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

Initiating pancreatic neuroendocrine tumor (pNET) screening in young MEN1 patients: results from the DutchMEN study group

Context: Nonfunctioning pancreatic neuroendocrine tumors (NF-pNETs) are highly prevalent and constitute an important cause of mortality in patients with multiple endocrine neoplasia type 1 (MEN1). Still, the optimal age to initiate screening for pNETs is under debate.Objective: The aim of this work is to assess the age of occurrence of clinically relevant NF-pNETs in young MEN1 patients.Methods: Pancreatic imaging data of MEN1 patients were retrieved from the DutchMEN Study Group database. Interval-censored survival methods were used to describe age-related penetrance, compare survival curves, and develop a parametric model for estimating the risk of having clinically relevant NF-pNET at various ages. The primary objective was to assess age at occurrence of clinically relevant NF-pNET (size >= 20 mm or rapid growth); secondary objectives were the age at occurrence of NF-pNET of any size and pNET-associated metastasized disease.Results: Five of 350 patients developed clinically relevant NF-pNETs before age 18 years, 2 of whom subsequently developed lymph node metastases. No differences in clinically relevant NF-pNET-free survival were found for sex, time frame, and type of MEN1 diagnosis or genotype. The estimated ages (median, 95% CI) at a 1%, 2.5%, and 5% risk of having developed a clinically relevant tumor are 9.5 (6.5-12.7), 13.5 (10.2-16.9), and 17.8 years (14.3-21.4), respectively.Conclusion: Analyses from this population-based cohort indicate that start of surveillance for NF-pNETs with pancreatic imaging at age 13 to 14 years is justified.The psychological and medical burden of screening at a young age should be considered.Clinical epidemiolog

Multiple Endocrine Neoplasia Type 1: The impact of screening : Results of the DutchMEN1 Study Group

The MEN1 syndrome is a hereditary disease characterized by the simultaneous occurrence of parathyroid, pituitary and duodenopancreatic neuroendocrine tumors. The prevalence of MEN1 is estimated at 3-4/100,000 with a high age-related penetrance of the three main manifestations. The clinical practice guideline for MEN1 recommends a strict screening protocol from an early age. The first part of this thesis elaborates on familial screening and the consequence of novel findings with regards to screening. The second part describes the impact of having the MEN1 syndrome and subsequent screening of the disease and its manifestations. Chapter 2 reveals the morbidity and mortality arising from lag times from diagnosis of the index case and subsequent family members. In general, individuals with longer lag times had more morbidity. It is concluded that an early diagnosis in relatives is imperative and will lead to less morbidity. The whole family should be screened within one year after a germline mutation is identified in the index case. It was previously proposed that blood type O was associated with a higher occurrence of neuroendocrine tumors in MEN1 and that blood type could be a useful addition to the current screening program. Chapter 3 shows that there was no association between blood type O and neuroendocrine tumors in the Dutch MEN1 cohort. Addition of the blood type to the screening program therefore seemed not of additional value. A recent study revealed an association between MEN1 and an early-onset elevated relative breast cancer risk of 2.83. Chapter 4 presents the results of a study assessing whether other risk factors were associated with this higher risk. The analysis revealed that breast cancer occurred at the age of 57.5 years in women without MEN1 and 45 years in women with MEN1 (P=0.03). Surveillance from the age of 40 seemed most appropriate. A biennial surveillance program was deemed justifiable considering the luminal type of breast cancer with a favourable disease course, which holds for the majority of breast cancers cases in MEN1. A MEN1 diagnosis holds lifelong implications. Screening for a MEN1 related manifestation is a major part of the disease. Chapter 5 reveals that the QOL in patients with MEN1 is impaired in comparison with the general population. Factors leading to a decreased QOL are being an index case, the presence of a pituitary tumor and being unemployed. Unemployment was an independent factor leading to a diminished QOL. Patients who had a pituitary tumor but reported not to have a pituitary tumor had a better QOL in comparison with patients who reported to have a pituitary tumor. The knowledge of having a manifestation seems an important factor. In this respect ignorance can truly be bliss. Chapter 6 shows that patients have more fear about disease occurrence in their family members than in themselves. Fear of disease occurrence is significantly related to QOL. The more aware patients are of the disease, the more fear they encounter. Since more fear leads to decreased QOL, physicians should be alert about the presence of this fear

High Fear of Disease Occurrence Is Associated With Low Quality of Life in Patients With Multiple Endocrine Neoplasia Type 1: Results From the Dutch MEN1 Study Group

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High Fear of Disease Occurrence Is Associated With Low Quality of Life in Patients With Multiple Endocrine Neoplasia Type 1: Results From the Dutch MEN1 Study Group

Diabetes mellitus: pathophysiological changes and therap

Impact of Delay in Diagnosis in Outcomes in MEN1: Results From the Dutch MEN1 Study Group

