Well-differentiated gastroenteropancreatic G3 NET: findings from a large single centre cohort.

Neuroendocrine neoplasms are known to have heterogeneous biological behavior. G3 neuroendocrine tumours (NET G3) are characterized by well-differentiated morphology and Ki67 > 20%. The prognosis of this disease is understood to be intermediate between NET G2 and neuroendocrine carcinoma (NEC). Clinical management of NET G3 is challenging due to limited data to inform treatment strategies. We describe clinical characteristics, treatment, and outcomes in a large single centre cohort of patients with gastroenteropancreatic NET G3. Data was reviewed from 26 cases managed at Queen Elizabeth Hospital, Birmingham, UK, from 2012 to 2019. Most commonly the site of the primary tumour was unknown and majority of cases with identifiable primaries originated in the GI tract. Majority of cases demonstrated somatostatin receptor avidity. Median Ki67 was 30%, and most cases had stage IV disease at diagnosis. Treatment options included surgery, somatostatin analogs (SSA), and chemotherapy with either platinum-based or temozolomide-based regimens. Estimated progression free survival was 4 months following initiation of SSA and 3 months following initiation of chemotherapy. Disease control was observed following treatment in 5/11 patients treated with chemotherapy. Estimated median survival was 19 months; estimated 1 year survival was 60% and estimated 2 year survival was 13%. NET G3 is a heterogeneous group of tumours and patients which commonly have advanced disease at presentation. Prognosis is typically poor, though select cases may respond to treatment with SSA and/or chemotherapy. Further study is needed to compare efficacy of different treatment strategies for this disease.

Pituitary metastases: presentation and outcomes from a pituitary center over the last decade.

PURPOSE: Highlight and characterize manifestations, diagnostic/management approaches and outcomes in a contemporary cohort of patients with pituitary metastases (PM) from a large European pituitary center-over 10 years. METHODS: Retrospective review of PM cases between 1/2009 and 12/2018. Clinical, laboratory, imaging data at PM detection and during follow-up were analysed. RESULTS: 18 cases were identified (14 females; median age at diagnosis 61.5 years). Most common primary malignancies were lung (39%) and breast (32%). Most frequent presenting manifestation was visual dysfunction (50%). Gonadotrophin, ACTH, TSH deficiency were diagnosed in 85%, 67%, 46% of cases, respectively; diabetes insipidus (DI) was present in 17%. 33% of cases were detected during investigation for symptoms unrelated to PM. PM management included radiotherapy (44%), transsphenoidal surgery (17%), transsphenoidal surgery and radiotherapy (6%) or monitoring only (33%). One-year survival was 49% with median survival from PM detection 11 months (range 2-47). CONCLUSIONS: In our contemporary series, clinical presentation of PM has evolved; we found increased prevalence of anterior hypopituitarism, decreased rates of DI and longer survival compared with older literature. Increased availability of diagnostic imaging, improvements in screening and recognition of pituitary disease and longer survival of patients with metastatic cancer may be contributing factors.

Effect of Valvular Surgery in Carcinoid Heart Disease: An Observational Cohort Study.

