Central lymph node dissection and permanent hypoparathyroidism after total thyroidectomy for papillary thyroid cancer: population-based study.

BACKGROUND: Papillary thyroid cancer is treated with total/near-total thyroidectomy (TT) with or without central lymph node dissection (CLND), depending on risk factors and tumour size. Balancing the risk of disease recurrence and surgical morbidity remains a challenge. A population-based nationwide study was undertaken to evaluate the risk of permanent hypoparathyroidism associated with CLND. METHOD: Data on patients with stage pT1-3 papillary thyroid cancer, who underwent TT with or without CLND between 1 July 2004 and 30 June 2014 were retrieved from the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery. Drug use was ascertained by cross-linking with the Swedish Prescribed Drug Register. Permanent hypoparathyroidism was defined as treatment with active D vitamin or oral calcium drugs for more than 6 months after surgery. Data were analysed separately for all patients and those who underwent TT + CLND. Univariable and multivariable logistic regression analyses were done, yielding odds ratios (ORs) with 95 per cent confidence intervals. RESULTS: A total of 722 patients were included in the study. Permanent hypoparathyroidism was more common in the TT + CLND group than the TT group: 30 of 265 patients (6·6 per cent) versus six of 457 (2·3 per cent) (P = 0·011). In multivariable logistic regression analysis, CLND was a risk factor for permanent hypoparathyroidism (OR 3·74, 95 per cent c.i. 1·46 to 9·59, based on use of combined therapy 6 months after surgery). In patients who had TT + CLND, node negativity was associated with a risk of permanent hypoparathyroidism (OR 3·08, 1·31 to 7·25). CONCLUSION: CLND is an independent risk factor for permanent hypoparathyroidism. Node negativity is associated with a higher risk of permanent hypoparathyroidism.

Mortality after surgery for primary hyperparathyroidism: results from a nationwide cohort.

BACKGROUND: Contemporary patients with primary hyperparathyroidism are often diagnosed with mildly raised serum calcium levels. Previous studies have reported increased mortality in patients with primary hyperparathyroidism. This retrospective cohort study aimed to examine whether contemporary patients operated for primary hyperparathyroidism have higher mortality than the general population, and whether mortality in these patients is associated with serum calcium concentration, adenoma weight or multiglandular disease. METHODS: Patients from a Swedish national cohort consisting of patients registered in the Scandinavian Quality Register for Thyroid, Parathyroid, and Adrenal Surgery 2003-2013, were matched with population controls. The National Patient Register, the Swedish Cause of Death Register, and socioeconomic data were cross-linked. End of follow-up was 10 years after surgery, 31 December 2015, or emigration. Mortality was analysed by standardized mortality ratio, Kaplan-Meier survival estimates, and univariable and multivariable Cox regression. Multiple imputation by chained equations was performed on missing data. RESULTS: After exclusions, there were 5009 patients with primary hyperparathyroidism and 14 983 controls. Multivariable Cox regression analysis adjusted for age, sex, Charlson Co-morbidity Index, marital status, level of education, disposable income, and period of surgery showed lower mortality in patients than controls (hazard ratio (HR) 0.83, 95 per cent c.i. 0.75 to 0.92). In univariable Cox regression of mortality in patients, serum calcium concentration (mmoles per litre) was associated with mortality (HR 2.20, 1.53 to 3.16). This association remained in multivariable Cox regression after multiple imputation (HR 1.79, 1.19 to 2.70). CONCLUSION: Mortality was not increased in patients operated for primary hyperparathyroidism compared with controls in a contemporary setting. Preoperative serum calcium concentration might, however, influence survival.

Complications after medullary thyroid carcinoma surgery: multicentre study of the SQRTPA and EUROCRINE® databases.

