| 1. |
- Bjarnadottir, Olöf, et al.
(författare)
-
Statin use, HMGCR expression, and breast cancer survival – The Malmö Diet and Cancer Study
- 2020
-
Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 10:1
-
Tidskriftsartikel (refereegranskat)abstract
- Statins, commonly used to treat hypercholesterolemia, have also been proposed as anti-cancer agents. The identification of a predictive marker is essential. The 3-hydroxy-3-methylglutaryl-coenzyme-A reductase (HMGCR), which is inhibited by statins, might serve as such a marker. Thorough antibody validation was performed for four different HMGCR antibodies. Tumor expression of HMGCR (#AMAb90619, CL0260, Atlas Antibodies, Stockholm, Sweden) was evaluated in the Malmö Diet and Cancer Study breast cancer cohort. Statin use and cause of death data were retrieved from the Swedish Prescribed Drug Register and Swedish Death Registry, respectively. Breast cancer-specific mortality (BCM) according to statin use and HMGCR expression were analyzed using Cox regression models. Three-hundred-twelve of 910 breast cancer patients were prescribed statins; 74 patients before and 238 after their breast cancer diagnosis. HMGCR expression was assessable for 656 patients; 119 showed negative, 354 weak, and 184 moderate/strong expressions. HMGCR moderate/strong expression was associated with prognostically adverse tumor characteristics as higher histological grade, high Ki67, and ER negativity. HMGCR expression was not associated with BCM. Neither was statin use associated with BCM in our study. Among breast cancer patients on statins, no or weak HMGCR expression predicted favorable clinical outcome. These suggested associations need further testing in larger cohorts.
|
|
| 2. |
- Inasu, Maria, et al.
(författare)
-
Statin use and patterns of breast cancer recurrence in the Malmö Diet and Cancer Study
- 2022
-
Ingår i: Breast. - : Elsevier BV. - 0960-9776. ; 61, s. 123-128
-
Tidskriftsartikel (refereegranskat)abstract
- Background: Accumulating evidence suggests that statins have a beneficial effect on breast cancer prognosis. Previous studies have reported a positive association between statin use and breast cancer survival; however, the relationship between statin use and patterns of breast cancer recurrence remains unclear. Patients and methods: We identified all Malmö Diet and Cancer Study (MDCS) participants diagnosed with incident invasive breast cancer between 2005 and 2014. The follow-up period began at breast cancer diagnosis and continued until the first invasive breast cancer recurrence event, death, emigration or the end of the follow-up (June 8, 2020). We estimated incidence rates (IRs) of recurrence and fit Cox regression models to compute crude and adjusted hazard ratios (HRs) with 95% confidence intervals (95% CIs) for disease recurrence to compare post-diagnosis statin users with non-users. Results: The final study cohort consisted of 360 eligible patients with a median follow-up of 8.6 years. Overall, there were 71 recurrences in 2932 total person-years. According to statin use, there were 14 recurrences in 595 person-years among statin users, and 57 recurrences in 2337 person-years in non-users. Statin use was associated with a reduced risk of breast cancer recurrence (HRadj = 0.88 [95% CI: 0.82–0.96]). Regarding the pattern of recurrence, statin use was associated with a reduced risk of distant recurrence (HRadj = 0.86 [95% CI: 0.80–0.94]) but not loco-regional recurrence (HRadj = 0.97 [95% CI: 0.87–1.08]). Conclusion: In the MDCS, statin use was associated with a reduced risk of distant breast cancer recurrence, whereas no association between statin use and loco-regional breast cancer recurrence was found. This site-based difference in disease recurrence may be explained by statin's inhibition of epithelial-mesenchymal transition.
|
|
| 3. |
- Abrams, Pascale, et al.
