24-hour Urine Calcium Predicts Reduced Fracture Incidence and Improved BMD After Surgery for Primary Hyperparathyroidism.

CONTEXT: Contemporary patients with primary hyperparathyroidism are diagnosed with milder disease than previously. Clinical and biochemical factors predictors with impact on fracture incidence and bone mineral density after surgery have not been firmly established. OBJECTIVE: To investigate predictors of fracture incidence and bone mineral density preoperatively and after surgery for primary hyperparathyroidism (pHPT). DESIGN: Prospectively collected surgical cohort with matched population controls. Data were cross-linked with the Swedish National Patient Register, the Prescribed Drug Register, and the Cause of Death Register. SETTING: Tertiary referral center. PATIENTS OR OTHER PARTICIPANTS: 709 patients with successful parathyroidectomy for pHPT, and 2,112 controls matched on sex, age, and municipality were included in the study. MAIN OUTCOME MEASURES: Fracture incidence, absolute change and ≥2.77% increase in bone mineral density of femoral neck, L2-L4 and distal third of radius at 1-year follow-up. RESULTS: Patients with pHPT had an increased fracture incidence before surgery but not after pHPT surgery. Fracture incidence after surgery was inversely related to preoperative 24-hour urine calcium (IRR for the highest tertile 220- mg/d 0.29, CI 95% 0.11-0.73). Serum and 24-hour urine calcium, parathyroid hormone, osteocalcin and adenoma weight were all associated with bone mineral density recovery after surgery. CONCLUSIONS: 24-hour urine calcium is the most important biochemical variable to predict a decreased fracture incidence and improved bone mineral density after surgery for pHPT.

Hypoparathyroidism and mortality after total thyroidectomy: A nationwide matched cohort study.

OBJECTIVE: Total thyroidectomy (TT) carries a risk of hypoparathyroidism (hypoPT). Recently, hypoPT has been associated with higher overall mortality rates. We aimed to evaluate the frequency of hypoPT and mortality in patients undergoing TT in Denmark covering 20 years. DESIGN: Retrospective Cohort study. PATIENTS AND MEASUREMENTS: Using population-based registries, we identified all Danish individuals who had undergone TT between January 1998 and December 2017. We included a comparison cohort by randomly selecting 10 citizens for each patient, matched on sex and birth year. HypoPT was defined as treatment with active vitamin D after 12 months postoperatively. We used cumulative incidence to calculate risks and Cox regression to compare the rate of mortality between patients and the comparison cohort. We evaluated patients in different comorbidity groups using the Charlson Comorbidity Index and by different indications for surgery. RESULTS: 7912 patients underwent TT in the period. The prevalence of hypoPT in the study period was 16.6%, 12 months postoperatively. After adjusting for potential confounders the risk of death due to any causes (hazard ratio; 95% confidence intervals) following TT was significantly increased (1.34; 1.15-1.56) for patients who developed hypoPT. However, subgroup analysis revealed mortality was only increased in malignancy cases (2.48; 1.99-3.10) whereas mortality was not increased when surgery was due to benign indications such as goitre (0.88; 0.68-1.15) or thyrotoxicosis (0.86; 0.57-1.28). CONCLUSIONS: The use of active vitamin D for hypoPT was prevalent one year after TT. Patients with hypoPT did not have an increased risk of mortality following TT unless the indication was due to malignancy.

Circulating endogenous sex steroids and risk of differentiated thyroid carcinoma in men and women.

