Treatment and long term safety outcomes of Peptide Receptor Radionuclide Therapy for metastatic neuroendocrine tumours: an Asian experience.

Peptide-receptor radionuclide therapy (PRRT) is a targeted molecular therapy used to treat neuroendocrine tumours (NET). It has been shown to be effective and well-tolerated in patients with metastatic neuroendocrine tumours in several centres in United States (US), Europe and Australia. Tolerability and efficacy data emerging from Asian centres remain few. Epidemiological evidence suggests that there are differences in neuroendocrine neoplasms between the population groups. We aim to describe the treatment and safety outcomes of PRRT in the Asian population. Methods One hundred and seven (107) patients with metastatic neuroendocrine tumour who had undergone PRRT treatment from January 2012 to March 2019 were included in this retrospective study. The response rates using RECIST1.1 and qualitative analysis were examined. The overall and progression free survival curves were also evaluated. Results The median progression free survival was 49 months. Response assessment after completion of treatment showed that 33(37.9%) of 87 patients had partial or complete response. Subgroup analysis comparing high- and low-grade NET showed that there was a significant difference in the time to progression curves. Comparison of the number of cycles and progression free and overall survival also showed a significant difference. Ten patients (9%) had grade 3 or more haematological toxicities. Four patients (4%) had grade 3/4 hepatobiliary toxicities, although the presence of extensive liver metastases was a confounding factor. None of the patients had grade 3/4 acute kidney injury. Conclusion Our results show that PRRT is safe and effective in the treatment of metastatic neuroendocrine tumour in the Asian population. There was a significant difference in the progression free survival curves between low-grade and high-grade NET, and in the progression free and overall survival comparing the number of cycles received.

Prolonged Hypokalemia and Delayed Diagnosis of Primary Aldosteronism: Clinical Course and Risk Factors.

INTRODUCTION: Primary Aldosteronism (PA) is a common cause of hypertension. However, diagnosis is often delayed, leading to poorer clinical outcomes. Hypokalemia with hypertension is characteristic of PA, and is an indication for screening. We evaluated if patients with PA had prolonged hypokalemia before diagnosis, the subsequent biochemical/clinical control, and factors associated with delayed diagnosis. METHODS: Our study included all PA patients with hypokalemia diagnosed between 2001 to 2022. Delayed diagnosis was defined as duration of hypokalemia of >1 year from first occurrence, to first evaluation by a PA specialist. Patients were reassessed post-adrenalectomy using the Primary Aldosteronism Surgery Outcomes criteria. We performed multivariable analysis to assess for factors associated with delayed diagnosis. RESULTS: Among 240 patients with PA who presented with hypokalemia, 122 (51%) patients had delayed diagnosis, with prolonged hypokalemia of median duration 4.5 (2.4-7.5) years. Patients with delayed diagnosis were older, had longer duration of hypertension, higher pill burden, lower renal function and more prevalent cardiovascular disease. Factors associated with delayed diagnosis included older age, presence of hyperlipidaemia, and less severe hypokalemia (serum potassium >3.0mmol/L). Compared to patients with early diagnosis, a lower proportion of those with delayed diagnosis underwent adrenal vein sampling (73% vs 58%), P<0.05. Sixty of 118 (50.8%) non-delayed, and 39 of 122 (32.0%) patients with delayed diagnosis underwent surgery. CONCLUSION: Despite manifestation of hypokalemia, many patients with PA fail to be promptly screened. Greater emphasis in hypertension guidelines, and efforts to improve awareness of PA amongst primary care physicians are urgently needed.

Expanding the use of salivary cortisol as a non-invasive outpatient test in the dynamic evaluation of suspected adrenal insufficiency.