BACKGROUND: Surgery is the curative therapy for patients with medullary thyroid carcinoma (MTC). In determining the extent of surgery, the risk of complications should be considered. The aim of this study was to assess procedure-specific outcomes and risk factors for complications after surgery for MTC. METHODS: Patients who underwent thyroid surgery for MTC were identified in two European prospective quality databases. Hypoparathyroidism was defined by treatment with calcium/active vitamin D. Recurrent laryngeal nerve (RLN) palsy was diagnosed on laryngoscopy. Complications were considered at least transient if present at last follow-up. Risk factors for at-least transient hypoparathyroidism and RLN palsy were identified by logistic regression analysis. RESULTS: A total of 650 patients underwent surgery in 69 centres at a median age of 56 years. Hypoparathyroidism, RLN palsy and bleeding requiring reoperation occurred in 170 (26·2 per cent), 62 (13·7 per cent) and 17 (2·6 per cent) respectively. Factors associated with hypoparathyroidism were central lymph node dissection (CLND) (odds ratio (OR) 2·20, 95 per cent c.i. 1·04 to 4·67), CLND plus unilateral lateral lymph node dissection (LLND) (OR 2·78, 1·20 to 6·43), CLND plus bilateral LLND (OR 2·83, 1·13 to 7·05) and four or more parathyroid glands observed (OR 4·18, 1·46 to 12·00). RLN palsy was associated with CLND plus LLND (OR 4·04, 1·12 to 14·58) and T4 tumours (OR 12·16, 4·46 to 33·18). After compartment-oriented lymph node dissection, N0 status was achieved in 248 of 537 patients (46·2 per cent). CONCLUSION: Complications after surgery for MTC are procedure-specific and may relate to the unavoidable consequences of radical dissection needed in some patients.

Evaluating risk factors for re-exploration due to postoperative neck hematoma after thyroid surgery: a nested case-control study.

PURPOSE: Postoperative bleeding after thyroid surgery remains a potentially lethal complication. Outpatient thyroidectomy is an increasing trend in the high volume centers. There is a need to identify risk factors for postoperative bleeding in order to select proper patients for outpatient thyroidectomy. This study aimed to investigate this issue using a national population-based register. MATERIAL AND METHOD: A nested case-control study on patients registered in the Swedish national register for endocrine surgery (SQRTPA) was performed. Patients with postoperative bleeding were matched 1:1 by age and gender to controls. Additional information on cases and controls was obtained from attending surgeons using a questionnaire. Risk factors for postoperative bleeding were evaluated with logistic regression and are presented as odds ratios (ORs) with 95% confidence intervals (CIs). The time of bleeding in relation to surgery was also investigated. RESULTS: There were 9494 operations, and 174 (1.8%) of them involved postoperative bleeding. In the whole cohort, patients with postoperative bleeding were older, 58 (46-69) vs. 49 (37-62) years, than patients without, p < 0.01. Male patients had a higher risk of bleeding, OR 2.18 (95% CI 1.58-2.99). In the case-control cohort, drain was an independent risk factor for bleeding, OR 1.64 (1.05-2.57). Two-thirds of patients bled within 6 h after surgery. The incidence of bleeding after 24 h was 10%. CONCLUSION: High age, male gender, and drain are independent risk factors for bleeding after thyroid surgery. Even with careful patient selection, prolonged observation might be necessary in thyroid surgery.

Mortality in patients with permanent hypoparathyroidism after total thyroidectomy.

BACKGROUND: Permanent hypoparathyroidism remains the most common adverse outcome after total thyroidectomy, but long-term effects of hypoparathyroidism are unknown. The aim was to investigate mortality in patients with permanent hypoparathyroidism after total thyroidectomy. METHODS: Data from the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery were linked with the Swedish National Prescription Register for Pharmaceuticals and the Swedish National Inpatient Register. Patients who underwent total thyroidectomy between 1 July 2005 and 30 June 2014 for benign thyroid disease, and who used active vitamin D for at least 6 months after surgery, were classified as having permanent hypoparathyroidism and included in the study cohort. Risk of death was assessed using Cox regression analysis, adjusting for age, sex, thyrotoxicosis and co-morbidity. RESULTS: There were 4899 patients, with a mean(s.d.) age of 46·3(15·8) years; 83·1 per cent were women, and 2932 patients (59·8 per cent) had thyrotoxicosis. In all, 246 patients (5·2 per cent) were classified as having permanent hypoparathyroidism. Mean(s.d.) follow-up was 4·4(2·4) years, and 109 patients (2·2 per cent) died during follow-up. Compared with patients without permanent hypoparathyroidism, the risk of death was significantly higher among patients with permanent hypoparathyroidism after total thyroidectomy (adjusted hazard ratio 2·09, 95 per cent c.i. 1·04 to 4·20). CONCLUSION: Permanent hypoparathyroidism after total thyroidectomy for benign disease is common and associated with an increased risk of death.

