Bone material properties and response to teriparatide in osteoporosis due to WNT1 and PLS3 mutations.

CONTEXT: Patients with osteoporosis-associated WNT1 or PLS3 mutations have unique bone histomorphometric features and osteocyte-specific hormone expression patterns. OBJECTIVE: To investigate the effects of WNT1 and PLS3 mutations on bone material properties. DESIGN: Transiliac bone biopsies were evaluated by quantitative backscattered electron imaging, immunohistochemistry, and bone histomorphometry. SETTING: Ambulatory patients. PATIENTS: Three pediatric and eight adult patients with WNT1 or PLS3 mutations. INTERVENTION: Bone mineralization density distribution and osteocyte protein expression was evaluated in 11 patients and repeated in six patients who underwent repeat biopsy after 24 months of teriparatide treatment. MAIN OUTCOME MEASURE: Bone mineralization density distribution and protein expression. RESULTS: Children with WNT1 or PLS3 mutations had heterogeneous bone matrix mineralization, consistent with bone modeling during growth. Bone matrix mineralization was homogenous in adults and increased throughout the age spectrum. Teriparatide had very little effect on matrix mineralization or bone formation in patients with WNT1 or PLS3 mutations. However, teriparatide decreased trabecular osteocyte lacunae size and increased trabecular bone FGF23 expression. CONCLUSION: The contrast between preserved bone formation with heterogeneous mineralization in children and low bone turnover with homogenous bone mineral content in adults suggests that WNT1 and PLS3 have differential effects on bone modeling and remodeling. The lack of change in matrix mineralization in response to teriparatide, despite clear changes in osteocyte lacunae size and protein expression, suggests that altered WNT1 and PLS3 expression may interfere with coupling of osteocyte, osteoblast, and osteoclast function. Further studies are warranted to determine the mechanism of these changes.

Osteosclerosis associated with hepatitis C.

We describe the first Finnish case of hepatitis C associated osteosclerosis. In which the patient's bone symptoms and bone density were resolved with hepatitis C treatment. Suspecting the possibility of osteosclerosis underlying bone pains in a hepatitis C patient is well-founded, although osteoporotic fractures are a more common problem.

Gender has to be taken into account in diagnosing adult growth hormone deficiency by the GHRH plus arginine test.

OBJECTIVE: Data on the effect of gender on the interpretation of the GHRH plus arginine stimulation test (GHRH+ARG test) is controversial. We validated the GHRH+ARG stimulation test in control subjects and patients with organic or idiopathic pituitary disease and a suspicion of adult growth hormone deficiency (AGHD) using the Immulite 2000 XPi GH assay. DESIGN: We studied 126 apparently healthy adults (median age 38.8years) and 34 patients with a suspicion of AGHD (median age 42.2years). Identification of AGHD with the GHRH+ARG test was investigated with commonly accepted BMI-related consensus cut-off limits for peak GH concentrations. Serum samples collected during the GHRH+ARG test were analysed for GH in 2014-2015. Serum IGF-1 concentrations were studied as a reference. RESULTS: In 14 of 65 (22%) control males the GH peak value was below the BMI-related cut-off limits for GH sufficiency indicating a false diagnosis of AGHD. All control females had a normal GHRH+ARG response. Median peak GH response was significantly (p<0.001) higher in female (39.3µg/L) than in male controls (21µg/L). According to consensus cut-offs all but one young female patient had a deficient response compatible with a diagnosis of AGHD. CONCLUSIONS: The GH response to stimulation by GHRH+ARG is gender-dependent, being lower in healthy males than in females. Gender should be considered when defining cut-off limits for peak GH concentrations in the GHRH+ARG test. The presently used BMI-related cut-off levels will lead to a significant misclassification of males as GH deficient.

A nationwide study on parathyroid carcinoma.