Background: Adrenal insufficiency (AI) is potentially life-threatening, and accurate diagnosis is crucial. The first-line diagnostic test, the adrenocorticotrophic hormone (ACTH) stimulation test, measures serum total cortisol. However, this is affected in states of altered albumin or cortisol-binding globulin levels, limiting reliability. Salivary cortisol reflects free bioactive cortisol levels and is a promising alternative. However, few studies are available, and heterogenous methodologies limit applicability. Methods: This study prospectively recruited 42 outpatients undergoing evaluation for AI, excluding participants with altered cortisol-binding states. Serum (immunoassay) and salivary (liquid chromatography tandem mass spectrometry) cortisol levels were sampled at baseline, 30 min, and 60 min following 250 µg synacthen administration. AI was defined as a peak serum cortisol level <500 nmol/L in accordance with guidelines. Results: The study recruited 21 (50%) participants with AI and 21 without AI. There were no significant differences in baseline characteristics, blood pressure, or sodium levels between groups. Following synacthen stimulation, serum and salivary cortisol levels showed good correlation at all timepoints (R2 = 0.74, P < 0.001), at peak levels (R2 = 0.72, P < 0.001), and at 60 min (R2 = 0.72, P < 0.001). A salivary cortisol cut-off of 16.0 nmol/L had a sensitivity of 90.5% and a specificity of 76.2% for the diagnosis of AI. Conclusion: This study demonstrates a good correlation between serum and salivary cortisol levels during the 250 µg synacthen test. A peak salivary cortisol cut-off of 16.0 nmol/L can be used for the diagnosis of AI. It is a less invasive alternative to evaluate patients with suspected AI. Its potential utility in the diagnosis of AI in patients with altered cortisol-binding states should be further studied.

Bariatric Surgery in Kidney Transplant Candidates and Recipients: Experience at an Asian Center.

Background: Kidney transplant (KT) candidates and recipients with obesity experience more frequent complications such as infection, poorer allograft outcomes, diabetes, and mortality, limiting their eligibility for transplantation. Bariatric surgery (BS) is not commonly performed among KT patients given concerns about immunosuppression absorption, wound healing, infections, and graft outcomes. Its role has not been described before in an Asian KT patient setting. Methods: A retrospective review of patients who underwent BS at the largest KT center in Singapore from 2008 to 2020 was conducted. Metabolic outcomes, immunosuppression doses, graft outcomes, and mortality were studied. Results: Seven patients underwent BS and KT (4 underwent BS before KT, 3 underwent BS after KT; 4 underwent sleeve gastrectomy, 3 underwent gastric bypass). Mean total weight losses of 23.8% at 1 year and 18.6% at 5 years post-BS were achieved. Among the five patients with diabetes, glycemic control improved after BS. There were no deaths in the first 90 days or graft loss in the first year after KT and BS. Patients who underwent BS after KT had no significant changes in immunosuppression dose. Conclusion: BS can be safely performed in KT recipients and candidates and results in sustainable weight losses and improvements in metabolic comorbidities. Although no major complications were observed in our study, close monitoring of this complex group of patients is imperative.

11C-Metomidate PET-CT versus adrenal vein sampling to subtype primary aldosteronism: a prospective clinical trial.