Thyroid cancer (TC) is substantially more common in women than in men, pointing to a possible role of sex steroid hormones. We investigated the association between circulating sex steroid hormones, sex hormone binding globulin (SHBG) and the risk of differentiated TC in men and women within the European Prospective Investigation into Cancer and nutrition (EPIC) cohort. During follow-up, we identified 333 first primary incident cases of differentiated TC (152 in pre/peri-menopausal women, 111 in post-menopausal women, and 70 in men) and 706 cancer-free controls. Women taking exogenous hormones at blood donation were excluded. Plasma concentrations of testosterone, androstenedione, dehydroepiandrosterone, estradiol, estrone and progesterone (in pre-menopausal women only) were performed using liquid chromatography/mass spectrometry method. SHBG concentrations were measured by immunoassay. Odds ratios (ORs) were estimated using conditional logistic regression models adjusted for possible confounders. No significant associations were observed in men and postmenopausal women, while a borderline significant increase in differentiated TC risk was observed with increasing testosterone (adjusted OR T3 vs T1: 1.68, 95% CI: 0.96-2.92, ptrend = .06) and androstenedione concentrations in pre/perimenopausal women (adjusted OR T3 vs T1: 1.78, 95% CI: 0.96-3.30, ptrend = .06, respectively). A borderline decrease in risk was observed for the highest progesterone/estradiol ratio (adjusted OR T3 vs T1: 0.54, 95% CI: 0.28-1.05, ptrend = .07). Overall, our results do not support a major role of circulating sex steroids in the etiology of differentiated TC in post-menopausal women and men but may suggest an involvement of altered sex steroid production in pre-menopausal women.

The role of 18F-fluoromethylcholine-positron emission tomography-computed tomography for preoperative localization of hyperfunctioning parathyroid glands with special emphasis on multiglandular disease: a retrospective cohort study.

Background: Primary hyperparathyroidism (PHPT) is a common endocrine disorder. Definitive treatment is surgical. Preoperative localization of diseased glands increases the chance of successful treatment. The aim of this study is to investigate the diagnostic performance of 18F-fluoromethylcholine-positron emission tomography-computed tomography (18F-FCh-PET-CT) in preoperative localization of diseased parathyroid glands, when first-line examinations were inconclusive. Methods: This is a retrospective study. All patients with PHPT who underwent 18F-FCh-PET-CT, after inconclusive ultrasound examination and 99mTc-methoxyisobutylisonitrile/single-photon emission CT-CT, were included in cohort I. Patients who were subsequently operated for their parathyroid disease, were included in cohort II. The performance of 18F-FCh-PET-CT was analyzed in two sets: per-lesion, and per-gland analysis. Results: Out of 52 patients in cohort I, 18F-FCh-PET-CT identified single or multiple parathyroid lesions in 43 patients (83%). Nine patients had multiglandular disease. Thirty-four (65%) patients were subsequently operated and included in cohort II. Forty-four lesions were removed from these patients and 33 patients (97%) were cured. 18F-FCh-PET-CT localized 40 out of 44 lesions, with per-lesion and per-gland sensitivities of 97% and 95%, and positive predictive values (PPVs) of 93% and 87%, respectively, in addition to a specificity of 97% and a negative predictive value (NPV) of 94% in the per-gland analysis. Comparable excellent results were detected in multiglandular disease with sensitivity of 94.1%, specificity of 89%, PPV of 84%, and NPV of 94%. Conclusions: Our study demonstrates the high diagnostic performance of 18F-FCh-PET-CT in the preoperative localization of diseased parathyroid gland in patients with PHPT, especially in multiglandular PHPT.

Total thyroidectomy: reduction in postoperative hypoparathyroidism.

