Background: Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and limited th... more Background: Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and limited therapeutic options. Mitotane is considered the standard first-line therapy with only 30% of the patients showing objective tumour response. Defining predictive factors for response is therefore of clinical importance.
Aims/hypothesis Several publications suggest an association between certain types of insulin and ... more Aims/hypothesis Several publications suggest an association between certain types of insulin and cancer, but with conflicting results. We investigated whether insulin glargine (A21Gly,B31Arg,B32Arg human insulin) is associated with an increased risk of cancer in a large population-based cohort study. Methods Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. In a cohort of incident users of insulin, the association between insulin glargine and other insulin analogues, respectively, and cancer was analysed in comparison with human insulin using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. The first hospital admission with a primary diagnosis of cancer was considered as the main outcome; secondary analyses were performed with specific cancers as outcomes. Results Of the 19,337 incident insulin users enrolled, 878 developed cancer. Use of insulin glargine was associated Electronic supplementary material The online version of this article (with a lower risk of malignancies in general in comparison with human insulin (HR 0.75, 95% CI 0.71, 0.80). In contrast, an increased risk was found for breast cancer (HR 1.58, 95% CI 1.22, 2.05). Dose-response relationships could not be identified. Conclusion/interpretation Users of insulin glargine and users of other insulin analogues had a lower risk of cancer in general than those using human insulin. Both associations might be a consequence of residual confounding, lack of adherence or competing risk. However, as in previous studies, we demonstrated an increased risk of breast cancer in users of insulin glargine in comparison with users of human insulin.
Mitotane is considered to be the drug of choice for patients with inoperable, recurrent and metas... more Mitotane is considered to be the drug of choice for patients with inoperable, recurrent and metastatic adrenocortical carcinoma, although a favourable effect of this drug on survival has never been documented. We evaluated the efficacy of mitotane treatment of 96 patients with adrenocortical carcinoma followed up in our department between 1959 and 1992. Complete tumour resection was the goal of
Two patients with polycythemia vera and an extra der(1)t(1;9) chromosome are reported. In one pat... more Two patients with polycythemia vera and an extra der(1)t(1;9) chromosome are reported. In one patient this was found as the sole abnormality. The other patient originally presented with trisomy 9 bat later developed an extra der(1) during the further course of the disease with disappearance of the extra chromosome 9. In situ hybridization studies on this latter patient proved that the centromere of chromosome 1 was involved in the formation of the derivative chromosome.
The presence of P-glycoprotein, associated with multiple drug resistance and present in the norma... more The presence of P-glycoprotein, associated with multiple drug resistance and present in the normal adrenal cortex, was studied in 15 cases of adrenocortical carcinoma. P-glycoprotein was found in eight tumours; no correlation was found with clinical presentation, steroid production or histological index. 10 patients received mitotane. Remarkably, 3 patients with P-glycoprotein-positive tumours achieved complete remission. On the other hand, 2 patients with P-glycoprotein-negative tumours showed progression of the disease despite mitotane treatment. These findings suggest that the expression of P-glycoprotein in adrenocortical carcinoma is not related to clinical manifestations, steroid production, histological index or response to mitotane therapy.
Thyroid cancer (TC), comprising less than 1% of all cancers in the Netherlands, has a good progno... more Thyroid cancer (TC), comprising less than 1% of all cancers in the Netherlands, has a good prognosis in general. Controversy still remains on the extent of surgical treatment and the indication for additional Iodine-131 (131I) therapy in the management of differentiated TC. The aim of this study was to describe (changes in) the treatment of TC and to determine independent
Sacral insufficiency fractures (SIF) usually occur in elderly women and are secondary to various ... more Sacral insufficiency fractures (SIF) usually occur in elderly women and are secondary to various conditions, mainly postmenopausal or steroid-induced osteoporosis and radiation therapy. They are often overlooked or confused clinically and radiographically with metastatic disease. We report a case of a 72-year-old woman who presented to our department with severe low-back pain. She was thoroughly investigated for the cause of
Colorectal cancer (CRC) patients with pre-existing diabetes have significantly lower rates of ove... more Colorectal cancer (CRC) patients with pre-existing diabetes have significantly lower rates of overall survival compared with patients without diabetes. Against this backdrop, the American Diabetes Association and American Cancer Society in 2010 reviewed the scientific literature concerning diabetes and cancer. One of the key issues identified for further investigation was the need for a better understanding of whether diabetes influences cancer prognosis above and beyond the prognosis conferred by each disease state independently. Whether the worsened survival of CRC patients with diabetes could be explained by less favourable patient-, tumour- and treatment-related characteristics has also been evaluated in numerous recent studies. However, as most studies did not account for all the various potential confounders, such as cancer stage, comorbidities and body mass index (BMI) in their analyses, the current evidence for the association between diabetes and survival in CRC patients re...
