Cholangiocarcinoma with carcinomatosis in a sugar glider.

A 7-y-old, castrated male, leucistic sugar glider (Petaurus breviceps) was presented because of a progressive history of lethargy, ataxia, diarrhea, and anorexia. Abdominal ultrasound revealed fluid in the abdomen and an infiltrative mass in the liver. Due to a poor prognosis, euthanasia was performed. Postmortem examination revealed a focally extensive, infiltrative, off-white, firm mass in the liver with adhesion to the omentum, mesentery, gastric serosa, and diaphragm. The remaining hepatic parenchyma was diffusely yellow. Histologically, the hepatic mass was consistent with metastatic cholangiocarcinoma (cholangiocellular carcinoma) with proliferation of neoplastic epithelial cells surrounded by marked desmoplasia. Neoplastic cells expanded and infiltrated the adjacent omentum, mesentery, and the serosal surfaces of the stomach, kidney, and small and large intestines. To our knowledge, cholangiocarcinoma has not been reported previously in a sugar glider.

The implementation of a cancer surveillance technical group based on health advocacy / La implementación de un grupo técnico de vigilancia del cáncer anclado en la advocacy en salud / A implementação de um grupo técnico de vigilância do câncer ancorado no advocacy em saúde

ABSTRACT Objective: To describe the process of implementing a cancer surveillance technical group based on the health advocacy framework. Method: Convergent Care Research addressing 11 representatives of the support and governance system of the healthcare network in a town in Santa Catarina, Brazil. Data were collected from June 2020 to July 2021 in online meetings called convergence groups. The analysis followed the apprehension, synthesis, theorization, and transference steps. Results: The motivations for creating the group included the town's cancer epidemiological context, the need to meet the annual health program, and the professionals' duties in this context. Based on the advocacy framework, the group associated the implementation process with concepts such as integrality, humanization, and professional practice in health. Along this path, strategies were acknowledged and supported the group, such as the establishment and appropriation of philosophical and theoretical bases, in addition to actions such as creating a statute, planning activities, developing instruments, and identifying priorities to implement tasks effectively. Conclusion: Knowledge was exchanged, and a process for providing integral and equitable healthcare in cancer surveillance was developed collectively. Hence, advocacy proved to be a theoretical pillar for the political action of the technical group's members, translating practice into patient rights advocacy.

RESUMEN Objetivo: describir el proceso de implementación de un grupo técnico de vigilancia del cáncer, fundamentado en el referencial de advocacy en salud. Métodos: Investigación Convergente Asistencial realizada con 11 profesionales, representantes de puntos de atención y del sistema de apoyo y gobernanza de la red de atención a la salud de un municipio de Santa Catarina, en Brasil. La recolección fue desarrollada de junio/2020 a julio/2021 en reuniones online denominadas grupos de convergencia. El análisis siguió las etapas de comprensión, síntesis, teorización y transferencia. Resultados: el grupo evidenció como motivaciones para su creación el escenario epidemiológico del cáncer en el municipio, la necesidad de atender la programación anual de salud, y los compromisos profesionales en este contexto. En su proceso de implementación, y a partir del referencial de advocacy en salud, el grupo lo asoció a otros conceptos como la integralidad, la humanización, y el ejercicio profesional en el área de la salud. En este recorrido, fueron reconocidas estrategias iniciales, como la definición y la apropiación de bases filosóficas y teóricas para anclar el grupo, así como estrategias de acciones desde la elaboración de un regimiento, planificación de actividades del grupo, construcción de instrumentos, e identificación de prioridades para implementación efectiva de los trabajos. Conclusión: hubo promoción e intercambio de conocimientos y, colectivamente, se estructuró un proceso para atención integral y ecuánime en la vigilancia del cáncer. Se confirmó el advocacy como pilar teórico para acción política de los profesionales en el grupo técnico, y sus prácticas se traducen en acciones de defesa de los derechos de los usuarios.