Objective: Total thyroidectomy is associated with a high risk of postoperative hypoparathyroidism, mainly due to the unintended surgical damage to the parathyroid glands or their blood supply. It is possible that surgeons who also perform parathyroid surgery see lower rates of postoperative hypoparathyroidism. In a single institution, we investigated the effects of restricting total thyroidectomy operations for Graves' disease to two surgeons who performed both thyroid and parathyroid surgeries. We aimed to evaluate the rates of postoperative hypoparathyroidism in a 10-year period with primary attention toward patients with Graves' disease. Design: Retrospective cohort study from a single institution. Methods: We defined the rate of permanent hypoparathyroidism after total thyroidectomy as the need for active vitamin D 6 months postoperatively. Between 2012 and 2016, seven surgeons performed all thyroidectomies. From January 2017, only surgeons also performing parathyroid surgery carried out thyroidectomies for Graves' disease. Results: We performed total thyroidectomy in 543 patients. The rate of permanent hypoparathyroidism decreased from 28% in 2012-2014 to 6% in 2020-2021. For patients with Graves' disease, the rate of permanent hypoparathyroidism decreased from 36% (13 out of 36) in 2015-2016 to 2% (1 out of 56) in 2020-2021. In cancer patients, the rate of permanent hypoparathyroidism decreased from 30% (14 out of 46) in 2012-2014 to 10% (10 out of 51) in 2020-2021. Conclusion: Restricting thyroidectomy to surgeons who also performed parathyroid operations reduced postoperative hypoparathyroidism markedly. Accordingly, we recommend centralisation of the most difficult thyroid operations to centres and surgeons with extensive experience in parathyroid surgery. Significance statement: Thyroid surgery is performed by many different surgeons with marked differences in outcome. Indeed, the risk of postoperative permanent hypoparathyroidism may be very high in low-volume centres. This serious condition affects the quality of life and increases long-term morbidity and the patients develop a life-long dependency of medical treatments. We encountered a high risk of hypoparathyroidism after the operation for Graves' disease and restricted the number of surgeons to two for these operations. Further, these surgeons were experienced in both thyroid and parathyroid surgeries. We show a dramatic reduction in postoperative hypoparathyroidism after this change. Accordingly, we recommend centralisation of total thyroidectomy to surgeons with experience in both thyroid and parathyroid procedures.

[Choosing Wisely in Sweden]. / Kloka kliniska val ­ att avstå det som inte gör nytta för patienten.

Overdiagnosis and overtreatment receive increasing attention. More than 20 percent of health expenditure is without patient benefit, so-called low-value care. Several national and international initiatives have been launched to minimize low-value care. Arguably, the most widely spread initiative is Choosing Wisely. First launched by the American Board of Internal Medicine in 2012, this campaign has spread to more than 20 countries. The Swedish Society of Medicine has identified low-value care as a significant problem in Swedish health care and  has established a working group to investigate if and how a campaign based on Choosing Wisely would be feasible in Sweden. Here, the working group reports on the history of Choosing Wisely, identifies potential challenges for deimplementation generally and in the Swedish context specifically.

Emerging Imaging Technologies for Parathyroid Gland Identification and Vascular Assessment in Thyroid Surgery: A Review From the American Head and Neck Society Endocrine Surgery Section.

Importance: Identification and preservation of parathyroid glands (PGs) remain challenging despite advances in surgical techniques. Considerable morbidity and even mortality result from hypoparathyroidism caused by devascularization or inadvertent removal of PGs. Emerging imaging technologies hold promise to improve identification and preservation of PGs during thyroid surgery. Observation: This narrative review (1) comprehensively reviews PG identification and vascular assessment using near-infrared autofluorescence (NIRAF)-both label free and in combination with indocyanine green-based on a comprehensive literature review and (2) offers a manual for possible implementation these emerging technologies in thyroid surgery. Conclusions and Relevance: Emerging technologies hold promise to improve PG identification and preservation during thyroidectomy. Future research should address variables affecting the degree of fluorescence in NIRAF, standardization of signal quantification, definitions and standardization of parameters of indocyanine green injection that correlate with postoperative PG function, the financial effect of these emerging technologies on near-term and longer-term costs, the adoption learning curve and effect on surgical training, and long-term outcomes of key quality metrics in adequately powered randomized clinical trials evaluating PG preservation.

Circulating vitamin D and breast cancer risk: an international pooling project of 17 cohorts.

