Dr Christine O'Neill

Background: Post-operative management after phaeochromocytoma resection includes monitoring of blood pressure and blood sugar, and vigilance for haemorrhage. Guidelines recommend 24¿h of continuous blood pressure monitoring, usually necessitating HDU/ICU admission. We hypothesised that most patients undergoing phaeochromocytoma resection do not require post-operative HDU/ICU admission. We aim to describe current Australian and New Zealand perioperative management of phaeochromocytoma and determine whether it is safe to omit HDU/ICU care for most patients. Methods: We collected retrospective data on patients undergoing excision of phaeochromocytoma in 12 centres around Australia and New Zealand between 2007 and 2019. Data collected included preoperative medical management, anaesthetic management, vasopressor support, HDU/ICU admission and complications. Results: A total of 223 patients were included in the study, 173 (77%) of whom were admitted to HDU/ICU post-operatively. The group of patients treated in ICU was similar to the group of patients treated on the ward in terms of demographic and tumour characteristics, and there were significant differences in the proportion of patients admitted to HDU/ICU between centres. Of patients admitted to ICU, 71 (41%) received vasopressor support. This was weaned within 24¿h in 55 (77%) patients. Patients with larger tumours (> 6¿cm) and a transfusion requirement are more likely to require prolonged inotropic support. Among patients admitted to the ward, there were no complications that required escalation of care. Conclusions: Although not widespread practice in Australia and New Zealand, it appears safe for the majority of patients undergoing minimally invasive resection of phaeochromocytoma to be admitted to the ward post-operatively.

Context: How lymph node metastasis (LNM)-associated mortality risk is affected by BRAF V600E in papillary thyroid cancer (PTC) remains undefined. Objective: To study whether BRAF V600E affected LNM-associated mortality in PTC. Design, Setting, and Participants: We retrospectively analyzed the effect of LNM on PTC-specific mortality with respect to BRAF status in 2638 patients (2015 females and 623 males) from 11 centers in 6 countries, with median age of 46 [interquartile range (IQR) 35-58] years and median follow-up time of 58 (IQR 26-107) months. Results: Overall, LNM showed a modest mortality risk in wild-type BRAF patients but a strong one in BRAF V600E patients. In conventional PTC (CPTC), LNM showed no increased mortality risk in wild-type BRAF patients but a robustly increased one in BRAF V600E patients; mortality rates were 2/659 (0.3%) vs 4/321 (1.2%) in non-LNM vs LNM patients (P = 0.094) with wild-type BRAF, corresponding to a hazard ratio (HR) (95% CI) of 4.37 (0.80-23.89), which remained insignificant at 3.32 (0.52-21.14) after multivariate adjustment. In BRAF V600E CPTC, morality rates were 7/515 (1.4%) vs 28/363 (7.7%) in non-LNM vs LNM patients (P < 0.001), corresponding to an HR of 4.90 (2.12-11.29) or, after multivariate adjustment, 5.76 (2.19-15.11). Adjusted mortality HR of coexisting LNM and BRAF V600E vs absence of both was 27.39 (5.15-145.80), with Kaplan-Meier analyses showing a similar synergism. Conclusions: LNM-associated mortality risk is sharply differentiated by the BRAF status in PTC; in CPTC, LNM showed no increased mortality risk with wild-type BRAF but a robust one with BRAF mutation. These results have strong clinical relevance.

Introduction: Conservative active surveillance has been proposed for low-risk papillary thyroid microcarcinoma (PTMC), defined as =1.0 cm and lacking clinical aggressive features, but controversy exists with accepting it as not all such PTMCs are uniformly destined for benign prognosis. This study investigated whether BRAF V600E status could further risk stratify PTMC, particularly low-risk PTMC, and can thus help with more accurate case selection for conservative management. Methods: This international multicenter study included 743 patients treated with total thyroidectomy for PTMC (584 women and 159 men), with a median age of 49 years (interquartile range [IQR], 39¿59 years) and a median follow-up time of 53 months (IQR, 25¿93 months). Results: On overall analyses of all PTMCs, tumour recurrences were 6.4% (32/502) versus 10.8% (26/241) in BRAF mutation-negative versus BRAF mutation-positive patients (P = 0.041), with a hazard ratio (HR) of 2.44 (95% CI (confidence interval), 1.15¿5.20) after multivariate adjustment for confounding clinical factors. On the analyses of low-risk PTMC, recurrences were 1.3% (5/383) versus 4.3% (6/139) in BRAF mutation-negative versus BRAF mutation-positive patients, with an HR of 6.65 (95% CI, 1.80¿24.65) after adjustment for confounding clinical factors. BRAF mutation was associated with a significant decline in the Kaplan¿Meier recurrence-free survival curve in low-risk PTMC. Conclusions: BRAF V600E differentiates the recurrence risk of PTMC, particularly low-risk PTMC. Given the robust negative predictive value, conservative active surveillance of BRAF mutation-negative low-risk PTMC is reasonable whereas the increased recurrence risk and other well-known adverse effects of BRAF V600E make the feasibility of long-term conservative surveillance uncertain for BRAF mutation-positive PTMC.