A Nested Case-Control Study on the Risk of Surgical Site Infection After Thyroid Surgery.

INTRODUCTION: It is unclear if antibiotic prophylaxis reduces the risk of surgical site infection (SSI) in thyroid surgery. This study assessed risk factors for SSI and antibiotic prophylaxis in subgroups of patients. METHOD AND DESIGN: A nested case-control study on patients registered in the Swedish National Register for Endocrine Surgery was performed. Patients with SSI were matched 1:1 by age and gender to controls. Additional information on patients with SSI and controls was queried from attending surgeons using a questionnaire. Risk factors for SSI were evaluated by logistic regression analysis and presented as odds ratio (OR) with 95% confidence interval (CI). RESULTS: There were 9494 operations; 109 (1.2%) patients had SSI. Patients with SSI were older (median 53 vs. 49 years) than patients without SSI p = 0.01 and more often had a cancer diagnosis 23 (21.1%) versus 1137 (12.1%) p = 0.01. In the analysis of patients with SSI versus controls, patients with SSI more often had post-operative drainage 68 (62.4%) versus 46 (42.2%) p = 0.01 and lymph node surgery 40 (36.7%) versus 14 (13.0%) p < 0.01, and both were independent risk factors for SSI, drain OR 1.82 (CI 1.04-3.18) and lymph node dissection, OR 3.22 (95% CI 1.32-7.82). A higher number of 26(62%) patients with independent risk factors for SSI and diagnosed with SSI did not receive antibiotic prophylaxis. Data were missing for 8 (31%) patients. CONCLUSION: Lymph node dissection and drain are independent risk factors for SSI after thyroidectomy. Antibiotic prophylaxis might be considered in patients with these risk factors.

Thyroid function and survival following breast cancer.

BACKGROUND: Thyroid function has been associated with breast cancer risk, and breast cancer cell growth and proliferation. It is not clear whether thyroid function affects prognosis following breast cancer but, if so, this could have an important clinical impact. The present study analysed prospectively collected measurements of free tri-iodothyronine (T3), free thyroxine (T4), thyroid-stimulating hormone (TSH) and thyroid peroxidase antibodies (TPO-Ab) in relation to breast cancer survival. METHODS: The Malmö Diet and Cancer Study is a prospective cohort study of 17 035 women in Sweden. Study enrolment was conducted between 1991 and 1996. Patients with incident breast cancer were identified through record linkage with cancer registries until 31 December 2006. Information on vital status was collected from the Swedish Cause of Death Registry, with the endpoint breast cancer mortality (31 December 2013). Hazard ratios (HRs) with 95 per cent confidence intervals (c.i.) were obtained by Cox proportional hazards analysis. RESULTS: Some 766 patients with incident breast cancer were identified, of whom 551 were eligible for analysis. Compared with patients in the first free T4 tertile, breast cancer mortality was lower among those in the second tertile (HR 0·49, 95 per cent c.i. 0·28 to 0·84). There was an indication, although non-significant, of lower breast cancer mortality among patients in the second TSH tertile (HR 0·63, 0·37 to 1·09) and in those with positive TPO-Ab status (HR 0·61, 0·30 to 1·23). Free T3 showed no clear association with mortality. CONCLUSION: In the present study, there was a positive association between free T4 levels and improved breast cancer survival.

Risk of recurrent laryngeal nerve palsy in patients undergoing thyroidectomy with and without intraoperative nerve monitoring.

