A Bayesian spatiotemporal model for prevalence estimation of a VRE outbreak in a tertiary care hospital.

BACKGROUND: There was a nosocomial outbreak of vancomycin-resistant enterococci (VRE) at the hospital between 1st January 2018 and 31st July 2020. The goals of this study were to describe weekly prevalence, and to identify possible effects of the introduction of selected infection control measures. METHODS: A room-centric analysis of 12 floors (243 rooms) of the main hospital building was undertaken, including data on 37,558 patients over 22,072 person-weeks for the first 2 years of the outbreak (2018-2019). Poisson Bayesian hierarchical models were fitted to estimate prevalence per room and per week, including both spatial and temporal random effects terms. RESULTS: Exploratory data analysis revealed significant variability in prevalence between departments and floors, along with sporadic spatial and temporal clustering during colonization 'flare-ups'. The oncology department experienced slightly higher prevalence over the 104-week study period [adjusted prevalence ratio (aPR) 4.8, 95% confidence interval (CI) 2.6-8.9; P<0.001; compared with general medicine], as did both the cardiac surgery (aPR 3.8, 95% CI 2.0-7.3; P<0.001) and abdominal surgery (aPR 3.7, 95% CI 1.8-7.6; P<0.001) departments. Estimated peak prevalence was reached in July 2018, at which point a number of new infection control measures (including the daily disinfection of rooms and room cleaning with ultraviolet light upon patient discharge) were introduced that resulted in decreasing prevalence (aPR 0.89 per week, 95% CI 0.87-0.91; P<0.001). CONCLUSION: Relatively straightforward but personnel-intensive cleaning with disinfectants and ultraviolet light provided tangible benefits in getting the outbreak under control. Despite additional complexity, Bayesian hierarchical models provide a more flexible platform to study transmission dynamics.

Evaluation of Ultra-low-dose Paediatric Cone-beam Computed Tomography for Image-guided Radiotherapy.

AIMS: In image-guided radiotherapy, daily cone-beam computed tomography (CBCT) is rarely applied to children due to concerns over imaging dose. Simulating low-dose CBCT can aid clinical protocol design by allowing visualisation of new scan protocols in patients without delivering additional dose. This work simulated ultra-low-dose CBCT and evaluated its use for paediatric image-guided radiotherapy by assessment of image registration accuracy and visual image quality. MATERIALS AND METHODS: Ultra-low-dose CBCT was simulated by adding the appropriate amount of noise to projection images prior to reconstruction. This simulation was validated in phantoms before application to paediatric patient data. Scans from 20 patients acquired at our current clinical protocol (0.8 mGy) were simulated for a range of ultra-low doses (0.5, 0.4, 0.2 and 0.125 mGy) creating 100 scans in total. Automatic registration accuracy was assessed in all 100 scans. Inter-observer registration variation was next assessed for a subset of 40 scans (five scans at each simulated dose and 20 scans at the current clinical protocol). This subset was assessed for visual image quality by Likert scale grading of registration performance and visibility of target coverage, organs at risk, soft-tissue structures and bony anatomy. RESULTS: Simulated and acquired phantom scans were in excellent agreement. For patient scans, bony atomy registration discrepancies for ultra-low-dose scans fell within 2 mm (translation) and 1° (rotation) compared with the current clinical protocol, with excellent inter-observer agreement. Soft-tissue registration showed large discrepancies. Bone visualisation and registration performance reached over 75% acceptability (rated 'well' or 'very well') down to the lowest doses. Soft-tissue visualisation did not reach this threshold for any dose. CONCLUSION: Ultra-low-dose CBCT was accurately simulated and evaluated in patient data. Patient scans simulated down to 0.125 mGy were appropriate for bony anatomy set-up. The large dose reduction could allow for more frequent (e.g. daily) image guidance and, hence, more accurate set-up for paediatric radiotherapy.

Recurrence of Phaeochromocytoma and Abdominal Paraganglioma After Initial Surgical Intervention.