RESUMO Objetivo: descrever o processo de implementação de um grupo técnico de vigilância do câncer fundamentado no referencial de advocacy em saúde. Métodos: Pesquisa Convergente Assistencial realizada com 11 profissionais representantes de pontos de atenção e do sistema de apoio e governança da rede de atenção à saúde de um município de Santa Catarina, Brasil. A coleta foi desenvolvida de junho/2020 a julho/2021 em reuniões online denominadas grupos de convergência. A análise seguiu as etapas de apreensão, síntese, teorização e transferência. Resultados: o grupo evidenciou como motivações para sua criação o cenário epidemiológico do câncer no município, a necessidade de atender a programação anual de saúde, e os compromissos profissionais neste contexto. Em seu processo de implementação, e a partir do referencial do advocacy em saúde, o grupo o associou a outros conceitos como a integralidade, a humanização, e o exercício profissional na área da saúde. Neste percurso, foram reconhecidas estratégias iniciais como a definição e a apropriação de bases filosóficas e teóricas para ancorar o grupo, bem como estratégias de ações desde a elaboração de um regimento, planejamento de atividade do grupo, construção de instrumentos, e identificação de prioridades para implementação efetiva dos trabalhos. Conclusão: houve promoção e compartilhamentos de conhecimentos e, coletivamente, estruturou-se um processo para atenção integral e equânime na vigilância do câncer. Confirmou-se o advocacy como pilar teórico para ação política dos profissionais no grupo técnico, e suas práticas traduzem-se em ações de defesa dos direitos dos usuários.

Restoring tumor immunogenicity with dendritic cell reprogramming.

Decreased antigen presentation contributes to the ability of cancer cells to evade the immune system. We used the minimal gene regulatory network of type 1 conventional dendritic cells (cDC1) to reprogram cancer cells into professional antigen-presenting cells (tumor-APCs). Enforced expression of the transcription factors PU.1, IRF8, and BATF3 (PIB) was sufficient to induce the cDC1 phenotype in 36 cell lines derived from human and mouse hematological and solid tumors. Within 9 days of reprogramming, tumor-APCs acquired transcriptional and epigenetic programs associated with cDC1 cells. Reprogramming restored the expression of antigen presentation complexes and costimulatory molecules on the surfaces of tumor cells, allowing the presentation of endogenous tumor antigens on MHC-I and facilitating targeted killing by CD8+ T cells. Functionally, tumor-APCs engulfed and processed proteins and dead cells, secreted inflammatory cytokines, and cross-presented antigens to naïve CD8+ T cells. Human primary tumor cells could also be reprogrammed to increase their capability to present antigen and to activate patient-specific tumor-infiltrating lymphocytes. In addition to acquiring improved antigen presentation, tumor-APCs had impaired tumorigenicity in vitro and in vivo. Injection of in vitro generated melanoma-derived tumor-APCs into subcutaneous melanoma tumors delayed tumor growth and increased survival in mice. Antitumor immunity elicited by tumor-APCs was synergistic with immune checkpoint inhibitors. Our approach serves as a platform for the development of immunotherapies that endow cancer cells with the capability to process and present endogenous tumor antigens.

Somatic mutations of CADM1 in aldosterone-producing adenomas and gap junction-dependent regulation of aldosterone production.

Aldosterone-producing adenomas (APAs) are the commonest curable cause of hypertension. Most have gain-of-function somatic mutations of ion channels or transporters. Herein we report the discovery, replication and phenotype of mutations in the neuronal cell adhesion gene CADM1. Independent whole exome sequencing of 40 and 81 APAs found intramembranous p.Val380Asp or p.Gly379Asp variants in two patients whose hypertension and periodic primary aldosteronism were cured by adrenalectomy. Replication identified two more APAs with each variant (total, n = 6). The most upregulated gene (10- to 25-fold) in human adrenocortical H295R cells transduced with the mutations (compared to wildtype) was CYP11B2 (aldosterone synthase), and biological rhythms were the most differentially expressed process. CADM1 knockdown or mutation inhibited gap junction (GJ)-permeable dye transfer. GJ blockade by Gap27 increased CYP11B2 similarly to CADM1 mutation. Human adrenal zona glomerulosa (ZG) expression of GJA1 (the main GJ protein) was patchy, and annular GJs (sequelae of GJ communication) were less prominent in CYP11B2-positive micronodules than adjacent ZG. Somatic mutations of CADM1 cause reversible hypertension and reveal a role for GJ communication in suppressing physiological aldosterone production.

