Correction to: Hip fracture trends in the United States, 2002 to 2015.

The name of the first author, E.M. Lewiecki, was rendered incorrectly in the original publication. The publisher regrets any inconvenience and is pleased to correct the error here.

Hip fracture trends in the United States, 2002 to 2015.

An analysis of United States (US) Medicare claims data from 2002 to 2015 for women aged ≥ 65 years found that age-adjusted hip fracture rates for 2013, 2014, and 2015 were higher than projected, resulting in an estimated increase of more than 11,000 hip fractures. INTRODUCTION: Hip fractures are a major public health concern due to high morbidity, mortality, and healthcare expenses. Previous studies have reported a decrease in the annual incidence of hip fractures in the US beginning in 1995, coincident with the introduction of modern diagnostic tools and therapeutic agents for osteoporosis. In recent years, there has been less bone density testing and fewer prescriptions for osteoporosis treatments. The large osteoporosis treatment gap raises concern of possible adverse effects on hip fracture rates. METHODS: We assessed hip fracture incidence in the US to determine if the previous decline in hip fracture incidence continued. Using 2002 to 2015 Medicare Part A and Part B claims for women ≥ 65 years old, we calculated age-adjusted hip fracture rates, weighting to the 2014 population. RESULTS: We found that hip fracture rates declined each year from 2002 to 2012 and then plateaued at levels higher than projected for years 2013, 2014, and 2015. CONCLUSIONS: The plateau in age-adjusted hip fracture incidence rate resulted in more than 11,000 additional estimated hip fractures over the time periods 2013, 2014, and 2015. We recommend further study to assess all factors contributing to this remarkable change in hip fracture rate and to develop strategies to reduce the osteoporosis treatment gap.

Inhibition of growth hormone receptor activation by pegvisomant may increase bone density in acromegaly.

Treatment of acromegaly with pegvisomant lowers serum IGF-1 and raises serum growth hormone. As both IGF-1 and GH are important for bone growth and remodeling, we were concerned that lowering of IGF-1 could cause loss of bone. To evaluate the effects of treatment of acromegaly with pegvisomant on bone mineral density (BMD) we developed an observational, prospective study. 7 acromegaly patients participated in the study. Male and female subjects aged 18 years or more were eligible to participate. Patients were eugonadal or on adequate gonadal replacement therapy for at least 3 years before participating in the study. These patients were treated with a mean dosage of 20 mg of pegvisomant daily for up to 7 years. Bone mineral density (BMD) was evaluated by dual X-ray absorbtiometry (DXA) at baseline, 8, and 18 months as a part of a prospective trial and periodically thereafter. Baseline mean serum insulin-like growth factor-1 (IGF-1) concentration±SD was elevated in all patients (679.86±138.21 ng/ml). The IGF-1 concentrations at 18 months decreased significantly from baseline (p=0.016). Wilcoxon signed-rank tests showed significant increases in the spine BMD from baseline to 18 months (p=0.016) and significant increases in the right hip BMD from baseline to 18 months (p=0.032). The range of the increases was 4.3-17.8% at 7 years. It is concluded that successful treatment of acromegaly with pegvisomant increases BMD.

Beyond RET: potential therapeutic approaches for advanced and metastatic medullary thyroid carcinoma.

Medullary thyroid carcinoma (MTC) is a rare calcitonin-producing neuroendocrine tumour that originates from the parafollicular C-cells of the thyroid gland. The RET proto-oncogene encodes the RET receptor tyrosine kinase, which has essential roles in cell survival, differentiation and proliferation. Activating mutations of RET are associated with the pathogenesis of MTC and have been demonstrated in nearly all hereditary and in 30-50% of sporadic MTC cases, making this receptor an excellent target for small-molecule inhibitors for this tumour. Clinical trials of small organic inhibitors of tyrosine kinase receptors (TKIs) targeting the RET receptor have shown efficacy for treatment of metastatic MTC with 30-50% of patients responding to these agents. Despite the importance of the RET receptor in MTC, it is clear that other signal transduction pathways, tyrosine kinase receptors, and tumour suppressor genes are involved in MTC tumourigenesis and progression. A better understanding of molecular cross-talk between these signal pathways and the RET receptor may lead to combinatorial therapy that will improve outcomes beyond what is currently possible with RET-directed TKIs. Finally, there is evidence that immunological-based therapy using dendritic cell vaccination strategies have been effective for reducing tumour mass in a small number of patients. The identification of additional MTC-specific tumour antigens and a better understanding of specific epitopes in these tumour antigens may lead to improvement of response rates.