BACKGROUND: Clinical and biochemical follow up after surgery for phaeochromocytoma is essential with long term studies demonstrating recurrence frequencies between 6% and 23%. AIM: To examine the characteristics and frequency of tumour recurrence in a regional endocrine referral centre, in patients with surgical resection of phaeochromocytoma (P) and abdominal paraganglioma (AP). METHODS: We identified a cohort of 52 consecutive patients who attended our Regional Endocrinology & Diabetes Centre and retrospectively reviewed their clinical, biochemical and radiological data (between 2002 and 2013). After confirmation of early post-operative remission by negative biochemical testing, tumour recurrence was defined by demonstration of catecholamine excess with confirmatory imaging. RESULTS: Phaeochromocytoma was confirmed histologically in all cases (43:P, 9:AP, mean-age:53 years). Open adrenalectomy was performed in 20 cases and laparoscopically in 32. Hereditary phaeochromocytoma was confirmed by genetic analysis in 12 (23%) patients. Median follow up time from initial surgery was 47 months, (range: 12 - 296 months), 49 patients had no evidence of tumour recurrence at latest follow-up. Three patients (6%) demonstrated tumour development, one in a patient with VHL which occurred in a contralateral adrenal gland, one sporadic case had local recurrence, and an adrenal tumour occurred in a patient with a SDHB gene mutation who had a previous bladder tumour. After initial surgery, the tumours occurred at 8.6, 12.0 and 17.7 years respectively. CONCLUSION: In this study tumour development occurred in 6% of patients. Although tumour rates were low, careful and sustained clinical and biochemical follow up is advocated, as new tumour development or recurrence may occur long after the initial surgery is performed.

Mitochondrial pharmacology: its future is now.

Mitochondrial medicine is an evolving discipline whose importance derives from the central function of mitochondria in adenosine triphosphate (ATP) production, generation of reactive oxygen species, and cell death by necrosis or apoptosis. Consequently, mitochondrial dysfunction plays an important role in the progression of aging and the pathophysiology of many common diseases and off-target drug effects. This provides an impetus for the development of mitochondrial pharmacology, and some promising therapeutic targets for mitochondrial protective therapy have been identified.

Clinical experience in the screening and management of a large kindred with familial isolated pituitary adenoma due to an aryl hydrocarbon receptor interacting protein (AIP) mutation.

CONTEXT: Germline AIP mutations usually cause young-onset acromegaly with low penetrance in a subset of familial isolated pituitary adenoma families. We describe our experience with a large family with R304* AIP mutation and discuss some of the diagnostic dilemmas and management issues. OBJECTIVE: The aim of the study was to identify and screen mutation carriers in the family. PATIENTS: Forty-three family members participated in the study. SETTING: The study was performed in university hospitals. OUTCOME: We conducted genetic and endocrine screening of family members. RESULTS: We identified 18 carriers of the R304* mutation, three family members with an AIP-variant A299V, and two family members who harbored both changes. One of the two index cases presented with gigantism and pituitary apoplexy, the other presented with young-onset acromegaly, and both had surgery and radiotherapy. After genetic and clinical screening of the family, two R304* carriers were diagnosed with acromegaly. They underwent transsphenoidal surgery after a short period of somatostatin analog treatment. One of these two patients is in remission; the other achieved successful pregnancy despite suboptimal control of acromegaly. One of the A299V carrier family members was previously diagnosed with a microprolactinoma; we consider this case to be a phenocopy. Height of the unaffected R304* carrier family members is not different compared to noncarrier relatives. CONCLUSIONS: Families with AIP mutations present particular problems such as the occurrence of large invasive tumors, poor response to medical treatment, difficulties with fertility and management of pregnancy, and the finding of AIP sequence variants of unknown significance. Because disease mostly develops at a younger age and penetrance is low, the timing and duration of the follow-up of carriers without overt disease requires further study. The psychological and financial impact of prolonged clinical screening must be considered. Excellent relationships between the family, endocrinologists, and geneticists are essential, and ideally these families should be managed in centers with specialist expertise.