CONTEXT: Carcinoid heart disease (NET-CHD) is associated with the development of symptom-limited exercise capacity and high rates of morbidity and mortality. OBJECTIVE: This study sought to determine the survival, cardiac function, and functional class following surgery. DESIGN AND SETTING, AND PATIENTS: This was a retrospective observational cohort study between 2005 and 2015 at a European Centre of Excellence for Neuroendocrine Tumours, Queen Elizabeth Hospital Birmingham. England consisting of 62 consecutive patients referred to the NET-Cardiology Service. INTERVENTIONS: Subjects were assessed at referral using transthoracic echocardiography (with saline contrast) and transesophageal echocardiography, and 77% with confirmed NET-CHD underwent cardiovascular magnetic resonance imaging. Symptomatic patients with concomitant severe valvular dysfunction were referred for surgery with stable NET disease. MAIN OUTCOME MEASURE: Survival of patients with proven NET-CHD following medical and surgical treatments was measure. RESULTS: In total, 47/62 patients were diagnosed with NET-CHD. Thirty-two patients (68%) underwent surgery with bioprosthetic valve replacements in all subjects; tricuspid, n = 31; pulmonary, n = 30; mitral, n = 3; and aortic, n = 3. Four patients underwent concomitant coronary artery bypass grafting. There were 4 (13%) early post-operative deaths. One- and 2-y survival rates after surgery were 75 and 69% compared with 45 and 15% in un-operated patients. Post-operatively, functional class was improved (pre-New York Heart Association Classification [NYHA], 2.6 [0.5] vs post-NYHA, 1.7 [1.1]), P < .05, right-ventricular (RV) size was reduced (136 ml/m(2) [25] vs 71 ml/m(2) [7]; P < .01) with preserved RV ejection fraction (61% ± 9 vs 55% ± 10; P = .26). CONCLUSION: Valve surgery improved functional class and resulted in RV reverse remodelling with improved survival rates at 2 y compared with those not proceeding to operation. These data highlight the importance of close collaboration between NET clinicians, cardiology, and cardiothoracic surgery teams. Early referral can improve functional capacity but more research is needed to define the selection of appropriate candidates and randomized data are needed to define the effect of surgery on prognosis.

Hepatitis B virus in HIV-infected patients in northeastern South Africa: prevalence, exposure, protection and response to HAART.

OBJECTIVE: Hepatitis B virus (HBV) and HIV are endemic infections in many African countries. The objectives of this study were to determine the levels of exposure to, and protection from, HBV, as well as the prevalence of HIV/HBV co-infection and the response of HBV to highly active anti-retroviral therapy (HAART) in a cross-section of HIV-infected patients in north-eastern South Africa. STUDY DESIGN: This was a laboratory-based, unmatched study. Three hundred and eighty patients were screened by ELISA for HBsAg, anti-HBc and anti-HBs. Samples non-reactive for HBsAg but reactive for anti-HBc were examined for occult HBV infection. Response to HAART was assessed by measuring HBV viral loads, seroconversion from HBeAg to anti-HBe, and levels of aminotransferase. RESULTS: Of the study population of 380, 60% (95% CI 54.8 - 64.9) were exposed to HBV based on HBsAg, anti-HBs or anti-HBc; 20% (95% CI 16.1 - 24.4) had active HBV infection, based on HBsAg serology, and 30% (95% CI 25.2 - 35.2) were protected, based on anti-HBs levels > or = 10 IU/l. Of 181 HBsAg-negative individuals, 61 had HBV occult infection (33.7%, 95% CI 26.9 - 41.1). The differences in prevalence were not statistically significant when gender, marital status and CD4+ cell counts were considered. Of 21 patients analysed, 80% showed adequate response to the first-line HAART regimen (stavudine/lamivudine/efavirenz or nevirapine) after 12 months of use. CONCLUSION: The study confirms the higher level (60%) of exposure to HBV in HIV patients in Limpopo Province, as well as the high (20%) prevalence of HBsAg positivity and occult hepatitis B (33.7%). However, further studies are warranted to corroborate the benefit of lamivudine-containing HAART regimens, as HIV/HBV co-infected patients have a higher liver-related mortality if hepatitis B is not treated.

'Sink or swim': an evaluation of the clinical characteristics of individuals with high bone mass.