OBJECTIVE: Adrenal vein sampling (AVS) is recommended to subtype primary aldosteronism, but it is technically challenging. We compared 11C-Metomidate-PET-computed tomography (PET-CT) and AVS for subtyping of primary aldosteronism. METHODS: Patients with confirmed primary aldosteronism underwent both AVS and 11C-Metomidate PET-CT (post-dexamethasone). All results were reviewed at a multidisciplinary meeting to decide on final subtype diagnosis. Primary outcome was accuracy of PET versus AVS to diagnosis of unilateral primary aldosteronism based on post-surgical biochemical cure. Secondary outcome was accuracy of both tests to final subtype diagnosis. RESULTS: All 25 patients recruited underwent PET and successful AVS (100%). Final diagnosis was unilateral in 22 patients, bilateral in two and indeterminate in one due to discordant lateralization. Twenty patients with unilateral primary aldosteronism underwent surgery, with 100% complete biochemical success, and 75% complete/partial clinical success. For the primary outcome, sensitivity of PET was 80% [95% confidence interval (95% CI): 56.3-94.3] and AVS was 75% (95% CI: 50.9-91.3). For the secondary outcome, sensitivity and specificity of PET was 81.9% (95% CI: 59.7-94.8) and 100% (95% CI: 15.8-100), and AVS was 68.2% (95% CI: 45.1-86.1) and 100% (95% CI: 15.8-100), respectively. Twelve out of 20 (60%) patients had both PET and AVS lateralization, four (20%) PET-only, three (15%) AVS-only, while one patient did not lateralize on PET or AVS. Post-surgery outcomes did not differ between patients identified by either test. CONCLUSION: In our pilot study, 11C-Metomidate PET-CT performed comparably to AVS, and this should be validated in larger studies. PET identified patients with unilateral primary aldosteronism missed on AVS, and these tests could be used together to identify more patients with unilateral primary aldosteronism. VIDEO ABSTRACT: http://links.lww.com/HJH/B918.

Bone mineral density following liver transplantation: a 10-year trend analysis.

We evaluated the prevalence of osteoporosis and annual changes in bone mineral density (BMD) over 10 years post-liver transplantation. BMD in the lumbar spine improved significantly post-transplantation, reaching a 12% increase at year 10. In contrast, BMD in the femoral neck and hip deteriorated and did not return to baseline levels. INTRODUCTION: This study (1) evaluated the prevalence of osteoporosis, and the annual changes in bone mineral density (BMD) over 10 years, and (2) identified the risk factors for worsened BMD in stable liver transplant recipients (LTRs). METHODS: LTRs who underwent liver transplantation (LT) at Singapore General Hospital between February 2006 and Mar 2019 were included. Demographic, clinical data, and BMD in the lumbar spine (LS), femoral neck (FN), and total hip (TH) were collected retrospectively from the medical records. RESULTS: Eighty-three patients (mean age: 55 ± 8 years) with a median follow-up of 80 months were included. The prevalence of osteoporosis increased significantly from 18.1% pre-LT to 34.3% post-LT (p = 0.021), and the incidence of osteoporosis was 18.2%. Worsened BMD (normal to osteopenia/osteopenia to osteoporosis) was found in 27.2% of LTRs. No significant risk factors were associated with worsened BMD, but females had a trend towards a higher odd (adjusted odds ratio: 3.54, 95%CI (0.61-20.5), p = 0.159). The LS BMD increased within 6-month post-LT and continued to improve throughout the entire follow-up period. In contrast, BMD in the FN and TH deteriorated and did not return to baseline levels post-LT. CONCLUSION: Prevalence of osteoporosis increased significantly post-LT. Over a 10-year follow-up, 27.2% of LTRs had worsened BMD status, and a possible risk factor may be female gender. While the LS BMD improved with time, the BMD in the FN and TH persisted below baseline throughout the follow-up period. Future studies should explore long-term therapies to improve BMD in the FN and TH post-LT.

Re-evaluating absent clinical success after adrenalectomy in unilateral primary aldosteronism.