Laboratory and animal research support a protective role for vitamin D in breast carcinogenesis, but epidemiologic studies have been inconclusive. To examine comprehensively the relationship of circulating 25-hydroxyvitamin D [25(OH)D] to subsequent breast cancer incidence, we harmonized and pooled participant-level data from 10 U.S. and 7 European prospective cohorts. Included were 10,484 invasive breast cancer cases and 12,953 matched controls. Median age (interdecile range) was 57 (42-68) years at blood collection and 63 (49-75) years at breast cancer diagnosis. Prediagnostic circulating 25(OH)D was either newly measured using a widely accepted immunoassay and laboratory or, if previously measured by the cohort, calibrated to this assay to permit using a common metric. Study-specific relative risks (RRs) for season-standardized 25(OH)D concentrations were estimated by conditional logistic regression and combined by random-effects models. Circulating 25(OH)D increased from a median of 22.6 nmol/L in consortium-wide decile 1 to 93.2 nmol/L in decile 10. Breast cancer risk in each decile was not statistically significantly different from risk in decile 5 in models adjusted for breast cancer risk factors, and no trend was apparent (P-trend = 0.64). Compared to women with sufficient 25(OH)D based on Institute of Medicine guidelines (50- < 62.5 nmol/L), RRs were not statistically significantly different at either low concentrations (< 20 nmol/L, 3% of controls) or high concentrations (100- < 125 nmol/L, 3% of controls; ≥ 125 nmol/L, 0.7% of controls). RR per 25 nmol/L increase in 25(OH)D was 0.99 [95% confidence intervaI (CI) 0.95-1.03]. Associations remained null across subgroups, including those defined by body mass index, physical activity, latitude, and season of blood collection. Although none of the associations by tumor characteristics reached statistical significance, suggestive inverse associations were seen for distant and triple negative tumors. Circulating 25(OH)D, comparably measured in 17 international cohorts and season-standardized, was not related to subsequent incidence of invasive breast cancer over a broad range in vitamin D status.

Sweetened beverages are associated with a higher risk of differentiated thyroid cancer in the EPIC cohort: a dietary pattern approach.

BACKGROUND: Dietary pattern analysis has gained particular interest, because it reflects the complexity of dietary intake. The aim of this study was to explore the associations between a posteriori dietary patterns, derived using a data-driven approach, and the risk of differentiated thyroid cancer (TC) in Europe. METHODS: This investigation included 450,064 adults from the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Dietary intake was assessed using validated country-specific dietary questionnaires. A posteriori dietary patterns were computed using principal component analyses. Cox regression was used to calculate multivariable adjusted hazard ratios (HRs) and 95% confidence intervals (CIs). RESULTS: After a mean follow-up time of 14 years, 712 first differentiated TCs were diagnosed. In the fully adjusted model, a dietary pattern characterized by alcohol consumption (basically beer and wine) was negatively associated with differentiated TC risk (HRQ4vs.Q1 = 0.75; 95% CI:0.60-0.94, P-trend = 0.005), while a dietary pattern rich in sweetened beverages was positively associated with differentiated TC risk (HRQ4vs.Q1 = 1.26; 95% CI:0.99-1.61; P-trend = 0.07). The remaining 8 dietary patterns were not related to differentiated TC risk. The intake of sweetened beverages was positively associated with differentiated TC risk (HR100mL/d = 1.05; 95% CI:1.00-1.11), especially with papillary TC risk (HR100mL/d = 1.07; 95% CI:1.01-1.13). Similar results were observed with sugary and artificially sweetened beverages. CONCLUSIONS: The investigation of dietary patterns detected that the consumption of sweetened beverages was associated with a higher risk of differentiated thyroid cancer. Our results are in line with the general dietary recommendations of reducing the consumption of sweetened beverages.

[Thyroid ultrasound and its role in the investigation of thyroid disease]. / Ultraljud värdefullt komplement i utredning av tyreoideasjukdom.