BACKGROUND: Vocal cord palsy occurs in 3-5 per cent of patients after thyroidectomy. To reduce this complication, intraoperative nerve monitoring (IONM) has been introduced, although its use remains controversial. This study investigated the risk of postoperative vocal cord palsy with and without the use of intermittent IONM. METHODS: Patients registered in the Scandinavian Quality Register for Thyroid, Parathyroid and Adrenal Surgery, 2009-2013, were included. Early palsy of the recurrent laryngeal nerve was diagnosed within 6 weeks after surgery. Permanent palsy was defined as that persisting after 6 months. Univariable and multivariable logistic regression analyses were used to examine risk factors for vocal cord palsy. RESULTS: The cohort consisted of 5252 patients undergoing thyroidectomy. IONM was used in 3277 operations (62·4 per cent); postoperative laryngoscopy was performed in 1757 patients (33·5 per cent). Early vocal cord palsy occurred in 217 patients (4·1 per cent), of which three were bilateral, all in the group without IONM. Permanent vocal cord palsy occurred in 62 patients (1·2 per cent). In the multivariable analysis of 1757 patients who had postoperative laryngoscopy, the use of IONM was not associated with a decreased risk of early vocal cord palsy (odds ratio (OR) 0·67, 95 per cent c.i. 0·44 to 1·01), but decreased the risk of permanent vocal cord palsy (OR 0·43, 0·19 to 0·93). [Correction added on 11 November 2016 after first publication: the word 'routine' has been removed from this section.] CONCLUSION: IONM reduced the risk of permanent vocal cord palsy. No bilateral recurrent laryngeal nerve injury occurred following IONM.

Prediction of permanent hypoparathyroidism after total thyroidectomy.

BACKGROUND: Hypoparathyroidism is a common complication with thyroid surgery. The ability to predict a high risk of permanent hypoparathyroidism is important for individual prognosis and follow-up. METHODS: Permanent hypoparathyroidism, defined as continuing need for vitamin D medication at 1-year post-operatively, was investigated in patients after total thyroidectomy. Blood levels of calcium and parathyroid hormone (PTH) were measured intra-operatively, the day after surgery and at 1 month post-operatively. Logistic regression analysis was performed to investigate the risk of vitamin D treatment at last follow-up, calculated as odds ratios (ORs) with 95 % confidence intervals (CIs). Patients were followed until cessation of vitamin D and/or calcium medication, until death, loss to follow-up, or end of follow-up, whichever came first. RESULTS: A total of 519 patients were included. The median (range) follow-up in patients unable to cease vitamin D was 2.7 (1.2-10.3) years. The rate of permanent hypoparathyroidism was 10/519, 1.9 %. Parathyroid auto-transplantation was performed in 90/519 (17.3 %) patients. None of these developed permanent hypoparathyroidism, nor did any patient with normal PTH day 1 (>1.6 pmol/l or 15 pg/ml). The adjusted risk (OR, 95 % CI) for permanent hypoparathyroidism for log PTH on day 1 was 0.25 (0.13-0.50). In patients not auto-transplanted and with unmeasurable PTH day 1 (<0.7 pmol/l or 6.6 pg/ml), 8/42 (19.2 %) developed permanent hypoparathyroidism. CONCLUSIONS: Auto-transplantation protects against permanent hypoparathyroidism, whereas low PTH day 1 is associated with high risk.

Risk factors for medically treated hypocalcemia after surgery for Graves' disease: a Swedish multicenter study of 1,157 patients.

BACKGROUND: For reasons that remain unclear, surgery for Graves' disease is associated with a higher risk of hypocalcemia than surgery for benign atoxic goiter. In the present study, we evaluated risk factors for postoperative hypocalcemia in patients undergoing operation for Graves' disease. METHODS: Data from 1,157 patients who underwent operation for Graves' disease between 2004 and 2008 were extracted from the Scandinavian database for Thyroid and Parathyroid Surgery. Risk factors for postoperative hypocalcemia (in-hospital i. v. calcium; treatment with vitamin D analog at discharge, at 6 weeks, and at 6 months postoperatively) were evaluated by logistic regression analysis. RESULTS: Risk factors for i. v. calcium were low hospital volume of thyroid surgery (odds ratio [OR]: 95 % confidence interval [95 % CI], 0.99: 0.99-1.00), age (0.95: 0.91-1.00), operative time (1.02: 1.01-1.02), university hospital (12.91: 2.68-62.30), and reoperation for bleeding (10.32: 1.51-70.69). The risk for treatment with vitamin D at discharge increased with operative time (1.01: 1.00-1.02), excised gland weight (1.01: 1.00-1.01), parathyroid autotransplantation (5.19: 2.28-11.84), and reoperation for bleeding (12.00: 2.43-59.28). At 6 weeks, vitamin D medication was associated with gland weight (1.00: 1.00-1.01), and preoperative medication with ß-blockers (4.20: 1.67-10.55). At 6 months, vitamin D medication was associated with gland weight (1.00: 1.00-1.01) and reoperation for bleeding (10.59: 1.58-71.22). CONCLUSIONS: Risk factors for medically treated hypocalcemia varied at different times of follow-up. Young age, operative time, type of hospital, and parathyroid autotransplantation were associated with early postoperatively hypocalcemia. Preoperative ß-blocker treatment was a risk factor at the first follow-up. At early and late follow-up, gland weight and reoperation for bleeding were associated with medically treated hypocalcemia.

