Health-related quality of life in adrenocortical carcinoma:Development of the disease-specific questionnaire ACC-QOL and results from the PROFILES registry

We aimed to develop a disease-specific adrenocortical carcinoma (ACC) health-related quality of life (HRQoL) questionnaire (ACC-QOL) and assess HRQoL in a population-based cohort of patients with ACC. Development was in line with European Organization for Research and Treatment of Cancer (EORTC) guidelines, though not an EORTC product. In phase I and II, we identified 90 potential HRQoL issues using literature and focus groups, which were reduced to 39 by healthcare professionals. Pilot testing resulted in 28 questions, to be used alongside the EORTC QLQ-C30. In Phase III, 100 patients with ACC were asked to complete the questionnaires twice in the PROFILES registry (3-month interval, respondents: first 67, second 51). Confirmatory factor analysis demonstrated the structural validity of 26 questions with their scale structure (mitotane side-effects, hypercortisolism/hydrocortisone effects, emotional effects). Internal consistency and reliability were good (Cronbach's alpha 0.897, Interclass correlation coefficient 0.860). Responsiveness analysis showed good discriminative ability (AUC 0.788). Patients diagnosed more than 5 years ago reported a good HRQoL compared with the Dutch reference population, but experienced residual fatigue and emotional problems. Patients who underwent recent treatment reported a lower HRQoL and problems in several domains. In conclusion, we developed an ACC-specific HRQoL questionnaire with good psychometric properties

Gestión del modelo de desinstitucionalización de adultos con alteraciones mentales en el sistema público de la Provincia de Buenos Aires

La alteración de la salud mental constituye un problema socio-sanitario. Las ciencias de la salud consideran modelos de causalidad multifactoriales con determinantes sociales. No se observa en esta investigación la inclusión de la Ciencia Administrativa como interdisciplina. Su incorporación permitiría integrar conocimientos administrativos para un eficaz y eficiente desempeño en las organizaciones de salud mental. Las fallas de planificación como proceso central en la formulación de estrategias constituyen un común denominador de los modelos descriptos. Los resultados encontrados, como indicadores del valor giro programa, 5 años de permanencia (rango 1 – 20); y producto del análisis cualitativo (respuestas a entrevistas) 6 años (máxima permanencia 26-27 años) afirman un bajo rendimiento de los programas existentes. Se observó contradicción en los modelos para compatibilizar el control del rendimiento con la autonomía de las diferentes divisiones, sistemas cerrados instrumentales de la sede central, responsables de las actividades dependientes de más de un coordinador con desempeño simultáneo en subproyectos sin conseguir resultados aceptables. La propuesta del nuevo modelo de gestión es una intervención de tipo social fragmentaria, sistematizada e incremental. Propone un rediseño de los procesos con la revisión de los recursos disponibles para alcanzar aumento del valor giro-paciente para la externación con reinserción social.Facultad de Ciencias Económica

Nuclear Receptors and Multiple Endocrine Neoplasia type 1 (MEN1)

Multiple Endocrine Neoplasia type 1 (MEN1) is an inherited syndrome that is characterized by the occurrence of tumours of the parathyroid glands, gastroenteropancreatic tumours, pitui-tary gland adenomas, as well as adrenal adenomas and neuro-endocrine tumours, often at a young age. MEN1 tumours can be treated mostly by surgical methods. However, some tumours have malignant potential. Most patients require repeated surgery during their lifetime. MEN1 is caused by germ line mutations of the MEN1 gene. The MEN1 gene is a tumour suppressor gene. This means that both alleles in a cell need to be inactivated before a cell can develop into a tumour cell. The MEN1 gene encodes a protein termed menin. Menin is a nuclear protein that is involved in regulation of gene transcription, but possibly also DNA repair and replication. Menin can both be a co-activator and a co-repressor of gene transcription by recruiting proteins that modify histone proteins. Menin was found to be an integral component of a complex that has histone methyl-transferase activity directed at lysine 4 of histone H3 (H3K4). H3K4 trimethy-lation (H3K4me3) is associated with activation of transcription. To explore the function of menin and hence the pathogenesis of MEN1, we studied the amino acid sequence of menin. We found that menin contains a potential nuclear receptor interaction motif. The nuclear receptor family consists of 48 receptors for steroid hormones, vitamins A and D and other lipophilic agents. It is known that nuclear receptors can play a role in endocrine tumourigenesis. By protein interaction experiments, reporter assays and chromatin precipitation experiments, we found that menin can indeed bind to nuclear receptors and co-activate nuclear receptor function by recruiting H3K4-me3 activity to nuclear receptor target genes. Menin is also important for the biological function of nuclear receptors; in the absence of menin mouse embryonic fibroblasts fail to undergo PPARgamma dependent adipogenesis. In parathyroid adenomas from MEN1 patients, vitamin D receptor target genes are expressed at lower levels, suggesting that loss of menin could lead to decreased nuclear receptor activity. The connection of menin and nuclear receptors might offer new perspectives for future therapy for MEN1 patients