Extended treatment of Cushing's disease with pasireotide: results from a 2-year, Phase II study.

In a previous 15-day, Phase II study of patients with de novo or persistent/recurrent Cushing's disease (core study), treatment with pasireotide 600 µg sc bid reduced urinary free cortisol (UFC) levels in 76% of patients and normalized UFC in 17%. The objective of this study was to evaluate the efficacy and safety of extended treatment with pasireotide. This was a planned, open-ended, single-arm, multicenter extension study (primary endpoint: 6 months). Patients aged ≥18 years with Cushing's disease who completed the core study could enter the extension if they achieved UFC normalization at core study end and/or obtained significant clinical benefit. Of the 38 patients who completed the core study, 19 entered the extension and 18 were included in the efficacy analyses (three responders, 11 reducers, four non-reducers in the core study). At data cut-off, median treatment duration in the extension was 9.7 months (range: 2 months to 4.8 years). At extension month 6, 56% of the 18 patients had lower UFC than at core baseline and 22% had normalized UFC. Of the four patients who remained on study drug at month 24, one had normalized UFC. Reductions in serum cortisol, plasma adrenocorticotropic hormone, body weight and diastolic blood pressure were observed. The most common adverse events were mild-to-moderate gastrointestinal disorders and hyperglycemia. Pasireotide offers a tumor-directed medical therapy that may be effective for the extended treatment of some patients with Cushing's disease.

Evaluation of SDHB, SDHD and VHL gene susceptibility testing in the assessment of individuals with non-syndromic phaeochromocytoma, paraganglioma and head and neck paraganglioma.

OBJECTIVES: Research studies have reported that about a third of individuals with phaeochromocytoma/paraganglioma (PPGL) have an inherited predisposition, although the frequency of specific mutations can vary between populations. We evaluated VHL, SDHB and SDHD mutation testing in cohorts of patients with non-syndromic PPGL and head and neck paraganglioma (HNPGL). DESIGN: Prospective, observational evaluation of NHS practice. PATIENTS: Individuals with PPGL/HNPGL referred to a supraregional genetics testing service over a 10-year period. MEASUREMENTS: Clinical (age, tumour site, malignancy, etc.), mutation frequencies and characteristics. RESULTS: A total of 501 probands with PPGL (n = 413) or HNPGL (n = 88) were studied. Thirty-one percent of patients with PPGL presented had a pathogenic mutation in SDHB, SDHD or VHL. Mutation detection rates were highest in those with a positive family history (62%), malignancy (53%), multiple tumours (33%) or PGL (44%). Twenty-eight percent of individuals with a single sporadic phaeochromocytoma had a mutation. Overall, 63% of patients with HNPGL had a mutation (92% of those with a family history, 89% of those with multicentric tumours and 34% of those with a single sporadic HNPGL). Penetrance was calculated in 121 SDHB mutation-positive probands and 187 of their mutation-positive relatives. Most relatives were asymptomatic and lifetime penetrance in non-proband SDHB mutation carriers was <50%. CONCLUSIONS: Practice-based evaluations of genetic testing in PPGL reveal high mutation detection rates. Although clinical criteria can be used to prioritize mutation testing, mutations were detected in 'low risk groups' indicating a need for comprehensive and inexpensive genetic testing strategies for PPGL and HNPGL.

Drug modification of LPS-stimulated human monocyte-derived dendritic cells.

