Comparative Effect of Zoledronate at 6 Versus 18 Months Following Denosumab Discontinuation.

Discontinuation of denosumab treatment is associated with rapid bone loss that could be prevented in many patients by zoledronate (ZOL) infusion given 6 months after the last denosumab injection. The effects, however, of zoledronate administration at a later time point are unknown. We aimed to compare the 1-year effect of ZOL infusion given 6 versus 18 months following the last Dmab injection. In this extension of a previously reported 2-year randomized clinical trial, we included initially treatment-naive postmenopausal women, who became osteopenic after approximately 2.5 years of denosumab therapy, and were subjected to a single ZOL infusion at 6 months (early-ZOL, n = 27) versus 18 months (late-ZOL, n = 15) after the last Dmab injection. Annual changes in lumbar spine (LS) and femoral neck (FN) bone mineral density (BMD), and markers of bone turnover (P1NP, CTx) at 6 and 12 months following ZOL infusion were assessed. LS BMD was maintained in both early-ZOL (+ 1.7%) and late-ZOL (+ 1.8%) infusion with no difference between groups (p = 0.949). FN BMD was maintained in early-ZOL (+ 0.1%) and increased in late-ZOL (+ 3.4%) infusion with no difference between groups (p = 0.182). Compared to 6 months after last Dmab injection, the overall LS BMD change of the late-ZOL group (- 3.5%) was significantly different (p = 0.007) from that of the early-ZOL group (+ 1.7%). P1NP and CTx gradually increased in the early-ZOL group, while profoundly decreased and remained suppressed in the late-ZOL infusion. A ZOL infusion 18 months following the last Dmab injection is still useful in terms of BMD maintenance and BTM suppression. However, there is no clear clinical benefit compared to the early infusion, while any theoretical advantage is counterbalanced from the expected bone loss, especially at the LS, and the risk of rebound-associated fractures.Trial Registration: NCT02499237; July 16, 2015.

Denosumab effects on bone density and turnover in postmenopausal women with low bone mass with or without previous treatment.

PURPOSE: Prior osteoporosis therapies may affect the skeletal response to denosumab. We compared the effect of denosumab (60 mg every 6 months for 12 months) on bone mineral density and bone metabolism parameters in postmenopausal women with low bone mass who were either treatment-naïve (n = 30), or previously treated either with zoledronic acid (n = 30), or teriparatide (n = 22). METHODS: We assessed lumbar spine bone mineral density (BMD) and measured serum concentrations of the bone turnover markers pro-collagen type 1 N-terminal propeptide (PINP) and C-terminal-cross-linking telopeptide of type 1 collagen (CTX), as well as sclerostin, dickkopf-1 (Dkk-1), and myostatin. RESULTS: Lumbar spine BMD increased equivalently in all three groups after 12 months of denosumab compared to baseline (p < 0.001). Serum PINP and CTX decreased significantly with denosumab in pre-treated women reaching the same nadir levels as in treatment-naïve patients (p < 0.001). Women pre-treated with teriparatide displayed lower baseline myostatin concentrations as compared to the other two groups (p < 0.001). Changes in lumbar spine BMD in teriparatide pre-treated women correlated with changes in bone turnover markers and myostatin. CONCLUSIONS: Denosumab induced similar increases in lumbar spine BMD in treatment-naïve and pre-treated patients and suppressed serum PINP and CTX to the same levels regardless of prior treatments. In teriparatide pre-treated patients the magnitude of change in bone turnover markers is associated with BMD response.

Loss of Efficacy of Pasireotide After its Re-Administration: is There a Reason Why?

Pasireotide is a recently approved medical treatment for persistent or recurrent Cushing's disease (CD). However, an escape from the initial successful response has not yet been described. A 42-year-old female presented with several symptoms indicative of hypercortisolism. Biochemical evaluation and imaging were consistent with CD due to a pituitary adenoma. Surgical excision of the adenoma was unsuccessful and gamma-knife radiosurgery was followed. Our patient remained hypercortisolemic thus treatment with pasireotide (900 mg subcutaneously twice daily) was decided. Biochemical and clinical remission was noted shortly thereafter. Moderate adverse events led to dose reduction to 600 mg subcutaneously twice daily. The patient remained in remission for 6 months, when treatment was discontinued due to cholecystitis. One month after cholecystectomy, pasireotide was restarted with no clinical or biochemical benefit that time. Pasireotide is an effective medical treatment for CD. Nevertheless, a loss of its initial efficacy may rarely be described.

Treatment compliance and severe adverse events limit the use of tyrosine kinase inhibitors in refractory thyroid cancer.