BACKGROUND: Adrenalectomy cures unilateral primary aldosteronism, and it improves or cures hypertension. However, a significant proportion of patients are classified with absent clinical success postsurgery, suggesting that surgery was ineffective. METHODS: We assessed all patients 6 to 12 months post-surgery for clinical outcomes using Primary Aldosteronism Surgical Outcomes (PASO), AVIS-2, and CONNsortium criteria. We estimated blood pressure changes after adjustment for changes in defined daily dosages of antihypertensive medications. We also reassessed all patients using PASO at their recent clinical visit. RESULTS: A total of 104 patients with unilateral primary aldosteronism underwent adrenalectomy at 2 tertiary centers from 2000 to 2019; 24 (23%), 31 (30%), and 54 (52%) patients were classified with absent clinical success using PASO, AVIS-2, and CONNsortium criteria, respectively. Among 24 patients with absent clinical success using PASO criteria, 10 had complete biochemical cure, 3 partial, 2 absent, and 9 had resolution of hypokalemia. On multivariable analysis, absent clinical success was associated with presence of hyperlipidemia, diabetes mellitus, and lower defined daily dosages at baseline. After adjustment for changes in defined daily dosages, 7 of 24 patients showed blood pressure improvement ≥20/10 mm Hg post-surgery. After a follow-up of mean 5.6 years, 12 of 24 patients showed partial or complete clinical success when reassessed using PASO criteria. Only 6 of 104 (5.8%) patients failed to show clinical improvement post-surgery using any of the 3 mentioned criteria or using PASO criteria at their recent clinical visit. CONCLUSION: Although some patients may be classified with absent clinical success post-surgery, the assessment of clinical outcomes remains subject to many variables. In patients with unilateral primary aldosteronism, evidenced by lateralization on AVS, unilateral adrenalectomy should remain the recommended treatment.

Clinicopathologic Characteristics and Survival of Patients with Gastroenteropancreatic Neuroendocrine Neoplasm in a Multi-Ethnic Asian Institution.

BACKGROUND: Epidemiological evidence suggests there are differences in gastroenteropancreatic neuroendocrine neoplasm (GEPNEN) among population groups. We aimed to contribute to the current evidence by evaluating the clinicopathological characteristics of GEPNEN in a multi-ethnic Asian group. MATERIALS AND METHODS: This was a retrospective chart review of patients diagnosed with GEPNEN at a tertiary medical institution at Singhealth Outram Campus, Singapore, between 1995 and 2015. RESULTS: Two hundred ninety-five patients were included in the evaluation, comprising Chinese (74.6%), Malay (4.4%), Indian (9.5%) and other (11.5%) ethnic backgrounds. The median age at diagnosis was 59 years; 52.5% were males. Distribution of disease stage at diagnosis was: localised (42.4%), regional (15.3%) and distant (38.0%). The three most common primary tumour sites were located in the pancreas (38.6%), rectum (19.7%) and stomach (9.5%), which varied significantly with ethnic background and age at diagnosis. Malay patients were younger (median 42 years) at diagnosis than Chinese (60 years). Patients with an appendiceal neuroendocrine neoplasm (NEN) (48 years) were younger compared to oesophageal NEN (66 years). Disease stage correlated with primary tumour site and grade (p < 0.001). Median overall survival (OS) for all GEPNEN was 10.2 years. Age at diagnosis, disease stage and grading were prognostic factors of OS in multivariable analyses. CONCLUSION: Our findings correspond with other studies that focus on GEPNEN incidences in Asian countries, with the pancreas, rectum and stomach being the most common primary tumour sites. Our findings suggest racial differences in primary tumour site and age at diagnosis. Further prospective population-based registries are required to understand these epidemiological differences.

Factors Associated with Resolution of Hypertension after Adrenalectomy in Patients with Primary Aldosteronism.

BACKGROUND: The aim of this study was to investigate the factors associated with resolution of hypertension after adrenalectomy in patients with primary aldosteronism. A secondary aim was to describe our use of the contralateral ratio in adrenal venous sampling (AVS) in the setting of suboptimal successful cannulation rates. METHODS: A retrospective review of patients who underwent AVS followed by unilateral adrenalectomy for primary aldosteronism was performed. RESULTS: Complete resolution of hypertension and hypokalemia was seen in 17 of 40 patients (42.5%), while a clinical improvement in hypertension was seen in 38 of 40 (95%). Shorter duration of hypertension, mean aldosteronoma resolution score (ARS), and a high ARS of 3 to 5 were associated with resolution of hypertension after adrenalectomy (P=0.02, P=0.02, and P=0.004, respectively). Of the individual components of ARS, only a duration of hypertension of ≤6 years was associated with resolution of hypertension after adrenalectomy (P=0.03). CONCLUSION: A shorter duration of hypertension was significantly associated with resolution of hypertension after adrenalectomy in patients with primary aldosteronism.