SUMMARY: High bone mineral density on routine dual energy X-ray absorptiometry (DXA) may indicate an underlying skeletal dysplasia. Two hundred fifty-eight individuals with unexplained high bone mass (HBM), 236 relatives (41% with HBM) and 58 spouses were studied. Cases could not float, had mandible enlargement, extra bone, broad frames, larger shoe sizes and increased body mass index (BMI). HBM cases may harbour an underlying genetic disorder. INTRODUCTION: High bone mineral density is a sporadic incidental finding on routine DXA scanning of apparently asymptomatic individuals. Such individuals may have an underlying skeletal dysplasia, as seen in LRP5 mutations. We aimed to characterize unexplained HBM and determine the potential for an underlying skeletal dysplasia. METHODS: Two hundred fifty-eight individuals with unexplained HBM (defined as L1 Z-score ≥ +3.2 plus total hip Z-score ≥ +1.2, or total hip Z-score ≥ +3.2) were recruited from 15 UK centres, by screening 335,115 DXA scans. Unexplained HBM affected 0.181% of DXA scans. Next 236 relatives were recruited of whom 94 (41%) had HBM (defined as L1 Z-score + total hip Z-score ≥ +3.2). Fifty-eight spouses were also recruited together with the unaffected relatives as controls. Phenotypes of cases and controls, obtained from clinical assessment, were compared using random-effects linear and logistic regression models, clustered by family, adjusted for confounders, including age and sex. RESULTS: Individuals with unexplained HBM had an excess of sinking when swimming (7.11 [3.65, 13.84], p < 0.001; adjusted odds ratio with 95% confidence interval shown), mandible enlargement (4.16 [2.34, 7.39], p < 0.001), extra bone at tendon/ligament insertions (2.07 [1.13, 3.78], p = 0.018) and broad frame (3.55 [2.12, 5.95], p < 0.001). HBM cases also had a larger shoe size (mean difference 0.4 [0.1, 0.7] UK sizes, p = 0.009) and increased BMI (mean difference 2.2 [1.3, 3.1] kg/m(2), p < 0.001). CONCLUSION: Individuals with unexplained HBM have an excess of clinical characteristics associated with skeletal dysplasia and their relatives are commonly affected, suggesting many may harbour an underlying genetic disorder affecting bone mass.

Impact of UK National Guidelines based on FRAX®--comparison with current clinical practice.

OBJECTIVE: To assess whether clinician-determined treatment intervention thresholds are in line with the assessment of fracture risk provided by FRAX® and treatment recommendations provided by UK guidelines produced by the National Osteoporosis Guidelines Group (NOGG). DESIGN, PATIENTS AND MEASUREMENTS: This was a retrospective cohort analysis of 288 patients consecutively referred for dual-energy X-ray absorptiometry (DXA) scanning from primary care immediately prior to the introduction of the FRAX® algorithm. In addition to DXA assessment, patients completed a clinical risk factor questionnaire which included risk factors used in the FRAX® algorithm. Initial risk assessment and treatment decisions were performed after DXA. FRAX® was used, retrospectively, with femoral neck T-score, to estimate fracture risk which was applied to NOGG to generate guidance on treatment intervention. Clinician- and NOGG-determined outcomes were audited for concordance. RESULTS: There was concordance between clinician and NOGG treatment decisions in 215 (74.6%) subjects. Discordance was observed in 73 (25.3%) subjects. In the discordant group, seven subjects were given lifestyle advice when NOGG recommended treatment, 42 given treatment when NOGG recommended lifestyle advice only, and 24 were referred to a metabolic bone clinic for further evaluation. The reasons for treatment differences in subjects recommended treatment by clinician but not NOGG were largely (90.2%) attributed to the use of lumbar spine bone mineral density (BMD). CONCLUSIONS: There is high concordance between clinician-determined and FRAX®-NOGG intervention. The absence of spine BMD from FRAX® is the primary source of discrepancy. This study provides some assurance of the validity of the treatment thresholds generated from FRAX®-NOGG in 'real-world' usage.

ACTH deficiency, higher doses of hydrocortisone replacement, and radiotherapy are independent predictors of mortality in patients with acromegaly.