Allelic imbalance of the mutant and wild-type RET allele in MEN 2A-associated medullary thyroid carcinoma.

Germline mutations of the RET proto-oncogene are responsible for the familial tumor syndrome called multiple endocrine neoplasia type 2 (MEN 2) that includes medullary thyroid carcinoma (MTC). Although inherited mutations of RET lead to tumor formation in patients with MEN 2, it is not understood why only selected cells develop into tumors. We have recently shown that duplication of the mutated RET allele or loss of the wild-type allele might represent mechanisms of tumorigenesis in patients with MEN 2A-related pheochromocytoma. We now analysed 19 DNA samples of MTC (15 of which were non-microdissected, four of which were microdissected) from patients with MEN 2A. Using polymorphic marker and phosphorimage densitometry analyses, we found allelic imbalance of the mutated and wild-type RET allele in six of 19 DNA MTC samples. Of note, two of the four microdissected tumor DNA samples showed allelic imbalance of RET, whereas only four of the 15 non-microdissected MTC samples did. These results underscore the significance of microdissection in the analysis of tumor DNA. In our study, some of the non-microdissected tumor DNA samples may have failed to display allelic imbalance of RET, because of contamination of tumor DNA with nonneoplastic DNA or noninformative microsatellite marker analysis. Taken together, our results suggest allelic imbalance between mutated and wild-type RET as a possible mechanism for tumor formation in some patients with MEN 2A-related MTC.

Evaluation and surgical resection of adrenal masses in patients with a history of extra-adrenal malignancy.

BACKGROUND: Adrenal abnormalities are often identified on imaging studies performed during the staging of patients presenting with a new malignancy or restaging of patients with a history of a malignancy. METHODS: We reviewed the records of patients who underwent surgical resection of an adrenal mass identified in the setting of previously or newly diagnosed extra-adrenal malignancy. RESULTS: Eighty-one patients with an adrenal mass and recently diagnosed malignancy (n = 24) or history of a malignancy (n = 57) underwent adrenalectomy. In 42 patients (52%) the adrenal mass was a metastasis. In 39 patients (48%) the adrenal mass was an additional primary adrenal tumor process: 19 pheochromocytomas, (14 syndrome-associated, 5 sporadic), 13 cortical adenomas, 3 adrenocortical carcinomas, 2 ganglioneuromas, and 2 cases of nodular hyperplasia. CONCLUSIONS: In this series nearly half of the patients with cancer and an adrenal mass had adrenal pathologic condition independent of their primary malignancy. Despite the presence of a newly diagnosed malignancy or history of malignancy, all patients with an adrenal mass should undergo a standard hormone evaluation to confirm that the mass is not a functional neoplasm. An assumption that the adrenal mass is metastatic disease will be wrong in up to 50% of such patients.

Nonfunctioning islet cell carcinoma of the pancreas: survival results in a contemporary series of 163 patients.

BACKGROUND: The natural history of nonfunctioning islet cell carcinoma of the pancreas is poorly defined. We therefore reviewed our institutional experience during a period of 12 years to define more clearly the natural history of this disease as a basis for individual therapeutic recommendations. METHODS: The records of all patients who had histologically or cytologically confirmed nonfunctioning islet cell carcinoma of the pancreas were retrospectively reviewed. Patients were grouped by extent of disease at diagnosis and by initial treatment. Survival distributions were estimated by Kaplan-Meier analysis. RESULTS: One hundred sixty-three patients with nonfunctioning islet cell carcinoma of the pancreas were identified. The overall median survival duration was 3.2 years. The median survival was 7.1 years in patients with localized disease who underwent a potentially curative resection and 5.2 years in those with locally advanced, unresectable, nonmetastatic disease (P = .04). Patients with metastatic disease that could not be resected had a median survival of 2.1 years. CONCLUSIONS: Patients with completely resected localized disease had a long median survival. Patients with nonmetastatic but unresectable locally advanced disease also had a surprisingly long median survival; major treatment-related morbidity may be hard to justify in this subgroup. The short median survival in patients with metastatic disease suggests that the frequent practice of observation in this patient subgroup needs to be reexamined and that continued investigation of regional and systemic therapies with novel agents is warranted.