Many drugs have been reported to convert dendritic cells (DCs) into a tolerogenic phenotype in vitro. However, there is evidence that an additional stimulus, such as lipopolysaccharide (LPS), may also be necessary for tolerogenic function in vivo. Little is known concerning the effects of drug modification on LPS-prestimulated DCs. In this study, monocyte-derived immature DCs were stimulated with LPS first and the influence investigated of six different agents on surface antigen expression, cytokine production and lymphocyte proliferation and cytotoxicity. Mycophenolic acid- and rapamycin-exposed DCs had little effect on surface antigen expression or functional activity towards lymphocytes. In contrast, treatment of immature dendritic cells with aspirin, dexamethasone, 1alpha,25-dihydroxyvitamin D3 (VD3) or butyric acid was associated with diminished expression of CD1a, CD1c, CD40, CD80 and CD83. Dendritic cell modification by aspirin, dexamethasone and VD3 were all associated with decreased production of tumour necrosis factor-alpha (TNFalpha). Furthermore, VD3 treatment was associated with a consistent and significant elevation of IL-6 production. Aspirin-, dexamethasone- VD3- and butyric acid-modified DCs suppressed interferon-gamma production, proliferation and cytotoxicity in co-culture with allogeneic mononuclear cells, but inconsistent results were obtained with different allogeneic combinations. Different drugs show varying effects on DC phenotype. No single agent was consistently effective in suppressing the stimulation of allogeneic mononuclear cells and future work is needed to explore drug combinations.

Effects of dehydroepiandrosterone sulphate (DHEAS) replacement on insulin action and quality of life in hypopituitary females: a double-blind, placebo-controlled study.

OBJECTIVE: Addition of dehydroepiandrosterone sulphate (DHEAS) to standard pituitary replacement may improve quality of life and glucose metabolism. Conflicting results from the previous work probably relate to differences in populations studied and assessment techniques used. We examined the effects of DHEAS on insulin action and the quality of life in female patients with hypopituitary hypoadrenalism. DESIGN: Randomized, double-blind, placebo-controlled, crossover design was used. Patients received either DHEAS 50 mg daily or placebo for 12 weeks. PATIENTS: Fourteen hypopituitary females on stable standard replacement therapy and with low DHEAS were enrolled. MEASUREMENTS: Insulin action by euglycaemic hyperinsulinaemic clamp and extensive quality of life parameters were assessed after each treatment. RESULTS: Serum DHEAS (DHEAS 5·4 ± 0·8 vs placebo <0·8 ± 0·0 µm; P < 0·001) and androstenedione (DHEAS 4·1 ± 0·8 vs placebo 1·3 ± 0·2 nm; P < 0·05) rose to within the normal range after DHEAS 50 mg daily. There were no differences between treatments in testosterone, sex hormone-binding globulin (SHBG) or IGF-1. Quality of life measures were unchanged after DHEAS. There were no differences between treatments in fasting glucose, serum insulin, HbA1c or in insulin action (glucose infusion rates required to maintain euglycaemia; DHEAS 21·9 ± 2·5 vs placebo 24·5 ± 2·1 µmol/kg/min; P = 0·4). Triglyceride concentrations were lower following DHEAS (DHEAS 1·24 ± 0·18 vs placebo 1·41 ± 0·19 mm; P < 0·05) but other lipid parameters remained unchanged. CONCLUSION: There were no differences compared with placebo in quality of life or insulin action after DHEAS replacement therapy for 12 weeks. These results do not provide evidence for the addition of DHEAS to standard hypopituitary replacement therapy.

100 cases of primary aldosteronism: careful choice of patients for surgery using adrenal venous sampling and CT imaging results in excellent blood pressure and potassium outcomes.

OBJECTIVE: Patients with primary aldosteronism (PA) who are suitable for surgery should undergo adrenal computerised tomography (CT) and adrenal venous sampling (AVS). A retrospective study was performed of 100 patients with PA. We determined the optimal AVS lateralisation ratio for unilateral disease and reviewed adrenalectomy outcomes evaluating which characteristics predicted hypertension cure. METHODS: AVS was performed in 93 patients. Lateralisation criteria were assessed using ROC curve analysis. The outcome of adrenalectomy was reviewed in 39 patients and predictive factors for cure determined using univariate and multivariate analysis. RESULTS: Of previously published criteria, ROC curve analysis found a cortisol corrected aldosterone affected to unaffected (Aldo/Cort A:U) cut-off of 2·0 was the best predictor of adenoma identifying 80·4% of patients. A novel ratio calculated by dividing the affected to unaffected ratio by the unaffected to peripheral ratio [(Aldo/Cort A:U)/(Aldo/Cort U:IVC)] was successful in identifying 87·0% of patients. Cure rate for blood pressure after adrenalectomy was 38·5% with improvement in 59·0%. On univariate analysis, predictors of post-operative hypertension were increased weight, raised creatinine, left ventricular hypertrophy (LVH) and male sex. On multivariate analysis, male sex and higher pre-operative systolic blood pressure were predictive. CONCLUSIONS: Patients with PA should have CT scanning and AVS. Aldo/Cort A:U >2·0 is the most accurate of previously published ratios in predicting unilateral disease. When patients were carefully selected for surgery, 97% had cure or improvement in blood pressure control. Further confirmatory work is required on a novel ratio which was even more predictive in our series.

