Cellular senescence in kidney biopsies is associated with tubular dysfunction and predicts CKD progression in childhood cancer patients with karyomegalic interstitial nephropathy.

Karyomegalic interstitial nephropathy (KIN) has been reported as an incidental finding in patients with childhood cancer treated with ifosfamide. It is defined by the presence of tubular epithelial cells (TECs) with enlarged, irregular, and hyperchromatic nuclei. Cellular senescence has been proposed to be involved in kidney fibrosis in hereditary KIN patients. We report that KIN could be diagnosed 7-32 months after childhood cancer diagnosis in 6/6 consecutive patients biopsied for progressive chronic kidney disease (CKD) of unknown cause between 2018 and 2021. The morphometry of nuclear size distribution and markers for DNA damage (γH2AX), cell-cycle arrest (p21+, Ki67-), and nuclear lamina decay (loss of lamin B1), identified karyomegaly and senescence features in TECs. Polyploidy was assessed by chromosome fluorescence in situ hybridization (FISH). In all six patients the number of p21-positive TECs far exceeded the typically small numbers of truly karyomegalic cells, and p21-positive TECs contained less lysozyme, testifying to defective resorption, which explains the consistently observed low-molecular-weight (LMW) proteinuria. In addition, polyploidy of TEC was observed to correlate with loss of lysozyme staining. Importantly, in the five patients with the largest nuclei, the percentage of p21-positive TECs tightly correlated with estimated glomerular filtration rate loss between biopsy and last follow-up (R2 = 0.93, p < 0.01). We conclude that cellular senescence is associated with tubular dysfunction and predicts CKD progression in childhood cancer patients with KIN and appears to be a prevalent cause of otherwise unexplained CKD and LMW proteinuria in children treated with DNA-damaging and cell stress-inducing therapy including ifosfamide. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

An aggressive lactotroph pituitary tumor in a young male: A pituitary carcinoma without metastasis.

This case report concerns a 31-year-old male with an aggressive pituitary tumor who presented initially with bitemporal hemianopsia and slightly elevated prolactin. On magnetic resonance imaging of the brain, there was a sellar mass with parasellar invasion to the lateral aspects of the internal carotid arteries, compressing the optic chiasm. On histopathological analysis, the diagnosis was made of a densely granulated lactotroph pituitary tumor with a Ki67 proliferation rate of 15%, a mitotic count of 6/10 high-power fields, and p53 positivity. Based on these features, the tumor was classified as a grade 2b tumor according to the Trouillas classification, and a more aggressive behavior of the tumor could be expected. In order to anticipate a future need for alternative drug treatments, the following analyses were undertaken: MGMT methylation (present) as well as the expression of estrogen receptor (negative), programmed-death ligand 1 (60 - 70% positive tumor cells), vascular endothelial growth factor-A and somatostatin receptor 2 (both positive). There was regrowth of residual tumor tissue, and the treatment consisted thus far of repeat surgery, cabergoline, pasireotide, and radiotherapy. Chemotherapy with temozolomide could not yet be initiated due to a concurrent infertility treatment. This case is unique because the tumor displays atypical characteristics, both in terms of morphology and behavior. It also illustrates how pathologists can play an important role in determining the diagnosis, prognosis, and possibilities for targeted therapy.

An aggressive poorly differentiated plurihormonal Pit-1-positive adenoma.