Background Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and limited the... more Background Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and limited therapeutic options. Mitotane is considered the standard first line therapy with only 30% of the patients showing objective tumour response. Defining predictive factors for response is therefore of clinical importance.The Epidermal Growth Factor Receptor (EGFR) has been implicated in the development of 1/3 of all malignancies. EGFR pathway members in ACC have been investigated, however without available clinical data and relation to survival.Methods In the present study mutation status of EGFR and downstream signalling pathways was evaluated in 47 ACC patients on mitotane using direct sequencing, a TaqMan allele-specific assay and immunohistochemistry. Archival formalin-fixed paraffin-embedded tumour tissue (FFPE) was used for all analyses. Patient data were obtained anonymously, after coupling with the collected tumour tissue.ResultsOne BRAF, two EGFR TK domain (c.2590G>A, p.864A>T),...
The Journal of Clinical Endocrinology & Metabolism, 2015
Background: Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occur... more Background: Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently.
The finding of an adrenal mass should induce a diagnostic work-up aimed at assessing autonomous h... more The finding of an adrenal mass should induce a diagnostic work-up aimed at assessing autonomous hormone production and differentiating between benign and (potentially) malignant lesions. The common differential diagnosis in adrenal incidentaloma consists of (non-)functioning adenoma, pheochromocytoma, myelolipoma, metastasis, and primary carcinoma. There remains a category of lesions that are hormonally inactive and display nonspecific imaging characteristics. We provide a succinct literature review regarding pathologies from this category. Imaging and histological characteristics are discussed, as well as clinical management. In conclusion, an adrenal mass may present a diagnostic challenge. After exclusion of most common diagnoses, it can be difficult to differentiate between possible pathologies based on preoperative diagnostic tests. Surgical resection of possibly harmful tumors is indicated, for example, lesions with malignant potential or risk of spontaneous hemorrhage. Resect...
A 29-year-old man presented to his primary care physician with nausea, severe weight loss and mus... more A 29-year-old man presented to his primary care physician with nausea, severe weight loss and muscle weakness. He had a hard, fixed neck swelling. He was severely hypercalcaemic with 10-fold increased parathyroid hormone (PTH) concentrations. A diagnosis of primary hyperparathyroidism was established and the patient was referred for parathyroidectomy. At neck exploration, an enlarged parathyroid gland with invasive growth into the thyroid gland was found and removed, lymph nodes were cleared and hemithyroidectomy was performed. A suspected diagnosis of parathyroid carcinoma was confirmed histologically. Serum calcium and PTH levels normalised post-operatively, but hyperparathyroidism recurred within 3 years of surgery. Over the following 17 years, control of hypercalcaemia represented the most difficult challenge despite variable success achieved with repeated surgical interventions, embolisations, radiofrequency ablation of metastases and treatment with calcimimetics, bisphosphonat...