A comparison of plasma-free metanephrines with plasma catecholamines in the investigation of suspected pheochromocytoma.

OBJECTIVE: To compare the diagnostic performance of plasma metanephrines by ELISA and plasma catecholamine measurements by HPLC in patients selected for clonidine suppression testing. METHODS: Plasma catecholamines adrenaline (ADR) and noradrenaline (NOR) were measured by HPLC and metanephrine with normetanephrine (NMN) by ELISA (n = 67). The diagnostic performance of metanephrines was determined by receiver operating characteristic (ROC) curve analysis. RESULTS: Phaeochromocytoma was confirmed by histological analysis in 14 patients and excluded in 53 patients by a negative clonidine suppression test (CST), abdominal computerized tomography scan and clinical follow-up (median 2.5 years). A sensitivity and specificity of 100 and 96%, respectively, was obtained by using our current CST diagnostic criteria for ADR and NOR values. ROC curve analysis revealed optimum sensitivity and specificity for plasma-free metanephrines using a threshold of 784 pmol/l at baseline and 663 pmol/l at 180 min. Baseline measurements of metanephrine with NMN showed 100% sensitivity and 98% specificity, as assessed by ROC curve analysis-derived criteria or when evaluated against published decision thresholds. A sensitivity and specificity of 100% was obtained for the combined measurements of metanephrine with NMN at 180 min. CONCLUSION: Plasma metanephrines (metanephrine with NMN) were equally effective as plasma catecholamines during CST. This study supports the use of measuring plasma metanephrines by ELISA as a less labour-intensive and equally effective biochemical test for phaeochromocytoma in patients with a high clinical suspicion. There was still overlap between groups with and without phaeochromocytoma at baseline under controlled conditions and clinically some patients still need to undergo clonidine suppression testing.

Evidence for epistasis between hemoglobin C and immune genes in human P. falciparum malaria: a family study in Burkina Faso.

Hemoglobin C (HbC) has been recently associated with protection against Plasmodium falciparum malaria. It is thought that HbC influences the development of immune responses against malaria, suggesting that the variation at the HbC locus (rs33930165) may interact with polymorphic sites in immune genes. We investigated, in 198 individuals belonging to 34 families living in Burkina Faso, statistical interactions between HbC and 11 polymorphisms within interleukin-4 (IL4), IL12B, NCR3, tumor necrosis factor (TNF) and lymphotoxin-α (LTA), which have been previously associated with malaria-related phenotypes. We searched for multilocus interactions by using the pedigree-based generalized multifactor dimensionality reduction approach. We detected 29 multilocus interactions for mild malaria, maximum parasitemia or asymptomatic parasitemia after correcting for multiple tests. All the single-nucleotide polymorphisms studied are included in several multilocus models. Nevertheless, most of the significant multilocus models included IL12B 3' untranslated region, IL12Bpro or LTA+80, suggesting that those polymorphisms play a particular role in the interactions detected. Moreover, we identified six multilocus models involving NCR3 that encodes the activating natural killer (NK) receptor NKp30, suggesting an interaction between HbC and genes involved in the activation of NK cells. More generally, our findings suggest an interaction between HbC and genes influencing the activation of effector cells for phenotypes related to mild malaria.

