| 1. |
- Casar Borota, Olivera, et al.
(författare)
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Corticotroph Aggressive Pituitary Tumors and Carcinomas Frequently Harbor ATRX Mutations
- 2021
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 106:4, s. 1183-1194
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Tidskriftsartikel (refereegranskat)abstract
- Context: Aggressive pituitary tumors (APTs) are characterized by unusually rapid growth and lack of response to standard treatment. About 1% to 2% develop metastases being classified as pituitary carcinomas (PCs). For unknown reasons, the corticotroph tumors are overrepresented among APTs and PCs. Mutations in the alpha thalassemia/mental retardation syndrome X-linked (ATRX) gene, regulating chromatin remodeling and telomere maintenance, have been implicated in the development of several cancer types, including neuroendocrine tumors. Objective: To study ATRX protein expression and mutational status of the ATRX gene in APTs and PCs. Design: We investigated ATRX protein expression by using immunohistochemistry in 30 APTs and 18 PCs, mostly of Pit-1 and T-Pit cell lineage. In tumors lacking ATRX immunolabeling, mutational status of the ATRX gene was explored. Results: Nine of the 48 tumors (19%) demonstrated lack of ATRX immunolabelling with a higher proportion in patients with PCs (5/18; 28%) than in those with APTs (4/30;13%). Lack of ATRX was most common in the corticotroph tumors, 7/22 (32%), versus tumors of the Pit-1 lineage, 2/24 (8%). Loss-of-function ATRX mutations were found in all 9 ATRX immunonegative cases: nonsense mutations (n = 4), frameshift deletions (n = 4), and large deletions affecting 22-28 of the 36 exons (n = 3). More than 1 ATRX gene defect was identified in 2 PCs. Conclusion: ATRX mutations occur in a subset of APTs and are more common in corticotroph tumors. The findings provide a rationale for performing ATRX immunohistochemistry to identify patients at risk of developing aggressive and potentially metastatic pituitary tumors.
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| 2. |
- Bengtsson, Daniel, 1975-, et al.
(författare)
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Corticotroph Pituitary Carcinoma in a Patient With Lynch Syndrome (LS) and Pituitary Tumors in a Nationwide LS Cohort
- 2017
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : OXFORD UNIV PRESS INC. - 0021-972X .- 1945-7197. ; 102:11, s. 3928-3932
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Tidskriftsartikel (refereegranskat)abstract
- Context: Lynch syndrome (LS) is a cancer-predisposing syndrome caused by germline mutations in genes involved in DNA mismatch repair (MMR). Patients are at high risk for several types of cancer, but pituitary tumors have not previously been reported. Case: A 51-year-old man with LS (MSH2 mutation) and a history of colon carcinoma presented with severe Cushing disease and a locally aggressive pituitary tumor. The tumor harbored a mutation consistent with the patients germline mutation and displayed defect MMR function. Sixteen months later, the tumor had developed into a carcinoma with widespread liver metastases. The patient prompted us to perform a nationwide study in LS. Nationwide Study: A diagnosis consistent with a pituitary tumor was sought for in the Swedish National Patient Registry. In 910 patients with LS, representing all known cases in Sweden, another two clinically relevant pituitary tumors were found: an invasive nonsecreting macroadenoma and a microprolactinoma (i.e., in total three tumors vs. one expected). Conclusion: Germline mutations in MMR genes may contribute to the development and/or the clinical course of pituitary tumors. Because tumors with MMR mutations are susceptible to treatment with immune checkpoint inhibitors, we suggest to actively ask for a family history of LS in the workup of patients with aggressive pituitary tumors.