Guidelines for diagnosis and therapy of MEN type 1 and type 2.

This is a consensus statement from an international group, mostly of clinical endocrinologists. MEN1 and MEN2 are hereditary cancer syndromes. The commonest tumors secrete PTH or gastrin in MEN1, and calcitonin or catecholamines in MEN2. Management strategies improved after the discoveries of their genes. MEN1 has no clear syndromic variants. Tumor monitoring in MEN1 carriers includes biochemical tests yearly and imaging tests less often. Neck surgery includes subtotal or total parathyroidectomy, parathyroid cryopreservation, and thymectomy. Proton pump inhibitors or somatostatin analogs are the main management for oversecretion of entero-pancreatic hormones, except insulin. The roles for surgery of most entero-pancreatic tumors present several controversies: exclusion of most operations on gastrinomas and indications for surgery on other tumors. Each MEN1 family probably has an inactivating MEN1 germline mutation. Testing for a germline MEN1 mutation gives useful information, but rarely mandates an intervention. The most distinctive MEN2 variants are MEN2A, MEN2B, and familial medullary thyroid cancer (MTC). They vary in aggressiveness of MTC and spectrum of disturbed organs. Mortality in MEN2 is greater from MTC than from pheochromocytoma. Thyroidectomy, during childhood if possible, is the goal in all MEN2 carriers to prevent or cure MTC. Each MEN2 index case probably has an activating germline RET mutation. RET testing has replaced calcitonin testing to diagnose the MEN2 carrier state. The specific RET codon mutation correlates with the MEN2 syndromic variant, the age of onset of MTC, and the aggressiveness of MTC; consequently, that mutation should guide major management decisions, such as whether and when to perform thyroidectomy.

Adrenal cortical carcinoma.

Adrenal cortical carcinoma is a rare endocrine tumor for which complete surgical resection is the only potentially curative treatment. Accurate preoperative evaluation (biochemical and radiographic) of the patient who presents with an adrenal mass maximizes the opportunity for the patient to undergo a complete, margin-negative resection of the primary tumor, which is the most powerful prognostic variable for long-term survival. The response to chemotherapy or mitotane is modest in patients with advanced disease. Hopefully, an improved understanding of the molecular pathogenesis of this challenging tumor will lead to the development of more effective therapies in the future.

[Germline mutations of the ret proto-oncogene in Chilean patients with hereditary and sporadic medullary thyroid carcinoma]. / Mutaciones de línea germinal del proto-oncogen ret en pacientes chilenos con cáncer medular tiroideo hereditario y esporádico.

BACKGROUND: Medullary thyroid carcinoma (MTC) may occur either as a sporadic or familial disease. Multiple endocrine neoplasia (MEN) type 2, inherited as an autosomal dominant disease, is characterized by MTC only (FMTC) or coexistence of MTC with other endocrine neoplasia (NEM 2A, 2B). Germline mutations of the RET proto-oncogene (cRet) are found in the inherited forms and in some apparently sporadic MTC cases. AIM: To study RET mutations in 8 families with MEN 2. MATERIAL AND METHODS: RET mutations were screened in peripheral blood DNA from 18 patients and 87 high risk carriers belonging to 8 MEN 2 families and 52 sporadic MTC. Exons 10, 11, 13, 14, 15 and 16 of the c-Ret were amplified by polymerase chain reaction (PCR) and examined by direct sequencing of PCR products and/or restriction enzyme analysis. RESULTS: Five MEN 2A and one FMTC families with a germline mutation at codon 634, one MEN 2A and one FMTC family carrying a mutation at codon 620 were identified. Mutations were found in 23 out of 87 high risk carriers. In addition, we detected a S891A (exon 15) germline mutation in a sporadic MTC patient and in one out of her three sons and V804M (exon 14) in another sporadic MTC case and in one out of his six relatives, indicating in both cases the presence of a sporadic misclassified familial disease. CONCLUSIONS: These results underscore the importance of routine application of c-Ret testing in all cases of MTC either familial or sporadic.