CONTEXT: A number of retrospective studies report that patients with acromegaly have increased morbidity and premature mortality, with standardized mortality ratios (SMR) of 1.3-3. Many patients with acromegaly develop hypopituitarism as a result of the pituitary adenoma itself or therapies such as surgery and radiotherapy. Pituitary radiotherapy and hypopituitarism have also been associated with an increased SMR. METHODS: Using the West MIDLANDS: Acromegaly database (n = 501; 275 female), we assessed the influence of prior radiotherapy and hypopituitarism (and replacement therapy) on mortality in patients with acromegaly. Median duration of follow-up was 14.0 yr (interquartile range, 7.9-21 yr). RESULTS: All-cause mortality was elevated [SMR, 1.7 (1.4, 2.0); P < 0.001]. On external analysis, prior radiotherapy, ACTH, and gonadotropin deficiency were associated with an elevated SMR [radiotherapy SMR, 2.1 (1.7-2.6); P = 0.006; ACTH deficiency SMR, 2.5 (1.9-3.2); P < 0.0005; and gonadotropin deficiency SMR, 2.1 (1.6-2.7); P = 0.037]. On internal analysis, the relative risk (RR) of mortality was increased in the radiotherapy [RR, 1.8 (1.2-2.8); P = 0.008] and ACTH-deficiency groups [RR, 1.7 (1.2-2.5); P = 0.004], but not in the gonadotropin- or TSH-deficiency groups. In the ACTH-deficient group, increased replacement doses of hydrocortisone greater than 25 mg/d were associated with increased mortality compared to lower doses. CONCLUSIONS: Radiotherapy and ACTH deficiency are significantly associated with increased mortality in patients with acromegaly. In ACTH-deficient patients, a daily dose of more than 25 mg hydrocortisone is associated with increased mortality compared to lower doses. These results have important implications for the treatment of patients with acromegaly and also raise issues as to the optimum hydrocortisone treatment regimens for ACTH-deficient patients.

Medical therapy in patients with acromegaly: predictors of response and comparison of efficacy of dopamine agonists and somatostatin analogues.

CONTEXT: Acromegaly is associated with increased morbidity and mortality. Treatment options include surgery, radiotherapy, and medical therapy. AIMS: The objective of the study was to examine the role of prolactin status, prior surgery, and radiotherapy on the response to medical therapy in patients with acromegaly and assess the relative efficacy of dopamine agonist therapy compared with somatostatin analog therapy. MATERIALS AND METHODS: A total of 276 patients with acromegaly received either dopamine agonists (DA) and/or somatostatin analogs (SSA). One hundred seventy-two patients had received surgery and 73 radiotherapy prior to receiving medical therapy. One hundred ninety-eight of 276 received DA, and 143 of 276 received SSA. GH and IGF-I values at baseline and after 12 months on therapy were analyzed. RESULTS: In the DA group, basal prolactin concentration did not predict response to therapy, GH percent reduction: hyperprolactinemia, 26.7% (-10.4 to 48) vs. normoprolactinemia, 34.8% (0.2-53.2), P = 0.58; IGF-I percent reduction: hyperprolactinemia 30.0% (9.2-43.1) vs. normoprolactinemia 16.8% (4-37), P = 0.45. Prior surgery was not associated with any difference in response to DA: GH percent reduction (P = 0.1) and IGF-I percent reduction (P = 0.08). By contrast, prior radiotherapy was associated with an enhanced efficacy of GH response to DA, P = 0.02. In the SSA group, there was no effect of prior surgery or radiotherapy on response of GH, but radiotherapy was associated with less marked IGF-I percent reduction (P = 0.05). SSA were more potent than DA at decreasing both GH [62.8% (20.7-85%) vs. 42.4% (-6.5 to 68.6), P < 0.008] and IGF-I [SSA 40.4% (0-64.3) vs. 8% (0-40.8), P = 0.05]. CONCLUSIONS: The effects of DA are irrespective of baseline prolactin concentrations. Prior radiotherapy is associated with differences in GH and IGF-I response to DA and SSA therapy.

Monitoring disease activity using GH and IGF-I in the follow-up of 501 patients with acromegaly.