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| 3. |
- Bengtsson, Daniel, 1975-
(författare)
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Cushing’s disease and aggressive pituitary tumours : Aspects on epidemiology, treatment, and long-term follow-up
- 2021
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis focuses on clinical and epidemiological aspects of aggressive pituitary tumours/carcinomas and Cushing’s disease. Pituitary carcinomas account for only 0.1-0.2% of the tumours originating from the anterior pituitary gland and are defined solely by the event of distant metastases, whereas aggressive pituitary tumours are defined by their clinical behaviour of rapid/progressive growth despite optimal treatment with surgery, radiotherapy and medical agents. The prognosis for individuals with aggressive tumours/carcinomas has been poor with few treatment options. However, case reports indicated better outcomes after treatment with the alkylating agent temozolomide. In study I and III, we investigated 24 patients (16 aggressive tumours and 8 carcinomas) given treatment with temozolomide. We found an initial response rate (tumour regression ≥30%) in 10/21 evaluable patients, with complete regression in two carcinomas. Favourable response was associated with low tumour expression of the DNA repair protein MGMT; in responders median 9% (range 5-20%) vs non-responders median 93% (50-100%). Our results also indicated a longer survival in patients with low MGMT. Out of 11 patients with MGMT >10%, nine died with an estimated median survival of 26 months (95% CI 14-38), whereas only 1/6 patients with lower MGMT died from tumour progression during a follow-up of median 83 months (range 12-161).One of the patients in study I and III had a corticotroph pituitary carcinoma and in addition, Lynch syndrome (LS), a hereditary cancer-predisposing syndrome caused by germline mutations in DNA mismatch repair (MMR) genes and primarily associated with colon and endometrial carcinomas. In study II, we investigated the characteristics of the pituitary carcinoma and found loss of MSH2 and MSH6 protein expression, consistent with the patient’s germline mutation in MSH2. This was the first published case of a pituitary tumour associated with LS. In addition, we identified all known Swedish patients with LS (n=910) and searched for diagnostic codes consistent with a pituitary tumour in the Swedish national patient register. We found in total three patients with clinically relevant pituitary tumours, the reported prevalence in the background population is around 1:1000.The last two studies in the thesis focused on Cushing’s disease (CD), i.e. an ACTH-secreting pituitary tumour resulting in excess levels of cortisol. CD is associated with multiple comorbidities and increased mortality. The reversibility of comorbidities and mortality risk after remission of cortisol levels have been under debate. Study IV examined psychiatric consequences of CD, measured by the use of psychotropic drugs. 179 patients with CD and a quadrupled matched control group were followed from diagnosis and at 5- and 10-year follow-up. We found that use of antidepressants remained at around 25% of patients with CD, regardless of remission status, at diagnosis and follow-up, whereas drugs for somatic comorbidities decreased. Use of antidepressants, sleeping pills and anxiolytics was higher in patients with CD compared to controls at diagnosis and 5-year follow-up. A cross-sectional analysis of 76 patients in sustained biochemical remission for median 9.3 years showed that 25% were taking antidepressants, a significantly higher use than controls, OR 2.0 (95% CI 1.1-3.8). In addition, patients with CD had a higher use of psychotropic drugs, already in the 5-year period before diagnosis.Study V investigated mortality and causes of death in 371 patients with CD, compared to a quadrupled matched control group. Follow-up was median 10.6 years (IQR 5.7-18.2) after time of diagnosis. Overall mortality was increased in patients with CD, HR 2.1 (95% CI 1.5-2.8) and remained elevated for patients in remission at last follow-up (n=303), HR 1.5 (1.02-2.2). For patients not in remission (n=31), HR was 5.6 (2.7-11.6). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death in patients with CD. Main conclusions of the thesis:Temozolomide improves outcome in patients with aggressive pituitary tumours/carcinomas and a low MGMT expression in the tumour predicts a favourable outcome. As additional therapies evolve, MGMT may help to tailor the treatment.Germline mutations in MMR genes may contribute to the development and clinical course of pituitary tumours and may be a novel cause of hereditary pituitary tumours.Patients with Cushing’s disease have a high use of psychotropic drugs that remains elevated despite achievement of biochemical remission, suggesting persisting negative effects on mental health and highlighting the need for long-term monitoring of psychiatric symptoms. In addition, psychiatric symptoms may be early and important signs of CD.Efforts to achieve biochemical remission are crucial to reduce mortality in CD. However, patients in remission still have an increased mortality compared to controls. This underscores the need for life-long monitoring and treatment of associated comorbidities in patients with CD.
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| 4. |
- Bengtsson, Daniel, 1975-, et al.
(författare)
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Increased Mortality Persists after Treatment of Cushing's Disease: A Matched Nationwide Cohort Study
- 2022
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Ingår i: Journal of the Endocrine Society. - : The Endocrine Society. - 2472-1972. ; 6:6
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Tidskriftsartikel (refereegranskat)abstract
- Context: Whether biochemical remission normalizes life expectancy in Cushing's disease (CD) patients remains unclear. Previous studies evaluating mortality in CD are limited by using the expected number of deaths in the background population instead of the actual number in matched controls. Objective and setting: To study mortality by time-to-event analysis in an unselected nationwide CD patient cohort. Design and participants: Longitudinal data from the Swedish Pituitary Register of 371 patients diagnosed with CD from 1991 to 2018 and information from the Swedish Cause of Death Register were evaluated. Four controls per patient (n = 1484) matched at the diagnosis date by age, sex, and residential area were included. Main outcome measures: Mortality and causes of death. Results: The median diagnosis age was 44 years (interquartile range 32-56), and the median follow-up was 10.6 years (5.7-18.0). At the 1-, 5-, 10-, 15-, and 20-year follow-ups, the remission rates were 80%, 92%, 96%, 91%, and 97%, respectively. Overall mortality was increased in CD patients compared with matched controls [hazard ratio (HR) 2.1 (95% CI 1.5-2.8)1. The HRs were 1.5 (1.02-2.2) for patients in remission at the last follow-up In = 303), 1.7 (1.03-2.8) for those in remission after a single pituitary surgery In = 177), and 5.6 (2.7-11.6) for those not in remission (n = 31). Cardiovascular diseases (32/66) and infections (12/66) were overrepresented causes of death. Conclusions: Mortality was increased in CD patients despite biochemical remission compared to matched controls. The study highlights the importance of careful comorbidity monitoring, regardless of remission status.