Promiscuity of pre-mRNA spliceosome-mediated trans splicing: a problem for gene therapy?

Trans splicing of messenger RNA has been used in experimental settings to replace mutant RNA sequences. We investigated the feasibility of utilizing trans splicing to replace a mutant RET protooncogene sequence known to inappropriately activate this tyrosine kinase receptor. We constructed a pre-trans-splicing molecule (PTM) consisting of a binding domain complementary to the target intron, the 3' splicing signal sequence (3'ss), derived from adenovirus major late transcript intron 1 and a molecular tag sequence. Accurately targeted trans splicing between the human RET exons and the PTM was demonstrated in NIH 3T3 cells cotransfected with the human RET minigene and the PTM. The efficiency of specific trans splicing was estimated to be no more than 15% in the cotransfection experiment. However, in addition to the targeted trans splicing, nontargeted trans splicing to RET exons was observed. Furthermore, the rapid amplification of 5' cDNA ends (5' RACE) analysis demonstrated that nontargeted trans splicing occurred with endogenously expressed pre-mRNAs in TT cells and that specific trans splicing to RET was a rare event. Attempts to reduce nonspecificity by the addition of a stem-loop to the trans-splicing construct designed to suppress nonspecific splicing failed to have the desired effect. These observations suggest that overexpression of a trans-splicing construct containing a 3'ss results in promiscuous trans splicing and raise significant questions about the specificity and usefulness of currently used trans-splicing approaches. In addition, these findings raise the possibility that nonspecific spliced products may be produced by a variety of gene therapy constructs.

Alternative ribonucleic acid processing in endocrine systems.

Alternative RNA processing is a mechanism for creation of protein diversity through selective inclusion or exclusion of RNA sequence during posttranscriptional processing. More than one-third of human pre-mRNAs undergo alternative RNA processing modification, making this a ubiquitous biological process. The protein isoforms produced have distinct and sometimes opposite functions, underscoring the importance of this process. This review focuses on important endocrine genes regulated by alternative RNA processing. We discuss how diverse events such as spermatogenesis or GH action are regulated by this process. We focus on several endocrine (calcitonin/calcitonin gene-related peptide) and nonendocrine (Drosophila doublesex and P-element and mouse c-src) examples to highlight recent progress in the elucidation of molecular mechanisms regulating this process. Finally, we outline methods (model systems and techniques) used by investigators in this field to study processing of individual pre-mRNAS:

Arthritic calcitonin/alpha calcitonin gene-related peptide knockout mice have reduced nociceptive hypersensitivity.

Peripheral inflammation induced with a knee joint injection of a mixture of kaolin/carrageenan (k/c) produces primary and secondary hyperalgesia. Inflammatory pain is thought to involve a variety of transmitters released from nerve terminals, including amino acids, substance P (SP) and calcitonin gene-related peptide (CGRP). In the present study, mice deficient in the calcitonin/alpha CGRP gene (CGRP(-/-)) displayed normal responses to noxious stimuli. However, the CGRP knockout mice failed to demonstrate development of secondary hyperalgesia after induction of knee joint inflammation in two tests that assess central sensitization, through testing at sites remote from the primary insult. Nociceptive behavioral responses were assessed using the hot-plate test and paw withdrawal latency (PWL) to radiant heat applied to the hindpaw. The CGRP(-/-) mice showed no signs of secondary hyperalgesia after development of knee joint inflammation, while the expected significant decrease in the PWL was observed in the CGRP(+/+) mice as control. The CGRP(-/-) mice also had a prolonged rather than a shortened response latency in the hot-plate test 4 h after knee joint injection of k/c. Immunohistological study showed that CGRP-like immunoreactivity (CGRP-LI) was absent in the spinal cord and dorsal root ganglia taken from the CGRP(-/-) mice. These results indicate that endogenous CGRP plays an important role in the plastic neurogenic changes occurring in response to peripheral inflammatory events including the development of nociceptive behaviors.