OBJECTIVE: The aim of the present study was to assess patient compliance with tyrosine kinase inhibitor (TKI) treatment used for refractory and progressive thyroid cancer, in addition to the efficacy and serious adverse events associated with these agents. METHODS: We retrospectively analyzed data from adult patients with metastatic differentiated or medullary thyroid cancer unresponsive to conventional treatment and treated with TKIs. Patients received treatment until disease progression or onset of serious adverse events, or until they expressed an intention to stop treatment. RESULTS: Twenty-four patients received TKIs. The median duration of treatment was four (range: 1-19) cycles. The most frequent adverse events were fatigue, nausea, diarrhea, hypertension, and stomatitis, and the most severe were nasal bleeding, diarrhea, heart failure, rhabdomyolysis, renal failure, QT prolongation, neutropenia, and severe fatigue. Dose reduction was required in eight patients, while five decided to terminate TKI therapy because adverse events impaired their everyday activities. During therapy, two patients showed a partial response and three showed stable disease. The lungs were the metastatic sites favoring a response to treatment. CONCLUSION: Patient selection and meticulous pretreatment education are necessary in order to ensure adherence with TKI therapy. If adverse events appear, dose reduction or temporary treatment interruption may be offered because some adverse events resolve with continuation of treatment. In the event of serious adverse events, treatment discontinuation is necessary.

Breast Metastasis from Medullary Thyroid Carcinoma in a Male Patient: Case Report and Review of the Literature.

Medullary thyroid carcinoma (MTC) is a rare malignancy that may metastasize to liver, lungs and bones. Breast is an unusual metastatic site for MTC and only 20 female cases have been reported in the literature. We present a male patient in whom histological examination and immunohistochemistry of a breast mass were indicative of breast metastasis from MTC. A 67-year-old man with recent diagnosis of MTC and metastases to cervical and upper mediastinum lymph nodes was referred to our department for further treatment. At first evaluation, diagnostic imaging techniques showed lung and bone metastases and three months later the presence of liver metastases. Due to the extension of the disease, treatment with vandetanib was decided, but serious adverse events led to its interruption after two weeks. During follow-up, patient developed a painful swelling in the right breast. Ultrasound and mammography showed the presence of multiple masses to the right breast suspicious for malignancy. Core needle biopsy and histological examination of the specimen confirmed the presence of metastatic MTC. Palliative external beam irradiation was used to relieve local pain and, after one month, the patient died. Consequently, breast masses should be cautiously evaluated, mainly in the presence of a known primary malignancy. Histological and/or cytopathological examination are requisite diagnostic tools, while external beam irradiation and tyrosine kinase inhibitors may be used as palliative therapies in the concurrent presence of breast metastases from MTC.

Papillary thyroid carcinomas in patients under 21 years of age: clinical and histologic characteristics of tumors ≤10 mm.

OBJECTIVE: To compare clinical and histologic characteristics of papillary thyroid carcinomas (PTCs) ≤10 mm in patients ≤21 years old with larger ones and with microcarcinomas in adults. STUDY DESIGN: Retrospective study of patients with PTC diagnosed between 1983 and 2012. Medical records were reviewed and information about age, sex, tumor size, intra/extrathyroid extension, lymph node, and distant metastases were collected. RESULTS: Patients ≤21 years old (n = 93) and adults (n = 1235) with PTC were identified. Among the former, 34 had PTC ≤10 mm (37.4%) and among the latter, 584 had papillary thyroid microcarcinoma (PTM) (47.3%), P = .082. Patients with tumors ≤10 mm less frequently had extrathyroidal extension and lymph node metastases compared with larger tumors (8.8% vs 33.3%, P = .017, and 60.0% vs 95.2%, P = .001, respectively). The percentage of PTC ≤10 mm increased with age (7.1%, 32.0%, and 48.1% in age groups ≤15, 15-18, and >18 to ≤21 years old, respectively; P = .016). Mean tumor size was larger (6.8 ± 2.7 vs 5.8 ± 2.8 mm, P = .030), and lymph nodes metastases were more frequent (41.2% vs 18.6%, P = .003) in patients ≤21 years of age compared with adults with PTM. The frequency of multifocal cancers decreased between 1983-1992, 1993-2002, and 2003-2012 (66.7%, 53.6%, and 27.1%, respectively, P = .019). CONCLUSIONS: The frequency of PTC ≤10 mm is low in children, increases in adolescents, and reaches that of adults at 18-21 years of age. Mean tumor size is larger and metastases to regional lymph nodes more frequent in comparison with PTM in adults. Whether their treatment and follow-up could be based on guidelines used for PTM in adults is questionable.

Thyroid cancer after in vitro fertilization: a retrospective, non-consecutive case-series analysis.