BACKGROUND: Parathyroid carcinoma (PC) is rare and diagnostically challenging. Reported outcomes are rather poor and the incidence might be increasing. MATERIAL AND METHODS: We performed a nationwide study on all cases (n= 32) diagnosed in 2000-2011 in Finland, and compared clinical and histopathological characteristics and outcome to atypical parathyroid (APA; n= 28) and parathyroid adenomas (PA; n= 72). The incidence in years 1955-1999 was compared to that in 2000-2013. RESULTS: Preoperatively, calcium and parathyroid hormone concentrations were higher in PC compared to APA and PA (1.76, 1.56 and 1.44 mmol/l, p < .001; and 989, 355 and 160 µmol/l, p < .001, respectively). Calcium was ≤1.77 mmol/l for all PAs. Hospitalization (44% vs. 22% and 3%, respectively, p = .01), renal (50% vs. 48% vs. 22%, respectively, p = .01) and bone (47% vs. 15% vs. 38%, respectively p = .002) manifestations were more common. PC and APA tumors were larger than PA (p < .001). Histopathological characteristics of PC compared to PA are increased mitotic activity (p= .001), chief cells (p = .003), diffuse growth pattern (p < .001), higher Ki67 (p< .001) and negative parafibromin (p < .001). One PC (1/18) and one APA (1/16) patient had a CDC73 mutation. After 6.7 (2-13.9) years of follow-up, 9.4% of PC had residual, 21% recurrent disease and 12.5% died of disease. Overall mortality did not differ between subgroups (p = .094). Recurrent PC was characterized by vascular invasion, lymph node metastases, high mitotic activity, necrosis and negative parafibromin. Incidence increased from 1.42 (range 0.52-2.14) to 7.14 (range 3.42-10.38)/10.000.000/years; (p < .001). CONCLUSIONS: PC associates with severe primary hyperparathyroidism and must be suspected if calcium ≥1.77 mmol/l. The prevalence of CDC73 germline mutations in PC and APA in Finland is 6%. PC has distinct histopathological characteristics and its incidence has increased over the past decades.

Osteocyte Protein Expression Is Altered in Low-Turnover Osteoporosis Caused by Mutations in WNT1 and PLS3.

Context: Osteocytes express proteins that regulate bone remodeling and mineralization. Objective: To evaluate the relationship between osteocyte-specific protein expression and bone histology in patients with monogenic osteoporosis due to wingless integration site 1 (WNT1) or plastin 3 (PLS3) mutations. Design and Setting: Cross-sectional cohort study at a university hospital. Participants: Six patients (four males; ages: 14 to 72 years) with a heterozygous WNT1 mutation and five patients (four males; ages: 9 to 70 years) with a heterozygous/hemizygous PLS3 mutation. Methods and Main Outcome Measures: Immunohistochemistry was performed for fibroblast growth factor 23 (FGF23), dentin matrix protein 1 (DMP1), sclerostin, and phosphorylated (phospho-)ß-catenin in iliac crest samples and compared with bone histomorphometry. Results: FGF23 expression in WNT1 patients was 243% that observed in PLS3 patients (P < 0.01). DMP1, sclerostin, and phospho-ß-catenin expression did not differ between groups. Serum phosphate correlated inversely with FGF23 expression (r = -0.79, P = 0.01) and serum ionized calcium correlated inversely with sclerostin expression (r = -0.60, P = 0.05). Phospho-ß-catenin expression correlated inversely with DMP1 expression (r = -0.88, P < 0.001), osteoid volume/bone volume (r = -0.68, P = 0.02), and bone formation rate (r = -0.78, P < 0.01). FGF23 expression did not correlate with DMP1 expression, sclerostin expression, or bone histomorphometry. Marrow adiposity was higher in WNT1 than in PLS3 patients (P = 0.04). Conclusions: Mutations that disrupt WNT signaling and osteocytic mechanosensing affect osteocyte protein expression. Abnormal osteocyte function may play a role in the pathogenesis of monogenetic forms of osteoporosis.

Teriparatide Treatment in Patients With WNT1 or PLS3 Mutation-Related Early-Onset Osteoporosis: A Pilot Study.