New advances in endocrine hypertension: from genes to biomarkers.

Hypertension (HT) is a major cardiovascular risk factor that affects 10% to 40% of the general population in an age-dependent manner. Detection of secondary forms of HT is particularly important because it allows the targeted management of the underlying disease. Among hypertensive patients, the prevalence of endocrine HT reaches up to 10%. Adrenal diseases are the most frequent cause of endocrine HT and are associated with excess production of mineralocorticoids (mainly primary aldosteronism), glucocorticoids (Cushing syndrome), and catecholamines (pheochromocytoma). In addition, a few rare diseases directly affecting the action of mineralocorticoids and glucocorticoids in the kidney also lead to endocrine HT. Over the past years, genomic and genetic studies have allowed improving our knowledge on the molecular mechanisms of endocrine HT. Those discoveries have opened new opportunities to transfer knowledge to clinical practice for better diagnosis and specific treatment of affected subjects. In this review, we describe the physiology of adrenal hormone biosynthesis and action, the clinical and biochemical characteristics of different forms of endocrine HT, and their underlying genetic defects. We discuss the impact of these discoveries on diagnosis and management of patients, as well as new perspectives related to the use of new biomarkers for improved patient care.

Advocacia do paciente na valorização do ser social e da família em tempos de COVID-19 / Defensa del paciente en la valoración del ser social y la familia en tiempos de COVID-19 / Patient advocacy in valuing social and family being in times of COVID-19

Resumo Objetivo compreender as estratégias utilizadas pelos enfermeiros intensivistas diante das situações que demandaram a advocacia do paciente, envolvendo a valorização do ser social e familiar no cenário da pandemia de COVID-19. Método estudo qualitativo, descritivo e exploratório, realizado nas cinco regiões do Brasil. Participaram do estudo 25 enfermeiros intensivistas. Os dados foram coletados por meio de uma entrevista semiestruturada e, posteriormente, submetidos à análise textual discursiva. Resultados os enfermeiros advogaram perante a equipe de saúde e pela presença da família dentro da Unidade de Terapia Intensiva. Com a pandemia de COVID-19, foram estabelecidas novas estratégias para advogar, promovendo a aproximação, de forma virtual, entre enfermeiros, pacientes e familiares, bem como a permanência dos familiares no ambiente de terapia intensiva, quando necessário, para que os enfermeiros conhecessem melhor o paciente e integrassem a família ao cuidado. Considerações finais e implicações para a prática as estratégias utilizadas para agir em prol do paciente se deram por meio da aproximação entre enfermeiros e familiares; por meio da instrução de familiares para que advoguem pelo paciente; e pela defesa da presença familiar dentro da Unidade de Terapia Intensiva.

Resumen Objetivo comprender las estrategias utilizadas por los enfermeros de cuidados intensivos frente a situaciones que exigían la defensa del paciente, involucrando la valorización del ser social y familiar en el escenario de la pandemia de COVID-19. Método estudio cualitativo, descriptivo y exploratorio, realizado en las cinco regiones de Brasil. 25 enfermeras de cuidados intensivos participaron en el estudio. Los datos fueron recolectados a través de una entrevista semiestructurada y posteriormente sometidos al análisis textual discursivo. Resultados los enfermeros abogaron ante el equipo de salud y por la presencia de la familia en la Unidad de Cuidados Intensivos. Con la pandemia del COVID-19, se establecieron nuevas estrategias para abogar, promoviendo el acercamiento virtual entre enfermeros, pacientes y familiares, así como la permanencia de los familiares en el ambiente de cuidados intensivos cuando sea necesario, para que los enfermeros puedan conocerse entre sí. mejorar al paciente e integrar a la familia en el cuidado. Conclusión e implicaciones para la práctica las estrategias utilizadas para actuar en nombre del paciente se llevaron a cabo a través del acercamiento entre enfermeras y familiares; instruyendo a los familiares para que defiendan al paciente; y por la defensa de la presencia familiar dentro de la Unidad de Cuidados Intensivos.

