Validating the risk of hypoparathyroidism after total thyroidectomy in a population-based cohort: plea for improved follow-up.

BACKGROUND: A previous nationwide study from Sweden showed that the rate of permanent hypoparathyroidism is high and under-rated in the Swedish Quality Register. This retrospective population-based study aimed to validate the rate and diagnosis of permanent hypoparathyroidism found in the previous study. A secondary aim was to assess the relationship between the rate of low parathyroid hormone (PTH) levels within 24 h after surgery and the rate of permanent hypoparathyroidism. METHODS: All patients who underwent total thyroidectomy from 2005 to 2015 in a region of Sweden were included. Data were retrieved from local health records, the National Patient Registry, the Swedish Prescribed Drug Registry, and the Swedish Quality Register. A strict definition of permanent hypoparathyroidism was used, including biochemical data and attempts to stop the treatment. RESULTS: A total of 1636 patients were included. Altogether, 143 patients (8.7 per cent) developed permanent hypoparathyroidism. Of these, 102 (6.2 per cent) had definitive permanent hypoparathyroidism, whereas 41 (2.5 per cent) had possible permanent hypoparathyroidism, because attempts to stop the treatment were lacking (28) or patients were lost to follow-up (13). The agreement between the Swedish Quality Register and the chart review was 29.3 per cent. A proportion of 23.2 per cent with a PTH level below the reference value corresponded to a 6.7 per cent rate of permanent hypoparathyroidism. CONCLUSION: The risk of permanent hypoparathyroidism after total thyroidectomy is high. Some patients are overtreated because attempts to stop the treatment are lacking. Quality registers might underestimate the risk of permanent hypoparathyroidism. Approximately one-quarter of all patients with low PTH levels immediately after surgery developed permanent hypoparathyroidism.

The parathyroid glands control calcium levels in the blood. If they do not make enough hormone, calcium levels are low. Parathyroid dysfunction can happen after thyroid surgery, if the glands are hurt or removed by mistake. This is a problem because people with this condition may have symptoms and need ongoing treatment with vitamin D and calcium. They might also face other health issues and need regular visits to their doctor. Finding out how often long-term parathyroid dysfunction happens can be tricky because it requires a full year of follow-up and attempts to stop the treatment. This information is often missing from many studies and registers. Some recent studies have shown that this condition is more common than previously thought. It would be helpful to have a quick way to know how common long-term parathyroid gland dysfunction will be within a unit or hospital, without having to wait for the follow-up. This would help doctors to assess how good they are at taking care of patients. It would also support research on new methods to avoid parathyroid dysfunction. The goal of the study was to see how often long-term parathyroid dysfunction occurs after thyroid surgery, using a strict definition and complete long-term follow-up. Another aim was to assess the link between low parathyroid hormone levels right after surgery and the rate of long-term parathyroid dysfunction. All individuals who had the entire thyroid gland removed for benign disease between 2005 and 2015 in a region of Sweden were included. Data were collected from local health records at six hospitals. Patient information, surgical details, blood tests, and treatment details were gathered from the medical charts. Data were also collected from the national quality register. A high rate of long-term parathyroid dysfunction was seen in this large study of 1636 patients, Some patients may have been overtreated, because no attempts had been made to stop the treatment. The rate of long-term parathyroid dysfunction in patients with a normal early parathyroid hormone level was very low. About 23 per cent of all patients had a low early parathyroid hormone level, which corresponded to a 6.7 per cent rate of long-term parathyroid dysfunction. The authors believe that parathyroid hormone measurement could help predict the rate of permanent hypoparathyroidism, but more studies are needed to be sure.

Positive Effect of Parathyroidectomy Compared to Observation on BMD in a Randomized Controlled Trial of Mild Primary Hyperparathyroidism.

Mild or asymptomatic disease is now the dominating presentation of primary hyperparathyroidism (PHPT). However, bone involvement with decreased bone mineral density (BMD) and an increased risk of fractures has been demonstrated. Indications for parathyroidectomy (PTX) in mild PHPT have been debated for years. There is a need of long-term randomized studies comparing PTX with observation without intervention (OBS). Here, we present bone health data from the Scandinavian Investigation of Primary Hyperparathyroidism (SIPH), a randomized controlled trial, comparing PTX to OBS. This study included 191 patients (96 OBS/95 PTX), and 129 patients (64 OBS/65 PTX) were followed for 10 years to the end of study (EOS). BMD was measured with dual-energy X-ray absorptiometry (DXA), peripheral fractures were noted, and spine radiographs were obtained for vertebral fracture assessment. There was a significant treatment effect of PTX on BMD compared with OBS for all analyzed compartments, most explicit for the lumbar spine (LS) and femoral neck (FN) (p < 0.001). The mean changes in T-score from baseline to 10 years were from 0.41 for radius 33% (Rad33) to 0.58 for LS greater in the PTX group than in the OBS group. There was a significant decrease in BMD for all compartments in the OBS group, most pronounced for FN, Rad33, and ultradistal radius (UDR) (p < 0.001). Even though there was a significant treatment effect of PTX compared with OBS, there was only a significant increase in BMD over time for LS (p < 0.001). We found no difference between groups in fracture frequency in the 10-year cohort, neither with modified intention-to-treat (mITT) analysis nor per protocol analysis. Because BMD is only a surrogate endpoint of bone health and PTX did not reduce fracture risk, observation could be considered a safe option for many patients with mild PHPT regarding bone health in a 10-year perspective. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Mortality and Morbidity in Mild Primary Hyperparathyroidism: Results From a 10-Year Prospective Randomized Controlled Trial of Parathyroidectomy Versus Observation.