CONTEXT: The aims of treatment in patients with acromegaly are to achieve serum GH/IGF-I concentrations associated with cure or normalization of mortality and alleviation of symptoms. OBJECTIVE AND METHODS: Using the West Midlands Acromegaly database (n = 501) we investigated the reliability of basal fasting GH in predicting nadir or mean GH during oral glucose tolerance test (OGTT) or GH day curve (GHDC), respectively, the degree of discordance between disease activity measured by GH and IGF-I values and the effect of radiotherapy on the above relationships. In total 773 OGTT and 507 GHDC were performed. RESULTS: Basal fasting GH was strongly correlated with nadir/mean GH on OGTT/GHDC (r = +0.87, P < 0.0001, r = +0.93, P < 0.0001, respectively). A basal GH < 2.5 microg/l was associated with a nadir/mean GH during OGTT/GHDC < 2.5 microg/l in 98.6% and 88.2% of cases, respectively. Elevated IGF-I was seen in 32.4% and 46.4% of patients with GH nadir values during OGTT < 1 and < 2.5 microg/l, respectively, and in 21.2% and 45.9% of GHDC with mean GH < 1 and < 2.5 microg/l, respectively. Radiotherapy increased the discordance in GH and IGF-I as markers of disease activity at GH < 2.5 microg/l (elevated IGF-I-values when OGTT nadir GH < 2.5 microg/l: radiotherapy 55.5%vs. no radiotherapy 36.9%, P = 0.002). CONCLUSIONS: There is a close relationship between a basal fasting GH < 2.5 microg/l and nadir/mean GH < 2.5 microg/l during OGTT/GHDC. There is a large discordance between disease activity when assessed by GH and IGF-I which is further increased by radiotherapy. These observations illustrate the challenge of defining appropriate biochemical end-points to achieve control of disease and normalization of mortality in acromegaly.

Growth hormone and its disorders.

Growth hormone (GH) is synthesised and secreted by the somatotroph cells of the anterior lobe of the pituitary gland. Its actions involve multiple organs and systems, affecting postnatal longitudinal growth as well as protein, lipid, and carbohydrate metabolism. GH hypersecretion results in gigantism or acromegaly, a condition associated with significant morbidity and mortality, while GH deficiency results in growth retardation in children and the GH deficiency syndrome in adults. This article, aimed at non-paediatric physicians, examines the clinical features, diagnosis, and current concepts in the management of these conditions.

Growth hormone and pituitary radiotherapy, but not serum insulin-like growth factor-I concentrations, predict excess mortality in patients with acromegaly.

Increased mortality in patients with acromegaly has been confirmed in a number of retrospective studies, but causative factors and relationship to serum IGF-I remain uncertain. The West Midlands Pituitary database contains details of 419 patients (241 female) with acromegaly. Serum IGF-I data from the Regional Endocrine Laboratory were available for 360 patients (86%). At diagnosis, mean age was 47 yr (range, 12-84) and mean duration of follow-up was 13 yr (0.5-48). Sixty-one percent were treated by surgery and 39% by nonsurgical means. Radiotherapy was used alone or as adjuvant therapy in 50%. All patients were registered with the Office of National Statistics to obtain information on deaths. At the date of analysis (31 December 2001), 95 of the 419 patients had died (43 males), giving a standardized mortality ratio of 1.26 [confidence interval (CI), 1.03-1.54; P = 0.046]. After controlling for age and sex, data indicated that mortality was increased in subjects with posttreatment GH levels more than 2 micro g/liter, compared with those with levels less than 2 micro g/liter [ratio of mortality rates (RR), 1.55 (range, 0.97-2.50); P = 0.068]. By contrast, a much smaller increase was observed for subjects with elevated posttreatment IGF-I levels compared with those with normal levels [RR, 1.20 (range, 0.71-2.03); P = 0.50]. Treatment with radiotherapy was associated with increased mortality [RR, 1.67 (range, 1.09-2.56); P = 0.018], with cerebrovascular disease the predominant cause of death [standardized mortality ratio, 4.42 (range, 2.71-7.22); P = 0.005]. These results confirm the increased mortality in acromegaly and suggest that reduction of GH levels to less than 2 micro g/liter is beneficial in terms of improving long-term outcome. The sole use of IGF-I as a marker for effective treatment of acromegaly is not justified by this data. This study also highlights the potential deleterious effect of radiotherapy.

Abnormal expression of 11 beta-hydroxysteroid dehydrogenase type 2 in human pituitary adenomas: a prereceptor determinant of pituitary cell proliferation.