Objective: Post-thyroidectomy hypocalcaemia is a significant cause of morbidity and prolonged hospitalization, usually due to transient parathyroid gland damage, treated with calcium and vitamin D supplementation. We present a randomized, double-blinded placebo-controlled trial of preoperative loading with high-dose cholecalciferol (300¿000 IU) to reduce post-thyroidectomy hypocalcaemia. Patients and Measurements: Patients (n¿=¿160) presenting for thyroidectomy at tertiary hospitals were randomized 1:1 to cholecalciferol (300¿000¿IU) or placebo 7¿days prior to thyroidectomy. Ten patients withdrew prior to surgery. The primary outcome was post-operative hypocalcaemia (corrected calcium <2.1¿mmol/L in first 180¿days). Results: The study included 150 patients undergoing thyroidectomy for Graves¿ disease (31%), malignancy (20%) and goitre (49%). Mean pre-enrolment vitamin D was 72¿±¿26¿nmol/L. Postoperative hypocalcaemia occurred in 21/72 (29%) assigned to cholecalciferol and 30/78 (38%) participants assigned to placebo (P¿=¿0.23). There were no differences in secondary end-points between groups. In pre-specified stratification, baseline vitamin D status did not predict hypocalcaemia, although most individuals were vitamin D replete at baseline. Post-hoc stratification by day 1 parathyroid hormone (PTH) (<10¿pg/mL, low vs =10¿pg/mL, normal) was explored due to highly divergent rates of hypocalcaemia in these groups. Using a Cox regression model, the hazard ratio for hypocalcaemia in the cholecalciferol group was 0.56 (95%CI 0.32-0.98, P¿=¿0.04) after stratification for Day 1 PTH. Further clinical benefits were observed in these subgroups. Conclusions: Pre-thyroidectomy treatment with high-dose cholecalciferol did not reduce the overall rate of hypocalcaemia following thyroidectomy. In subgroups stratified by day 1 PTH status, improved clinical outcomes were noted.

Background: Precise risk stratification-based treatment of solitary intrathyroidal papillary thyroid cancer (SI-PTC) that is larger than 1.0cm and 4.0cm or less is undefined. Methods: A genetic-clinical risk study was performed on BRAF V600E in 955 patients (768 women and 187 men) with SI-PTC, with median age of 46 years and median clinical follow-up time of 64 months at 11 medical centers in six countries. The chisquare test or, for analyses with small numbers, Fisher's exact test was performed to compare recurrence rates. Recurrencefree probability was estimated by Kaplan-Meier (KM) analysis, and the independent effect of BRAF mutation on the recurrence was analyzed by Cox regression and Cox proportional hazard analyses. All statistical tests were two-sided. Results: Recurrence of SI-PTC larger than 1.0cm and 4.0cm or less was 9.5% (21/221) vs 3.4% (11/319) in BRAF mutation vs wild-type BRAF patients, with a hazard ratio (HR) of 3.03 (95% confidence interval [CI] = 1.46 to 6.30) and a patient age- and sex-adjusted hazard ratio of 3.10 (95% CI=1.49 to 6.45, P = .002). Recurrence rates of SI-PTC larger than 2.0cm and 4.0cm or less were 16.5% (13/79) vs 3.6% (5/139) in mutation vs wild-type patients (HR=5.44, 95% CI=1.93 to 15.34; and adjusted HR=5.58, 95% CI=1.96 to 15.85, P = .001). Recurrence rates of SI-PTC larger than 3.0cm and 4 cmor less were 30.0% (6/20) vs 1.9% (1/54) in mutation vs wild-type patients (HR=18.40, 95% CI=2.21 to 152.98; and adjusted HR=14.73, 95% CI=1.74 to 124.80, P = .01). Recurrences of mutation-positive SI-PTC were comparable with those of counterpart invasive solitary PTC, around 20% to 30%, in tumors larger than 2.0cm to 3.0 cm. BRAF mutation was associated with a statistically significant decrease in recurrence-free patient survival on KM analysis, particularly in SI-PTC larger than 2.0cm and 4.0cm or less. Similar results were obtained in conventional SI-PTC. The negative predictive values of BRAF mutation for recurrence were 97.8% (95% CI=96.3% to 98.8%) for general SI-PTC and 98.2% (95% CI=96.3% to 99.3%) for conventional SI-PTC. Conclusions: BRAF V600E identifies a subgroup of SI-PTC larger than 1.0cm and 4.0cm or less, particularly tumors larger than 2.0cm and 4.0cm or less, that has high risk for recurrence comparable with that of invasive solitary PTC, making more aggressive treatment reasonable.