Structure of the mouse calcitonin/calcitonin gene-related peptide alpha and beta genes.

We report the cloning, genomic organization and sequence of the mouse alpha-CALC and beta-CALC genes. The two genes share extensive sequence homology. The transcription units of both genes contain 6 exons. Transcripts of the alpha-CALC gene were found to alternatively include exon 4 or exons 5 and 6. For the beta-CALC gene exon 4 was not detected in transcripts derived from this gene. The predicted mouse alpha-CGRP was found to be identical to rat alpha-CGRP, however, beta-CGRP predicted amino acid sequences revealed three amino acid differences suggesting these residues are not critical to CGRP function.

Limitations of size as a criterion in the evaluation of adrenal tumors.

BACKGROUND: Size has been considered to be the single best predictor of malignancy in adrenal neoplasms that have been identified incidentally. However, small adrenal cortical cancers have been reported from multiple centers. METHODS: We retrospectively evaluated the value of tumor size and other clinical parameters in the prediction of the presence of adrenal malignancy. RESULTS: The records of 117 patients who underwent evaluation for tumors of the adrenal gland were reviewed. The median tumor size of the adrenal cortical carcinomas (n = 38 carcinomas) was 9.2 cm (range, 1.7-30 cm); 5 cancers (13.5%) were smaller than 5.0 cm. The median overall size of the benign tumors, excluding pheochromocytomas, was 4.0 cm (n = 38 carcinomas); 10 benign tumors (26%) were larger than 5.0 cm. The imaging features of 4 of 5 small adrenal cancers predicted malignancy; the remaining patients had hormonally functioning tumors. The imaging features of 7 of 10 large benign adrenal tumors predicted benign histologic features, including 5 of 5 myelolipomas. CONCLUSIONS: Although size remains a good predictor of the histologic features and clinical behavior of adrenal neoplasms, both small adrenal cortical cancers and large benign tumors occur with measurable frequency. High-quality imaging studies may be helpful in the identification of relatively small adrenal cancers and of characteristic benign lesions that may be selectively followed.

Duplication of the mutant RET allele in trisomy 10 or loss of the wild-type allele in multiple endocrine neoplasia type 2-associated pheochromocytomas.

Inherited mutations of the RET proto-oncogene are tumorigenic in patients with multiple endocrine neoplasia type 2 (MEN 2). However, it is not understood why only few of the affected cells in the target organs develop into tumors. Genetic analysis of nine pheochromocytomas from five unrelated patients with MEN 2 showed either duplication of the mutant RET allele in trisomy 10 or loss of the wild-type RET allele. Our results suggest a "second hit" causing a dominant effect of the mutant RET allele, through either duplication of the mutant allele or loss of the wild-type allele, as a possible mechanism for pheochromocytoma tumorigenesis in patients with MEN 2.

Multiple endocrine neoplasias.

The multiple endocrine neoplasia syndromes form a distinct group of genetic tumor syndromes. They include multiple endocrine neoplasia types 1 and 2, von Hippel Lindau syndrome, neurofibromatosis, and Carney complex. Research over the past decade has identified a molecular basis for each of these syndromes. This knowledge has revolutionized not only the clinical management but also has illuminated the field of human cancer research by the identification of new and important genes critical for regulation of cell growth, differentiation, and death. This review focuses on the structure, physiologic function, and molecular abnormalities of the genes involved in these syndromes.

Pituitary carcinoma containing gonadotropins: treatment by radical excision and cytotoxic chemotherapy: case report.