Nederlands tijdschrift voor geneeskunde, Jan 9, 2002
To evaluate the treatment of patients with differentiated (papillary or follicular) thyroid cance... more To evaluate the treatment of patients with differentiated (papillary or follicular) thyroid cancer in general hospitals in the south-east of the Netherlands during the period 1983-1996, in relation to the 1987 national consensus recommendations. Population-based, retrospective, descriptive. For the period 1 January 1983-31 December 1996, data on the histology, TNM-stage and treatment (hospital, specialist, type of operation, referral for 131I therapy) of all 236 patients with differentiated thyroid cancer were obtained from the cancer registry of the Comprehensive Cancer Centre South, Eindhoven, the Netherlands. The treatment was compared with the recommendations from the consensus meeting in 1987. Data on 219 patients (137 papillary, 82 follicular thyroid carcinoma) treated in the general hospitals in the region were studied; the 17 remaining patients had been referred from outside the region. Patients were treated at all hospitals in the region; the number of specialists per hospi...
Background Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options ... more Background Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate effi cacy in patients with advanced adrenocortical carcinoma.
ABSTRACT The incidence of ACC in the Netherlands, a small country in Western Europe with a popula... more ABSTRACT The incidence of ACC in the Netherlands, a small country in Western Europe with a population of 16.5 million people, is about 20–30 patients a year. Because of the rarity of the disease, the chance of encountering an inexperienced doctor is high. The diagnosis of ACC is often delayed or missed, and patients may be treated incorrectly. The Dutch Adrenal Network is a national cooperation which was founded to gather knowledge and experience in order to improve the quality and efficiency of ACC patient care in the Netherlands.
To assess and evaluate the short-term results of radio-iodine treatment using an extended dosimet... more To assess and evaluate the short-term results of radio-iodine treatment using an extended dosimetric method. Sixty-five patients with Graves disease (GD) and 32 patients with toxic multinodular goitre (TMG) received a pre-therapeutic dosage of Na123I. The overall indicative radiation dose (Dind) and the indicative dosage (Aind) was calculated for the individual patient using the dosimetric results found. In the therapeutic setting dosimetric measurements were performed again. The quotient of the administered dose (A) and the indicative dosage and the quotient of the absorbed radiation dose (Dabs) and the indicative radiation dose were used to evaluate treatment results after 1 year of follow-up. Clinical outcome after 1 year for GD was 26% hyper-, 48% eu- and 26% hypothyroidism and for TMG 32, 59 and 9%, respectively. Within the percentile range P25-P75 of A/Aind these results were 27, 46 and 27% for GD and 36, 64 and 0% for TMG. Within the percentile range P25-P75 of Dabs/Dind these results were 23, 59 and 18% for GD and 33, 67 and 0 for TMG. Correlation coefficients between pre- and therapeutic dosimetric measurements in GD and TMG were 0.76 and 0.38, respectively. The short-term outcome after 1 year of follow-up is 48 and 59% euthyroidism for GD and TMG, respectively. Clinical outcome within the percentile range P25-P75 of A/Aind did not change these results. Within the percentile range P25-P75 of Dabs/Dind euthyroidism was achieved in 59% and 67% for GD and TMG, respectively. The pre-therapeutic values inaccurately represent the therapeutic values for GD and even more for TMG.
Mitotane is the drug of choice in medical treatment of adrenocortical carcinoma. The antineoplast... more Mitotane is the drug of choice in medical treatment of adrenocortical carcinoma. The antineoplastic effect seems to be correlated with a minimum plasma level of 14 mg/L, but plasma concentration build-up is in general slow due to the long elimination half-life. Consequently, the therapeutic effect sets in after weeks or even months. The objective of this study was to develop a pharmacokinetic model that enables clinicians to adjust dosing based on a target drug exposure, which facilitates personalized therapy. Data on dosing and plasma level measurements performed throughout mitotane therapy were retrospectively collected in a population of 29 patients from 2 hospitals. A population pharmacokinetic model was constructed based on data from 20 patients using iterative 2-stage Bayesian fitting (MWPharm). The model was validated in an independent sample of 9 patients. The concentration-time data were best described by a 3-compartment model. The model estimated mitotane clearance at 0.94 ± 0.37 L/h and a volume of distribution in the steady state at 161 ± 68 L/kg of lean body mass. The mean prediction error was 14% ± 13%. A pharmacokinetic model was developed, which characterized mitotane by slow clearance and large volume of distribution. The model seems to be able to predict mitotane levels in individual patients with an error margin of 14%. The model enables one to adapt dosing based on individual plasma level measurements in prospective setting, which improves the accuracy of the prediction. We expect that individualization of mitotane dosing leads to anticipated and more rapid attainment of the therapeutic levels and potentially to improved clinical management of mitotane treatment.