Purpose For the past 65 years, patient age at diagnosis has been widely used as a major mortality risk factor in the risk stratification of papillary thyroid cancer (PTC), but whether this is generally applicable, particularly in patients with different BRAF genetic backgrounds, is unclear. The current study was designed to test whether patient age at diagnosis is a major mortality risk factor. Patients and Methods We conducted a comparative study of the relationship between patient age at diagnosis and PTCspecific mortality with respect to BRAF status in 2,638 patients (623 men and 2,015 women) with a median age of 46 years (interquartile range, 35 to 58 years) at diagnosis and a median follow-up time of 58 months (interquartile range, 26 to 107 months). Eleven medical centers from six countries participated in this study. Results There was a linear association between patient age and mortality in patients with BRAF V600E mutation, but not in patients with wild-type BRAF, in whom the mortality rate remained low and flat with increasing age. Kaplan-Meier survival curves rapidly declined with increasing age in patients with BRAF V600E mutation but did not decline in patients with wild-type BRAF, even beyond age 75 years. The association between mortality and age in patients with BRAF V600E was independent of clinicopathologic risk factors. Similar results were observed when only patients with the conventional variant of PTC were analyzed. Conclusion The long-observed age-associated mortality risk in PTC is dependent on BRAF status; age is a strong, continuous, and independent mortality risk factor in patients with BRAF V600E mutation but not in patients with wild-type BRAF. These results question the conventional general use of patient age as a high-risk factor in PTC and call for differentiation between patients with BRAF V600E and wild-type BRAF when applying age to risk stratification and management of PTC.

Purpose To test whether the prognostic risk of male sex in papillary thyroid cancer (PTC) is determined by BRAF V600E and can thus be stratified by BRAF status. Patients and Methods We retrospectively investigated the relationship between male sex and clinicopathologic outcomes in PTC, particularly mortality, with respect to BRAF status in 2,638 patients (male, n = 623; female, n = 2,015) from 11 centers in six countries, with median age of 46 years (interquartile range, 35-58 years) at diagnosis and median follow-up time of 58 months (interquartile range, 26-107 months). Results Distant metastasis rates in men and women were not different in wild-type BRAF PTC but were different in BRAF V600E PTC: 8.9% (24 of 270) and 3.7% (30 of 817; P = .001), respectively. In wild-type BRAF PTC, mortality rates were 1.4% (five of 349) versus 0.9% (11 of 1175) in men versus women (P = .384), with a hazard ratio (HR) of 1.59 (95% CI, 0.55 to 4.57), which remained insignificant at 0.70 (95% CI, 0.23 to 2.09) after clinicopathologic multivariable adjustment. In BRAF V600E PTC, mortality rates were 6.6% (18 of 272) versus 2.9% (24 of 822) in men versus women (P = .006), with an HR of 2.43 (95% CI, 1.30 to 4.53), which remained significant at 2.74 (95% CI, 1.38 to 5.43) after multivariable adjustment. In conventional-variant PTC, male sex similarly had no effect in wild-type BRAF patients; mortality rates in BRAF V600E patients were 7.2% (16 of 221) versus 2.9% (19 of 662) in men versus women (P = .004), with an HR of 2.86 (95% CI, 1.45 to 5.67), which remained significant at 3.51 (95% CI, 1.62 to 7.63) after multivariable adjustment. Conclusion Male sex is a robust independent risk factor for PTC-specific mortality in BRAF V600E patients but not in wild-type BRAF patients. The prognostic risk of male sex in PTC can thus be stratified by BRAF status in clinical application.