Although a firm association between fertility treatment and thyroid cancer has not been established, the widespread use of IVF, as a substantial reservoir of subclinical thyroid cancer disease and evidence suggesting an estrogen-dependent behavior may render thyroid cancer patients after IVF a distinct subpopulation of particular interest. Thus, a retrospective, non-consecutive case-series analysis of patients with history of thyroid cancer after in vitro fertilization was conducted. Twelve female patients with thyroid cancer who had previously undergone IVF treatment were identified within the cohort of thyroid cancer patients followed in our institution. All cases of thyroid cancer were papillary thyroid carcinoma (PTC) on histology and median tumor size (25th and 75th percentile) was 12 mm (7 and 17 mm). Thyroid cancer was diagnosed after a median of 4 years (2 and 6 years) from the last IVF cycle and at the time of diagnosis lymph node metastases were present in five patients (42%) and distant metastases where seen in four of them. Collectively, these data suggest that an aggressive pattern of PTC might be present in this distinct subpopulation. This preliminary observation may be explained, at least in part, by the delay in the diagnosis.

Predictive factors that influence the course of medullary thyroid carcinoma.

BACKGROUND: Medullary thyroid cancer (MTC) is an infrequent form of thyroid cancer. We aimed to examine how gender and histological characteristics influence the rate of recurrence/persistent disease, distant metastases and survival and also to define specific characteristics of MTC microcarcinomas. METHODS: The medical records of 85 patients with MTC were reviewed. The following characteristics were recorded: year of diagnosis, age at diagnosis, sex, tumor size, number of tumor foci, lymph node metastases, thyroid capsule and vascular invasion, infiltration of thyroid parenchyma and extrathyroid extension, and distant metastases. RESULTS: During follow-up (mean 78.8 months), persistent disease occurred in 40 patients, local recurrences in 5 and distant metastases in 32 patients. Local and distant disease appeared more frequently in patients with larger tumors (p < 0.005) and lymph node metastases (p < 0.01). In addition, patients with invasive tumors had local and distant disease more frequently. The percentage of males who had persistent disease and/or local recurrence was significantly higher than the percentage of males who did not (p < 0.05). Similar results were observed for distant disease (p < 0.01). Independent predictors of recurrence and persistent disease was the presence of lymph node metastases at diagnosis (risk ratio 11.66) and of distant metastases were the presence of lymph node metastases at diagnosis (risk ratio 17.42) and the presence of vascular invasion (risk ratio 2.41). Fifteen patients died due to MTC during follow-up (17.6 %). Patients who died were more frequently males, and had thyroid capsule invasion, extrathyroidal extension, vascular invasion and metastatic disease. CONCLUSIONS: Male sex, tumor size and invasive characteristics of the tumor are negative predictive factors for evolution of MTC.

Acute adrenal insufficiency following arthroplasty: a case report and review of the literature.

BACKGROUND: Acute adrenal insufficiency is a potentially lethal condition rarely caused by bilateral adrenal haemorrhage due to heparin use. Most of the times, it is difficult to establish the diagnosis, as symptoms are not specific. Few cases have been reported in the literature. CASE PRESENTATION: A 52-year-old Caucasian woman presented with abdominal pain, vomiting and weakness nine days after arthroplasty and heparin use. Hyperkalemia, low cortisol and high adrenocorticotropic hormone levels were found, indicating adrenal insufficiency. Magnetic resonance imaging of the upper abdomen was compatible with preceding adrenal haemorrhage. Hydrocortisone and fludrocortisone were administered. Review of the literature revealed 36 cases of postoperative adrenal haemorrhage which are presented briefly. CONCLUSION: Postoperative acute adrenal insufficiency due to haemorrhage is a rare condition. If patients are treated based on clinical suspicion, they have good chances to survive. Hydrocortisone is given permanently in the majority of the patients.

Parathyroid involvement in thyroid cancer: an unforeseen event.

BACKGROUND: Parathyroid metastatic disease from thyroid cancer has not been studied extensively, mainly due to the need for parathyroid preservation during thyroid surgery. METHODS: We reviewed files from 1,770 patients with thyroid cancer followed up in our department and 10 patients with parathyroid metastases (0.5%) were identified. Patient and tumor characteristics were recorded. RESULTS: Six out of ten patients had metastases from papillary thyroid cancer, three from follicular thyroid cancer and one from anaplastic thyroid cancer. In nine patients parathyroid infiltration from thyroid cancer was found in direct contact with the thyroid cancer, and in one patient metastatic foci were observed not in continuity with the thyroid cancer. CONCLUSIONS: Parathyroid involvement, although infrequent, may occur in thyroid cancer independently of patient age and tumor size. The clinical significance of such event is not clear. The influence on disease outcome remains to be elucidated.

99mTc pertechnetate thyroid scan leads to serendipitous detection of metastatic thyroid cancer.

99mTc pertechnetate is considered insensitive in detecting thyroid carcinoma metastases. We report the case of a 71-year-old male patient, in whom metastasis of an unknown thyroid cancer was diagnosed incidentally on a routine 99mTc pertechnetate scan, performed for the assessment of nodular thyroid disease. Marked tracer accumulation was unexpectedly noted on the left frontal region, where a palpable, painless, soft tissue mass was present. Surgical excision of the mass revealed metastatic poorly differentiated thyroid carcinoma synchronous to soft tissue and adjacent bone.