SUMMARY: In July 2017, a 35-year-old woman was referred to our care for treatment of a large pituitary mass with an unusually high growth rate. She presented with right-sided ptosis and diplopia (n. III palsy), increasing retrobulbar pain and vertigo. Although laboratory investigations were consistent with acromegaly, she exhibited no clear phenotypic traits. During transsphenoidal surgery aimed at biopsy, typical adenomatous tissue was encountered, upon which it was decided to proceed to debulking. Histopathological analysis demonstrated a poorly differentiated plurihormonal Pit-1-positive adenoma with focal growth hormone (GH) and prolactin positivity, positive SSTR2 staining and a Ki-67 of 20-30%. Postoperative magnetic resonance imaging (MRI) examination revealed a large tumour remnant within the sella invading the right cavernous sinus with total encasement of the internal carotid artery and displacement of the right temporal lobe. As a consequence, she was treated additionally with radiotherapy, and a long-acting first-generation somatostatin analogue was prescribed. Subsequently, the patient developed secondary hypocortisolism and diabetes mellitus despite adequate suppression of GH levels. In September 2019, her symptoms recurred. Laboratory evaluations indicated a notable loss of biochemical control, and MRI revealed tumour progression. Lanreotide was switched to pasireotide, and successful removal of the tumour remnant and decompression of the right optic nerve was performed. She received adjuvant treatment with temozolomide resulting in excellent biochemical and radiological response after three and six courses. Symptoms of right-sided ptosis and diplopia remained. Evidence for systemic therapy in case of tumour progression after temozolomide is currently limited, although various potential targets can be identified in tumour tissue. LEARNING POINTS: Poorly differentiated plurihormonal Pit-1-positive adenoma is a potentially aggressive subtype of pituitary tumours. This subtype can express somatostatin receptors, allowing treatment with somatostatin analogues. A multidisciplinary approach involving an endocrinologist, neurosurgeon, pituitary pathologist, neuroradiologist, radiation oncologist and medical oncologist is key for the management of patients with aggressive pituitary tumours, allowing the successful application of multimodality treatment. Temozolomide is first-line chemotherapy for aggressive pituitary tumours and carcinomas. Further development of novel targeted therapies, such as peptide receptor radionuclide therapy (PRRT), vascular endothelial growth factor (VEGF) receptor-targeted therapy, tyrosine kinase inhibitors, mammalian target of rapamycin (mTOR) inhibitors and immune checkpoint inhibitors, is needed.

Detection by fluorescence of pituitary neuroendocrine tumour (PitNET) tissue during endoscopic transsphenoidal surgery using bevacizumab-800CW (DEPARTURE trial): study protocol for a non-randomised, non-blinded, single centre, feasibility and dose-finding trial.

INTRODUCTION: Achieving gross total resection and endocrine remission in pituitary neuroendocrine tumours (PitNET) can be challenging, especially in PitNETs with cavernous sinus (CS) invasion, defined as a Knosp grade of 3 or 4. A potential target to identify PitNET tissue is vascular endothelial growth factor A (VEGF-A), which expression is known to be significantly higher in PitNETs with CS invasion. METHODS AND ANALYSIS: The aim of this non-randomised, non-blinded, single centre, feasibility and dose-finding phase 1 trial is to determine the feasibility of intraoperative fluorescence imaging detection of PitNET tissue during endoscopic transsphenoidal surgery using the VEGF-A targeting optical agent bevacizumab-800CW (4, 5, 10 or 25 mg). Nine to fifteen patients with a PitNET with a Knosp grade of 3 or 4 will be included. Secondary objectives are: (1) To identify the optimal tracer dose for imaging of PitNET tissue during transsphenoidal surgery for further development in a phase 2 fluorescence molecular endoscopy trial. (2) To quantify fluorescence intensity in vivo and ex vivo with multidiameter single-fibre reflectance, single-fibre fluorescence (MDSFR/SFF) spectroscopy. (3) To correlate and validate both the in vivo and ex vivo measured fluorescence signals with histopathological analysis and immunohistochemical staining. (4) To assess the (sub)cellular location of bevacizumab-800CW by ex vivo fluorescence microscopy. Intraoperative, three imaging moments are defined to detect the fluorescent signal. The tumour-to-background ratios are defined by intraoperative fluorescence in vivo measurements including MDSFR/SFF spectroscopy data and by ex vivo back-table fluorescence imaging. After inclusion of three patients in each dose group, an interim analysis will be performed to define the optimal dose. ETHICS AND DISSEMINATION: Approval was obtained from the Medical Ethics Review Board of the University Medical Centre Groningen. Results will be disseminated through national and international journals. The participants and relevant patient support groups will be informed about the results. TRIAL REGISTRATION NUMBER: NCT04212793.

Postoperative use of somatostatin analogs and mortality in patients with acromegaly.