Context: Individualized management, incorporating papillary thyroid cancer (PTC) variant-specific risk, is conceivably a useful treatment strategy for PTC, which awaits comprehensive data demonstrating differential risks of PTC variants to support. Objective: This study sought to establish the differential clinicopathological risk of major PTC variants: conventional PTC (CPTC), follicular-variant PTC (FVPTC), and tall-cell PTC (TCPTC). Methods: Thiswasa retrospective study of clinicopathological outcomes of 6282 PTC patients (4799 females and 1483 males) from 26 centers and The Cancer Genome Atlas in 14 countries with a median age of 44 years (interquartile range, 33â¿"56 y) and median follow-up time of 37 months (interquartile range, 15â¿"82 mo). Results: The cohort consisted of 4702 (74.8%) patients with CPTC, 1126 (17.9%) with FVPTC, and 239 (3.8%) with TCPTC. The prevalence of high-risk parameters was significantly different among the three variants, including extrathyroidal invasion, lymph node metastasis, stages III/IV, disease recurrence, mortality, and the use (need) of radioiodine treatment (all P > .001), being highest in TCPTC, lowest in FVPTC, and intermediate in CPTC, following an order of TCPTC>CPTC¿FVPTC. Recurrence and mortality in TCPTC, CPTC, and FVPTC were 27.3 and 6.7%, 16.1 and 2.5%, and 9.1 and 0.6%, corresponding to events per 1000 person-years (95% confidence interval [CI]) of 92.47 (64.66â¿"132.26) and 24.61 (12.31â¿" 49.21), 34.46 (30.71â¿"38.66), and 5.87 (4.37â¿"7.88), and 24.73 (18.34 â¿"33.35) and 1.68 (0.54 â¿"5.21), respectively. Mortality hazard ratios of CPTC and TCPTC over FVPTC were 3.44 (95% CI, 1.07â¿"11.11) and 14.96 (95% CI, 3.93â¿"56.89), respectively. Kaplan-Meier survival analyses showed the best prognosis in FVPTC, worst in TCPTC, and intermediate in CPTC in disease recurrence-free probability and disease-specific patient survival. This was particularly the case in patients at least 45 years old. Conclusion: This large multicenter study demonstrates differential prognostic risks of the three major PTC variants and establishes a unique risk order of TCPTC > CPTC ¿ FVPTC, providing important clinical implications for specific variant-based management of PTC.

Context: TERT promoter mutations have been associated with adverse prognosis in papillary thyroid carcinomas (PTCs). Objective: We investigated the association between TERT promoter mutations and survival from PTC. Design: Retrospective observational cohort study. Patients: Eighty consecutive patients with PTC who underwent surgery between 1990 and 2003. Measurements: TERT promoter was genotyped in DNA from 80 archival PTCs by Sanger sequencing. Median follow-up was 106¿months (range 1¿270). Outcomes analysis was stratified according to disease and overall survival status. For each parameter, relative risk (RR) adjusted for age at first surgery and gender was estimated. Both univariate and multivariate analyses were performed using logistic regression, Kaplan¿Meier survival analysis and Cox regression models. Results: PTCs from 11 patients (14%) contained either C228T or C250T TERT promoter mutation. TERT mutations were significantly associated with adverse prognostic features such as older age (P¿=¿0·002), male gender (P¿=¿0·01) and Stage IV disease (P¿=¿0·03). Four patients died from PTC during follow-up: 3 patients with TERT mutations (27%) and one without (1·5%). Disease-related mortality rate with or without TERT mutations was 33·7 vs 1·6 per 1000 patient-years respectively, that is 10 (95% CI¿=¿1·0¿104·1, P¿=¿0·05) fold higher, after adjustment for age at first surgery and gender. The combination of TERT promoter mutation and BRAFV600E significantly increased disease-related death risk (P¿=¿0·002). TERT mutations increased expression of a reporter gene in thyroid cells containing BRAFV600E. Conclusions: TERT promoter mutations are a major indicator of death due to PTCs. Conversely, absence of TERT mutations portends better survival.

