive compounds, such as polyphenols, which have been highlighted for their remarkable health benefits. Specially, maqui berries have shown great antioxidant activity and anti-inflammatory effects on some inflammatory diseases. The objectives of the present study were to explore the therapeutic effects of maqui berries on acute-phase inflammation in Crohn's disease. Balb/c mice were exposed to 2,4,6-trinitrobenzene sulfonic acid (TNBS) via intracolonic administration. Polyphenolic maqui extract (Ach) was administered orally daily for 4 days after TNBS induction (Curative Group), and for 7 days prior to the TNBS induction until sacrifice (Preventive Group). Our results showed that both preventive and curative Ach administration inhibited body weight loss and colon shortening, and attenuated the macroscopic and microscopic damage signs, as well as significantly reducing transmural inflammation and boosting the recovery of the mucosal architecture and its muco-secretory function. Additionally, Ach promotes macrophage polarization to the M2 phenotype and was capable of down-regulating significantly the expression of inflammatory proteins COX-2 and iNOS, and at the same time it regulates the antioxidant Nrf-2/HO-1 pathway. In conclusion, this is the first study in which it is demonstrated that the properties of Ach as could be used as a preventive and curative treatment in Crohn's disease.

Autohemotherapy with ozone as a possible effective treatment for Fibromyalgia.

OBJECTIVE: The objective of this study is to evaluate the effectiveness of autohemotherapy with ozone in the management of fibromyalgia (FM). DESIGN: 20 FM patients (according to the criteria of the American College of Rheumatology), were treated with 10 sessions of ozone hemotherapy (2 sessions per week) with a concentration of 30-60 mcgr/ml. The health condition of the patients was evaluated before and after treatment, through the Fibromyalgia Impact Questionnaire (FIQ). Blood samples were obtained from all patients by venous puncture for biochemical routine analysis and serotonin levels in serum and the following peripheral blood mononuclear cells (BMCs) were isolated for oxidative stress quantification: reactive oxygen species (ROS) generation, and lipid peroxidation (LP) and protein carbonyl (PC) content, as these are signs of oxidative cell damage. RESULTS: All patients treated with ozone reported an improvement in sleep and mental alertness, a marked decrease of asthenia accompanied by a decrease of FIQ as well as tender points, and a moderate increase of serotonin levels. Also, an important decrease of LP and PC was observed; ROS also decreased, although less obvious, which indicates a reduction in oxidative stress levels. CONCLUSIONS: The autohemotherapy with ozone in patients with FM showed an important decline of tender points and FIQ score, as well as a decrease of oxidative stress levels. This treatment allows patients to face life with greater vitality and less drug use, diminishing harmful side effects. Further investigation should be carried out, including groups with more patients and clinical trials, to elucidate the effect of ozone therapy in patients suffering from FM.

Mature Cystic Teratoma of the Lung With a Somatic-Like Malignant Component in a Patient With Testicular Germ-Cell Tumor / Teratoma quístico maduro de pulmón con componente maligno de tipo somático en un paciente con un tumor testicular de células germinales

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Recurrent Cutaneous Angiosarcoma of the Scalp With Aberrant Expression of S100: A Case Report.

Angiosarcoma (AS) is a malignant mesenchymal neoplasm of endothelial origin with a predominantly lymphatic immunophenotype, which accounts for less than 1% of all sarcomas. Cutaneous AS of the scalp is associated with high rates of local recurrence and a poor prognosis. Histologically, poorly differentiated AS often comprises solid epithelioid cells, although rare variants involving spindle cells have been reported; diagnosis requires immunohistochemical analysis using vascular cell markers. We report on a cutaneous spindle-cell AS of the scalp in a female patient; key features included spontaneous regression after biopsy, local recurrence 2 years later, and aberrant nuclear staining for S100 protein in an area of the tumor not expressing CD34 or D2-40. Tumor cells exhibited positivity for vascular markers CD31, CD34, D2-40, ERG and FLI-1 and were negative for myoid markers (αSMA and desmin), epithelial (EMA and cytokeratin AE1/AE3) and melanocyte markers (HMB45 and melan-A). Cutaneous spindle-cell AS of the scalp is a rare variant with a poor prognosis. Diagnosis of spindle-cell AS was confirmed by immunohistochemical analysis using CD31, CD34, ERG, FLI-1, podoplanin (D2-40), and claudin-5. Although a number of authors have noted aberrant expression of cytokeratins, CD30, CD117 and neuroendocrine markers (synaptophysin and chromogranin A) in AS, intense positive nuclear staining for S100 protein in neoplastic cells has not hitherto been observed. This article reports on a spindle-cell AS of the scalp notable for aberrant expression of S100, spontaneous regression and recurrence 2 years later at the same site and displaying identical histological and immunohistochemical features.

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.

Calcifilaxis en una paciente sin insuficiencia renal avanzada / Calciphylaxis in a patient without advanced renal failure

La calcifilaxis es una enfermedad poco frecuente, aunque presenta una elevada tasa de mortalidad debido sobre todo a complicaciones como sepsis o gangrena. Generalmente se asocia a insuficiencia renal severa y en otras ocasiones a alteraciones del metabolismo calcio-fósforo o al uso de corticoides para enfermedades autoinmunes. Se presenta como lesiones cutáneas que se pueden ulcerar o infectar, debiendo diferenciarlas de las lesiones de causa vascular mediante el estudio histológico de la biopsia de la lesión. La biopsia cutánea muestra alteraciones histológicas características que facilitan el diagnóstico diferencial de esta patología. Para su tratamiento, se deben identificar y corregir los posibles factores implicados en su aparición. El tiosulfato de sodio es útil para el tratamiento. Presentamos el caso de una paciente con insuficiencia renal leve que padeció dicha entidad con buena evolución tras tratamiento (AU)