Hypocalcaemia after total thyroidectomy for Graves' disease and for benign atoxic multinodular goitre.

PURPOSE: Postoperative hypocalcaemia has been reported to be more common after total thyroidectomy (TT) for Graves' disease than after TT for benign atoxic multinodular goitre (MNG). The reasons for this potential association are not clear. In the present study, the frequency and risk factors of hypocalcaemia after TT for Graves' vs MNG were compared. METHODS: Between January 1999 and October 2009, patients with first-time surgery for Graves' disease or MNG treated with a TT were included in the study. Postoperative hypocalcaemia was defined by symptoms, calcium levels and treatment with calcium and/or vitamin D analogues during postoperative hospital stay, at discharge, and at the 6-week and 6-month follow-ups. Outcomes were compared with Mann-Whitney, chi(2) and Fishers' exact test where appropriate and by multivariable logistic regression analysis. RESULTS: There were 128 patients with Graves' disease and 81 patients with MNG. Patients with Graves' disease were younger than patients with MNG (median age, 35 vs 51 years, p < 0.001). Symptoms of hypocalcaemia were more common in patients with Graves' disease (p < 0.001; OR, 95 % CI 3.26, 1.48-7.14), but the frequency of biochemical hypocalcaemia, postoperative levels of parathyroid hormone (PTH) and treatment with calcium and vitamin D did not differ between groups of patients. CONCLUSION: Apart from more frequent symptoms of hypocalcaemia in patients with Graves' disease, there was no difference in the overall frequency of biochemical hypocalcaemia, low levels of PTH and/or treatment with calcium and vitamin D.

Metabolic syndrome and rare gynecological cancers in the metabolic syndrome and cancer project (Me-Can).

BACKGROUND: Risk factors for rare gynecological cancers are largely unknown. Initial research has indicated that the metabolic syndrome (MetS) or individual components could play a role. MATERIALS AND METHODS: The Metabolic syndrome and Cancer project cohort includes 288,834 women. During an average follow-up of 11 years, 82 vulvar, 26 vaginal and 43 other rare gynecological cancers were identified. Hazard ratios (HRs) were estimated fitting Cox proportional hazards regression models for tertiles and standardized z-scores [with a mean of 0 and a standard deviation (SD) of 1] of body mass index (BMI), blood pressure, glucose, cholesterol, triglycerides and MetS. Risk estimates were corrected for random error in the measurement of metabolic factors. RESULTS: The MetS was associated with increased risk of vulvar [HR 1.78, 95% confidence interval (CI) 1.30-2.41) and vaginal cancer (HR 1.87, 95% CI 1.07-3.25). Among separate MetS components, 1 SD increase in BMI was associated with overall risk (HR 1.43, 95% CI 1.23-1.66), vulvar (HR 1.36, 95% CI 1.11-1.69) and vaginal cancer (HR 1.79, 95% CI 1.30-2.46). Blood glucose and triglyceride concentrations were associated with increased risk of vulvar cancer (HR 1.98, 95% CI 1.10-3.58 and HR 2.09, 95% CI 1.39-3.15, respectively). CONCLUSION: The results from this first prospective study on rare gynecological cancers suggest that the MetS and its individual components may play a role in the development of these tumors.

Serum calcium and the risk of prostate cancer.