A Parathyroid-Gut Axis: Hypercalcemia and the Pathogenesis of Gastrinoma in Multiple Endocrine Neoplasia 1

Patients with multiple endocrine neoplasia 1 (MEN1) syndrome have a germline mutation in the MEN1 gene. Loss of the wild-type allele can initiate endocrine tumorigenesis. Microscopic and macroscopic pituitary, parathyroid, and pancreatic tumors (referred to as the 3 P's) show loss of the wild-type MEN1 allele up to 100%. In contrast, the duodenal gastrinoma pathogenesis in MEN1 syndrome follows a hyperplasia-to-neoplasia sequence. Gastrinomas have loss of heterozygosity of the MEN1 locus in <50%, and invariably coincide with linear, diffuse, or micronodular gastrin-cell hyperplasia. The factor initiating the gastrin-cell hyperplasia-to-neoplasia sequence is unknown. In this perspective, we argue that hypercalcemia may promote the gastrin-cell hyperplasia-to-neoplasia sequence through the calcium sensing receptor. Hypercalcemia is present in almost all patients with MEN1 syndrome due to parathyroid adenomas. We propose a parathyroid-gut axis, which could well explain why patients with MEN1 syndrome are regularly cured of duodenal gastrinoma after parathyroid surgery, and might cause MEN1 syndrome phenocopies in MEN1-mutation negative individuals with parathyroid adenomas. This perspective on the pathogenesis of the gastrin-cell hyperplasia and neoplasia sequence sheds new light on tumorigenic mechanisms in neuroendocrine tumors and might open up novel areas of gastrinoma research. It may also shift focus in the treatment of MEN1 syndrome-related gastrinoma to biochemical prevention

Expression of p27(KiP1)and p18(Ink4c) in human multiple endocrine neoplasia type 1-related pancreatic neuroendocrine tumors

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Genome Methylation Accurately Predicts Neuroendocrine Tumor Origin: An Online Tool

PURPOSE: The primary origin of neuroendocrine tumor metastases can be difficult to determine by histopathology alone, but is critical for therapeutic decision making. DNA methylation-based profiling is now routinely used in the diagnostic workup of brain tumors. This has been enabled by the availability of cost-efficient array-based platforms. We have extended these efforts to augment histopathologic diagnosis in neuroendocrine tumors. EXPERIMENTAL DESIGN: Methylation data was compiled for 69 small intestinal, pulmonary, and pancreatic neuroendocrine tumors. These data were used to build a ridge regression calibrated random forest classification algorithm (neuroendocrine neoplasm identifier, NEN-ID). The model was validated during 3 × 3 nested cross-validation and tested in a local and an external cohort (n = 198 cases). RESULTS: NEN-ID predicted the origin of tumor samples with high accuracy (>95%). In addition, the diagnostic approach was determined to be robust across a range of possible confounding experimental parameters, such as tumor purity and array quality. A software infrastructure and online user interface were built to make the model available to the scientific community. CONCLUSIONS: This DNA methylation-based prediction model can be used in the workup for patients with neuroendocrine tumors of unknown primary. To facilitate validation and clinical implementation, we provide a user-friendly, publicly available web-based version of NEN-ID

Management of Multiple Secreting Paragangliomas in a Succinate Dehydrogenase Subunit D (SDHD) Variant Carrier

Management of functional intrathoracic sympathetic paragangliomas in succinate dehydrogenase subunit D (SDHD) mutation carriers is challenging, and there is no uniform guideline for treatment to date. The risks of potential malignant behavior and long-term cardiovascular morbidity have to be weighed against the risks of treatment complications. We report the multidisciplinary and shared decision-making approach that resulted in successful surgical removal of 3 paragangliomas in a SDHD mutation carrier. (C) 2020 by The Society of Thoracic SurgeonsOtorhinolaryngolog