Abstract Objective to understand the strategies used by intensive care nurses in the face of situations that required patient advocacy, involving the appreciation of social and family being during the COVID-19 pandemic. Method this is a qualitative, descriptive and exploratory study, carried out in the five regions of Brazil. A total of 25 intensive care nurses participated in the study. Data were collected through a semi-structured interview and subsequently subjected to discursive textual analysis. Results nurses advocated before the health team and for the family's presence within the Intensive Care Unit. With the COVID-19 pandemic, new strategies were established to advocate, promoting virtual rapprochement between nurses, patients and family members as well as the permanence of family members in intensive care environments when necessary so that nurses could know patients better and integrate the family into care. Conclusion and implications for practice the strategies used to act on behalf of patients were carried out for rapprochement between nurses and family members; for instructing family members to advocate for patients; and for the defense of family presence within the Intensive Care Unit.

Vascular and hormonal interactions in the adrenal gland.

Primary aldosteronism is the most common form of secondary arterial hypertension, due to excessive aldosterone production from the adrenal gland. Although somatic mutations have been identified in aldosterone producing adenoma, the exact mechanisms leading to increased cell proliferation and nodule formation remain to be established. One hypothesis is that changes in vascular supply to the adrenal cortex, due to phenomena of atherosclerosis or high blood pressure, may influence the morphology of the adrenal cortex, resulting in a compensatory growth and nodule formation in response to local hypoxia. In this review, we will summarize our knowledge on the mechanisms regulating adrenal cortex development and function, describe adrenal vascularization in normal and pathological conditions and address the mechanisms allowing the cross-talk between the hormonal and vascular components to allow the extreme tissue plasticity of the adrenal cortex in response to endogenous and exogenous stimuli. We will then address recent evidence suggesting a role for alterations in the vascular compartment that could eventually be involved in nodule formation and the development of primary aldosteronism.

Identification of risk loci for primary aldosteronism in genome-wide association studies.

Primary aldosteronism affects up to 10% of hypertensive patients and is responsible for treatment resistance and increased cardiovascular risk. Here we perform a genome-wide association study in a discovery cohort of 562 cases and 950 controls and identify three main loci on chromosomes 1, 13 and X; associations on chromosome 1 and 13 are replicated in a second cohort and confirmed by a meta-analysis involving 1162 cases and 3296 controls. The association on chromosome 13 is specific to men and stronger in bilateral adrenal hyperplasia than aldosterone producing adenoma. Candidate genes located within the two loci, CASZ1 and RXFP2, are expressed in human and mouse adrenals in different cell clusters. Their overexpression in adrenocortical cells suppresses mineralocorticoid output under basal and stimulated conditions, without affecting cortisol biosynthesis. Our study identifies the first risk loci for primary aldosteronism and highlights new mechanisms for the development of aldosterone excess.

Single-cell transcriptional profiling informs efficient reprogramming of human somatic cells to cross-presenting dendritic cells.

Type 1 conventional dendritic cells (cDC1s) are rare immune cells critical for the induction of antigen-specific cytotoxic CD8+ T cells, although the genetic program driving human cDC1 specification remains largely unexplored. We previously identified PU.1, IRF8, and BATF3 transcription factors as sufficient to induce cDC1 fate in mouse fibroblasts, but reprogramming of human somatic cells was limited by low efficiency. Here, we investigated single-cell transcriptional dynamics during human cDC1 reprogramming. Human induced cDC1s (hiDC1s) generated from embryonic fibroblasts gradually acquired a global cDC1 transcriptional profile and expressed antigen presentation signatures, whereas other DC subsets were not induced at the single-cell level during the reprogramming process. We extracted gene modules associated with successful reprogramming and identified inflammatory signaling and the cDC1-inducing transcription factor network as key drivers of the process. Combining IFN-γ, IFN-ß, and TNF-α with constitutive expression of cDC1-inducing transcription factors led to improvement of reprogramming efficiency by 190-fold. hiDC1s engulfed dead cells, secreted inflammatory cytokines, and performed antigen cross-presentation, key cDC1 functions. This approach allowed efficient hiDC1 generation from adult fibroblasts and mesenchymal stromal cells. Mechanistically, PU.1 showed dominant and independent chromatin targeting at early phases of reprogramming, recruiting IRF8 and BATF3 to shared binding sites. The cooperative binding at open enhancers and promoters led to silencing of fibroblast genes and activation of a cDC1 program. These findings provide mechanistic insights into human cDC1 specification and reprogramming and represent a platform for generating patient-tailored cDC1s, a long-sought DC subset for vaccination strategies in cancer immunotherapy.