Context: We previously identified 2 Finnish families with dominantly inherited, low-turnover osteoporosis caused by mutations in WNT1 or PLS3. Objective, Design, and Setting: This prospective, longitudinal, uncontrolled study was undertaken to evaluate whether these patients respond to teriparatide. Patients and Intervention: We recruited 6 adults (median age, 54 years); 3 with a WNT1 missense mutation, c.652T>G, and 3 with a PLS3 splice mutation, c.73-24T>A, to receive teriparatide 20 µg daily for 24 months. Five patients had previously used bisphosphonates. Main Outcome Measures: Outcome measures included lumbar spine and hip bone mineral density (BMD) by dual-energy X-ray absorptiometry, distal radius peripheral quantitative computed tomography, spinal radiography, serum bone turnover markers, paired iliac crest biopsies. Results: All patients showed increases in formation markers procollagen type 1 amino-terminal propeptide (90% to 398%) and osteocalcin (50% to 280%) and in resorption markers cross-linked C-terminal telopeptide of type I collagen (58% to 457%) and tartrate-resistant acid phosphatase 5b (20% to 68%) in first 6 months. Lumbar spine BMD increased 5.2% to 7.9% in 5 patients and femoral neck BMD 2.6% to 7.8% in 4 patients in 24 months. Distal radius cortical volumetric BMD decreased 5.4% to 26.1%. In histomorphometric analyses, osteoid indices increased more consistently in patients with WNT1 vs PLS3 mutation. Eroded surface decreased 44% to 100% in all patients. Adipocyte number increased in 5 patients studied. Conclusions: Patients with WNT1 or PLS3 mutation-related osteoporosis responded to teriparatide treatment. Future studies are needed to evaluate whether observed changes translate to fracture resistance.

How well are the optimal serum 25OHD concentrations reached in high-dose intermittent vitamin D therapy? a placebo-controlled study on comparison between 100 000 IU and 200 000 IU of oral D3 every 3 months in elderly women.

OBJECTIVE: Intermittent dosing may improve adherence to vitamin D therapy. Dosing regimen should maintain optimal serum 25-hydroxyvitamin D (25OHD) levels over all the year. We compared two dosing regimens, the primary outcome being the percentage of 25OHD measurements reaching the targets of 75 nmol/l or 50 nmol/l after baseline. DESIGN: Randomized, placebo-controlled parallel group comparison. PATIENTS: Sixty women aged 75·0 ± 2·9 years. INTERVENTIONS: 100 000 IU (group 1D) or 200 000 IU (2D) of vitamin D3 or placebo orally every 3 months plus calcium 1 g daily for 1 year. MEASUREMENTS: Serum 25OHD, 1,25-dihydroxyvitamin D, PTH, sclerostin, ionized calcium, urinary calcium, renal function, bone turnover markers. RESULTS: Serum 25OHD increased, but the difference between two doses was of borderline significance (P = 0·0554; area under curve analysis). Immediate postadministrative increases were higher in the 2D vs 1D group (P < 0·05) after 3 and 6 months' dosing. In the 1D and 2D groups, 51·2% and 57·7% of all on-treatment measurements reached the target of 75 nmol/l. PTH levels differed marginally (P = 0·0759) due to tendency to lowering immediately after vitamin D boluses. Urinary calcium differed between the groups (P = 0·0193) due to increases 1 week after vitamin D dosing. CONCLUSIONS: The doses of 100 000 or 200 000 IU of oral cholecalciferol every 3 months were not capable of stabilizing 25OHD levels over the target of 75 nmol/l over the year. To improve the efficacy of high-dose vitamin D therapy, the interval between boluses has to be shortened instead of increasing their size.

[Licorice as the cause of elevated blood pressure and headache?]. / Lakritsiko kohonneen verenpaineen ja päänsäryn syynä?