(författare)
-
GH replacement in hypopituitarism improves lipid profile and quality of life independently of changes in obesity variables
- 2008
-
Ingår i: European Journal of Endocrinology. - 0804-4643 .- 1479-683X. ; 159:6, s. 825-832
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: GH deficiency (GHD) in adults is characterized by elevated body mass index (BMI), increased waist girth (WG) and increased fat mass (FM). Information about how these indicators of obesity affect the lipid profile and quality of life (QoL) of GHD subjects is scarce. It is also unclear how changes in these indicators brought about by GH replacement influence lipids and QoL. Design and methods: Adult GHD Subjects from the Pfizer International Metabolic Database were grouped according to BMI (n = 291 with BMI < 25 kg/m(2), n = 372 with BMI 25-30 kg/m(2), n = 279 with BMI > 30 kg/m(2)), WG (n = 508 with normal WG, n = 434 with increased WG) and FM (n = 357) and according to changes in these variables after 1 year of GH replacement. Serum IGF-1 concentrations, lipid concentrations and QoL using the QoL Assessment of GHD in Adults questionnaire were assessed at baseline and after 1 year of treatment. Results: At baseline, total and low-density lipoprotein (LDL) cholesterol were similarly elevated in the BMI and WG groups, but high-density lipoprotein (HDL) cholesterol decreased and triglycerides increased with increasing BMI and WG. QoL was progressively poorer with increasing BMI and WG. After 1 year of GH replacement, total and LDL cholesterol and QoL improved in all BMI, WG and FM groups. Conclusions: Variables of obesity adversely affect the already unfavourable lipid profile in GHD Subjects by decreasing HDL cholesterol, but do not counteract the positive effect of GH replacement on LDL cholesterol. Similarly, QoL is influenced by obesity, but responds equally well to GH treatment independent of BMI, WG and FM.
|
|
| 4. |
- Abs, Roger, et al.
(författare)
-
Determinants of cardiovascular risk in 2589 hypopituitary GH-deficient adults - a KIMS database analysis.
- 2006
-
Ingår i: European Journal of Endocrinology. - : Oxford University Press (OUP). - 0804-4643 .- 1479-683X. ; 155:1, s. 79-90
-
Tidskriftsartikel (refereegranskat)abstract
- Objective: The aim of the present study was to clarify the relationship between GH deficiency (GHD) andsome cardiovascular risk factors and to analyse the effect of GH replacement therapy in a large numberof patients over a prolonged period of time.Design: Data for analysis were retrieved from KIMS (Pfizer International Metabolic Database). Serumconcentrations of total cholesterol, high-density lipoprotein (HDL)-cholesterol, low-density lipoprotein(LDL)-cholesterol and triglycerides were obtained from 2589 patients at baseline and from 1206patients after 1 and 2 years of GH replacement therapy. Body mass index (BMI), waist and hip, restingblood pressure and body composition were also measured.Results: At baseline, the unfavourable effects of GHD were most obvious in the lipid profiledemonstrating elevated mean total and LDL-cholesterol, in the increased waist circumference and theelevated BMI. The cholesterol concentration, BMI and body composition were significantly adverselyaffected by a number of factors, including age, sex and the use of anti-epileptic drugs. The therapeuticeffect of GH was essentially uniform across the whole population. GH replacement reduced significantlythe mean total and LDL-cholesterol, the waist circumference and the fat mass and was maintainedduring 2 years.Conclusions: This analysis of a large number of patients confirmed that GHD adults present with anincreased cardiovascular risk. The sustained improvement of the adverse lipid profile and bodycomposition suggests that GH replacement therapy may reduce the risk of cardiovascular disease andthe premature mortality seen in hypopituitary patients with untreated GHD.
|
|
| 5. |
|
|
| 6. |
- Arlien-Soborg, Mai C., et al.
(författare)
-
Acromegaly management in the Nordic countries: A Delphi consensus survey
- 2024
-
Ingår i: CLINICAL ENDOCRINOLOGY. - : WILEY. - 0300-0664 .- 1365-2265.