BACKGROUND: Primary hyperparathyroidism (PHPT) is a common endocrine disorder associated with increased risk for fractures, cardiovascular disease, kidney disease, and cancer and increased mortality. In mild PHPT with modest hypercalcemia and without known morbidities, parathyroidectomy (PTX) is debated because no long-term randomized trials have been performed. OBJECTIVE: To examine the effect of PTX on mild PHPT with regard to mortality (primary end point) and key morbidities (secondary end point). DESIGN: Prospective randomized controlled trial. (ClinicalTrials.gov: NCT00522028). SETTING: Eight Scandinavian referral centers. PATIENTS: From 1998 to 2005, 191 patients with mild PHPT were included. INTERVENTION: Ninety-five patients were randomly assigned to PTX, and 96 were assigned to observation without intervention (OBS). MEASUREMENTS: Date and causes of death were obtained from the Swedish and Norwegian Cause of Death Registries 10 years after randomization and after an extended observation period lasting until 2018. Morbidity events were prospectively registered annually. RESULTS: After 10 years, 15 patients had died (8 in the PTX group and 7 in the OBS group). Within the extended observation period, 44 deaths occurred, which were evenly distributed between groups (24 in the PTX group and 20 in the OBS group). A total of 101 morbidity events (cardiovascular events, cerebrovascular events, cancer, peripheral fractures, and renal stones) were also similarly distributed between groups (52 in the PTX group and 49 in the OBS group). During the study, a total of 16 vertebral fractures occurred in 14 patients (7 in each group). LIMITATION: During the study period, 23 patients in the PTX group and 27 in the OBS group withdrew. CONCLUSION: Parathyroidectomy does not appear to reduce morbidity or mortality in mild PHPT. Thus, no evidence of adverse effects of observation was seen for at least a decade with respect to mortality, fractures, cancer, cardiovascular and cerebrovascular events, or renal morbidities. PRIMARY FUNDING SOURCE: Swedish government, Norwegian Research Council, and South-Eastern Norway Regional Health Authority.

Effects of Parathyroidectomy on Quality of Life: 10 Years of Data From a Prospective Randomized Controlled Trial on Primary Hyperparathyroidism (the SIPH-Study).

Primary hyperparathyroidism (PHPT) was previously considered a disease presenting with multiorgan involvement and a wide range of symptoms. Today, the disease presents with no symptoms or mild symptomatology in most patients. Data regarding nonspecific symptoms such as pain, fatigue, memory loss, depression, and other neuropsychiatric signs have been ambiguous, and results from prospective long-term randomized control trials are lacking. The Scandinavian Investigation on Primary Hyperparathyroidism (SIPH) is a prospective randomized controlled trial (RCT) with 10-year follow up, comparing parathyroidectomy (PTX) to observation without any treatment (OBS). From 1998 to 2005, 191 patients with mild PHPT were included from Sweden, Norway, and Denmark. A total of 95 patients were randomized to PTX and 96 to OBS. The generic Short Form-36 survey (SF-36) and the Comprehensive Psychopathological Rating Scale (CPRS) were studied at baseline, 2, 5, and 10 years after randomization. After 10 years, the PTX group scored significantly better on vitality (PTX 65.1 ± 20.2 versus OBS 57.4 ± 22.7; p = .017) compared to the OBS group in SF-36. We found no differences between the groups in the physical subscales. The OBS group had no significant change in any of the SF-36 scores throughout the study. The CPRS showed an improvement of symptoms in both groups for single items and sum scores after 10 years compared to baseline. There were, however, no significant differences between the two groups in the CPRS data. The results of this large and long-term RCT indicate improvement in some of the mental domains of SF-36 following PTX. However, the treatment effects between the groups were subtle with uncertain clinical significance. The observation group had stable SF-36 values and improvement in CPRS symptom-scores. Thus, in considering only quality of life (QoL) and in the absence of declines in renal and skeletal parameters, it may be safe to observe patients with mild PHPT for a decade. © 2020 American Society for Bone and Mineral Research (ASBMR).