Colocalization of Wnt/ß-Catenin and ACTH Signaling Pathways and Paracrine Regulation in Aldosterone-producing Adenoma.

CONTEXT: Aldosterone-producing adenomas (APAs) are a common cause of primary aldosteronism (PA). Despite the discovery of somatic mutations in APA and the characterization of multiple factors regulating adrenal differentiation and function, the sequence of events leading to APA formation remains to be determined. OBJECTIVE: We investigated the role of Wnt/ß-catenin and adrenocorticotropin signaling, as well as elements of paracrine regulation of aldosterone biosynthesis in adrenals with APA and their relationship to intratumoral heterogeneity and mutational status. METHODS: We analyzed the expression of aldosterone-synthase (CYP11B2), CYP17A1, ß-catenin, melanocortin type 2 receptor (MC2R), phosphorlyated cAMP response element-binding protein (pCREB), tryptase, S100, CD34 by multiplex immunofluorescence, and immunohistochemistry-guided reverse transcription-quantitative polymerase chain reaction. Eleven adrenals with APA and 1 with micronodular hyperplasia from patients with PA were analyzed. Main outcome measures included localization of CYP11B2, CYP17A1, ß-catenin, MC2R, pCREB, tryptase, S100, CD34 in APA and aldosterone-producing cell clusters (APCCs). RESULTS: Immunofluorescence revealed abundant mast cells and a dense vascular network in APA, independent of mutational status. Within APA, mast cells were localized in areas expressing CYP11B2 and were rarely colocalized with nerve fibers, suggesting that their degranulation is not controlled by innervation. In these same areas, ß-catenin was activated, suggesting a zona glomerulosa cell identity. In heterogeneous APA with KCNJ5 mutations, MC2R and vascular endothelial growth factor A expression was higher in areas expressing CYP11B2. A similar pattern was observed in APCC, with high expression of CYP11B2, activated ß-catenin, and numerous mast cells. CONCLUSION: Our results suggest that aldosterone-producing structures in adrenals with APA share common molecular characteristics and cellular environment, despite different mutation status, suggesting common developmental mechanisms.

Somatic mutations of GNA11 and GNAQ in CTNNB1-mutant aldosterone-producing adenomas presenting in puberty, pregnancy or menopause.

Most aldosterone-producing adenomas (APAs) have gain-of-function somatic mutations of ion channels or transporters. However, their frequency in aldosterone-producing cell clusters of normal adrenal gland suggests a requirement for codriver mutations in APAs. Here we identified gain-of-function mutations in both CTNNB1 and GNA11 by whole-exome sequencing of 3/41 APAs. Further sequencing of known CTNNB1-mutant APAs led to a total of 16 of 27 (59%) with a somatic p.Gln209His, p.Gln209Pro or p.Gln209Leu mutation of GNA11 or GNAQ. Solitary GNA11 mutations were found in hyperplastic zona glomerulosa adjacent to double-mutant APAs. Nine of ten patients in our UK/Irish cohort presented in puberty, pregnancy or menopause. Among multiple transcripts upregulated more than tenfold in double-mutant APAs was LHCGR, the receptor for luteinizing or pregnancy hormone (human chorionic gonadotropin). Transfections of adrenocortical cells demonstrated additive effects of GNA11 and CTNNB1 mutations on aldosterone secretion and expression of genes upregulated in double-mutant APAs. In adrenal cortex, GNA11/Q mutations appear clinically silent without a codriver mutation of CTNNB1.