In Europe thyroid ultrasound has been used at outpatient endocrine clinics since many years, and in southern Sweden only during the last years. Ultrasound has a role in the investigation of Graves' disease, subacute thyroiditis, gestational thyrotoxicosis, postpartum thyroiditis, amiodarone thyrotoxicosis and goiter with or without adenoma, but adenomas are usually investigated by endocrine surgeons in Sweden. If widely used the risk for detection of incidentaloma increases. Indications have to be strictly used to avoid further investigations. If an adenoma is localized, the risk for malignancy and requirement of aspiration is estimated by use of the EU-TIRADS classification based on morphology and size. The aspirate is judged by the Bethesda classification, which determines if further investigation is needed. The use of ultrasound at the outpatient clinic has improved the diagnostic quality and follow-up of thyroid patients.

Adherence to mediterranean diet and the risk of differentiated thyroid cancer in a European cohort: The EPIC study.

Background: The Mediterranean diet (MD) has been proposed as a healthy diet with a potential to lower the incidence of several types of cancer, but there is no data regarding thyroid cancer (TC). We investigated the association between MD adherence, and its components, and the differentiated TC risk within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort. Methods: Over 450,000 men and women from nine European countries were followed up for a mean of 14.1 years, during which 712 differentiated TC cases were identified. Adherence to MD was estimated using the relative MD (rMED) score, an 18-point scale including alcohol, and the adapted rMED (arMED) score, a 16-point scale excluding alcohol. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox regression models adjusted for potential confounding factors. Results: Adherence to the arMED score was not associated with the risk of differentiated TC (HRhigh vs. low adherence = 0.94, 95% CI: 0.70-1.25; p-trend 0.27), while a suggestive, but non-statistically significant inverse relationship was observed with rMED (HRhigh vs. low adherence = 0.88, 95% CI: 0.68-1.14; p-trend 0.17). Low meat (HRlow vs. high meat intake = 0.81, 95% CI: 0.67-0.99; p-trend = 0.04) and moderate alcohol (HRmoderate vs. non-moderate intake = 0.88, 95% CI: 0.75-1.03) intake were related with lower differentiated TC risk. Conclusions: Our study shows that a high adherence to MD is not strongly related to differentiated TC risk, although further research is required to confirm the impact of MD and, especially, meat intake in TC risk.

Surgical Aspects of Primary Hyperparathyroidism.

Parathyroidectomy (PTX) is the treatment of choice for symptomatic primary hyperparathyroidism (PHPT). It is also the treatment of choice in asymptomatic PHPT with evidence for target organ involvement. This review updates surgical aspects of PHPT and proposes the following definitions based on international expert consensus: selective PTX (and reasons for conversion to an extended procedure), bilateral neck exploration for non-localized or multigland disease, subtotal PTX, total PTX with immediate or delayed autotransplantation, and transcervical thymectomy and extended en bloc PTX for parathyroid carcinoma. The systematic literature reviews discussed covered (i) the use of intraoperative PTH (ioPTH) for localized single-gland disease and (ii) the management of low BMD after PTX. Updates based on prospective observational studies are presented concerning PTX for multigland disease and hereditary PHPT syndromes, histopathology, intraoperative adjuncts, localization techniques, perioperative management, "reoperative" surgery and volume/outcome data. Postoperative complications are few and uncommon (<3%) in centers performing over 40 PTXs per year. This review is the first global consensus about surgery in PHPT and reflects the current practice in leading endocrine surgery units worldwide. © 2022 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Inflammatory potential of the diet and association with risk of differentiated thyroid cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort.