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| 5. |
- Bengtsson, Daniel, 1975-, et al.
(författare)
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Long-Term Outcome and MGMT as a Predictive Marker in 24 Patients With Atypical Pituitary Adenomas and Pituitary Carcinomas Given Treatment With Temozolomide
- 2015
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 100:4, s. 1689-1698
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Tidskriftsartikel (refereegranskat)abstract
- Context/Objective: Locally aggressive pituitary tumors (LAPT) and pituitary carcinomas respond poorly to conventional therapy and cytotoxic drugs. Temozolomide (TMZ) is an oral alkylating drug with good tolerability, approved for treatment of malignant gliomas. The experience of its use in pituitary tumors is limited. Design and Setting: We report on 24 patients with aggressive pituitary tumors (16 LAPTs, 8 carcinomas) treated with TMZ for a median of 6 months (range 1-23). Follow-up ranged from 4 to 91 months with a median of 32.5 months. 19/24 tumors were hormone secreting (PRL 9, ACTH 4, GH 4, GH/PRL 2). Ki-67 was 2-50% in LAPTs, and 5-80% in carcinomas. Main Outcome: Response to TMZ and the association with tumor expression of O6-methylguanine DNA methyltransferase (MGMT), MLH1, MSH2, and MSH6, examined by immunohistochemistry. Results: Complete tumor regression occurred in two carcinomas and persisted at follow-up after 48 and 91 months, respectively. Partial regress of tumor mass ranging from 35% to 80% occurred in 5 LAPTs and 2 carcinomas. Another patient with LAPT had a 71% decrease in prolactin levels without change in tumor volume. Three LAPTs could not be evaluated. Median MGMT staining was 9% (5-20%) in responders vs 93% (50-100%) in nonresponders. Loss of MSH2 and MSH 6 was observed in a single patient who had a rapid development of resistance to TMZ. Conclusions: This study shows that TMZ is a valuable treatment option for patients with uncontrolled pituitary tumors. The data suggest that tumoral MGMT staining below 50% is associated with a high likelihood of treatment response.
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| 6. |
- Bengtsson, Daniel, et al.
(författare)
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Psychotropic Drugs in Patients with Cushing's Disease Before Diagnosis and at Long-Term Follow-Up: A Nationwide Study
- 2021
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Ingår i: Journal of Clinical Endocrinology & Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 106:6, s. 1750-1760
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Tidskriftsartikel (refereegranskat)abstract
- Context: Psychiatric symptoms are common in Cushing's disease (CD) and seem only partly reversible following treatment. Objective: To investigate drug dispenses associated to psychiatric morbidity in CD patients before treatment and during long-term follow-up. Design: Nationwide longitudinal register-based study. Setting: University Hospitals in Sweden. Subjects: CD patients diagnosed between 1990 and 2018 (N = 372) were identified in the Swedish Pituitary Register. Longitudinal data was collected from 5 years before, at diagnosis, and during follow-up. Four matched controls per patient were included. Cross-sectional subgroup analysis of 76 patients in sustained remission was also performed. Main outcome measures: Data from the Swedish Prescribed Drug Register and the Patient Register. Results: In the 5-year period before and at diagnosis, use of antidepressants (odds ratio [OR] 2.2 [95% confidence interval (CI) 1.3-3.7]) and 2.3 [1.6-3.5]), anxiolytics [2.9 (1.6-5.3) and 3.9 (2.3-6.6)], and sleeping pills [2.1 (1.2-3.7) and 3.8 (2.4-5.9)] was more common in CD than controls. ORs remained elevated at 5-year follow-up for antidepressants [2.4 (1.53.9)] and sleeping pills [3.1 (1.9-5.3)]. Proportions of CD patients using antidepressants (26%) and sleeping pills (22%) were unchanged at diagnosis and 5-year follow-up, whereas drugs for hypertension and diabetes decreased. Patients in sustained remission for median 9.3 years (interquartile range 8.1-10.4) had higher use of antidepressants [OR 2.0 (1.1-3.8)] and sleeping pills [2.4 (1.3-4.7)], but not of drugs for hypertension. Conclusions: Increased use of psychotropic drugs in CD was observed before diagnosis and remained elevated regardless of remission status, suggesting persisting negative effects on mental health. The study highlights the importance of early diagnosis of CD, and the need for long-term monitoring of mental health.
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