Item does not contain fulltextOBJECTIVE: Identifying a germline mutation in the multiple endocrine neoplasia type 1 (MEN1) gene in an index case has consequences for a whole family. Eligible family members should be offered genetic counseling and MEN1 mutation testing. Subsequently, clinical screening of mutation carriers according to the guidelines should be initiated. We assessed whether there is a lag time from MEN1 diagnosis of the index case to MEN1 diagnosis of family members. In addition, we determined whether this lag time was associated with an increased morbidity and mortality risk. DESIGN: A cohort study was performed using the Dutch MEN1 database, including >90% of the Dutch MEN1 population >16 years of age (n = 393). RESULTS: Fifty-eight MEN1 families were identified, of whom 57 were index cases and 247 were non-index cases (n = 304). The median lag time in MEN1 diagnosis of family members was 3.5 (range, 0-30) years. At the time of MEN1 diagnosis, 30 (12.1%) non-index cases had a duodenopancreatic neuroendocrine tumor, of whom 20% had metastases with a mean lag time of 10.9 years, in comparison with 7.1 years without metastases. Twenty-five (10.1%) non-index cases had a pituitary tumor, of whom 80% had a microadenoma and 20% had a macroadenoma, with mean lag times of 7.2 and 10.6 years, respectively. Ninety-five (38.4%) non-index cases had a primary hyperparathyroidism with a mean lag time of 9.5 years in comparison with seven patients without a primary hyperparathyroidism with a mean lag time of 3 years (P = .005). Ten non-index cases died because of a MEN1-related cause that developed during or before the lag time. CONCLUSION: There is a clinically relevant delay in MEN1 diagnosis in families because of a lag time between the diagnosis of an index case and the rest of the family. More emphasis should be placed on the conduct of proper counseling and genetic testing in all eligible family members

Development and Internal Validation of a Multivariable Prediction Model for Adrenocortical-Carcinoma-Specific Mortality

Simple Summary Adrenocortical carcinoma is a rare and aggressive cancer. Great variability in clinical course is observed, ranging from patients with extreme long survival to aggressive tumors with prompt fatal outcome. This heterogeneity in survival makes it complicated to tailor treatment strategies for an individual patient. Therefore we sought to identify prognostic factors associated with ACC specific mortality. We analyzed the data of 160 ACC patients and developed a clinical prediction model including age, modified European Network for the Study of Adrenal Tumors (mENSAT) stage, and radical resection. This easy-to-use prediction model for ACC-specific mortality has the potential to guide clinical decision making if externally validated. Adrenocortical carcinoma (ACC) has an incidence of about 1.0 per million per year. In general, survival of patients with ACC is limited. Predicting survival outcome at time of diagnosis is a clinical challenge. The aim of this study was to develop and internally validate a clinical prediction model for ACC-specific mortality. Data for this retrospective cohort study were obtained from the nine centers of the Dutch Adrenal Network (DAN). Patients who presented with ACC between 1 January 2004 and 31 October 2013 were included. We used multivariable Cox proportional hazards regression to compute the coefficients for the prediction model. Backward stepwise elimination was performed to derive a more parsimonious model. The performance of the initial prediction model was quantified by measures of model fit, discriminative ability, and calibration. We undertook an internal validation step to counteract the possible overfitting of our model. A total of 160 patients were included in the cohort. The median survival time was 35 months, and interquartile range (IQR) 50.7 months. The multivariable modeling yielded a prediction model that included age, modified European Network for the Study of Adrenal Tumors (mENSAT) stage, and radical resection. The c-statistic was 0.77 (95% Confidence Interval: 0.72, 0.81), indicating good predictive performance. We developed a clinical prediction model for ACC-specific mortality. ACC mortality can be estimated using a relatively simple clinical prediction model with good discriminative ability and calibration.Diabetes mellitus: pathophysiological changes and therap

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

The Management of Neuroendocrine Tumors of the Lung in MEN1: Results From the Dutch MEN1 Study Group

Item does not contain fulltextINTRODUCTION: Multiple endocrine neoplasia type 1 (MEN1)-related neuroendocrine tumors (NETs) of the lung are mostly indolent, with a good prognosis. Nevertheless, cases of aggressive lung NET do occur, and therefore the management of individual patients is challenging. AIM: To assess tumor growth and the survival of patients with MEN1-related lung NETs at long-term follow-up. METHODS: The population-based Dutch MEN1 Study Group database (n = 446) was used to identify lung NETs by histopathological and radiological examinations. Tumor diameter was assessed. Linear mixed models and the Kaplan-Meier method were used for analyzing tumor growth and survival. Molecular analyses were performed on a lung NET showing particularly aggressive behavior. RESULTS: In 102 patients (22.9% of the total MEN1 cohort), 164 lesions suspected of lung NETs were identified and followed for a median of 6.6 years. Tumor diameter increased 6.0% per year. The overall 15-year survival rate was 78.0% (95% confidence interval: 64.6-94.2%) without lung NET-related death. No prognostic factors for tumor growth or survival could be identified. A somatic c.3127A > G (p.Met1043Val) PIK3CA driver mutation was found in a case of rapid growing lung NET after 6 years of indolent disease, presumably explaining the sudden change in course. CONCLUSION: MEN1-related lung NETs are slow growing and have a good prognosis. No accurate risk factors for tumor growth could be identified. Lung NET screening should therefore be based on well-informed, shared decision-making, balancing between the low absolute risk of an aggressive tumor in individuals and the potential harms of frequent thoracic imaging