Objective To assess the effect of somatostatin analogs (SSAs) on mortality in relation to disease control of acromegaly after pituitary surgery. Design A retrospective study in two large tertiary referral centers in The Netherlands. Methods Overall, 319 patients with acromegaly in whom pituitary surgery was performed as primary therapy between January 1980 and July 2017 were included. Postoperative treatment with SSA was prescribed to 174 (55%) patients because of persistent or recurrent disease. Disease control at last visit was assessed by IGF1 standard deviation score (SDS). Adequate disease control was defined as IGF1 SDS ≤2. Univariate determinants of mortality and standardized mortality ratios (SMRs) were calculated for groups with and without SSA at any moment postoperatively and at last visit. Results In total, 27 deaths were observed. In univariate analysis, determinants of mortality were inadequate disease control (relative risk (RR): 3.41, P = 0.005), surgery by craniotomy (RR: 3.53, P = 0.013) and glucocorticoid substitution (RR: 2.11, P = 0.047). There was a strong trend toward increased mortality for patients who used SSA (RR: 2.01, P = 0.067) and/or dopamine agonists (RR: 2.54, P = 0.052) at last visit. The SMR of patients with adequate disease control who used SSA at any moment postoperatively (1.07, P = 0.785) and at last visit (1.19; P = 0.600) was not increased. Insufficiently controlled patients had a significantly raised SMR (3.92, P = 0.006). Conclusions Postoperative use of SSA is not associated with increased mortality in patients with acromegaly who attain adequate disease control. In contrast, inadequate disease control, primary surgery by craniotomy and glucocorticoid substitution are associated with increased mortality.

Higher hydrocortisone dose increases bilirubin in hypopituitary patients- results from an RCT.

BACKGROUND: Bilirubin has anti-oxidative and anti-inflammatory properties, which may explain its proposed protective effects on the development of cardiometabolic disorders. Glucocorticoids affect heme oxygenase regulation in vitro, which plays a key role in bilirubin production. Effects of variations in glucocorticoid exposure on circulating bilirubin levels in humans are unknown. Here we tested whether a higher hydrocortisone replacement dose affects circulating bilirubin in hypopituitary patients. MATERIALS AND METHODS: A randomized double-blind cross-over study (ClinicalTrials.gov, number NCT01546992) was performed in 47 patients with secondary adrenal failure [10-week exposure to a higher hydrocortisone dose (0·4-0·6 mg/kg body weight) vs. 10 weeks of a lower hydrocortisone dose (0·2-0·3 mg/kg body weight)]. RESULTS: Plasma total bilirubin was increased by 10% from 7 to 8 µM in response to the higher hydrocortisone dose (P = 0·033). This effect was inversely related to age (P = 0·042), but was unaffected by sex, obesity and (replacement for) other hormonal insufficiencies. The higher hydrocortisone dose also resulted in lower alkaline phosphatase (P = 0·006) and aspartate aminotransferase activities (P = 0·001). CONCLUSION: Bilirubin is modestly increased in response to higher glucocorticoid exposure in humans, in conjunction with lower alkaline phosphatase and aspartate aminotransferase activities, which are supposed to represent biomarkers of a pro-inflammatory state and enhanced liver fat accumulation.

Brain abnormalities on MRI in non-functioning pituitary adenoma patients treated with or without postoperative radiotherapy.

BACKGROUND AND PURPOSE: To assess and compare brain abnormalities on Magnetic Resonance Imaging (MRI) in non-functioning pituitary macro-adenoma (NFA) patients treated with or without postoperative radiotherapy (RT). MATERIAL AND METHODS: In 86 NFA patients, treated between 1987 and 2008 at the University Medical Center Groningen, white-matter lesions (WMLs), cerebral atrophy, brain infarctions and abnormalities of the temporal lobes and hippocampi were assessed on pre- and post-treatment MRI scans in patients treated with (n=47) or without RT. RESULTS: The median MRI follow-up time for RT patients was 10 (range 1-22) years and 5 (range 1-21) years in patients treated without RT. In RT patients the cumulative incidence of WMLs was significantly lower compared to patients treated without RT (log-rank test RR 0.49, 95% CI 0.25-0.97, p=.042). The cumulative incidences of cerebral atrophy, brain infarctions, abnormalities of the temporal lobes and hippocampi, and the severity of WMLs and cerebral atrophy ratings were not significantly different between the two treatment groups. CONCLUSIONS: Brain abnormalities on MRI are not observed more frequently in NFA patients treated with RT compared to patients treated with surgery-alone. Furthermore, RT was not associated with an increased severity of WMLs and cerebral atrophy ratings in this cohort of NFA patients.