In a previous study using data from the regional cancer registry of the Comprehensive Cancer Cent... more In a previous study using data from the regional cancer registry of the Comprehensive Cancer Centre South, Eindhoven, The Netherlands, we concluded that in the majority of cases surgical treatment was in accordance with the consensus recommendations, but that about 40% of patients with differentiated thyroid cancer from a number of regional hospitals had not been referred for 131I therapy. However, in a subsequent study using patient data from these hospitals, it became clear that almost all patients had in fact been referred for therapy but to centres outside the 131I therapy region. The conclusion of the study should therefore be altered: the great majority of patients with differentiated thyroid cancer in the south-east of The Netherlands (1983-96) were referred for 131I treatment and therefore the primary surgical and the follow-up treatment complied with the 1987 consensus guidelines.
Aims/hypothesis Adherence to glucose-lowering drug (GLD) treatment regimens is crucial for metabo... more Aims/hypothesis Adherence to glucose-lowering drug (GLD) treatment regimens is crucial for metabolic control and improving prognosis. Because a diagnosis of cancer might have an impact on adherence to medication, this study explored changes in adherence to GLDs following a cancer diagnosis.
Background: Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and limited th... more Background: Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and limited therapeutic options. Mitotane is considered the standard first-line therapy with only 30% of the patients showing objective tumour response. Defining predictive factors for response is therefore of clinical importance.
Aims/hypothesis Several publications suggest an association between certain types of insulin and ... more Aims/hypothesis Several publications suggest an association between certain types of insulin and cancer, but with conflicting results. We investigated whether insulin glargine (A21Gly,B31Arg,B32Arg human insulin) is associated with an increased risk of cancer in a large population-based cohort study. Methods Data for this study were obtained from dispensing records from community pharmacies individually linked to hospital discharge records from 2.5 million individuals in the Netherlands. In a cohort of incident users of insulin, the association between insulin glargine and other insulin analogues, respectively, and cancer was analysed in comparison with human insulin using Cox proportional hazard models with cumulative duration of drug use as a time-varying determinant. The first hospital admission with a primary diagnosis of cancer was considered as the main outcome; secondary analyses were performed with specific cancers as outcomes. Results Of the 19,337 incident insulin users enrolled, 878 developed cancer. Use of insulin glargine was associated Electronic supplementary material The online version of this article (with a lower risk of malignancies in general in comparison with human insulin (HR 0.75, 95% CI 0.71, 0.80). In contrast, an increased risk was found for breast cancer (HR 1.58, 95% CI 1.22, 2.05). Dose-response relationships could not be identified. Conclusion/interpretation Users of insulin glargine and users of other insulin analogues had a lower risk of cancer in general than those using human insulin. Both associations might be a consequence of residual confounding, lack of adherence or competing risk. However, as in previous studies, we demonstrated an increased risk of breast cancer in users of insulin glargine in comparison with users of human insulin.
Mitotane is considered to be the drug of choice for patients with inoperable, recurrent and metas... more Mitotane is considered to be the drug of choice for patients with inoperable, recurrent and metastatic adrenocortical carcinoma, although a favourable effect of this drug on survival has never been documented. We evaluated the efficacy of mitotane treatment of 96 patients with adrenocortical carcinoma followed up in our department between 1959 and 1992. Complete tumour resection was the goal of
Two patients with polycythemia vera and an extra der(1)t(1;9) chromosome are reported. In one pat... more Two patients with polycythemia vera and an extra der(1)t(1;9) chromosome are reported. In one patient this was found as the sole abnormality. The other patient originally presented with trisomy 9 bat later developed an extra der(1) during the further course of the disease with disappearance of the extra chromosome 9. In situ hybridization studies on this latter patient proved that the centromere of chromosome 1 was involved in the formation of the derivative chromosome.