Somatic mutations in adrenals from patients with primary aldosteronism not cured after adrenalectomy suggest common pathogenic mechanisms between unilateral and bilateral disease.

OBJECTIVE: Primary aldosteronism (PA) is the most common form of secondary and curable hypertension. Different germline and somatic mutations are found in aldosterone-producing adenoma (APA) and familial forms of the disease, while the causes of bilateral adrenal hyperplasia (BAH) remain largely unknown. Adrenalectomy is the recommended treatment for patients with APA; however, 6% of patients are not cured and show persistent PA after surgery suggesting BAH. The objective of this study was to analyze clinical data of patients with APA without biochemical success after adrenalectomy as well as the histological and genetic characteristics of their adrenal glands. DESIGN AND METHODS: Clinical data of 12 patients with partial and absent biochemical cure were compared to those from 39 PA patients with hormonal cure after surgery. Histological, morphological, and genetic characterization of the adrenals was carried out by CYP11B2 and CYP11B1 immunostaining and by CYP11B2-guided NGS. RESULTS: Patients with absent hormonal cure displayed a longer duration of arterial hypertension and lower lateralization index of aldosterone production. In ten patients, APAs expressing CYP11B2 were identified. No difference in histological and morphological characteristics was observed between patients with or without a hormonal cure. Somatic mutations in APA driver genes were identified in all CYP11B2 positive APAs; CACNA1D mutations were the most frequent genetic abnormality. CONCLUSIONS: Patients with partial and absent biochemical cure were diagnosed later and exhibited a lower lateralization index of aldosterone production, suggesting asymmetric aldosterone production in the context of BAH. Somatic mutations in adrenal glands from those patients indicate common mechanisms underlying BAH and APA.

Pathogenesis and treatment of primary aldosteronism.

Early diagnosis and appropriate treatment of primary aldosteronism, the most frequent cause of secondary hypertension, are crucial to prevent deleterious cardiovascular outcomes. In the past decade, the discovery of genetic abnormalities responsible for sporadic and familial forms of primary aldosteronism has improved the knowledge of the pathogenesis of this disorder. Mutations in genes encoding ion channels and pumps lead to increased cytosolic concentrations of calcium in zona glomerulosa cells, which triggers CYP11B2 expression and autonomous aldosterone production. Improved understanding of the mechanisms underlying the disease is key to improving diagnostics and to developing and implementing targeted treatments. This Review provides an update on the genetic abnormalities associated with sporadic and familial forms of primary aldosteronism, their frequency among different populations and the mechanisms explaining excessive aldosterone production and adrenal nodule development. The possible effects and uses of these findings for improving the diagnostics for primary aldosteronism are discussed. Furthermore, current treatment options of primary aldosteronism are reviewed, with particular attention to the latest studies on blood pressure and cardiovascular outcomes following medical or surgical treatment. The new perspectives regarding the use of targeted drug therapy for aldosterone-producing adenomas with specific somatic mutations are also addressed.

Evaluation of interbody fusion two years after llif procedure / Avaliação da fusão intersomática dois anos depois de procedimento de llif / Evaluación de la fusión intersomática dos años después del procedimiento de llif

ABSTRACT Objectives The LLIF technique, extreme lateral interbody fusion, reaches the disc laterally through the psoas muscle, offering adequate access to the disc space with the added benefit of preventing iatrogenic injury to abdominal vascular structures (aorta and vena cava), the sympathetic plexus (reduces incidence of retrograde ejaculation) and neural structures, that is, preservation of the spinal nerves that cross the posterior aspect of the muscle. The objective of this study is to verify the rates of interbody fusion with the LLIF technique. Methods Retrospective, single center, comparative, non-randomized study. The presence of bone mass with increased hypotransparency in the areas of fusion will be analyzed. For the evaluation of the fusion, the Classification of interbody fusion success: Brantigan, Steffee, Fraser (BSF) will be used. Results Fifty-nine (86%) patients presented complete fusion of the approached level (BSF-3) six months after the procedure. One year after the procedure, 87% of the patients had complete fusion. Similar results were confirmed at two years. Conclusions We conclude that the technique of lateral interbody arthrodesis is safe and effective for the treatment of low back pain, with a fusion rate of 90% in two years. Level of Evidence III. Retrospective study, single center, non-randomized.