Diagnosis, treatment and clinical perspectives of acromegaly.

Acromegaly is an insidious disease of the pituitary caused by a growth hormone-secreting adenoma. Generally, the diagnosis is made rather late in the course of the disease. Currently, acromegaly can be cured in about half of the patients with the disease by expert surgery. The remainder of non-surgically cured patients often can be effectively treated with somatostatin analogs; either with the new generation of dopaminergic drugs or with Pegvisomant, a GH-receptor blocking agent. However, at the time of diagnosis many patients suffer from serious comorbidities, including hypertension, heart disease, arthrosis, sleep apnea and diabetes mellitus. Recent reports have shown that mortality risk can be normalized. Nevertheless, all efforts should be undertaken to treat comorbidities. New strategies for surgery and medical treatment are discussed.

Cognition and brain abnormalities on MRI in pituitary patients.

PURPOSE: The extent to which cognitive dysfunction is related to specific brain abnormalities in patients treated for pituitary macroadenoma is unclear. Therefore, we compared brain abnormalities seen on Magnetic Resonance Imaging (MRI) in patients treated for nonfunctioning pituitary macroadenoma (NFA) with or without impairments in cognitive functioning. METHODS: In this cross-sectional design, a cohort of 43 NFA patients was studied at the University Medical Center Groningen. White matter lesions (WMLs), cerebral atrophy, (silent) brain infarcts and abnormalities of the temporal lobes and hippocampi were assessed on pre-treatment and post-treatment MRI scans. Post-treatment cognitive examinations were performed using a verbal memory and executive functioning test. We compared our patient cohort with large reference populations representative of the Dutch population. RESULTS: One or more impairments on both cognitive tests were frequently observed in treated NFA patients. No treatment effects were found with regard to the comparison between patients with and without impairments in executive functioning. Interestingly, in patients with one or more impairments on verbal memory function, treatment with radiotherapy had been given more frequently (74% in the impaired group versus 40% in the unimpaired group, P=0.025). Patients with or without any brain abnormality on MRI did not differ in verbal memory or executive functioning. CONCLUSIONS: Brain abnormalities on MRI are not observed more frequently in treated NFA patients with impairments compared to NFA patients without impairments in verbal memory or executive functioning. Conversely, the absence of brain abnormalities on MRI does not exclude impairments in cognition.

Incidence, causative mechanisms, and anatomic localization of stroke in pituitary adenoma patients treated with postoperative radiation therapy versus surgery alone.

PURPOSE: To assess and compare the incidence of stroke and stroke subtype in pituitary adenoma patients treated with postoperative radiation therapy (RT) and surgery alone. METHODS AND MATERIALS: A cohort of 462 pituitary adenoma patients treated between 1959 and 2008 at the University Medical Center Groningen in The Netherlands was studied. Radiation therapy was administered in 236 patients. The TOAST (Trial of ORG 10172 in Acute Stroke Treatment) and the Oxfordshire Community Stroke Project classification methods were used to determine causative mechanism and anatomic localization of stroke. Stroke incidences in patients treated with RT were compared with that observed after surgery alone. Risk factors for stroke incidence were studied by log-rank test, without and with stratification for other significant risk factors. In addition, the stroke incidence was compared with the incidence rate in the general Dutch population. RESULTS: Thirteen RT patients were diagnosed with stroke, compared with 12 surgery-alone patients. The relative risk (RR) for stroke in patients treated with postoperative RT was not significantly different compared with surgery-alone patients (univariate RR 0.62, 95% confidence interval [CI] 0.28-1.35, P=.23). Stroke risk factors were coronary or peripheral artery disease (univariate and multivariate RR 10.4, 95% CI 4.7-22.8, P<.001) and hypertension (univariate RR 3.9, 95% CI 1.6-9.8, P=.002). There was no difference in TOAST and Oxfordshire classification of stroke. In this pituitary adenoma cohort 25 strokes were observed, compared with 16.91 expected (standard incidence ratio 1.48, 95% CI 1.00-1.96, P=.049). CONCLUSIONS: In pituitary adenoma patients, an increased incidence of stroke was observed compared with the general population. However, postoperative RT was not associated with an increased incidence of stroke or differences in causative mechanism or anatomic localization of stroke compared with surgery alone. The primary stroke risk factor was pre-existent coronary or peripheral artery disease.