Phaeochromocytoma presenting with pseudo-intestinal obstruction and lactic acidosis.

Phaeochromocytomas are rare neuroendocrine tumours with variable clinical signs and symptoms. Hypertension, tachycardia, sweating and headaches are cardinal manifestations. Although nausea and abdominal pain are the more common gastrointestinal features, rare gastrointestinal spectrums have been reported that can mimic abdominal emergencies. Metabolic effects of hypercatecholaminaemia are vast and one such rare presentation is lactic acidosis. We describe a case of phaeochromocytoma presenting with both intestinal pseudo-obstruction as well as lactic acidosis. This case report highlights the importance of having a high index of suspicion for and early recognition of the gastrointestinal and metabolic manifestations of phaeochromocytomas.

Carbimazole-induced myositis in the treatment of Graves' disease: a complication in genetically susceptible individuals?

A 24-year-old Chinese woman with Graves' disease presented with myositis two months after treatment with carbimazole. The patient's myositis resolved with hydration and cessation of carbimazole. No other causes of myositis were found, and a change in the medication to propylthiouracil was uneventful. Review of the literature suggests a possible genetic susceptibility, as the majority of reported cases are Asian in origin, similar to patients who present with thyroid periodic paralysis. Changing the antithyroid drugs (ATDs) administered, decreasing the dose of pre-existing ATDs in the treatment regimen or addition of levothyroxine has been shown to result in clinical improvement of this complication. These observations suggest various mechanisms of carbimazole-induced myositis in the treatment of Graves' disease, including the direct effect of ATDs on myocytes, immune-related responses secondary to ATDs and rapid decrements in thyroid hormone with ensuing myositis.

Day 1 post-operative fasting hyperglycemia may affect graft survival in kidney transplantation.

BACKGROUND: Early post-operative hyperglycemia is commonly encountered in patients without pre-existing diabetes mellitus who are undergoing kidney transplantation. The aim of this study was to determine the effect of early post-operative hyperglycemia on graft and patient survival after kidney transplantation in our center. MATERIAL AND METHODS: This was a single-center retrospective review of solitary kidney recipients transplanted in our center between January 1998 and December 2007. Of a total of 432 patients, 377 were eligible for the study. Fasting plasma glucose (FPG) levels at day 1 (D1) and day 5 (D5) after transplantation were recorded. Hyperglycemia was defined as FPG ≥ 7.0 mmol/l. Outcome events recorded included deaths and graft failures. RESULTS: The mean age at transplantation was 43.2 ± 9.5 years and 50.4% were male. The mean FPG levels at D1 and D5 were 7.5 ± 1.3 mmol/L and 5.3 ± 1.3 mmol/L, respectively; 64.2% of recipients had FPG ≥ 7.0 mmol/L on D1 and this was reduced to 8.5% on D5. Recipients with D1 FPG ≥ 7.0 mmol/L had significantly poorer graft survival (39 events) compared to those without D1 hyperglycemia (6 events), with a hazard ratio of 3.708 (95% CI, 1.568-8.766, P=0.003). There was a trend towards better patients survival in recipients with D1 FPG <7.0 mmol/L (P=0.056). CONCLUSIONS: D1 post-transplantation hyperglycemia may be associated with increased risk of graft failure. It is thus important to closely monitor glucose levels during the early post-transplantation period so that high risk patients can be identified and appropriate measures can be implemented to improve the long-term outcome.

Dopamine-secreting carotid body paragangliomas-biochemical control with radiotherapy.