Association of a Prophylactic Surgical Approach to Stage IV Small Intestinal Neuroendocrine Tumors With Survival.

IMPORTANCE: Primary tumor resection and mesenteric lymph node dissection in asymptomatic patients with stage IV small intestinal neuroendocrine tumors (SI-NETs) are controversial. OBJECTIVE: To determine the association of locoregional surgery (LRS) performed at diagnosis with outcomes in patients with asymptomatic SI-NETs and distant metastases. DESIGN, SETTING, AND PARTICIPANTS: This cohort study included asymptomatic patients with stage IV SI-NETs diagnosed from January 1, 1985, through December 31, 2015, and identified using the prospective database of SI-NETs from Uppsala University Hospital, Uppsala, Sweden. Patients included were treated at a tertiary referral center and followed up until May 31, 2016, with data from the Swedish National Patient Register. The 363 patients with stage IV SI-NETs without abdominal symptoms were divided between those who underwent prophylactic up-front surgery within 6 months from diagnosis combined with oncologic treatment (hereafter referred to as LRS group [n = 161]) and those who underwent nonsurgical treatment or delayed surgery as needed combined with oncologic treatment (hereafer referred to as delayed LRS group [n = 202]). EXPOSURES: Prophylactic up-front surgery within 6 months from diagnosis combined with oncologic treatment vs nonsurgical treatment or delayed surgery as needed combined with oncologic treatment. MAIN OUTCOMES AND MEASURES: Overall survival (OS), length of hospital stay (LOS), postoperative morbidity and mortality, and reoperation rates measured from baseline. Propensity score matching was performed between the 2 groups. RESULTS: The 363 patients included 173 women (47.7%) and 190 men (52.3%), with a mean (SD) age at diagnosis of 62.4 (11.1) years. Two isonumerical groups with 91 patients in each resulted after propensity score matching. The LRS and delayed LRS groups were comparable in median OS (7.9 years [range, 5.1-10.7 years] vs 7.6 years [range, 5.8-9.5 years]; hazard ratio [HR], 0.98; 95% CI, 0.70-1.37; log-rank P = .93) and cancer-specific survival (7.7 years [range, 4.5-10.8 years] vs 7.6 years [range, 5.6-9.7 years]; HR, 0.99; 95% CI, 0.71-1.40; log-rank P = .99). No difference was found in 30-day mortality (0 patients in both matched groups) or postoperative morbidity (2 [2.2%] vs 1 [1.1%]; P > .99), median LOS (73 days [range, 2-270 days] vs 76 days [range, 0-339 days]; P = .64) or LOS due to local tumor-related symptoms (7.0 days [range, 0-90 days] vs 11.5 days [range, 0-69 days]; P = .81), or incisional hernia repairs (4 patients [4.4%] in both groups; P > .99). Patients in the LRS group underwent more reoperative procedures (13 [14.3%]) compared with those in the delayed LRS group (3 [3.3%]) owing to intestinal obstruction (P < .001). CONCLUSIONS AND RELEVANCE: Prophylactic up-front LRS conferred no survival advantage in asymptomatic patients with stage IV SI-NETs. Delayed surgery as needed was comparable in all examined outcomes and was associated with fewer reoperations for intestinal obstruction. The value of a priori LRS in the presence of distant metastases is challenged and needs to be elucidated in a randomized clinical study.

Effect of Surgery Versus Observation: Skeletal 5-Year Outcomes in a Randomized Trial of Patients With Primary HPT (the SIPH Study).

Mild primary hyperparathyroidism (PHPT) is known to affect the skeleton, even though patients usually are asymptomatic. Treatment strategies have been widely discussed. However, long-term randomized studies comparing parathyroidectomy to observation are lacking. The objective was to study the effect of parathyroidectomy (PTX) compared with observation (OBS) on bone mineral density (BMD) in g/cm2 and T-scores and on biochemical markers of bone turnover (P1NP and CTX-1) in a prospective randomized controlled study of patients with mild PHPT after 5 years of follow-up. Of 191 patients with mild PHPT randomized to either PTX or OBS, 145 patients remained for analysis after 5 years (110 with validated DXA scans). A significant decrease in P1NP (p < 0.001) and CTX-1 (p < 0.001) was found in the PTX group only. A significant positive treatment effect of surgery compared with observation on BMD (g/cm2 ) was found for the lumbar spine (LS) (p = 0.011), the femoral neck (FN) (p < 0.001), the ultradistal radius (UDR) (p = 0.042), and for the total body (TB) (p < 0.001) but not for the radius 33% (Rad33), where BMD decreased significantly also in the PTX group (p = 0.012). However, compared with baseline values, there was no significant BMD increase in the PTX group, except for the lumbar spine. In the OBS group, there was a significant decrease in BMD (g/cm2 ) for all compartments (FN, p < 0.001; Rad33, p = 0.001; UDR, p = 0.006; TB, p < 0.001) with the exception of the LS, where BMD was stable. In conclusion, parathyroidectomy improves BMD and observation leads to a small but statistically significant decrease in BMD after 5 years. Thus, bone health appears to be a clinical concern with long-term observation in patients with mild PHPT. © 2017 American Society for Bone and Mineral Research.