AIP mutation in pituitary adenomas in the 18th century and today.

Gigantism results when a growth hormone-secreting pituitary adenoma is present before epiphyseal fusion. In 1909, when Harvey Cushing examined the skeleton of an Irish patient who lived from 1761 to 1783, he noted an enlarged pituitary fossa. We extracted DNA from the patient's teeth and identified a germline mutation in the aryl hydrocarbon-interacting protein gene (AIP). Four contemporary Northern Irish families who presented with gigantism, acromegaly, or prolactinoma have the same mutation and haplotype associated with the mutated gene. Using coalescent theory, we infer that these persons share a common ancestor who lived about 57 to 66 generations earlier.

Evaluation of the clonidine suppression test in the diagnosis of phaeochromocytoma.

The aim of this study is to review the experience of the clonidine suppression test in a regional endocrine centre and to compare the diagnostic sensitivity and specificity using various previous published criteria. The design used is retrospective study. The subjects include 56 patients in whom clonidine suppression tests had been performed from 1995 to 2000: 15 with phaeochromocytoma and 41 patients in whom the diagnosis was excluded using a combination of biochemical testing, abdominal computed tomography scanning and clinical follow-up. Plasma catecholamines were measured by high pressure liquid chromatography on basal samples and at hourly intervals for 3 h after the administration of clonidine 300 µg orally and the following diagnostic criteria were applied: plasma noradrenaline+adrenaline>2.96 nmol l(-1) at 3 h post-clonidine or a baseline plasma adrenaline plus noradrenaline>11.82 nmol l(-1); plasma noradrenaline>2.96 nmol l(-1) at 3 h post-clonidine and plasma noradrenaline>2.96 nmol l(-1) and <50% fall in noradrenaline at 3 h post-clonidine. The results obtained is that mean plasma noradrenaline plus adrenaline fell across the test in 40/41 patients in the non-phaeochromocytoma patients and was lowest at 3 h (basal 2.28 ± 0.14 vs 1.36 ± 0.11 nmol l(-1), P<0.001). In the phaeochromocytoma group, clonidine had a variable effect on adrenaline plus noradrenaline levels with increases in 7/15. Using an abnormal result as a 3 h level of noradrenaline plus adrenaline>2.96 mmol l(-1) gave a sensitivity of 93% and specificity of 95%. When a 3 h noradrenaline>2.96 mmol l(-1) was used, sensitivity was 87% and specificity 95%. Using the former criteria, noradrenaline plus adrenaline>2.96 mmol l(-1), 1/15 in the phaeochromocytoma group had a normal result after clonidine suppression testing. Two of 41 in the non-phaeochromocytoma group had a false-positive result. Under carefully controlled conditions, the clonidine suppression test is well tolerated, safe and accurate for use in the investigation of patients with suspected phaeochromocytoma.

Advances in the genetics of familial renal cancer.

We discuss recent advances in the diagnosis and management of renal cell cancer (RCC) given the enhanced molecular genetics knowledge in this area. A number of hereditary renal cancer syndromes have been described, including von Hippel-Lindau disease, Birt-Hogg-Dubé syndrome, hereditary leiomyomatosis/RCC syndrome, and hereditary papillary renal cancer. Early molecular diagnosis now facilitates the management and prevention of RCC in families. Recommendations for screening in families are discussed.

Is there value in routine screening for Cushing's syndrome in patients with diabetes?