Physicians are familiar with the effect on potassium metabolism of glycyrrhizine acid contained in licorice and salmiac. Even so, glycyrrhizine acid as the cause of even severe symptoms may escape attention, especially in an emergency situation. We describe a patient, who sought medical advice from an endocrinologist for recurrent, severe and symptomatic hypertension. After the patient had stopped eating salmiac and licorice, the headache that had persisted for years disappeared, fluctuations in weight stabilized and occasional edemas of the lower limbs vanished. Since the cessation of using licorice products normalized the blood pressure, it is likely that the patient had licorice-induced hypertension.

[Hemolysis and metastatic cancer in an elderly man]. / Iäkkään miehen hemolyysi ja levinnyt syöpä.

Sometimes correct diagnoses is reached after many years and even after decades. Our patient had for decades suffered from a hemolytic disease, life-threatening, metastatic cancer at the age of almost 90 years was also suspected. The patient was finally diagnosed as having mild hereditary spherocytosis and the associated paraspinal extramedullar hematopoiesis as well as an osteoporotic vertebral fracture caused by osteoporosis.

Expression of Stem Cell-associated Marker HES77 in Rectal Neuroendocrine Tumors.

BACKGROUND: Expression of novel stem cell-associated marker human embryonic stem cell 77 (HES77) was studied in rectal neuroendocrine tumors (NETs), which comprise 10 to 15% of gastroenteropancreatic NETs, some with metastatic potential. MATERIALS AND METHODS: WHO 2010 classification was applied, and immunohistochemical positivity for HES77 was assessed in 72 primary tumors and 6 metastases. Correlations were calculated between HES77 expression, metastasis and patient survival. RESULTS: Expression of HES77 strongly positively correlated with metastatic potential and poorer prognosis. The proliferative index determined in the metastasis did not correlate with patient survival. CONCLUSION: Novel stem cell-associated marker HES77 has a strong prognostic value in patients with rectal NETs and may be useful in selecting those who are at-risk for developing metastatic disease, and who may benefit from intensive adjuvant therapy. Proliferative index in the metastasis did not predict for outcome. Characterization of the HES77 epitope would certainly enhance the interest in the antibody.

Health-related quality of life is impaired in primary hyperparathyroidism and significantly improves after surgery: a prospective study using the 15D instrument.

Health-related quality of life (HRQoL) is frequently impaired in primary hyperparathyroidism (PHPT) but it is unclear if surgery is beneficial. The objective was to prospectively assess HRQoL in PHPT (n=124) with the 15D instrument before and after surgery, to compare it with that of a comparable sample of the general population (n=4295), and search for predictors of HRQoL and its change. HRQoL, and clinical and laboratory parameters were measured before and at 6 and 12 months after surgery. Regression techniques were used to search for predictors of HRQoL and gains from treatment. Before surgery, PHPT patients had significantly lower mean 15D score compared to controls (0.813 vs 0.904, P<0.001). Excretion, mental function, discomfort and symptoms, distress, depression, vitality, and sexual activity were most impaired (all P<0.001). Number of medications (P=0.001) and subjective symptoms (P<0.05) but not calcium or parathyroid hormone (PTH) predicted impaired HRQoL. Serum 25-hydroxyvitamin D (25OHD) was of borderline significance (P=0.051). Compared to baseline, mean 15D score improved significantly 6 months after surgery (0.813 vs 0.865, P<0.001) and the effect sustained at 1 year (0.878, P<0.001). The improvement was clinically important in 77.4% of patients (P<0.001). Educational level independently predicted improvement (P<0.005). HRQoL is severely impaired in PHPT but improves significantly after surgery. The 15D is a sensitive tool for assessing HRQoL and recognizing patients likely to benefit from surgery.

PROX1 is involved in progression of rectal neuroendocrine tumors, NETs.