Evolving management strategies in head and neck paragangliomas: A single-centre experience with 147 patients over a 60-year period

Otorhinolaryngolog

Health-Related Quality of Life in Adrenocortical Carcinoma: Development of the Disease-Specific Questionnaire ACC-QOL and Results from the PROFILES Registry

Simple Summary Patients with the rare cancer adrenocortical carcinoma are exposed to many symptoms and treatment side-effects. Research on how this can affect their health-related quality of life (HRQoL) is limited, however. This article includes the first assessment of HRQoL in a population-based cohort of patients with adrenocortical carcinoma with the European Organization for Research and Treatment of Cancer QLQ-C30 questionnaire and the newly developed disease-specific additional questionnaire ACC-QOL. The ACC-QOL has good psychometric properties in terms of validity, reliability, and responsiveness. Patients diagnosed more than 5 years ago reported a relatively good HRQoL compared with the Dutch reference population, but experienced residual fatigue and emotional problems. Patients after additional surgery reported a slightly lower HRQoL due to physical limitations. Patients who had recently received mitotane or chemotherapy reported a worse HRQoL and problems in many domains. This knowledge and the new disease-specific questionnaire can aid future research, side-effect monitoring, treatment guidance, and shared decision making. We aimed to develop a disease-specific adrenocortical carcinoma (ACC) health-related quality of life (HRQoL) questionnaire (ACC-QOL) and assess HRQoL in a population-based cohort of patients with ACC. Development was in line with European Organization for Research and Treatment of Cancer (EORTC) guidelines, though not an EORTC product. In phase I and II, we identified 90 potential HRQoL issues using literature and focus groups, which were reduced to 39 by healthcare professionals. Pilot testing resulted in 28 questions, to be used alongside the EORTC QLQ-C30. In Phase III, 100 patients with ACC were asked to complete the questionnaires twice in the PROFILES registry (3-month interval, respondents: first 67, second 51). Confirmatory factor analysis demonstrated the structural validity of 26 questions with their scale structure (mitotane side-effects, hypercortisolism/hydrocortisone effects, emotional effects). Internal consistency and reliability were good (Cronbach's alpha 0.897, Interclass correlation coefficient 0.860). Responsiveness analysis showed good discriminative ability (AUC 0.788). Patients diagnosed more than 5 years ago reported a good HRQoL compared with the Dutch reference population, but experienced residual fatigue and emotional problems. Patients who underwent recent treatment reported a lower HRQoL and problems in several domains. In conclusion, we developed an ACC-specific HRQoL questionnaire with good psychometric properties.Metabolic health: pathophysiological trajectories and therap

Health-related quality of life in adrenocortical carcinoma: Development of the disease-specific questionnaire ACC-QOL and results from the PROFILES registry

We aimed to develop a disease-specific adrenocortical carcinoma (ACC) health-related quality of life (HRQoL) questionnaire (ACC-QOL) and assess HRQoL in a population-based cohort of patients with ACC. Development was in line with European Organization for Research and Treatment of Cancer (EORTC) guidelines, though not an EORTC product. In phase I and II, we identified 90 potential HRQoL issues using literature and focus groups, which were reduced to 39 by healthcare professionals. Pilot testing resulted in 28 questions, to be used alongside the EORTC QLQ-C30. In Phase III, 100 patients with ACC were asked to complete the questionnaires twice in the PROFILES registry (3-month interval, respondents: first 67, second 51). Confirmatory factor analysis demonstrated the structural validity of 26 questions with their scale structure (mitotane side-effects, hypercortisolism/hydrocortisone effects, emotional effects). Internal consistency and reliability were good (Cronbach’s alpha 0.897, Interclass correlation coefficient 0.860). Responsiveness analysis showed good discriminative ability (AUC 0.788). Patients diagnosed more than 5 years ago reported a good HRQoL compared with the Dutch reference population, but experienced residual fatigue and emotional problems. Patients who underwent recent treatment reported a lower HRQoL and problems in several domains. In conclusion, we developed an ACC-specific HRQoL questionnaire with good psychometric properties