Long-Term Surveillance of Treated Hyperparathyroidism for Multiple Endocrine Neoplasia Type 1: Recurrence or Hypoparathyroidism?

BACKGROUND: Primary hyperparathyroidism (HPT) in multiple endocrine neoplasia type 1 (MEN1) is surgically treated with either a subtotal parathyroidectomy removing 3 or 3,5 glands (SPX), less than 3 glands (LSPX), or a total parathyroidectomy with autotransplantation (TPX). Previous studies with shorter follow-up have shown that LSPX and SPX are associated with recurrent HPT, and TPX with hypocalcemia and substitution therapy. We examined the situation after long-term follow-up (median 20,6 years). METHODS: Sixty-nine patients with MEN1 HPT underwent 110 operations, the first operation being 31 LSPX, 30 SPX, and 8 TPX. Thirty patients underwent reoperative surgery in median 120 months later, as completion to TPX (n = 12), completion of LSPX to SPX (n = 9), extirpation of single glands (n = 3) still resulting in LSPX, and resection of forearm grafts (n = 3). Nine patients underwent a second, and 2 a third reoperation. In 24 patients genetic testing confirmed MEN1, and in the remaining heredity and phenotype led to the diagnosis. RESULTS: TPX had higher risk for hypoparathyroidism necessitating substitution therapy, at latest follow-up 50%, compared to SPX (16% after 3-6 months; none at latest follow-up). Recurrent HPT was common after LSPX, leading to 24 reoperations in 17 patients. No need for substitution therapy after SPX indicated forthcoming recurrent disease. Not having hypocalcemia in the postoperative period and less radical surgery than TPX were significantly associated to risk for recurrence. Further, mutation in exon 3 in the MEN1 gene may eventually be linked to risk of recurrence. CONCLUSION: LSPX is highly associated with recurrence and TPX with continuous hypoparathyroidism, also after long-term follow-up. SPX should be the chosen method in the majority of patients with MEN1 HPT.

Effects of parathyroidectomy versus observation on the development of vertebral fractures in mild primary hyperparathyroidism.

CONTEXT: Mild primary hyperparathyroidism (PHPT) is a common disease especially in middle-aged and elderly women. The diagnosis is frequently made incidentally and treatment strategies are widely discussed. OBJECTIVE: To study the effect of parathyroidectomy (PTX) compared with observation (OBS) on biochemistry, safety, bone mineral density (BMD), and new fractures. DESIGN: Prospective, randomized controlled study (SIPH study), with a 5-year follow-up. SETTING: The study was conducted at multicenter, tertiary referral centers. PATIENTS: Of 191 randomized patients with mild PHPT, biochemical data were available for 145 patients after 5 years, with a mean age at inclusion of 62.8 years (OBS group, 9 males) and 62.1 years (PTX group, 10 males). INTERVENTION: Parathyroidectomy vs observation. MAIN OUTCOME MEASURES: Biochemistry, BMD, and new radiographic vertebral fractures. RESULTS: Serum-calcium and PTH-levels normalized after surgery and did not deteriorate by observation. BMD Z-scores were normal at inclusion in the lumbar spine (LS) and femoral neck (FN). For LS, BMD Z-scores were stable for 5 years with observation, but decreased in FN (P < .02). After surgery, BMD Z-scores increased significantly in both compartments (P < .02 for both), with a highly significant treatment effect of surgery compared to observation (P < .001). During follow-up, five new clinically unrecognized vertebral fractures were found in 5 females, all in the OBS group (P = .058). CONCLUSION: Even though new vertebral fractures occurred only in the observation group, the frequency was not significantly different from the surgery group. Longer follow-up is needed before firm conclusions can be drawn about the long-term safety of observation, as opposed to surgery.

Long-term results of surgery for small intestinal neuroendocrine tumors at a tertiary referral center.

BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) are uncommon, with an annual incidence of about 1 per 100,000 individuals. The primary tumor (PT) is generally small, but nevertheless the majority of patients have mesenteric lymph node metastases and liver metastases at diagnosis. Our aim was to identify prognostic factors for survival and to evaluate outcome after surgery in SI-NET patients. MATERIAL AND METHODS: We included 603 consecutive patients (325 men; age at diagnosis 63 ± 11 years [mean ± SD]) with histopathologically verified SI-NET, who were diagnosed between 1985 and 2010. Hospital charts were reviewed and were scrutinized for carcinoid heart disease (CHD), flush and/or diarrhea, proliferation by Ki-67 index, mesenteric lymph node metastases (m.lgllm), distant abdominal lymph node metastases (da.lgllm), liver tumor load (LTL), extra-abdominal metastases (EAM), locoregional resective surgery, as well as debulking of LTL, and adverse events after surgery. RESULTS: Median overall survival (OS) was 8.4 years; 5-year OS was 67%, and 5-year relative survival was 74%. Independent prognostic factors by univariate and multivariate analysis were age at diagnosis, CHD, m.lgllm, da.lgllm, LTL, EAM, peritoneal carcinomatosis (PC), and proliferation. Locoregional resective surgery was associated with increased survival on crude and multivariate analysis. The 30-day mortality in our institution after initial locoregional resective surgery was 0.5% (1/205). CONCLUSIONS: For the first time, m.lgllm and da.lgllm, LTL, PC, and EAM are demonstrated to be independent prognostic factors by multivariate analysis. Locoregional removal of the PT/m.lgllm. was a positive prognostic factor by crude and adjusted analysis and may influence survival.

Recurrent genomic alterations in benign and malignant pheochromocytomas and paragangliomas revealed by whole-genome array comparative genomic hybridization analysis.

Pheochromocytomas and abdominal paragangliomas are adrenal and extra-adrenal catecholamine-producing tumours. They arise due to heritable cancer syndromes, or more frequently occur sporadically due to an unknown genetic cause. The majority of cases are benign, but malignant tumours are observed. Previous comparative genomic hybridization (CGH) and loss of heterozygosity studies have shown frequent deletions of chromosome arms 1p, 3q and 22q in pheochromocytomas. We applied high-resolution whole-genome array CGH on 53 benign and malignant pheochromocytomas and paragangliomas to narrow down candidate regions as well as to identify chromosomal alterations more specific to malignant tumours. Minimal overlapping regions (MORs) were identified on 16 chromosomes, with the most frequent MORs of deletion (> or = 32%) occurring on chromosome arms 1p, 3q, 11p/q, 17p and 22q, while the chromosome arms 1q, 7p, 12q and 19p harboured the most common MORs of gain (> or = 14%). The most frequent MORs (61-75%) in the pheochromocytomas were identified at 1p, and the four regions of common losses encompassed 1p36, 1p32-31, 1p22-21 and 1p13. Tumours that did not show 1p loss generally demonstrated aberrations on chromosome 11. Gain of chromosomal material was significantly more frequent among the malignant cases. Moreover, gain at 19q, trisomy 12 and loss at 11q were positively associated with malignant pheochromocytomas, while 1q gain was commonly observed in the malignant paragangliomas. Our study revealed novel and narrow recurrent chromosomal regions of loss and gain at several autosomes, a prerequisite for identifying candidate tumour suppressor genes and oncogenes involved in the development of adrenal and extra-adrenal catecholamine-producing tumours.

Prophylactic cholecystectomy in midgut carcinoid patients.

BACKGROUND: Patients with midgut carcinoid (MGC) tumors are commonly treated with somatostatin analogs. Adverse effects of these drugs include impairment of gallbladder function, formation of gallstones, and cholecystitis. Prophylactic cholecystectomy has been advocated, but data to support this recommendation are sparse. We have analyzed a cohort of 235 patients with MGC focusing on the risk for gallstone formation and complications thereof. METHODS: Forty-eight of the 235 patients had been cholecystectomized before surgery for MGC. Of the remaining 187 patients, 144 were treated with somatostatin analogs. Eighteen of the 187 patients had their gall bladder removed during the primary carcinoid surgery. RESULTS: Twenty-two of the 144 somatostatin-analog-treated patients developed complications, such as gallbladder empyema (n = 1), cholangitis (n = 2), acute cholecystitis (n = 6), acute pancreatitis (n = 1) or acute pancreatitis and cholecystitis (n = 1), or biliary colic (n = 11). Ninety-two of the 144 were examined during surgery, by computed tomography, or by ultrasound, most for reasons other than gallbladder-related indications, and 63% (58/92) of these examinations revealed gallstones. Of the 43 patients not treated with somatostatin analogs, only 3 patients suffered from biliary colic and underwent cholecystectomy. CONCLUSIONS: In our study the incidence of gallstone-related complications seems to be higher than in the general population. We recommend that prophylactic cholecystectomy is liberally performed during laparotomy for MGC if patients are planned to undergo treatment with somatostatin analogs.

Stenting of the superior mesenteric vein in midgut carcinoid disease with large mesenteric masses.