Low maternal education is associated with increased growth velocity in the first year of life and in early childhood: the ABCD study.

UNLABELLED: The objective of this study is first to examine the relation of maternal education and growth velocity during the first year of life and early childhood (1-5 years). The second objective is to determine the potential explanatory role of standardized birth weight, maternal smoking during pregnancy, maternal prepregnancy body mass index (BMI), and infant feeding practice in this relation. We used longitudinal growth data of 1,684 participants with Dutch ethnicity participating in a population-based cohort study (Amsterdam Born Children and their Development study). Growth velocity of weight and of weight-for-length were calculated by subtracting the weight and weight-for-length standard deviation scores (SDS), respectively of two time periods. In the first year of life, children with low-educated mothers had an increase in SDS of 0.26 (95 % confidence interval (CI) 0.08-0.45) for weight compared to children with high-educated mothers. In early childhood, children with low-educated mothers had a 0.27 SDS (95 % CI 0.11-0.42) increase for weight-for-length, compared to children with high-educated mothers. Using path analysis, these inequalities could partly be explained by maternal smoking, duration of breastfeeding, maternal age, and maternal BMI. CONCLUSION: Children with low-educated mothers had an increased weight gain during the first year of life and an increased weight-for-length gain in early childhood compared to children with high-educated mothers. Although underlying mechanisms were not completely clarified, an optimal duration of breastfeeding, cessation of maternal smoking, and reduction of maternal BMI seem to reduce these educational inequalities in early growth and possible adverse consequences of accelerated growth.

Smoking overrules many other risk factors for small for gestational age birth in less educated mothers.

BACKGROUND: Although there is convincing evidence for the association between small for gestational age (SGA) and socioeconomic status (SES), it is not known to what extent explanatory factors contribute to this association. AIM: To examine to what extent risk factors could explain educational inequalities in SGA. STUDY DESIGN: In this study fully completed data were available for 3793 pregnant women of Dutch origin from a population-based cohort (ABCD study). Path-analysis was conducted to examine the role of explanatory factors in the relation of maternal education to SGA. RESULTS: Low-educated pregnant women had a higher risk of SGA offspring compared to the high-educated women (OR 1.98, 95% CI 1.35-2.89). In path-analysis, maternal cigarette smoking and maternal height explained this association. Maternal age, hypertension, chronic disease, late entry into antenatal care, neighborhood income, underweight, environmental cigarette smoking, drug abuse, alcohol use, caffeine intake, fish intake, folic acid intake, anxiety, and depressive symptoms did not play a role in the association between maternal education and SGA birth. CONCLUSION: Among a large array of potential factors, the elevated risk of SGA birth among low-educated women appeared largely attributable to maternal smoking and to a lesser extent to maternal height. To reduce educational inequalities more effort is required to include low-educated women especially in prenatal intervention programs such as smoking cessation programs instead of effort into reducing other SGA-risk factors, though these factors might still be relevant at the individual level.

Suboptimal maternal vitamin D status and low education level as determinants of small-for-gestational-age birth weight.

PURPOSE: This study aimed firstly to investigate the contribution of maternal 25(OH) vitamin D to the association of maternal education and small-for-gestational-age birth weight (SGA) and secondly to examine whether the contribution of 25(OH) vitamin D differs by overweight, season, and maternal smoking. METHODS: Logistic regression analysis was carried out in this study, using data of 2,274 pregnant women of Dutch ethnicity from the ABCD study, a population-based cohort study in the Netherlands. Maternal 25(OH) vitamin D was measured in early pregnancy. Stratified analyses were conducted for overweight, season of blood sampling, and smoking. RESULTS: Low-educated women had lower 25(OH) vitamin D levels compared to high-educated women, and women in the lowest 25(OH) vitamin D quartile had a higher risk of SGA offspring. In addition, low-educated women had a higher risk of SGA offspring (OR 1.95 [95% CI: 1.20-3.14]). This association decreased with 7% after adjustment for 25(OH) vitamin D (OR 1.88 [95% CI 1.16-3.04]). In stratified analyses, adjustment for 25(OH) vitamin D resulted in a decrease in OR of about 17% in overweight women and about 15% in women who conceived in wintertime. CONCLUSIONS: 25(OH) vitamin D appears to be a modifiable contributor to the association between low maternal education and SGA offspring, particularly in overweight women and women who conceived in the winter period. In those women, increasing the intake of vitamin D, either through dietary adaptation or through supplementation in order to achieve the recommendation, could be beneficial.