PROX1 is a homeobox transcription factor involved in the development of the lens, liver and heart and found upregulated in colorectal cancers. We studied PROX1 expression by immunohistochemistry in rectal neuroendocrine tumors (NETs). Approximately 10 to 15 % of gastroenteropancreatic NETs occur in the rectum, and some may metastasize. Yet little is known about the molecular pathogenesis of rectal NETs or their metastasis propensity. The objectives were to find out whether PROX1 plays a role in progression of rectal NETs and whether it has value as prognostic marker. In grading of rectal NETs, we applied the WHO 2010 classification. We carried out immunohistochemical staining of PROX1 on 72 primary tumors and six metastases and evaluated nuclear positivity in each tumor. Correlation between PROX1 expression, metastasis and patient survival was then assessed. Annexin A1, a downstream target of PROX1, was immunohistochemically assessed in 18 tumors. PROX1 protein was detected in about half of the tumors, with stronger expression in metastasized cases. PROX1 expression correlated with tumor metastasis and patient prognosis. Annexin A1 was negative in most of the high-grade tumors correlating strongly with grade and metastatic potential. Our results indicate that immunohistochemical detection of PROX1 correlates with a more malignant phenotype in rectal NETs. High PROX1 expression was associated with increased metastatic potential and poor patient survival but not as strongly as grade by the WHO 2010 classification. PROX1 may be involved in progression of rectal NETs as a part of the Wnt pathway.

Cinacalcet Treatment in an Adolescent With Concurrent 22q11.2 Deletion Syndrome and Familial Hypocalciuric Hypercalcemia Type 3 Caused by AP2S1 Mutation.

CONTEXT: The 22q11.2 deletion syndrome (DS) is a common multiple anomaly syndrome in which typical features include congenital heart defects, facial dysmorphism, and palatal anomalies. Hypocalcemia due to hypoparathyroidism is a common endocrine manifestation resulting from variable parathyroid hypoplasia, but hypercalcemia has not previously been reported in 22q11.2 DS. CASE DESCRIPTION: Our patient is a 16-year-old adolescent male with dysmorphic facial features and delayed motor and speech development. At 2 years of age, 22q11.2 DS was confirmed by fluorescence in situ hybridization. In contrast to hypoparathyroidism that is usually seen in 22q11.2 DS, this patient had early childhood-onset hypercalcemia with inappropriately high PTH levels and hypocalciuria. Genomic DNA was obtained from the proband and screened for calcium-sensing receptor (CASR) mutations with negative results. No parathyroid tissue could be localized by imaging or surgical exploration. As a result of symptomatic hypercalcemia, the patient was treated with a calcimimetic (cinacalcet). During the treatment, plasma calcium normalized with mild symptoms of hypocalcemia. After discontinuation of cinacalcet, calcium returned to high pretreatment levels. Further DNA analysis of adaptor protein-2 σ subunit (AP2S1) showed a heterozygous missense mutation c.44 G>T, resulting in a p.R15L substitution; the mutation was absent in the healthy parents and two siblings. CONCLUSIONS: Hypercalcemia in our patient with 22q11.2 DS could be explained by the de novo mutation in AP2S1. Identification of a genetic cause for hypercalcemia is helpful in guiding management and avoiding unnecessary treatment.

(99m)Technetium Sestamibi-(123)Iodine Scintigraphy Is More Accurate Than (99m)Technetium Sestamibi Alone before Surgery for Primary Hyperparathyroidism.