BACKGROUND: Midgut carcinoid (MGC) tumors generally develop in the small intestine and in >50% of cases also present with lymph node metastases in the mesentery. The majority of these tumors are surgically resectable, but a fraction are inoperable and may cause obstruction of the superior mesenteric vein (SMV), often associated with stasis of the intestinal wall and severe symptoms. These symptoms include severe abdominal pain, attacks of diarrhea, and malnutrition. METHODS: Seven patients with severe MGC including a large fibrotic inoperable mesenteric mass and severe symptoms were studied. After an obstructed SMV and signs of venous stasis in the small intestine were demonstrated, an expandable stent was inserted after puncturing an intrahepatic portal venous branch. The associated venography, patient symptoms, and radiological signs on computed tomography (CT) scans were evaluated. RESULTS: Four patients demonstrated resolution of their symptoms. In one patient who had intra-abdominal lymph leakage/chyloperitoneum, a complete normalization of the circulation followed and the intra-abdominal lymph leakage stalled. The venographies demonstrated normalization of the venous blood flow through the SMV, and CT scans demonstrated reduction in the thickness of the intestinal wall. In two cases there were no changes in the symptoms, and in one case a slight worsening of the symptoms ensued. In general, reductions of symptoms were associated with the degree of normalization of venous blood flow. CONCLUSIONS: We conclude that in selected patients with MGC stenting of the SMV may improve symptoms.

Surgical treatment of Graves' disease: evidence-based approach.

BACKGROUND: The optimal treatment of Graves disease (GD) is still controversial. Surgery is one treatment option along with radioactive iodine (RAI) and antithyroid medication. In this evidence-based review, we examine four issues: (1) Is surgery better than RAI or long-term antithyroid medication? (2) What is the recommended surgical approach? (3) How does the presence of Graves' ophthalmopathy (GO) influence the role of surgery? (4) What is the role of surgery in children with GD? METHODS: We conducted a systematic review of the literature using evidence-based criteria regarding these four issues. RESULTS: (1) There are no recommendations reaching any grade of evidence for which treatment to choose for adults with GD. (2) Total thyroidectomy has complication rates equal to those seen with lesser resections but it has higher cure rates and negligible recurrence rates (Level I-IV data leading to a grade A recommendation). (3) Data support surgery when severe GO is present, but RAI combined with glucocorticoids may be equally safe (Level II-IV data, grade B recommendation). The extent of thyroid resection does not influence the outcome of GO (Level II data, grade B recommendation). (4) Based on the available data, definitive treatment can be advocated for children (Level IV data, grade C recommendation) using either RAI or surgery. No recommendation can be given as to whether RAI or surgery is preferred owing to the lack of studies addressing this issue. Increased cancer risk with RAI in children below the age of 5 years supports surgery in this setting (Level I data, grade A recommendation). CONCLUSION: If surgery is considered for definitive management, evidence-based criteria support total thyroidectomy as the surgical technique of choice for GD. Available evidence also supports surgery in the presence of severe endocrine GO. Children with GD should be treated with an ablative strategy. Whether this is achieved by total thyroidectomy or RAI may still be debatable. Data on long-term cancer risk are missing or conflicting; and until RAI has proven harmless in children, we continue to recommend surgery in this group.

High success rate of parathyroid reoperation may be achieved with improved localization diagnosis.

INTRODUCTION: Because of the difficulty of reoperative parathyroid surgery, preoperative imaging studies have been increasingly adopted. We report the use of consistently applied localization diagnosis to yield high success rates in parathyroid reoperations. METHODS: Parathyroid reoperation was performed after previous parathyroid surgery in 144 patients with nonmalignant hyperparathyroidism (HPT) between 1962 and 2007. From the year 2000, 46 patients who underwent parathyroid reoperation and 14 patients who were subjected to thyroid surgery before primary parathyroid operation were investigated with sestamibi scintigraphy (MIBI), 11C-methionine PET/CT (met-PET), surgeon-performed ultrasound (US), US-guided fine-needle aspiration biopsy (US-FNA), and selective venous sampling (SVS) with rapid PTH (Q-PTH) analyses. When imaging was considered adequate, additional studies were generally not obtained. RESULTS: Reversal of hypercalcemia was achieved by reoperation in 134 of 144 (93%) of all patients with previous parathyroid surgery. In patients operated from year 2000, MIBI had 90% sensitivity and 88% predictive value, met-PET 79% sensitivity and 87% predictive value, and US 72% sensitivity and 93% predictive value. SVS with Q-PTH analyses provided accurate localization or regionalization in 11 of 11 recently selected patients. Q-PTH analyses in fine-needle aspirations verified parathyroid origin of excised specimens, and intraoperative Q-PTH helped decide when operations could be terminated. In patients subjected to the algorithm of imaging procedures, reversal of hypercalcemia and apparent cure was obtained after the reoperation in 45 of 46 patients with previous parathyroid surgery, implying a success rate of 98%, and in all patients with previous thyroid surgery. CONCLUSIONS: Reoperative parathyroid surgery is challenging. Results can be improved by consistently applied sensitive methods of preoperative imaging, and reoperative procedures may then achieve nearly the same success rates as primary operations.

Cyclin-dependent kinase 4 (CDK4) expression in pancreatic endocrine tumors.