Explaining socioeconomic inequalities in childhood blood pressure and prehypertension: the ABCD study.

Much remains to be understood about the socioeconomic inequalities in hypertension that continue to exist. We investigated the association of socioeconomic status with blood pressure and prehypertension in childhood. In a prospective cohort, 3024 five- to six-year-old children had blood pressure measurements and available information on potential explanatory factors, namely birth weight, gestational age, smoking during pregnancy, pregnancy-induced hypertension, familial hypertension, maternal body mass index, breastfeeding duration, domestic tobacco exposure, and body mass index. The systolic and diastolic blood pressures of children from mid-educated women were 1.0-mm Hg higher (95% CI, 0.4-1.7) and 0.9-mm Hg higher (95% CI, 0.3-1.4), and the blood pressures of children with low-educated women were 2.2-mm Hg higher (95% CI, 1.4-3.0) and 1.7-mm Hg higher (95% CI, 1.1-2.4) compared with children with high-educated women. Children with mid- (odds ratio, 1.50; 95% CI, 1.18-1.92) or low-educated mothers (odds ratio, 1.80; 95% CI, 1.35-2.42) were more likely to have prehypertension compared with children with high-educated mothers. Using path analyses, birth weight, breastfeeding duration, and body mass index were determined as having a role in the association of maternal education with offspring blood pressure and prehypertension. The socioeconomic gradient in hypertension appears to emerge from childhood as the results show a higher blood pressure and more prehypertension in children from lower socioeconomic status families. Socioeconomic disparities could be reduced by improving 3 factors in particular, namely birth weight, breastfeeding duration, and body mass index, but other factors might also play a role.

Effects of previous growth hormone excess and current medical treatment for acromegaly on cognition.

BACKGROUND: In untreated acromegaly patients, decreased cognitive functioning is reported to be associated with the degree of growth hormone (GH) and IGF-1 excess. Whether previous GH excess or current medical treatment for acromegaly specifically affects cognition remains unclear. The aim of this study was to compare cognitive functioning of patients who are treated for acromegaly with patients with non-functioning pituitary adenomas (NFA). In addition, we assessed the influence of prolonged medical treatment after initial transsphenoidal surgery on cognition. DESIGN: In this cross-sectional study, 74 patients participated, who were treated for acromegaly (n = 50; median [interquartile range] age: 53 [45-65] years) or NFA (n = 24; age: 63 [59-70] years). The NFA patients were selected for a high likelihood of normal GH secretion based on an IGF-1 z-score within the normal range (> -2) and zero or one axis substituted. Of the acromegaly patients, 28 had achieved remission, while 22 were biochemically controlled with long-acting somatostatin analogues and/or pegvisomant. Memory and executive functioning were assessed by the 15 Words Test and the Ruff Figural Fluency Test, and reported as z-scores. RESULTS: The total patient group scored significantly poorer than the reference population on memory and executive functioning (P < 0·001). However, cognitive test performance was not significantly different between acromegaly patients with a persistent disease, acromegaly patients in remission and NFA patients. CONCLUSION: The total patient group scored worse compared with reference populations. We found no association between previous GH excess and cognition. In addition, current medical treatment for GH excess in acromegaly was not related to memory and executive functioning.

The incidence of second tumours and mortality in pituitary adenoma patients treated with postoperative radiotherapy versus surgery alone.