Head and neck paragangliomas that are exclusively or predominantly dopamine-secreting are rare. Surgery and/or radiotherapy are modalities for locoregional tumoral control. Little is known about the efficacy of radiotherapy for biochemical control in such tumors. We report a 62-year-old Chinese man with bilateral carotid body tumors which were exclusively dopamine secreting. The left-sided tumor invaded the skull base and encased the left carotid artery. Surgery was not performed due to high risk of morbidity and mortality. The patient received external beam radiotherapy to bilateral neck regions. Progressive decline and eventual normalization of urinary dopamine excretion was seen together with a slight reduction in tumor size. This is the first report demonstrating the efficacy of radiotherapy for both biochemical and locoregional control of functioning carotid body paragangliomas.

Incidence and risk factors for development of new-onset diabetes after kidney transplantation.

INTRODUCTION: New-onset diabetes after transplantation (NODAT) is an increasingly recognised metabolic complication of kidney transplantation that is associated with increased morbidity and mortality. This study aimed to determine the incidence of NODAT and identify risk factors for development of NODAT among kidney allograft recipients in a single centre. MATERIALS AND METHODS: We retrospectively reviewed all kidney allograft recipients in our centre between 1998 and 2007. NODAT were determined using criteria as per American Diabetes Association guidelines. Logistic regression analyses were performed to identify predictors of NODAT. RESULTS: Among 388 patients included in the analysis, NODAT was reported in 94 patients (24.2%) after a median follow-up time of 52.1 months. The cumulative incidence of NODAT was 15.8%, 22.8% and 24.5% at 1, 3, and 5 years following transplantation. Seven clinical factors were independent predictors of NODAT: older age, HLA B13 and B15 phenotypes, use of sirolimus, acute rejections, higher pre-transplant and post-transplant (day 1) plasma glucose levels. Patients with NODAT had poorer outcomes in both graft and patient survival. CONCLUSION: Our study demonstrates a significant risk and burden of NODAT in an Asian transplant population. Risk stratification and aggressive monitoring of blood glucose early post-transplantation is necessary to identify high-risk patients so that appropriate tailoring of immunosuppression and early institution of lifestyle modifications can be implemented.

Insulinoma in a patient with normal results from prolonged fast and glucagon-induced hypoglycemia.

OBJECTIVE: To describe a man with a functioning insulinoma and normal results from two 72-hour fasts who developed hypoglycemia secondary to exaggerated insulin response following glucagon stimulation. METHODS: We report the patient's clinical findings, laboratory findings, and clinical course. We also review the literature for previously reported cases and possible mechanisms. RESULTS: A 49-year-old man presented with hypoglycemic symptoms initially occurring after jogging and well-documented symptomatic hypoglycemia occurring during an evening meal. A 72-hour fast was associated with a serum glucose concentration of 50 mg/dL, suppressed insulin and C-peptide levels, and mildly elevated ß-hydroxybutyrate. Another documented episode of hypoglycemia occurring 3 hours postprandially was associated with elevated insulin and C-peptide and suppressed ß-hydroxybutyrate. A second 72-hour fast provoked asymptomatic hypoglycemia (glucose concentration at 60 hours: 32 mg/dL) with suppressed insulin and measurable ß-hydroxybutyrate. After 72 hours of fasting, glucagon administration led to a decrease in glucose from 50 to 18 mg/dL, elevations in insulin and C-peptide, and suppression of ß-hydroxybutyrate. Computed tomography revealed a mass lesion in the pancreatic tail. Distal pancreatectomy was performed, and the resected specimen demonstrated immunostaining for insulin. Hypoglycemic symptoms resolved postoperatively. CONCLUSIONS: Normal results from a prolonged fast do not preclude an insulinoma and may demonstrate exaggerated insulin secretion from the insulinoma following glucagon administration. In addition to examining the glucose response to glucagon as a surrogate for insulinoma diagnosis, measurement of serum insulin levels following glucagon administration may provide a further clue to the diagnosis of insulinoma.