BACKGROUND: Recent studies have suggested an association between high dietary intake of calcium and the risk of prostate cancer. Calcium-rich diet has been suggested to affect the serum levels of Vitamin D, and thereby promote cancer. We conducted the largest study of the association between prediagnostic serum levels of calcium and the risk of prostate cancer. OUTLINE: We examined the incidence of prostate cancer in relation to prediagnostic serum calcium levels in a prospective cohort study of 22,391 healthy Swedish men, of which 1,539 incident cases of prostate cancer were diagnosed during the 30 years of follow-up until December 2006. MATERIAL AND METHODS: Serum levels of calcium were measured at baseline, and categorized into quartiles. Cox regression was used to estimate the adjusted hazard ratios (HR) with 95% confidence intervals (CI). RESULTS: We found no evidence of an association between prediagnostic serum levels of calcium and risk of prostate cancer (HR for trend = 0.99 [95% CI;0.94-1.03]). However, a moderate significant negative association was seen in men with a BMI above 25 and aged below 45 years at baseline (Highest vs. lowest quartile, HR = 0.63 [95% CI;0.40-0.99]). CONCLUSION: These data do not support the hypothesis that high serum calcium levels is a risk factor for prostate cancer. On the contrary, the data suggest that high serum levels of calcium in young overweight men may be a marker for a decreased risk of developing prostate cancer.

Serum vitamin D (25OHD3) levels and the risk of different subtypes of breast cancer: A nested case-control study.

BACKGROUND: Previous studies regarding the association between serum 25-hydroxyvitamin D (25OHD3) and breast cancer risk have not been conclusive. The aim of this study was to investigate the potential association between pre-diagnostic serum 25OHD3 levels and the risk of different subtypes of breast cancer. MATERIALS AND METHODS: The study was based on The Malmö Diet and Cancer Study recruiting 17,035 women from 1991 to 1996. A total of 764 incident breast cancers with matched controls were analysed for 25OHD3 in samples collected at baseline, before diagnosis. A logistic regression analysis was used to calculate odds ratios with 95% confidence intervals for tertiles of 25OHD3 in relation to different subtypes of breast cancer, i.e. defined according to tumour type, tumour size, lymph node involvement, histological grade, oestrogen receptor (ER) status, progesterone receptor (PgR) status, Ki67, cyclin D1 and p27. RESULTS: As compared to the 1st tertile of 25OHD3, the second tertile had a statistically significantly lower risk of ER negative tumours, PgR negative tumours and tumours with a high expression of Ki67, A similar pattern was seen in relation to large tumours (≥21 mm), grade III tumours, and tumours with low p27 expression, but these associations did not reach statistical significance. The third tertile had a similar risk as the first tertile. CONCLUSIONS: We found that women with low levels of 25OHD3, as compare to women in the middle tertile, had a high risk of breast tumours with an unfavourable prognosis.

Hyperparathyroidism and new onset diabetes after renal transplantation.

BACKGROUND: Secondary hyperparathyroidism persists after renal transplantation in a substantial number of patients. Primary hyperparathyroidism and secondary hyperparathyroidism are both associated with abnormalities in glucose metabolism, such as insufficient insulin release and glucose intolerance. The association of hyperparathyroidism and diabetes after renal transplantation has, as far as we know, not been studied. Our aim was to investigate whether hyperparathyroidism is associated with new-onset diabetes mellitus after transplantation (NODAT) during the first year posttransplantation. STUDY DESIGN: In a retrospective study, we analyzed data on patient characteristics, treatment details, and parathyroid hormone (PTH) in 245 adult nondiabetic patients who underwent renal transplantation between January 2000 and June 2011. RESULTS: The first year cumulative incidence of NODAT was 15%. The first serum PTH value after transplantation was above normal range in 74% of the patients. In multiple logistic regression analysis, PTH levels above twice normal range (>13.80 pmol/L) were significantly associated with NODAT (odds ratio [OR], 4.25; 95% confidence interval [CI], 1.13-15.92; P = .03) compared with PTH within normal range (≤6.9 pmol/L). Age between 45 and 65 years (OR, 2.80; 95% CI, 1.07-7.36; P = .04) compared with age <45 years was also associated with NODAT. CONCLUSION: We found a strong association between hyperparathyroidism and NODAT in the first year after renal transplantation. Both conditions are common and have a negative impact on graft and patient survivals. Our results should be confirmed in prospective studies.