-
Tidskriftsartikel (refereegranskat)abstract
- ObjectiveAcromegaly is associated with increased morbidity and mortality if left untreated. The therapeutic options include surgery, medical treatment, and radiotherapy. Several guidelines and recommendations on treatment algorithms and follow-up exist. However, not all recommendations are strictly evidence-based. To evaluate consensus on the treatment and follow-up of patients with acromegaly in the Nordic countries.MethodsA Delphi process was used to map the landscape of acromegaly management in Denmark, Sweden, Norway, Finland, and Iceland. An expert panel developed 37 statements on the treatment and follow-up of patients with acromegaly. Dedicated endocrinologists (n = 47) from the Nordic countries were invited to rate their extent of agreement with the statements, using a Likert-type scale (1-7). Consensus was defined as >= 80% of panelists rating their agreement as >= 5 or <= 3 on the Likert-type scale.ResultsConsensus was reached in 41% (15/37) of the statements. Panelists agreed that pituitary surgery remains first line treatment. There was general agreement to recommend first-generation somatostatin analog (SSA) treatment after failed surgery and to consider repeat surgery. In addition, there was agreement to recommend combination therapy with first-generation SSA and pegvisomant as second- or third-line treatment. In more than 50% of the statements, consensus was not achieved. Considerable disagreement existed regarding pegvisomant monotherapy, and treatment with pasireotide and dopamine agonists.ConclusionThis consensus exploration study on the management of patients with acromegaly in the Nordic countries revealed a relatively large degree of disagreement among experts, which mirrors the complexity of the disease and the shortage of evidence-based data.
|
|
| 7. |
- Brabant, Georg, et al.
(författare)
-
Clinical implications of residual growth hormone (GH) response to provocative testing in adults with severe GH deficiency
- 2007
-
Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 92:7, s. 2604-2609
-
Tidskriftsartikel (refereegranskat)abstract
- Context: The diagnosis of GH deficiency (GHD) in adults is based on provocative tests of GH release, all influenced by clinical factors. It is unknown whether the amount of residual GH reserve under the cutoff value has any physiological implication. Objectives: We used a large pharmacoepidemiological database of adult GHD (KIMS) and tested the impact of confounding factors on GH release of no greater than 3 µg/liter after an insulin tolerance test (ITT) and evaluated its potential physiological role. Design, Settings, and Patients: A total of 1098 patients fulfilled the criteria of having a GH peak of no greater than 3 µg/liter during ITT as well as documented IGF-I levels. Outcomes: The impact of underlying hypothalamic-pituitary disease, age, gender, body weight, as well as treatment modalities such as irradiation on peak GH level to ITT was evaluated, and the correlations between GH peak and targets of GH action were analyzed. Results: The GH response to ITT was regulated by gender, age, and the number of additional pituitary deficiencies. In a multivariate evaluation, the extent of hypothalamic-pituitary dysfunction was the most important single predictor of GH peak in ITT. GH peaks in ITT were positively related to IGF-I levels and high-density lipoprotein-cholesterol, as well as inversely to triglycerides. Conclusions: Even in adult severe GHD, GH release appears to be regulated by factors defined to play an important role in normal GH secretion. The impact of very low GH release on IGF-I and lipid parameters indicates a persistent physiological role of low GH concentrations in severely affected patients with GHD.
|
|
| 8. |
|
|
| 9. |
- Feldt, Maria, et al.
(författare)
-
Statin-induced anti-proliferative effects via cyclin D1 and p27 in a window-of-opportunity breast cancer trial.