OBJECTIVE AND IMPORTANCE: Pituitary carcinomas are extremely rare. Cases reported in the medical literature in the 20th century included tumors that produced adrenocorticotropic hormone, prolactin, growth hormone, and/or thyrotropin. CLINICAL PRESENTATION: Here we present a 22-year-old woman with a pituitary carcinoma that was immunohistochemically positive for luteinizing hormone and follicle-stimulating hormone at both the primary and metastatic sites. The patient exhibited elevated serum levels of alpha-subunit. INTERVENTION: The patient had experienced failure of previous treatments, including standard surgery and radiotherapy, and presented to us for radical resection of the tumor, with exenteration of the involved cavernous sinus. She was pretreated with cytotoxic chemotherapy and continued to receive this therapy after surgery. CONCLUSION: This is the only documented case of a gonadotropin-staining pituitary carcinoma for which hormone production was proven in both the primary and metastatic tumors. Many benign "nonsecreting" pituitary adenomas actually produce subclinical amounts of gonadotropins, and malignant nonfunctional pituitary neoplasms may do the same.

Relative contributions of technetium Tc 99m sestamibi scintigraphy, intraoperative gamma probe detection, and the rapid parathyroid hormone assay to the surgical management of hyperparathyroidism.

HYPOTHESIS: Technetium Tc 99m sestamibi scintigraphy, intraoperative gamma probe detection, and the rapid parathyroid hormone assay have been used to permit a directed operation in patients with hyperparathyroidism. We hypothesized that the coordinated use of these techniques might be particularly useful in patients who require a second operation for hyperparathyroidism. DESIGN: Retrospective analysis was performed to determine the specific contribution of these technologies to the surgical management of patients with hyperparathyroidism who underwent evaluation by at least 2 of these techniques between April 1996 and October 1999. SETTING: Patients were evaluated and treated by an endocrine tumor surgery group within a tertiary care referral center. PATIENTS: Coordinated application of 99mTc-sestamibi scintigraphy, intraoperative gamma probe detection, and/or the rapid parathyroid hormone assay was performed in 32 patients. RESULTS: Twenty-eight of 32 patients had primary hyperparathyroidism, 3 had multiple endocrine neoplasia type 1, and 1 had secondary hyperparathyroidism. The surgical procedure was an initial cervical exploration in 19 and a second operative procedure in 13. Parathyroidectomy was successful in all patients. A directed anatomic operation was performed in 24 patients, including 11 patients who underwent second operative procedures and 9 patients who underwent minimally invasive procedures under local anesthesia. A directed operation was facilitated by sestamibi scan in 22 of 24 patients, intraoperative gamma probe detection in 5 of 23 patients, and the rapid parathyroid hormone assay in 15 of 15 patients. CONCLUSIONS: Coordinated application of 99mTc-sestamibi scintigraphy, intraoperative gamma probe detection, and the rapid parathyroid hormone assay allows for successful directed reoperative parathyroidectomy; a minimally invasive procedure may be performed in selected patients.

Use of long-term intravenous phosphate infusion in the palliative treatment of tumor-induced osteomalacia.

Tumor-induced osteomalacia is characterized by paraneoplastic defects in vitamin D metabolism, proximal renal tubular functions, and phosphate transport. The resulting hypophosphatemia can cause generalized pain and muscle weakness, which significantly affect the quality of life of the patients. Palliative treatment with calcium, vitamin D, and phosphate replacement is indicated for patients in whom the causative tumor cannot be completely resected. In this report we describe a case of tumor-induced osteomalacia in whom adequate oral doses of phosphate could not be used because of gastrointestinal side-effects. Long term (3-6 months) iv phosphate infusion delivered by ambulatory infusion pumps in combination with oral calcium and vitamin D was used successfully to decrease pain and increase muscle strength. Careful monitoring of serum calcium, phosphate, and creatinine levels and reliable microinfusion technology have allowed the long term use of iv phosphate infusion without serious morbidity. This patient received repeated (three times) phosphate infusions over 8 yr, resulting in laboratory and symptomatic improvement after each course. However, this patient did suffer two episodes of central venous catheter-related infection. Because of potentially serious complications, such as severe hypocalcemia, calcified right ventricular thrombi, and nephrocalcinosis, long term iv phosphate infusion should be reserved for patients who cannot tolerate adequate doses of oral phosphate and for whom the benefits outweigh the risks.