Pathogenic ALK translocations have been reported in papillary thyroid carcinoma (PTC). We developed and validated a screening algorithm based on immunohistochemistry (IHC), followed by fluorescence in situ hybridization (FISH) in IHC-positive cases to identify ALK-rearranged PTC. IHC and FISH were performed in a cohort of 259 thyroid carcinomas enriched for aggressive variants. IHC was positive in 8 cases, 6 confirmed translocated by FISH (specificity 75%). All 251 IHC-negative cases were FISH negative (sensitivity 100%). Having validated this approach, we performed screening IHC, followed by FISH in IHC-positive cases in an expanded cohort. ALK translocations were identified in 11 of 498 (2.2%) of all consecutive unselected PTCs and 3 of 23 (13%) patients with diffuse sclerosing variant PTCs. No ALK translocations were identified in 36 PTCs with distant metastases, 28 poorly differentiated (insular) carcinomas, and 20 anaplastic carcinomas. All 14 patients with ALK translocations were female (P=0.0425), and translocations occurred at a younger age (mean 38 vs. 48 y, P=0.0289 in unselected patients). ALK translocation was an early clonal event present in all neoplastic cells and mutually exclusive with BRAF V600E mutation. ALK translocation was not associated with aggressive clinicopathologic features (size, stage, metastasis, vascular invasion, extrathyroidal extension, multifocality, risk for recurrence, radioiodine resistance). We conclude that 2.2% of PTCs are ALK-translocated and can be identified by screening IHC followed by FISH. ALK translocations may be more common in young females and diffuse sclerosing variant PTC but do not connote more aggressive disease.

Purpose: To investigate the prognostic value of BRAFV600E mutation for the recurrence of papillary thyroid cancer (PTC) Patients and Methods: This was a retrospective multicenter study of the relationship between BRAF V600E mutation and recurrence of PTC in 2,099 patients (1,615 women and 484 men), with a median age of 45 years (interquartile range [IQR], 34 to 58 years) and a median follow-up time of 36 months (IQR, 14 to 75 months) Results: The overall BRAF V600E mutation prevalence was 48.5% (1,017 of 2,099). PTC recurrence occurred in 20.9% (213 of 1,017) of BRAFV600E mutation-positive and 11.6% (125 of 1,082) of BRAFV600E mutation-negative patients. Recurrence rates were 47.71 (95% CI, 41.72 to 54.57) versus 26.03 (95% CI, 21.85 to 31.02) per 1,000 person-years in BRAF mutation-positive versus - Negative patients (P <.001), with a hazard ratio (HR) of 1.82 (95% CI, 1.46 to 2.28), which remained significant in a multivariable model adjusting for patient sex and age at diagnosis, medical center, and various conventional pathologic factors. Significant association between BRAF mutation and PTC recurrence was also found in patients with conventionally low-risk disease stage or II and micro-PTC and within various subtypes of PTC. For example, in BRAF mutation-positive versus - Negative follicular-variant PTC, recurrence occurred in 21.3% (19 of 89) and 7.0% (24 of 342) of patients, respectively, with recurrence rates of 53.84 (95% CI, 34.34 to 84.40) versus 19.47 (95% CI, 13.05 to 29.04) per 1,000 person-years (P <.001) and an HR of 3.20 (95% CI, 1.46 to 7.02) after adjustment for clinicopathologic factors. BRAF mutation was associated with poorer recurrence-free probability in Kaplan-Meier survival analyses in various clinicopathologic categories. Conclusion: This large multicenter study demonstrates an independent prognostic value of BRAF V600E mutation for PTC recurrence in various clinicopathologic categories.