CONTEXT: Subclinical Cushing's syndrome has been described among diabetic populations in recent years, but no consensus has emerged about the value of screening. METHODS: We enrolled 201 consecutive patients attending our diabetes clinic and 79 controls. Patients with at least two of the following three criteria were offered screening using a 2300 h salivary cortisol test: glycosylated hemoglobin of at least 7%, body mass index of at least 25 kg/m(2), and a history of hypertension or blood pressure of at least 140/90 mm Hg. Results are expressed as mean +/- sem. RESULTS: Mean nighttime salivary cortisol levels were similar in the two groups (8.5 +/- 1.0 nmol/liter for diabetic patients vs. 5.8 +/- 1.0 nmol/liter for controls). Forty-seven patients (23%) had a value of at least 10 nmol/liter, which was set as a conservative threshold above which further investigation would be performed. Thirty-five (75%) agreed to further testing with a 1-mg overnight dexamethasone test. Of the remaining 12 patients, 10 were followed up clinically for at least 1 yr, and no evidence was found of the syndrome evolving. In 28 patients, serum cortisol suppressed to 60 nmol/liter or less. Of the seven patients who failed this test, four agreed to a 2 mg/d 48-h dexamethasone test, with serum cortisol suppressing to 60 nmol/liter or less in all four. Three declined this test but had normal 24-h urinary free cortisol levels. No patient had clinical features of hypercortisolism. CONCLUSIONS: The 1-3% detection rates of three recently published series have not been realized at our center where we studied a group using criteria making patients more likely to have hypercortisolism. Our results do not support the validity of screening patients without clinical features of Cushing's syndrome in the diabetes clinic.

Tumor risks and genotype-phenotype-proteotype analysis in 358 patients with germline mutations in SDHB and SDHD.

Succinate dehydrogenase B (SDHB) and D (SDHD) subunit gene mutations predispose to adrenal and extraadrenal pheochromocytomas, head and neck paragangliomas (HNPGL), and other tumor types. We report tumor risks in 358 patients with SDHB (n=295) and SDHD (n=63) mutations. Risks of HNPGL and pheochromocytoma in SDHB mutation carriers were 29% and 52%, respectively, at age 60 years and 71% and 29%, respectively, in SDHD mutation carriers. Risks of malignant pheochromocytoma and renal tumors (14% at age 70 years) were higher in SDHB mutation carriers; 55 different mutations (including a novel recurrent exon 1 deletion) were identified. No clear genotype-phenotype correlations were detected for SDHB mutations. However, SDHD mutations predicted to result in loss of expression or a truncated or unstable protein were associated with a significantly increased risk of pheochromocytoma compared to missense mutations that were not predicted to impair protein stability (most such cases had the common p.Pro81Leu mutation). Analysis of the largest cohort of SDHB/D mutation carriers has enhanced estimates of penetrance and tumor risk and supports in silicon protein structure prediction analysis for functional assessment of mutations. The differing effect of the SDHD p.Pro81Leu on HNPGL and pheochromocytoma risks suggests differing mechanisms of tumorigenesis in SDH-associated HNPGL and pheochromocytoma.

Long term effect of external pituitary irradiation on IGF1 levels in patients with acromegaly free of adjunctive treatment.

OBJECTIVE: It is established that external pituitary irradiation (EPI) effectively reduces serum GH levels in acromegaly. However, its effect in normalising serum IGF1 has been disputed. We looked at the number of our patients who achieved persistently normal IGF1 levels whilst free of adjunctive treatment for at least 1 year after EPI. PATIENTS AND DESIGN: We identified 63 acromegalic patients between 1964 and 2004 who received EPI. Six were excluded: three had surgery after EPI, two had no medical records available, and one had a pituitary Yttrium implant. MEASUREMENTS: Patients received 4500-5000 cGy in fractionated doses. IGF1 levels were correlated with their respective age-related reference ranges. RESULTS: After EPI, the number of patients with normal IGF1 and free of adjunctive medical treatment for at least 1 year were four patients by 3 years, nine patients by 5 years and seventeen by 10 years, with the current number of 25/57 (44%). Concordance between IGF1 levels and random GH dropped from 90% at the time of EPI to 65% at 3 years, 66% at 5 years and 71% at 10 years. CONCLUSIONS: We have demonstrated that, with time, EPI achieves a normal IGF1 in significant numbers of patients with acromegaly, thus obviating the need for life-long expensive medical therapy. For each patient this benefit has to be weighed against the possibility of new hypopituitarism as a result of the treatment. Any decision to use EPI is easier in the context of pre-existent hypopituitarism.