RESUMO Objetivos A técnica LLIF, fusão intersomática extremo lateral, alcança o disco lateralmente através do músculo psoas, oferecendo acesso adequado ao espaço discal, com benefício adicional de preservação de lesão iatrogênica de estruturas vasculares abdominais (aorta e veia cava), do plexo simpático (reduz a incidência de ejaculação retrógrada) e de estruturas neurais, ou seja, preservação dos nervos espinhais que cruzam o aspecto posterior do músculo. O objetivo do trabalho é verificar os índices da fusão intersomática com a técnica de LLIF. Métodos Estudo retrospectivo, em centro único, comparativo e não randomizado. Será analisada a presença de massa óssea, com aumento da hipotransparência nas áreas de fusão. Para a avaliação de fusão, será utilizada a Classification of interbody fusion success: Brantigan, Steffee, Fraser (BSF). Resultados Cinquenta e nove (86%) pacientes apresentaram fusão completa do nível abordado (BSF-3) seis meses após o procedimento. Depois de um ano do procedimento, 87% dos pacientes apresentaram fusão completa. Resultados similares foram constatados em dois anos. Conclusões Concluímos que a técnica de artrodese intersomática por via lateral é segura e eficaz para o tratamento da dor lombar baixa, com taxa de fusão de 90% em dois anos. Nível de Evidência III. Estudo Retrospectivo, centro único, não randomizado.

RESUMEN Objetivo La técnica LLIF, fusión intersomática extremo-lateral, alcanza el disco lateralmente a través del músculo psoas, ofreciendo acceso adecuado al espacio discal con el beneficio adicional de preservación de la lesión iatrogénica de estructuras vasculares abdominales (aorta y vena cava), del plexo simpático (reduce incidencia de eyaculación retrógrada) y estructuras neurales, o sea, preservación de los nervios espinales que cruzan el aspecto posterior del músculo. El objetivo del trabajo es verificar los índices de fusión intersomática con la técnica de LLIF. Métodos Estudio retrospectivo, en centro único, comparativo y no aleatorizado. Será analizada la presencia de masa ósea, con aumento de hipotransparencia en las áreas de fusión. Para la evaluación de fusión, se utilizará la Classification of Interbody Fusion Success: Brantigan, Steffee, Fraser (BSF). Resultados Cincuenta y nueve (86%) pacientes presentaron fusión completa del nivel abordado (BSF-3) seis meses después del procedimiento. Un año después del procedimiento, 87% de los pacientes presentaron fusión completa. Resultados similares fueron constatados en dos años. Conclusiones Concluimos que la técnica de artrodesis intersomática por vía lateral es segura y eficaz para el tratamiento del dolor lumbar bajo, con una tasa de fusión del 90% en 2 años. Nivel de Evidencia III. Retrospective study, single center, non-randomized.

Genetic and Genomic Mechanisms of Primary Aldosteronism.

Aldosterone-producing adenoma (APA) and bilateral adrenal hyperplasia are the main cause of primary aldosteronism (PA), the most frequent form of secondary hypertension. Mutations in ion channels and ATPases have been identified in APA and inherited forms of PA, highlighting the central role of calcium signaling in PA development. Different somatic mutations are also found in aldosterone-producing cell clusters in adrenal glands from healthy individuals and from patients with unilateral and bilateral PA, suggesting additional pathogenic mechanisms. Recent mouse models have also contributed to a better understanding of PA. Application of genetic screening in familial PA, development of surrogate biomarkers for somatic mutations in APA, and use of targeted treatment directed at mutated proteins may allow improved management of patients.

Genetic, Cellular, and Molecular Heterogeneity in Adrenals With Aldosterone-Producing Adenoma.