Objectives. Studies comparing outcome of single-(99m)Tc-methoxyisobutylisonitrile ((99m)Tc-sestamibi) and dual-tracer (99m)Tc-sestamibi scintigraphy in combination with (123)I before primary surgery of primary hyperparathyroidism (PHPT) are scarce. Methods. We compared (99m)Tc-sestamibi/(123)I and (99m)Tc-sestamibi in a single-centre retrospective series of 269 PHPT patients. The results were related to laboratory, surgical and histological findings. Results. (99m)Tc-sestamibi/(123)I and (99m)Tc-sestamibi were positive in 206 (76.6%) and 111 (41.3%) of 269 patients, respectively (P < 0.001). Accuracies for (99m)Tc-sestamibi/(123)I and (99m)Tc-sestamibi were 63.4% and 34.9%, respectively (96% CI, P < 0.001). Prevalence of multiglandular disease was 15.2%. In multiglandular disease, (99m)Tc-sestamibi/(123)I and (99m)Tc-sestamibi revealed 43.8 and 22.1% of pathological glands, respectively (P < 0.001). Cure rate was similar for patients with (191/206; 92.7%) and without (59 of 63; 93.7%) a positive (99m)Tc-sestamibi/(123)I finding. Duration of targeted surgery (one or two quadrants) was 21 and 15 minutes shorter than bilateral neck exploration, respectively (both P < 0.001). Higher serum calcium (P = 0.014) and PTH (P = 0.055) concentrations and larger tumours (P < 0.001) characterized the 206 patients with a positive preoperative scan who were cured by removal of a single adenoma. Conclusions. (99m)Tc-sestamibi/(123)I scintigraphy is more accurate than (99m)Tc-sestamibi before surgery of PHPT. However, outcome of surgery is not determined by scintigraphy alone.

A novel splice mutation in PLS3 causes X-linked early onset low-turnover osteoporosis.

Genetic factors play an important role in the development of osteoporosis. Several monogenic forms of osteoporosis have been recognized, most recently an X-chromosomal form resulting from mutations in the gene encoding plastin 3 (PLS3). PLS3 is a protein involved in actin bundle formation in the cytoskeleton. We present a large family with early onset osteoporosis and X-linked inheritance. Phenotyping was performed on 19 family members and whole-exome sequencing on 7 family members (5 with a diagnosis of early onset osteoporosis and 2 with normal bone parameters). Osteoporosis had its onset in childhood and was characterized by recurrent peripheral fractures, low bone mineral density (BMD), vertebral compression fractures, and significant height loss in adulthood. Males were in general more severely affected than females. Bone histomorphometry findings in 4 males and 1 female showed severe trabecular osteoporosis, low amount of osteoid, and decreased mineral apposition rate, indicating impaired bone formation; resorption parameters were increased in some. All affected subjects shared a single base substitution (c.73-24T > A) in intron 2 of PLS3 on Xq23. The mutation, confirmed by Sanger sequencing, segregated according to the skeletal phenotype. The mutation introduces a new acceptor splice site with a predicted splice score of 0.99 and, thereby, as confirmed by cDNA sequencing, induces the insertion of 22 bases between exons 2 and 3, causing a frameshift and premature termination of mRNA translation (p.Asp25Alafs*17). The mutation affects the first N-terminal calcium-binding EF-hand domain and abolishes all calcium- and actin-binding domains of the protein. Our results confirm the role of PLS3 mutations in early onset osteoporosis. The mechanism whereby PLS3 affects bone health is unclear, but it may be linked to osteocyte dendrite function and skeletal mechanosensing. Future studies are needed to elucidate the role of PLS3 in osteoporosis and to define optimal treatment.

Cyclin A predicts metastatic potential of rectal neuroendocrine tumors.

Rectal neuroendocrine tumors (NETs) are rare tumors representing 10% to 15% of gastroenteropancreatic NETs. The grade of these tumors, according to the World Health Organization (WHO) 2010 classification and based on Ki-67 index and mitotic count, correlates with their metastatic potential. We studied the expression of a cell cycle regulatory protein, cyclin A, in rectal NETs. Our tumor series of rectal NETs comprised 73 tumors, of which 71 cases were available for immunohistochemistry. We assessed how well expression of cyclin A predicts the occurrence of metastatic lesions. Expression of cyclin A correlated well with metastatic potential because all tumors with high expression (≥5%) were metastatic. Cyclin A expression and WHO 2010 grade were independent prognostic factors. Cyclin A failed to recognize 3 metastatic tumors classified as grade 2 tumors. On the other hand, 2 grade 2 tumors with low expression of cyclin A remained local. The WHO 2010 classification showed excellent prognostic accuracy for rectal NETs. Additional reliable prognostic tools would nevertheless be valuable. This study showed cyclin A expression to correlate well with metastatic potential. Both cyclin A and WHO 2010 grade were very specific in identifying patients at risk for metastasis (100% versus 96%). Grade was more sensitive (100% versus 60%). Tumors with strong expression of both cyclin A and Ki-67 were all metastatic, and these patients will require careful monitoring and may benefit from adjuvant therapy.