The physiological effects of glucocorticoids (GCs) are, at least in part, mediated by inhibition of cell proliferation. Two isozymes of 11 beta-hydroxysteroid dehydrogenase (11 beta-HSD) interconvert cortisol (F) and inactive cortisone (E), and are thus able to modulate GC action at an autocrine level. Previously, we have demonstrated absent expression of 11 beta-HSD2 in normal pituitaries; however, in a small number of pituitary tumors analysed, 11 beta-HSD2 was readily demonstrable. Here we have used real-time RT-PCR to quantify expression of mRNA for 11 beta-HSD1 and 2 in 105 human pituitary tumors and have performed enzyme expression and activity studies in primary pituitary cultures. Overall, pituitary tumors expressed lower levels of 11 beta-HSDl mRNA compared with normals (0.2-fold, P<0.05). In contrast, expression of 11 beta-HSD2 mRNA was 9.8-fold greater in tumors than in normals (P<0.001). Enzyme assays showed significant 11 beta-HSD2 activity (71.9+/-22.3 pmol/h/mg protein (mean+/-s.d.)) but no detectable 11 beta-HSDl activity. Proliferation assays showed that addition of glycyrrhetinic acid (an 11 beta-HSD2 inhibitor) resulted in a 30.3+/-7.7% inhibition of cell proliferation. In summary, we describe a switch in expression from 11 beta-HSDl to 11 beta-HSD2 in neoplastic pituitary tissue. We propose that abnormal expression of 11 beta-HSD2 acts as a proproliferative prereceptor determinant of pituitary cell growth, and may provide a novel target for future tumor therapy.

A pilot study of the prevalence of hepatitis C virus antibodies and hepatitis C virus RNA in southern Cameroon.

Information is lacking on the prevalence of hepatitis C virus (HCV) infection in most African countries. An algorithm based on a combination of enzyme immunoassays (EIAs) with different formats (a commercial test, an HCV antibody [Ab] III test, and an HCV core Ab EIA) was used to estimate the prevalence of HCV infection in different population groups from southern Cameroon. An overall high prevalence was observed, with a significant increasing trend for both sexes with respect to age. A high proportion (67.4%) of HCV-positive sera were viremic as demonstrated by the reverse transcription-polymerase chain reaction. We conclude that the prevalence of HCV is high in southern Cameroon and increases linearly with age.

Genotypic subtypes of HIV-1 in Cameroon.

OBJECTIVE: The only two HIV-1 strains (ANT70 and MVP5180) reported to date from Cameroon are members of the outlier clade (group O). In this study, we assessed the prevalence of group O viruses and other HIV-1 subtypes in Cameroon. DESIGN: A phylogenetic analysis of 18 HIV-1 strains isolated from seropositive individuals from Yaoundé and Douala, Cameroon. METHODS: A 900 base-pair fragment of the env gene coding for V3, V4, V5, and the beginning of gp41 of 17 out of 18 HIV-1 isolates from Cameroon was amplified, cloned and sequenced using polymerase chain reaction. A phylogenetic tree was constructed. RESULTS: The overall env nucleotide sequence divergence among the Cameroon isolates ranged from 6.1 to 27.5%. In a phylogenetic tree, six subtypes were identified when compared with 23 reference strains of different geographic origin. Of these 17 Cameroonian strains, 11 (61%) were of subtype A of which the interpatient distances at the sequence level varied from 6.1% to 18.3% (average, 11.9%). Three (17%) strains were of subtype F, and the other three strains (6% each) belonged to subtypes B, E and H, respectively. The remaining isolate was classified as belonging to group O, on the basis of the sequence of part of the pol gene. A very broad spectrum of different tetrameric amino-acid sequences was observed at the apex of the V3 loop. Eleven strains contained the tetrameric globally predominant GPGQ sequence at the tip of the V3 motif. Two strains had the GPGR sequence typical of the American and European HIV-1 strains. The remaining tetrameric sequences included GPGS, GSGQ, GRGQ, and GLGR. CONCLUSION: These findings on a limited number of viruses suggest extensive env gene diversity of HIV-1 strains from Cameroon, and could have implications for vaccine development in Africa.