The presence of P-glycoprotein, associated with multiple drug resistance and present in the norma... more The presence of P-glycoprotein, associated with multiple drug resistance and present in the normal adrenal cortex, was studied in 15 cases of adrenocortical carcinoma. P-glycoprotein was found in eight tumours; no correlation was found with clinical presentation, steroid production or histological index. 10 patients received mitotane. Remarkably, 3 patients with P-glycoprotein-positive tumours achieved complete remission. On the other hand, 2 patients with P-glycoprotein-negative tumours showed progression of the disease despite mitotane treatment. These findings suggest that the expression of P-glycoprotein in adrenocortical carcinoma is not related to clinical manifestations, steroid production, histological index or response to mitotane therapy.
Thyroid cancer (TC), comprising less than 1% of all cancers in the Netherlands, has a good progno... more Thyroid cancer (TC), comprising less than 1% of all cancers in the Netherlands, has a good prognosis in general. Controversy still remains on the extent of surgical treatment and the indication for additional Iodine-131 (131I) therapy in the management of differentiated TC. The aim of this study was to describe (changes in) the treatment of TC and to determine independent
Sacral insufficiency fractures (SIF) usually occur in elderly women and are secondary to various ... more Sacral insufficiency fractures (SIF) usually occur in elderly women and are secondary to various conditions, mainly postmenopausal or steroid-induced osteoporosis and radiation therapy. They are often overlooked or confused clinically and radiographically with metastatic disease. We report a case of a 72-year-old woman who presented to our department with severe low-back pain. She was thoroughly investigated for the cause of
Colorectal cancer (CRC) patients with pre-existing diabetes have significantly lower rates of ove... more Colorectal cancer (CRC) patients with pre-existing diabetes have significantly lower rates of overall survival compared with patients without diabetes. Against this backdrop, the American Diabetes Association and American Cancer Society in 2010 reviewed the scientific literature concerning diabetes and cancer. One of the key issues identified for further investigation was the need for a better understanding of whether diabetes influences cancer prognosis above and beyond the prognosis conferred by each disease state independently. Whether the worsened survival of CRC patients with diabetes could be explained by less favourable patient-, tumour- and treatment-related characteristics has also been evaluated in numerous recent studies. However, as most studies did not account for all the various potential confounders, such as cancer stage, comorbidities and body mass index (BMI) in their analyses, the current evidence for the association between diabetes and survival in CRC patients re...
Background Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and limited the... more Background Adrenocortical carcinoma (ACC) is a rare disease with a poor prognosis and limited therapeutic options. Mitotane is considered the standard first line therapy with only 30% of the patients showing objective tumour response. Defining predictive factors for response is therefore of clinical importance.The Epidermal Growth Factor Receptor (EGFR) has been implicated in the development of 1/3 of all malignancies. EGFR pathway members in ACC have been investigated, however without available clinical data and relation to survival.Methods In the present study mutation status of EGFR and downstream signalling pathways was evaluated in 47 ACC patients on mitotane using direct sequencing, a TaqMan allele-specific assay and immunohistochemistry. Archival formalin-fixed paraffin-embedded tumour tissue (FFPE) was used for all analyses. Patient data were obtained anonymously, after coupling with the collected tumour tissue.ResultsOne BRAF, two EGFR TK domain (c.2590G>A, p.864A>T),...
The Journal of Clinical Endocrinology & Metabolism, 2015
Background: Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occur... more Background: Recurrence of adrenocortical carcinoma (ACC) even after complete (R0) resection occurs frequently.