- 2015
-
Ingår i: Journal of Translational Medicine. - : Springer Science and Business Media LLC. - 1479-5876. ; 13:133
-
Tidskriftsartikel (refereegranskat)abstract
- Cholesterol lowering statins have been demonstrated to exert anti-tumoral effects on breast cancer by decreasing proliferation as measured by Ki67. The biological mechanisms behind the anti-proliferative effects remain elusive. The aim of this study was to investigate potential statin-induced effects on the central cell cycle regulators cyclin D1 and p27.
|
|
| 10. |
- Feldt, Maria
(författare)
-
Targeting the role of statins in breast cancer – through translationally edged clinical trials
- 2021
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- AbstractBreast cancer incidence is increasing, and despite major progress in the treatment, breast cancer is still the leading cause of death from cancer among women. Thus, there is a constant need for new treatment options. Statins are peroral drugs that have been widely used since the early 1990s, due to their well-documented effect of lowering plasma cholesterol levels and preventing cardiovascular disease. Statins have also been recognized for their pleiotropic effects extending beyond their plasma cholesterol-lowering properties, and preclinical experiments have shown that statins exert anti-tumoral effects in breast cancer cell lines. Further, epidemiological studies have shown reduced breast cancer recurrence and mortality among statin users. These findings have led to the conduction of the phase II, window-of-opportunity, MAmmary cancer and STatins trial (MAST), aiming to further explore the statin effects of breast cancer. Papers I and II are based the MAST trial, which included 50 patients who received a high dose of atorvastatin (80mg/day) for two weeks during the treatment-free window between diagnosis and breast surgery. Before the start of atorvastatin treatment, core needle tumor biopsies were taken from the tumors and blood samples were collected. After two weeks of atorvastatin treatment, tumor tissue was retrieved during the standard surgical procedure and, at the same time, new blood samples were collected.In paper I, the protein expression of the cell-cycle regulators cyclin D1 and p27 was evaluated by immunohistochemistry on paired samples of formalin-fixed paraffin-embedded tumor tissue, before and after atorvastatin treatment. Project I revealed a significant down‐regulated expression of the oncogene cyclin D1 and a significant up‐regulated expression of the tumor suppressor p27 following two weeks of statin treatment.In paper II, fresh frozen paired tumor samples pre- and post-atorvastatin treatment were analyzed by extracting lipids from the tumor samples. Cholesterol levels were then measured using a cholesterol quantification assay in order to evaluate changes in the cholesterol levels. The expression of the LDL-receptor (LDLR) was analyzed by immunohistochemistry on formalin-fixed paraffin-embedded tumor tissue, pre- and post-atorvastatin treatment. Project II revealed a statin-induced up-regulation of the LDLR and preserved intratumoral cholesterol levels. In vitro experiments on MCF-7 cells treated with atorvastatin were performed for comparison on the cellular level and showed no significant changes in the intracellular cholesterol levels after atorvastatin treatment. There was a higher expression of the LDLR, in agreement with the clinical findings, but it was non-significant.Paper III is based on the large, prospective population-based Malmo Diet and Cancer Study. Tumor expression of HMGCR, the ratelimiting enzyme of the cholesterol biosynthesis pathway, which is inhibited by statins, was assessed by immunohistochemistry on tissue microarrays from 657 women diagnosed with primary invasive breast cancer between the years of 1991–2010. Tumoral expression of HMGCR was found to be associated with unfavorable tumor characteristics. The associations between statin use, HMGCR expression, and breast cancer mortality were investigated but no statistically significant associations were found.Paper IV is a descriptive publication of a clinical phase II trial – ABC-SE – in which the effect and tolerability of atorvastatin in combination with endocrine based treatment among patients with advanced breast cancer will be compared to standard endocrine based treatment. The goal of this study is to improve the understanding of the mechanisms behind resistance to endocrine treatment of breast cancer, and also to test the hypothesis that the addition of statins will enhance the effect of the endocrine based treatment. In conclusion, these results demonstrate new insights into the mechanisms of statins in breast cancer, which together with earlier published studies, and hopefully the results from the ABC-SE trial, will form the basis for future conduction of large, phase III randomized clinical trials, which are needed to clarify the role of statins in breast cancer.
|
|