Comparison of two growth hormone stimulation tests and their cut-off limits in healthy adults at an outpatient clinic.

OBJECTIVE: A peak GH less than 3 µg/L to insulin tolerance test (ITT) is commonly used as a threshold indicating severe adult GH deficiency (GHD). This cut-off is based on results obtained by polyclonal radioimmunoassays preferably under standard conditions at hospital. Our aim was to evaluate the validity of this cut-off limit using two currently used immunometric GH assays and to compare GH responses in the ITT and the GH releasing hormone + arginine (GHRH + ARG) test in healthy adults at our outpatient endocrine unit. DESIGN: ITT was performed on 73 subjects and the GHRH + ARG test on those 28 who showed insufficient response to the ITT. METHODS: GH was measured by an immunofluorometric and immunochemiluminometric assay. RESULTS: GH peak above 3 µg/L was observed in 56% of the healthy volunteers with adequate hypoglycemia in the ITT. Among the 28 subjects with a peak GH below 3 µg/L, only two overweight men had a GH peak response below the commonly used cut-off limit of 9.1 µg/L in the GHRH + ARG test. CONCLUSIONS: Lean healthy adults could erroneously be classified as GH deficient by the ITT while their results in the GHRH + ARG test were normal. The GH results are highly dependent on the immunoassay used, but false positive results in the ITT are often obtained even if lower cutoff limits determined on the basis on the calibration of the GH assay are used. Confounding factors seemed to blunt the GH response to the ITT more than to the GHRH + ARG test at our outpatient clinic.

Planar scintigraphy with 123I/99mTc-sestamibi, 99mTc-sestamibi SPECT/CT, 11C-methionine PET/CT, or selective venous sampling before reoperation of primary hyperparathyroidism?

UNLABELLED: All patients with primary hyperparathyroidism should undergo localization studies before reoperation, but it is not known which method is most accurate. The purpose of this prospective study was to compare the performance of planar scintigraphy with (123)I/(99m)Tc-sestamibi, (99m)Tc-sestamibi SPECT (SPECT/CT), (11)C-methionine PET/CT, and selective venous sampling (SVS) in persistent primary hyperparathyroidism. METHODS: Twenty-one patients referred for reoperation of persistent hyperparathyroidism were included and investigated with (123)I/(99m)Tc-sestamibi, SPECT/CT (n = 19), (11)C-methionine PET/CT, and SVS (n = 18) before reoperation. All patients had been operated on 1-2 times previously because of hyperparathyroidism. The results of the localization studies were compared with operative findings, histology, and biochemical cure. RESULTS: Eighteen (86%) of 21 patients were biochemically cured. Nineteen parathyroid glands (9 adenomas, 1 atypical adenoma, and 9 hyperplastic glands) were removed from 17 patients, and 1 patient who was biochemically cured had an unclear histology result. The accuracy for localizing a pathologic parathyroid gland to the correct side of the neck was 59% (95% confidence interval [CI], 36%-79%) for (123)I/(99m)Tc-sestamibi, 19% (95% CI, 5%-42%) for SPECT/CT, 65% (95% CI, 43%-84%) for (11)C-methionine PET/CT, and 40% (95% CI, 19%-65%) for SVS (P < 0.01 for (123)I/(99m)Tc-sestamibi vs. SPECT/CT). The corresponding accuracy for the correct quadrant or more specific site was 48% (95% CI, 27%-69%) for (123)I/(99m)Tc-sestamibi, 14% (95% CI, 3%-36%) for SPECT/CT, 61% (95% CI, 39%-80%) for (11)C-methionine PET/CT, and 25% (95% CI, 9%-49%) for SVS (P < 0.02 for (123)I/(99m)Tc-sestamibi vs. SPECT/CT). In the 3 patients not cured, preoperative (123)I/(99m)Tc-sestamibi and SPECT/CT remained negative, SVS was false predictive in all, and (11)C-methionine PET/CT in 1. (11)C-methionine PET/CT accurately revealed the pathologic gland in 4 of 8 (50%) patients with a negative (123)I/(99m)Tc-sestamibi scan result, all of whom were biochemically cured after reoperation. CONCLUSION: Planar scintigraphy with (123)I/(99m)Tc-sestamibi performs well in complicated primary hyperparathyroidism and is recommended as first-line imaging before reoperation. (11)C-methionine PET/CT provides valuable additional information if (123)I/(99m)Tc-sestamibi scan results remain negative. (99m)Tc-sestamibi SPECT/CT and SVS provide no additional information, compared with the combined results of (123)I/(99m)Tc-sestamibi and (11)C-methionine PET/CT imaging.