Calciphylaxis is a relatively rare disease associated with high mortality rates due to potential complications of sepsis or gangrene. It is observed mainly in patients with severe kidney disease, and in other cases it is associated with altered calcium-phosphorus metabolism or to the use of corticosteroids in the treatment of autoimmune diseases. It is characterized by painful skin lesions that may become ulcerated or infected. We must differentiate them from vascular lesions through a histological study of the lesion biopsy. The skin biopsy shows characteristic histological findings that facilitate differential diagnosis. As a treatment we must identify and correct risk factors involved in its development. Sodium thiosulphate has proved to be an effective treatment. We present the case of a patient with mild kidney disease who suffered calciphylaxis with good outcome after treatment (AU)

Carcinoma epidermoide de laringe sincrónico con carcinoma medular de tiroides. Presentación de un caso / Invasive laryngeal squamous cell carcinoma synchronous with medullary thyroid carcinoma. A case report

Los tumores sincrónicos se definen como tumores que se presentan dentro de un período de 6 meses del diagnóstico del primer tumor. Presentamos a un paciente varón de 65 años, fumador con carcinoma de laringe invasivo. Se realiza una laringectomía radical con vaciamiento cervical bilateral y hemitiroidectomía izquierda ante sospecha de posible extensión de la lesión laríngea. La literatura recoge algunos casos de carcinomas de laringe sincrónicos con carcinoma de tiroides, siendo en la mayor parte de los casos asociado a un carcinoma papilar de tiroides en varones de entre 47 y 62 años. Nosotros presentamos un caso de carcinoma laríngeo invasivo de células escamosas sincrónico con un carcinoma medular de tiroides y ganglios cervicales positivos para metástasis de carcinoma epidermoide, del que se conocen muy pocos casos en la literatura (AU)

Synchronous tumours are defined as those presenting within 6 months subsequent to the diagnosis of the primary tumour. We present a case of invasive laryngeal carcinoma in a 65 year old male smoker who underwent radical laryngectomy with bilateral cervical dissection and hemi-thyroidectomy due to suspicion of tumour invasion. There are a few case reports of laryngeal carcinoma synchronous with thyroid carcinoma, the majority being papillary thyroid carcinoma in males aged between 47 and 62. We present a case of invasive squamous cell laryngeal carcinoma synchronous with thyroid medullary carcinoma and cervical lymph glands positive for metastases from epidermoide carcinoma (AU)

Hipertensión portal de causa no cirrótica por didanosina: una causa infrecuente de hemorragia digestiva / Non-cirrhotic portal hypertension associated with didanosine: An unusual cause of gastrointestinal bleeding

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Carcinoma de próstata con componente de células pequeñas. Diagnóstico inicial en metástasis ganglionar con patrón de carcinoma neuroendocrino de células grandes. Descripción de un caso / Initial diagnosis of small cell carcinoma of prostate in a nodal metastasis of large cell neuroendocrine carcinoma. A case report

El carcinoma de próstata es el tumor maligno más prevalente en el varón. La glándula prostática normal está constituida por 3 tipos celulares: el luminal o secretor, el basal y el neuroendocrino. Las células neuroendocrinas se distribuyen en toda la extensión de la glándula prostática, con mayor frecuencia en los conductos que en el tejido acinar. La diferenciación neuroendocrina es un hallazgo frecuente en los carcinomas prostáticos, en su mayoría de modo focal, y en los casos en que la diferenciación es extensa, se asocia con refractariedad a la terapia hormonal o enfermedad agresiva. Describimos un caso de un carcinoma de próstata poco diferenciado de células pequeñas con diferenciación neuroendocrina con componente minoritario de adenocarcinoma convencional, resaltando el hallazgo del tumor primario mediante el diagnóstico de una metástasis ganglionar de carcinoma neuroendocrino de células grandes (AU)

Prostate carcinoma is the most common malignant tumour in men. The normal prostate gland is composed of three cell types: luminal, basal and neuroendocrine. Neuro-endocrine cells are found throughout the prostate gland, although are more frequent in ducts than in the acinar tissue. Neuroendocrine differentiation is often seen in prostatic carcinomas, usually focally, but, when differentiation is extensive, it is associated with failed hormonal therapy or aggressive disease. We describe a case of a poorly differentiated small cell prostate carcinoma with neuroendocrine differentiation that had a small component of conventional adenocarcinoma. Thus, a nodal metastasis of large cell neuroendocrine carcinoma led to the diagnosis of the primary tumour (AU)

Collision tumour involving a rectal gastrointestinal stromal tumour with invasion of the prostate and a prostatic adenocarcinoma.

BACKGROUND: Gastrointestinal stromal tumours (GISTs) are the most common primary mesenchymal neoplasia in the gastrointestinal tract, although they represent only a small fraction of total gastrointestinal malignancies in adults (<2%). GISTs can be located at any level of the gastrointestinal tract; the stomach is the most common location (60-70%), in contrast to the rectum, which is most rare (4%). When a GIST invades into the adjacent prostate tissue, it can simulate prostate cancer. In this study, we report on a case comprising the unexpected collision between a rectal GIST tumour and a prostatic adenocarcinoma. FINDINGS: We describe the complexity of the clinical, endoscopic and radiological diagnosis, of the differential diagnosis based on tumour biopsy, and of the role of neoadjuvant therapy using imatinib prior to surgical treatment. CONCLUSIONS: Although isolated cases of coexisting GISTs and prostatic adenocarcinomas have previously been described, this is the first reported case in the medical literature of a collision tumour involving a rectal GIST and prostatic adenocarcinoma components. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/1238437468776331.