The finding of an adrenal mass should induce a diagnostic work-up aimed at assessing autonomous h... more The finding of an adrenal mass should induce a diagnostic work-up aimed at assessing autonomous hormone production and differentiating between benign and (potentially) malignant lesions. The common differential diagnosis in adrenal incidentaloma consists of (non-)functioning adenoma, pheochromocytoma, myelolipoma, metastasis, and primary carcinoma. There remains a category of lesions that are hormonally inactive and display nonspecific imaging characteristics. We provide a succinct literature review regarding pathologies from this category. Imaging and histological characteristics are discussed, as well as clinical management. In conclusion, an adrenal mass may present a diagnostic challenge. After exclusion of most common diagnoses, it can be difficult to differentiate between possible pathologies based on preoperative diagnostic tests. Surgical resection of possibly harmful tumors is indicated, for example, lesions with malignant potential or risk of spontaneous hemorrhage. Resect...
A 29-year-old man presented to his primary care physician with nausea, severe weight loss and mus... more A 29-year-old man presented to his primary care physician with nausea, severe weight loss and muscle weakness. He had a hard, fixed neck swelling. He was severely hypercalcaemic with 10-fold increased parathyroid hormone (PTH) concentrations. A diagnosis of primary hyperparathyroidism was established and the patient was referred for parathyroidectomy. At neck exploration, an enlarged parathyroid gland with invasive growth into the thyroid gland was found and removed, lymph nodes were cleared and hemithyroidectomy was performed. A suspected diagnosis of parathyroid carcinoma was confirmed histologically. Serum calcium and PTH levels normalised post-operatively, but hyperparathyroidism recurred within 3 years of surgery. Over the following 17 years, control of hypercalcaemia represented the most difficult challenge despite variable success achieved with repeated surgical interventions, embolisations, radiofrequency ablation of metastases and treatment with calcimimetics, bisphosphonat...
Nederlands tijdschrift voor geneeskunde, Jan 9, 2002
To evaluate the treatment of patients with differentiated (papillary or follicular) thyroid cance... more To evaluate the treatment of patients with differentiated (papillary or follicular) thyroid cancer in general hospitals in the south-east of the Netherlands during the period 1983-1996, in relation to the 1987 national consensus recommendations. Population-based, retrospective, descriptive. For the period 1 January 1983-31 December 1996, data on the histology, TNM-stage and treatment (hospital, specialist, type of operation, referral for 131I therapy) of all 236 patients with differentiated thyroid cancer were obtained from the cancer registry of the Comprehensive Cancer Centre South, Eindhoven, the Netherlands. The treatment was compared with the recommendations from the consensus meeting in 1987. Data on 219 patients (137 papillary, 82 follicular thyroid carcinoma) treated in the general hospitals in the region were studied; the 17 remaining patients had been referred from outside the region. Patients were treated at all hospitals in the region; the number of specialists per hospi...
Background Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options ... more Background Adrenocortical carcinoma is a rare, aggressive cancer for which few treatment options are available. Linsitinib (OSI-906) is a potent, oral small molecule inhibitor of both IGF-1R and the insulin receptor, which has shown acceptable tolerability and preliminary evidence of anti-tumour activity. We assessed linsitinib against placebo to investigate effi cacy in patients with advanced adrenocortical carcinoma.
ABSTRACT The incidence of ACC in the Netherlands, a small country in Western Europe with a popula... more ABSTRACT The incidence of ACC in the Netherlands, a small country in Western Europe with a population of 16.5 million people, is about 20–30 patients a year. Because of the rarity of the disease, the chance of encountering an inexperienced doctor is high. The diagnosis of ACC is often delayed or missed, and patients may be treated incorrectly. The Dutch Adrenal Network is a national cooperation which was founded to gather knowledge and experience in order to improve the quality and efficiency of ACC patient care in the Netherlands.