BACKGROUND/AIMS: Pancreatic endocrine tumors (PETs) occur sporadically, in association with the multiple endocrine neoplasia type 1 (MEN1) and the von Hippel-Lindau syndromes. CDK4 is central to the cell cycle control in pancreatic beta cells, and we have assessed whether CDK4 expression is deregulated in 18 human sporadic or familial PETs. METHODS: Real-time quantitative PCR, immunohistochemistry, DNA sequencing, and Western blot analysis were used. RESULTS: CDK4 mRNA was expressed in all PETs within the range of the arbitrary control. CDK4 protein was absent in normal pancreatic islets but distinctly expressed in all PETs as determined by immunohistochemistry. CDK4 expression was confirmed by Western blot analysis. No significant differences of CDK4 expression were observed between the groups of benign and malignant PETs or between tumors with or without MEN1 gene mutations. CDK4 expression was not due to gene amplification, and no mutations were identified in coding exons and RNA splice sites. c-Myc is known to be overexpressed in PETs and directly augments CDK4 expression in other cell types. Analysis of consecutive tissue sections for CDK4 and c-Myc showed overlapping homo- or heterogeneous immunostaining in all 18 PETs. CONCLUSION: We conclude that CDK4 and c-Myc is generally expressed in benign and malignant PETs, and regardless of MEN1 mutational status. Targeting of CDK4 may present an alternative to traditional chemotherapy of PETs in the future.

Upregulated expression of PDGF receptor beta in endocrine pancreatic tumors and metastases compared to normal endocrine pancreas.

Platelet-derived growth factor receptor (PDGFR) beta signaling is involved in autocrine growth stimulation of tumor cells, tumor angiogenesis and regulation of tumor interstitial fluid pressure. Development of PDGFR antagonists has further increased the interest for PDGFR as targets for anticancer treatments. Malignant endocrine pancreatic tumors (EPTs) express PDGFR beta both in stroma and on tumor cells. To investigate the role of PDGFR beta signaling in EPTs we compared PDGFR beta expression in normal endocrine pancreas to malignant EPTs and metastases. PDGFR beta expression was examined by immunohistochemistry using specific polyclonal antibodies in ten tissue samples from normal endocrine pancreas, 21 from primary EPTs and 19 from metastases. In eight patients we compared the expression in normal endocrine pancreas to the corresponding primary tumor and metastases, in two patients normal tissue to the primary tumor and in 11 patients primary tumors to the corresponding metastases. Six of ten tissues containing normal pancreas stained negative for PDGFR beta on endocrine cells, while seven of ten stained positive in the stroma. Eighteen of 21 (86%) primary tumors stained positive for PDGFR beta on tumor cells and all had positive stroma stainings. All 19 metastases stained positive for PDGFR beta on tumor cells and in evaluable stroma (n=16). We have found that PDGFR beta is more frequently expressed in primary EPTs and metastases as compared to normal endocrine pancreatic tissue. This is also true for PDGFR beta expression in the corresponding stroma. We suggest that new therapeutic options to inhibit the growth and spread of EPTs could include targeting of PDGFR beta.

Bilateral adrenalectomy for ectopic Cushing's syndrome-discussions on technique and indication.

BACKGROUND: Tumors producing adrenocorticotropic hormone (ACTH) or corticotropin releasing hormone (CRH) often remain undiagnosed until severe Cushing's syndrome appears, and it may be difficult to distinguish from Cushing's syndrome due to pituitary tumors. Many patients suffer from disease spread, with metastases in the liver or other locations, and the main symptoms may be mineral disturbances, diabetes mellitus, or psychological symptoms from the severe hypercortisolism. Bilateral adrenalectomy may alleviate this situation, but is sometimes a troublesome procedure in these severely ill patients. METHODS: We have retrospectively investigated 8 patients with ectopic Cushing's syndrome who have undergone bilateral adrenalectomy at the University Hospital in Uppsala. In addition, another 5 patients who underwent bilateral adrenalectomy for other reasons (recurrent pituitary Mb Cushing or bilateral hyperplasia) were scrutinized for technical considerations. Indications, timing of surgery, and operative procedures were studied to identify signs that may support our approach to management in the future. RESULTS: Curative surgery was not possible in any of the cases with ectopic Cushing's syndrome. Of the 13 operated patients, handport-assisted laparoscopic adrenalectomy was successfully performed bilaterally in 5 patients and unilaterally in combination with contralateral open surgery in 1 patient; conventional open surgery was performed on 7 patients, 3 of which were conversions from intitial handport-assisted procedures. Non-fatal complications occurred in 4 out of 10 patients. CONCLUSIONS: We conclude that bilateral handport-assisted laparoscopic adrenalectomy is safe, and that all surgical techniques in these severely ill patients may be troublesome and technically demanding. Early surgical intervention may reduce the technical disadvantages. Moreover, bilateral adrenalectomy can substantially reduce the symptoms of Cushing's syndrome, although effects on mortality are not obvious.