The effectiveness of teriparatide in the clinical practice--attenuation of the bone mineral density outcome by increasing age and bisphosphonate pretreatment.

BACKGROUND: Teriparatide is a potent anabolic agent for severe osteoporosis. OBJECTIVES: A primary objective of this retrospective study was to define the efficacy of teriparatide in terms of bone mineral density (BMD) changes and relief of back pain in clinical practice. METHODS: The patient population comprises 119 osteoporotic patients treated with teriparatide for median 539 (range 179-926) days. RESULTS: The mean BMD gain was 0.9% in the total hip (P = 0.0075), 2.1% in the femoral neck (P = 0.0006), and 8.5% in the lumbar spine (P = 0.0085). In the whole patient population age associated inversely with BMD changes in the total hip (P = 0.019) and in the femoral neck (P = 0.0036). A history of significant bisphosphonate pretreatment (n = 90) reduced BMD response in the total hip (P = 0.039). The total exposure of any prior bisphosphonate was negatively correlated with BMD response in the total hip (P = 0.0421). Half of the patients reported relief of back pain during the treatment. Leg pain, nausea, and dizziness were most frequent adverse concerns. CONCLUSIONS: Teriparatide works in clinical practice as well as in clinical trials. Younger subjects benefited more than older patients from teriparatide in the total hip and in the femoral neck. Bisphosphonate pretreatment attenuated teriparatide-induced BMD gain.

BRAF V600E mutation does not predict recurrence after long-term follow-up in TNM stage I or II papillary thyroid carcinoma patients.

The BRAF V600E mutation may serve as a marker of disease recurrence in well-differentiated papillary thyroid cancer (PTC). Our aim was to study if TNM stage I or II PTC patients, with and without recurrence after long-term follow-up would differ in BRAF status. BRAF status was retrospectively determined in tumour tissue from a cohort of low-risk PTC patients (n = 461) with and without recurrence after 16 years of follow-up. Initial treatment was total thyroidectomy (TTE) and radioiodine remnant ablation (RRA). Forty-six patients (9.9%) experienced disease recurrence. BRAF mutation was positive in 66% (17/26) of patients with and 68% (17/25) without recurrence (p = NS). Fifty per cent of BRAF positive and 53% of BRAF negative patients experienced disease recurrence (p = NS). Time to recurrence was 52 (range 18-144) and 36 (range 16-71) months, respectively (p = NS). Primary tumour size, nodal metastasis and local infiltration at presentation did not differ between BRAF positive and negative patients (2.0 vs 2.2 cm, 21% vs 35% and 6% vs 12%, respectively, all p = NS). Taken together, BRAF V600E is common in Finnish patients with low-risk PTC but does not predict recurrence after long-term follow-up after initial treatment with TTE and RRA.