To assess and evaluate the short-term results of radio-iodine treatment using an extended dosimet... more To assess and evaluate the short-term results of radio-iodine treatment using an extended dosimetric method. Sixty-five patients with Graves disease (GD) and 32 patients with toxic multinodular goitre (TMG) received a pre-therapeutic dosage of Na123I. The overall indicative radiation dose (Dind) and the indicative dosage (Aind) was calculated for the individual patient using the dosimetric results found. In the therapeutic setting dosimetric measurements were performed again. The quotient of the administered dose (A) and the indicative dosage and the quotient of the absorbed radiation dose (Dabs) and the indicative radiation dose were used to evaluate treatment results after 1 year of follow-up. Clinical outcome after 1 year for GD was 26% hyper-, 48% eu- and 26% hypothyroidism and for TMG 32, 59 and 9%, respectively. Within the percentile range P25-P75 of A/Aind these results were 27, 46 and 27% for GD and 36, 64 and 0% for TMG. Within the percentile range P25-P75 of Dabs/Dind these results were 23, 59 and 18% for GD and 33, 67 and 0 for TMG. Correlation coefficients between pre- and therapeutic dosimetric measurements in GD and TMG were 0.76 and 0.38, respectively. The short-term outcome after 1 year of follow-up is 48 and 59% euthyroidism for GD and TMG, respectively. Clinical outcome within the percentile range P25-P75 of A/Aind did not change these results. Within the percentile range P25-P75 of Dabs/Dind euthyroidism was achieved in 59% and 67% for GD and TMG, respectively. The pre-therapeutic values inaccurately represent the therapeutic values for GD and even more for TMG.
Mitotane is the drug of choice in medical treatment of adrenocortical carcinoma. The antineoplast... more Mitotane is the drug of choice in medical treatment of adrenocortical carcinoma. The antineoplastic effect seems to be correlated with a minimum plasma level of 14 mg/L, but plasma concentration build-up is in general slow due to the long elimination half-life. Consequently, the therapeutic effect sets in after weeks or even months. The objective of this study was to develop a pharmacokinetic model that enables clinicians to adjust dosing based on a target drug exposure, which facilitates personalized therapy. Data on dosing and plasma level measurements performed throughout mitotane therapy were retrospectively collected in a population of 29 patients from 2 hospitals. A population pharmacokinetic model was constructed based on data from 20 patients using iterative 2-stage Bayesian fitting (MWPharm). The model was validated in an independent sample of 9 patients. The concentration-time data were best described by a 3-compartment model. The model estimated mitotane clearance at 0.94 ± 0.37 L/h and a volume of distribution in the steady state at 161 ± 68 L/kg of lean body mass. The mean prediction error was 14% ± 13%. A pharmacokinetic model was developed, which characterized mitotane by slow clearance and large volume of distribution. The model seems to be able to predict mitotane levels in individual patients with an error margin of 14%. The model enables one to adapt dosing based on individual plasma level measurements in prospective setting, which improves the accuracy of the prediction. We expect that individualization of mitotane dosing leads to anticipated and more rapid attainment of the therapeutic levels and potentially to improved clinical management of mitotane treatment.
In a previous study using data from the regional cancer registry of the Comprehensive Cancer Cent... more In a previous study using data from the regional cancer registry of the Comprehensive Cancer Centre South, Eindhoven, The Netherlands, we concluded that in the majority of cases surgical treatment was in accordance with the consensus recommendations, but that about 40% of patients with differentiated thyroid cancer from a number of regional hospitals had not been referred for 131I therapy. However, in a subsequent study using patient data from these hospitals, it became clear that almost all patients had in fact been referred for therapy but to centres outside the 131I therapy region. The conclusion of the study should therefore be altered: the great majority of patients with differentiated thyroid cancer in the south-east of The Netherlands (1983-96) were referred for 131I treatment and therefore the primary surgical and the follow-up treatment complied with the 1987 consensus guidelines.
Aims/hypothesis Adherence to glucose-lowering drug (GLD) treatment regimens is crucial for metabo... more Aims/hypothesis Adherence to glucose-lowering drug (GLD) treatment regimens is crucial for metabolic control and improving prognosis. Because a diagnosis of cancer might have an impact on adherence to medication, this study explored changes in adherence to GLDs following a cancer diagnosis.
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Papers by Harm Haak