Background: The prognostic influence of lateral neck nodal metastases present at the time of diagnosis of papillary thyroid cancer (PTC) remains controversial. This study aims to document disease outcomes and nodal recurrence rates in such patients. Methods: Patients with PTC and lateral neck nodal metastases who underwent concurrent total thyroidectomy, central and lateral compartment neck dissection between 2000 and 2010 were identified from the prospectively maintained surgical databases of The University of Sydney and University of Wisconsin Endocrine Surgical Units. Disease outcomes and nodal recurrence rates were compared at 12 months post-operatively and in longer-term follow-up. Results: During this 11-year period, 121 patients were identified. Mean age was 45 years; 58% were female and 98% underwent post-operative radioactive iodine ablation. At a median follow-up of 31 months (range 12-140), there were no disease-specific deaths and disease-free survival (defined by stimulated serum thyroglobulin (Tg) < 2.0µg/L, negative clinical and radiological examination) was 66%. Of the 50 patients with persistently elevated Tg measured 12 months post-operatively, 15 developed clinical lateral neck nodal recurrence. All have undergone re-operative surgery. Elevated stimulated Tg at 12 months post-operatively and a nodal ratio of >30% were significantly associated with an increased risk of lateral neck nodal recurrence. Conclusion: With total thyroidectomy, formal compartmental neck dissection and radioactive iodine treatment, disease-free survival can be achieved in the majority of patients with PTC and synchronous lateral neck nodal metastases. A persistently elevated Tg post-operatively and a high ratio of metastatic nodes identify patients at increased risk of locoregional recurrence. © 2013 Royal Australasian College of Surgeons.

Importance: BRAF V600E is a prominent oncogene in papillary thyroid cancer (PTC), but its role in PTC-related patient mortality has not been established. Objective: To investigate the relationship between BRAF V600E mutation and PTC-related mortality. Design, Setting, and Participants: Retrospective study of 1849 patients (1411 women and 438 men) with amedian age of 46 years (interquartile range, 34-58 years) and an overall median follow-up time of 33 months (interquartile range, 13-67 months) after initial treatment at 13 centers in 7 countries between 1978 and 2011. Main Outcomes and Measures: Patient deaths specifically caused by PTC. Results: Overall, mortality was 5.3% (45/845; 95% CI, 3.9%-7.1%) vs 1.1% (11/1004; 95% CI, 0.5%-2.0%) ( P < .001) in BRAF V600E-positive vs mutationnegative patients. Deaths per 1000 person-years in the analysis of all PTC were 12.87 (95% CI, 9.61-17.24) vs 2.52 (95% CI, 1.40-4.55) in BRAF V600E-positive vs mutation-negative patients; the hazard ratio (HR) was 2.66 (95% CI, 1.30-5.43) after adjustment for age at diagnosis, sex, and medical center. Deaths per 1000 person-years in the analysis of the conventional variant of PTC were 11.80 (95% CI, 8.39-16.60) vs 2.25 (95% CI, 1.01-5.00) in BRAF V600E-positive vs mutation-negative patients; the adjusted HR was 3.53 (95% CI, 1.25-9.98). When lymph node metastasis, extrathyroidal invasion, and distant metastasis were also included in the model, the association of BRAF V600E with mortality for all PTC was no longer significant (HR, 1.21; 95% CI, 0.53-2.76). A higher BRAF V600E-associated patient mortality was also observed in several clinicopathological subcategories, but statistical significance was lost with adjustment for patient age, sex, and medical center. For example, in patients with lymph node metastasis, the deaths per 1000 person-years were 26.26 (95% CI, 19.18-35.94) vs 5.93 (95% CI, 2.96-11.86) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 4.43 [95% CI, 2.06-9.51]; adjusted HR, 1.46 [95% CI, 0.62-3.47]). In patients with distant tumor metastasis, deaths per 1000 person-years were 87.72 (95% CI, 62.68-122.77) vs 32.28 (95% CI, 16.14-64.55) in BRAF V600E-positive vs mutation-negative patients (unadjusted HR, 2.63 [95% CI, 1.21-5.72]; adjusted HR, 0.84 [95% CI, 0.27-2.62]). Conclusions and Relevance: In this retrospective multicenter study, the presence of the BRAF V600E mutation was significantly associated with increased cancer-related mortality among patients with PTC. Because overall mortality in PTC is low and the association was not independent of tumor features, how to use BRAF V600E to manage mortality risk in patients with PTC is unclear. These findings support further investigation of the prognostic and therapeutic implications of BRAF V600E status in PTC. ©2013 American Medical Association. All rights reserved.