BACKGROUND AND PURPOSE: To assess and compare the incidence of intra- and extracranial tumours and mortality in pituitary adenoma patients treated with postoperative radiotherapy and surgery alone. PATIENTS AND METHODS: A total of 462 pituitary adenoma patients were treated between 1959 and 2008 at the University Medical Center Groningen in The Netherlands. Postoperative radiotherapy was administered on indication in 236 patients. RESULTS: The median follow-up time was 14 (range 1-49) years in patients treated with radiotherapy and 6 (range 1-34) years in patients treated with surgery alone. Three radiotherapy patients developed an intracranial tumour compared to one patient treated with surgery alone. The numbers of extracranial tumours per follow-up year were 6.5 (95% CI 2.5-10.5) and 5.1 (95% CI 1.9-8.2) in patients treated with and without a technique with vertex field and central body axis irradiation and 7.1 (CI 95% 2.9-11.2) in surgery alone patients. Forty-five patients treated with radiotherapy died compared to twenty-four patients treated with surgery alone (log-rank test RR 1.26, 95% CI 0.77-2.08, p=0.36). CONCLUSION: In this study postoperative radiotherapy and a radiotherapy treatment technique with vertex field and central body axis irradiation were not associated with an increased incidence of second tumours and mortality in pituitary adenoma patients.

Educational inequalities in perinatal outcomes: the mediating effect of smoking and environmental tobacco exposure.

OBJECTIVE: Socioeconomic status (SES) is adversely associated with perinatal outcomes. This association is likely to be mediated by tobacco exposure. However, previous studies were limited to single perinatal outcomes and devoted no attention to environmental tobacco exposure. Therefore, this study aimed firstly to explain the role of maternal smoking in the association between maternal education and preterm birth (PTB), low birth weight (LBW) and small for gestational age (SGA), and secondly to explain whether environmental tobacco smoke mediates these associations further. STUDY DESIGN: This study was nested in a population-based cohort study in the Netherlands, the Amsterdam Born Children and their Development (ABCD) study. Analyses were done in a sample of 3821 pregnant women of Dutch origin, using logistic regression analysis. RESULTS: Least educated women, who were more often smoking and exposed to environmental tobacco smoke, had a significantly higher risk of PTB (OR 1.95 [95% CI: 1.19-3.20]), LBW (OR 2.41 [95% CI: 1.36-4.27]) and SGA (OR 1.90 [95% CI 1.32-2.74]) than highly educated women. The mediating effect of smoking in the least educated women was 43% for PTB, 55% for LBW and 66% for SGA. Environmental tobacco smoke did not explain these associations further. After adjustment for maternal smoking, the association between lower maternal education and pregnancy outcomes was no longer significant. CONCLUSIONS: Smoking explains to a considerable extent the association between lower maternal education and adverse perinatal outcomes. Therefore, tobacco-interventions in lower educated women should be primarily focussed on maternal smoking to reduce PTB, LBW, and SGA. Additional attention to environmental tobacco exposure does not seem to reduce educational inequalities in perinatal outcomes.

Quality of life is impaired in association with the need for prolonged postoperative therapy by somatostatin analogs in patients with acromegaly.

OBJECTIVE: To assess the influence of long-acting somatostatin analogs (SSTA) after initial pituitary surgery on long-term health-related quality of life (HR-QoL) in relation to disease control in patients with acromegaly. DESIGN: This is a cross-sectional study in two tertiary referral centers in The Netherlands. PATIENTS AND METHODS: One hundred and eight patients with acromegaly, in whom transsphenoidal (n=101, 94%) or transcranial (n=7, 6%) surgery was performed. Subsequently, 46 (43%) received additional radiotherapy and 41 (38%) were on postoperative treatment with SSTA because of persistent or recurrent disease at the time of study. All subjects filled in standardized questionnaires measuring HR-QoL. Disease control at the time of study was assessed by local IGF1 SDS. RESULTS: IGF1 SDS were slightly higher in patients treated with SSTA in comparison with patients without use of SSTA (0.85±1.52 vs 0.25±1.21, P=0.026), but the percentage of patients with insufficient control (IGF1 SDS >2) was not different (17 vs 9%, P=0.208). Patients using SSTA reported poorer scores on most subscales of the RAND-36 and the acromegaly QoL and on all subscales of the multidimensional fatigue inventory-20. A subgroup analysis in patients with similar IGF1 levels (SSTA+, n=26, IGF1 SDS 0.44±0.72 vs SSTA-, n=44, IGF1 SDS 0.41±0.65) revealed worse scores on physical functioning, physical fatigue, reduced activity, vitality, and general health perception across all HR-QoL questionnaires in patients treated with SSTA. CONCLUSION: QoL is impaired in association with the need for prolonged postoperative therapy by SSTA in patients with acromegaly despite similar IGF1 levels.