PURPOSE: Chronic inflammation is thought to initiate or promote differentiated thyroid cancer (DTC) and previous studies have shown that diet can modulate this inflammatory process. We aimed to evaluate the association of several dietary scores reflecting the inflammatory potential of the diet with DTC risk. METHODS: Within the EPIC cohort, 450,063 participants were followed during a mean period of 14 years, and 712 newly incident DTC cases were identified. Associations between four dietary inflammatory scores [the dietary inflammatory index (DII®) and two energy-adjusted derivatives (the E-DIIr and the E-DIId), and the Inflammatory Score of the Diet (ISD)] and DTC risk were evaluated in the EPIC cohort using multivariable Cox regression models. RESULTS: Positive associations were observed between DTC risk and the DIIs (HR for 1 SD increase in DII: 1.11, 95%CI: 1.01, 1.23, similar results for its derivatives), but not with the ISD (HR for 1 SD increase: 1.04, 95% CI 0.93, 1.16). CONCLUSION: Diet-associated inflammation, as estimated by the DII and its derivatives, was weakly positively associated with DTC risk in a European adult population. These results suggesting that diet-associated inflammation acts in the etiology of DTC need to be validated in independent studies.

Relationship between somatostatin receptor expressing tumour volume and health-related quality of life in patients with metastatic GEP-NET.

For patients with gastroenteropancreatic neuroendocrine tumours (GEP-NET), health-related quality of life (HRQoL) is important. Meanwhile, whether tumour volume is associated with HRQoL is unknown. Hence, the aim of this study was to assess if total somatostatin receptor expressing tumour volume is correlated with HRQoL in patients with metastatic GEP-NET. Some 71 patients were included in the study. HRQoL and NET-specific symptoms were assessed with EORTC QLQ-C30 and EORTC GI.NET21. A summary score was calculated from the output of the QLQ-C30. Total somatostatin receptor expressing tumour volume was retrospectively evaluated on somatostatin receptor imaging with positron emission tomography-computed tomography (68 Ga-DOTA-TATE/TOC PET-CT) in each patient. Simple and multiple linear regression were used to evaluate the correlation between tumour volume and HRQoL, controlling for potential confounders. No correlation was found between total somatostatin receptor expressing tumour volume and QLQ-C30 summary score. Weak positive correlations were found between total tumour volume and the specific symptoms dyspnoea, diarrhoea and flushing. To the best of our knowledge, this is the first study to evaluate the association between total somatostatin expressing tumour volume and HRQoL. Our results indicate that, while tumour volume is weakly associated with symptom severity of the carcinoid syndrome, other factors might impact more on overall HRQoL.

The diagnostic utility of DNA copy number analysis of core needle biopsies from soft tissue and bone tumors.

Morphologic and immunohistochemical analysis of preoperative core needle biopsies (CNB) is important in the management of patients with soft tissue and bone tumors (STBTs). Most SBTB subtypes have more or less extensive DNA copy number aberrations (CNA), potentially providing useful diagnostic information. To evaluate the technical feasibility of single nucleotide polymorphism (SNP) array analysis and the diagnostic usefulness of the copy number profiles, we studied CNBs from 171 patients with suspected STBTs. SNP array analysis could be performed on 168 (98%) of the samples. The CNA profile was compatible with the CNB diagnosis in 87% of the cases. Discrepant cases were dominated by false-negative results due to nonrepresentative material or contamination with normal cells. 70 genomic profiles were indicative of specific histopathologic tumor entities and in agreement with the corresponding CNB diagnoses in 83%. In 96 of the cases with aberrant CNA profiles, the SNP profiles were of sufficient quality for segmentation, allowing clustering analysis on the basis of the Jaccard similarity index. The analysis of these segment files showed three major CNA clusters, based on the complexity levels and the predominance of gains versus losses. For 43 of these CNB samples, we had SNP array data also from their corresponding surgical samples. In 33 of these pairs, the two corresponding samples clustered next to each other, with Jaccard scores ranging from 0.61 to 0.99 (median 0.96). Also, for those tumor pairs that did not cluster together, the Jaccard scores were relatively high (median 0.9). 10 cases showed discrepant results, mainly due to varying degrees of normal cell contamination or technical issues. Thus, the copy number profile seen in a CNB is typically highly representative of the major cell population in the tumor.