25-Hydroxyvitamin D3 1alpha-hydroxylase expression in breast cancer and use of non-1alpha-hydroxylated vitamin D analogue.

INTRODUCTION: The cytochrome P450 mitochondrial enzyme 25-hydroxyvitamin D3 1alpha-hydroxylase (1alpha-hydroxylase) of renal tubule cells hydroxylates the major circulating form of vitamin D (25(OH)D3) to the active systemic hormone 1,25(OH)2D3. Local production of 1,25(OH)2D3 appears to occur also at other sites where 1alpha-hydroxylase is expressed for autocrine/paracrine regulation. To reduce risks of hypercalcemia during treatment with vitamin D, we have previously suggested use of non-1alpha-hydroxylated vitamin D analogues to target tissues where 1alpha-hydroxylase is expressed, including the parathyroid glands in secondary hyperparathyroidism. The present study was undertaken to examine expression of 1alpha-hydroxylase in breast cancer and to investigate whether a non-1alpha-hydroxylated vitamin D analogue displayed biological function. In addition, expression of the 25-hydroxyvitamin D3 24-hydroxylase (24-hydroxylase) and the vitamin D receptor (VDR) was investigated. METHODS: The expression of 1alpha-hydroxylase, 24-hydroxylase and VDR was investigated in breast cancer specimens (n = 19) and normal breast tissues (n = 10) by immunohistochemistry and/or RT-PCR. Consecutive cryosections of 6 mum essentially free of immune cells were used in the analyses. The effect of vitamin D analogues on transcriptional activation was analyzed in transiently transfected MCF-7 breast cancer cells. RESULTS: 1alpha-hydroxylase protein was demonstrated in 79% and 100% of breast cancer specimens and normal breast, respectively. The overall relative mRNA levels of 1alpha-hydroxylase and 24-hydroxylase in normal breast compared to breast tumors were: 1alpha-hydroxylase, 1 +/- 0.07 versus 0.7 +/- 0.05, respectively (p < 0.001); 24-hydroxylase, 1 +/- 0.08 verus 2.1 +/- 0.2, respectively (p < 0.001). The VDR was expressed in 95% of the tumors as expected, with mRNA levels of 1 +/- 0.09 and 1.4 +/- 0.12 (p < 0.05) in breast cancer and normal breast, respectively. The ketoconazole-sensitive transcription activation potential of the non-1alpha-hydroxylated vitamin D analogue prodrug of EB1089 (EB1285) was demonstrated in MCF-7 cells, which express 1alpha-hydroxylase. The activity of EB1285 was about 20% of 1,25(OH)2D3. CONCLUSION: These results demonstrate nearly normal expression levels of 1alpha-hydroxylase, 24-hydroxylase and VDR in the majority of investigated breast cancer specimens. A non-1alpha-hydroxylated vitamin D analogue displayed activity in breast cancer cells. Such analogues may present future therapeutic options for proliferative disorders where 1alpha-hydroxylase is expressed.

Midgut carcinoid tumours: surgical treatment and prognosis.

Midgut carcinoids originating in the small intestine are the most common cause of the carcinoid syndrome. These tumours typically progress slowly and have an extended disease course, and although they often present with metastases at diagnosis, surgical treatment has become increasingly important for their management. Surgery should include efforts to remove mesenteric metastases, which may cause severe long-term abdominal complications with typical fibrotic intestinal entrapment and small-bowel ischaemia due to compression of mesenteric vessels. Attempts should also be made to surgically remove or ablate liver metastases, since this may provide considerable palliation of the carcinoid syndrome. For patients with the carcinoid syndrome surgery is combined with continuous biotherapy with long-acting somatostatin analogues, which may alleviate symptoms and stabilize disease or slow progression. Favourable survival and appreciable quality of life can be expected with this combined treatment, even in patients with advanced midgut carcinoids.

Pancreatic tumours as part of the MEN-1 syndrome.

Pancreaticoduodenal tumours (PETs) occur in a majority of MEN-1 patients, and have appeared as a major cause of disease-related death. Previous discussions about treatment have mainly dealt with management of various functioning tumours and clinical syndromes of hormone excess. However, hormonal syndromes often occur late with MEN-1 pancreatic tumours, and when developed indicate presence of metastases in up to 50% of the patients. Prospective screening is therefore recommended in MEN-1 with biochemical markers and endoscopic ultrasound for early detection of PETs, and early surgery before metastases have developed. Surgery is recommended in patients with or without hormonal syndromes in absence of disseminated liver metastases. The suggested operation includes enucleation of tumours in the head of the pancreas, excision of duodenal gastrinomas together with clearance of lymph node metastases, and distal 80% subtotal pancreatic resection as prophylaxis against tumour recurrence. This strategy with early and aggressive surgery is believed to reduce the risks for malignant progression.