Aldosterone-producing adenoma (APA) cause primary aldosteronism-the most frequent form of secondary hypertension. Somatic mutations in genes coding for ion channels and ATPases are found in APA and in aldosterone-producing cell clusters. We investigated the genetic, cellular, and molecular heterogeneity of different aldosterone-producing structures in adrenals with APA, to get insight into the mechanisms driving their development and to investigate their clinical and biochemical correlates. Genetic analysis of APA, aldosterone-producing cell clusters, and secondary nodules was performed in adrenal tissues from 49 patients by next-generation sequencing following CYP11B2 immunohistochemistry. Results were correlated with clinical and biochemical characteristics of patients, steroid profiles, and histological features of the tumor and adjacent adrenal cortex. Somatic mutations were identified in 93.75% of APAs. Adenoma carrying KCNJ5 mutations had more clear cells and cells expressing CYP11B1, and fewer cells expressing CYP11B2 or activated ß-catenin, compared with other mutational groups. 18-hydroxycortisol and 18-oxocortisol were higher in patients carrying KCNJ5 mutations and correlated with histological features of adenoma; however, mutational status could not be predicted using steroid profiling. Heterogeneous CYP11B2 expression in KCNJ5-mutated adenoma was not associated with genetic heterogeneity. Different mutations were identified in secondary nodules expressing aldosterone synthase and in independent aldosterone-producing cell clusters from adrenals with adenoma; known KCNJ5 mutations were identified in 5 aldosterone-producing cell clusters. Genetic heterogeneity in different aldosterone-producing structures in the same adrenal suggests complex mechanisms underlying APA development.

Old and new genes in primary aldosteronism.

Primary aldosteronism (PA) is the most common form of secondary hypertension affecting 5%-10% of patients with arterial hypertension. In PA, high blood pressure is associated with high aldosterone and low renin levels, and often hypokalemia. In a majority of cases, autonomous aldosterone production by the adrenal gland is caused by an aldosterone producing adenoma (APA) or bilateral adrenal hyperplasia (BAH). During the last ten years, a better knowledge of the pathophysiology of PA came from the discovery of somatic and germline mutations in different genes in both sporadic and familial forms of the disease. Those genes code for ion channels and pumps, as well as proteins involved in adrenal cortex development and function. Targeted next generation sequencing following immunohistochemistry guided detection of aldosterone synthase expression allows detection of somatic mutations in up to 90% of APA, while whole exome sequencing has discovered the genetic causes of four different familial forms of PA. The identification, in BAH, of somatic mutations in aldosterone producing cell clusters open new perspectives in our understanding of the bilateral form of the disease and the development of new therapeutic approaches.

Expression quantitative trait loci in ABC transporters are associated with survival in 5-FU treated colorectal cancer patients.

The chemotherapeutic efficacy in colorectal cancer (CRC) is limited due to the inter-individual variability in drug response and the development of tumour resistance. ATP-binding cassette (ABC) transporters are crucial in the development of resistance by the efflux of anticancer agents from cancer cells. In this study, we identified 14 single nucleotide polymorphisms (SNPs) in 11 ABC transporter genes acting as an expression of quantitative trait loci (eQTLs), i.e. whose variation influence the expression of many downstream genes. These SNPs were genotyped in a case-control study comprising 1098 cases and 1442 healthy controls and analysed in relation to CRC development risk and patient survival. Considering a strict correction for multiple tests, we did not observe any significant association between SNPs and CRC risk. The rs3819720 polymorphism in the ABCB3/TAP2 gene was statistically significantly associated with shorter overall survival (OS) in the codominant, and dominant models [GA vs. GG, hazard ratio (HR) = 1.48; P = 0.002; AA vs. GG, HR = 1.70; P = 0.004 and GA + AA vs. GG, HR = 1.52; P = 0.0006]. Additionally, GA carriers of the same SNP displayed worse OS after receiving 5-FU based chemotherapy. The variant allele of rs3819720 polymorphism statistically significantly affected the expression of 36 downstream genes. Screening for eQTL polymorphisms in relevant genes such as ABC transporters that can regulate the expression of several other genes may help to identify the genetic background involved in the individual response to the treatment of CRC patients.