Long-Term Follow-Up, Association between CARD15/NOD2 Polymorphisms, and Clinical Disease Behavior in Crohn's Disease Surgical Patients.

BACKGROUND: CARD15/NOD2 is the most significant genetic susceptibility in Crohn's disease (CD) even though a relationship between the different polymorphisms and clinical phenotype has not been described yet. The study is aimed at analyzing, in a group of CD patients undergoing surgery, the relationship between CARD15/NOD2 polymorphisms and the clinical CD behavior after a long-term follow-up, in order to identify potential clinical biomarkers of prognosis. METHODS: 191 surgical CD patients were prospectively characterized both for the main single nucleotide polymorphisms of CARD15/NOD2 and for many other environmental risk factors connected with the severe disease form. After a mean follow-up of 7.3 years, the correlations between clinical features and CD natural history were analyzed. RESULTS: CARD15/NOD2 polymorphisms were significantly associated with younger age at diagnosis compared to wild type cases (p < 0.05). Moreover, patients carrying a 3020insC polymorphism presented a larger Δ between diagnosis and surgery (p = 0.0344). Patients carrying an hz881 and a 3020insC exhibited, respectively, a lower rate of responsiveness to azathioprine (p = 0.012), but no difference was found in biologic therapy. Finally, the risk of surgical recurrence was significantly associated, respectively, to age at diagnosis, to familial CD history, to diagnostic delay, to arthritis, and to the presence of perioperative complications. CONCLUSIONS: 3020insC CARD15 polymorphism is associated with an earlier CD onset, and age at CD diagnosis < 27 years was confirmed to have a detrimental effect on its clinical course. In addition, the familiarity seems to be connected with a more aggressive postoperative course. Finally, for the first time, we have observed a lower rate of responsiveness to azathioprine in patients carrying an hz881 and a 3020insC.

Natural History of MEN1 GEP-NET: Single-Center Experience After a Long Follow-Up.

BACKGROUND: The multiple endocrine neoplasia type 1 syndrome (MEN1) natural history is poorly evaluated, and few single-institution experiences about hereditary gastroenteropancreatic neuroendocrine tumors (GEP-NET) are reported. Our purpose is to analyze the role of GEP-NET in MEN1-related death, as well as the behavior of these lesions during follow-up. METHODS: The study population consists of 77 patients diagnosed with MEN1 GEP-NET, regularly followed up since 1990. Extensive clinical data were prospectively recorded. Statistical analysis was performed both on the whole population of 77 patients and on two subgroups including patients who, during the long lasting study period, underwent GEP-NET surgery (50 pts) and who did not (27 pts), respectively. RESULTS: Twenty-five males (32.5%) and 52 females (67.5%) were enrolled. Sixty-four patients had MEN1 family history (83.1%), and genetic mutation was detected in 67 cases (87%). The mean age at GEP-NET diagnosis was 41.4 years (SD = 13.6); 16 patients (20.8%) had GEP-NET diagnosed before age 30 and 12 cases (15.6%) before 1996. The mean interval time between MEN1 diagnosis and GEP-NET detection was 5.7 years (range -11/37; SD = 8.1 years). Overall, the mean follow-up time from MEN1 diagnosis was 15.8 years (SD = 9.7 years) and from GEP-NET diagnosis was 9.6 years (SD = 6.9 years). Gastrinoma was the most frequent functioning GEP-NET and pancreatoduodenectomy the most adopted surgery. GEP-NET progression affected 12 patients within the non-surgical group, while 18 subjects developed progression after surgery. CONCLUSIONS: Our single-center data provide information on epidemiologic, clinical and pathological features of GEP-NET in MEN1 making possible to clarify their natural history.

Prevalence of osteoporosis in the Italian population and main risk factors: results of BoneTour Campaign.

BACKGROUND: BoneTour is a campaign conducted throughout the Italian territory for the assessment of Italian people bone status and for the prevention of osteoporosis. METHODS: A total of 7305 sequential subjects of both sexes were screened, collecting clinical data through the FRAX™ questionnaire, and measuring heel bone stiffness by Quantitative Ultrasonography (QUS). The 10-year risk for hip and major osteoporotic fractures was calculated taking into account personal or family history of fragility fracture, smoking, alcohol abuse, rheumatoid arthritis, prolonged steroids assumption. Additional risk factors were evaluated, including early menopause, poor sunlight exposure, low dietary calcium intake, physical inactivity, number of pregnancies, months of lactation, tobacco cigarettes smoked per year, specific causes of secondary osteoporosis. Through a correlation study, the influence of each factor on the development of osteoporosis was analyzed. RESULTS: As many as 18 % of women suffer from osteoporosis, as defined by QUS T-score. The calculation of FRAX™ confirmed the weight of the already known risk factors. The correlation study revealed the significance of some additional factors, such as hyperthyroidism, nephrolithiasis, Crohn disease, ulcerative colitis, celiac disease, poor sun exposure, and oophorectomy before age 50. CONCLUSIONS: The high prevalence of secondary osteoporosis in the Italian population clearly indicates the importance of additional risk factors not yet included in the FRAX™ algorithm, for which preventive measures should be considered. Screening campaigns may allow both early diagnosis and access to treatment.

Intraoperative PTH monitoring: a new approach based on the identification of the "true" time origin of the decay curve.

Some published criteria for intraoperative monitoring of PTH serum concentrations may cause misleading results, since the timing of samples measured between the pre-incision and pre-excision phase of surgery is often unrecorded. In our opinion this information is critical, as the time of an intermediate sample during surgical manipulation may represent the "true" beginning of the PTH decay. We modified the usual criterion of monitoring (cut-off at 10 minutes after clamping) proposing a further check at manipulation in case the primary check at clamping produces an apparently negative result. On the basis of a mathematical model, false negative curves were simulated by means of a time shift. This shift was assumed to be the interval between manipulation and clamping. Analysing the decay curve, we used the 50% cut-off at 10 minutes after the supposed "true" origin (clamping or manipulation). Using a rapid immunochemiluminometric assay (ICMA), data were collected from 22 patients successfully operated for parathyroid adenoma. The check at clamping correctly diagnosed 13 patients. Among the 9 false negative cases, 6 were correctly diagnosed considering the manipulation as the baseline value. In the remaining 3 patients, diagnosis required prolonged observation of the curves. In case the iPTH decay does not follow the expected curve, it can be useful to check the decay normalising to a pre-excision value. The advantages of our criterion are both the prompt recognition of false negative results and the construction of a "true" decay curve for each patient, supporting the surgeon during the excision of hyperfunctioning parathyroid tissue.

Sarcomatoid carcinoma of the kidney in a MEN1 patient: case report and genetic profile.

Renal tumors are exceedingly rare in Multiple Endocrine Neoplasia type 1 (MEN1), a pleyotropic hereditary cancer disorder affecting the endocrine system. Herein we report a unique case of renal sarcomatoid carcinoma with concomitant ipsilateral non-secreting adrenal adenoma occurring in a young male MEN1 patient, previously operated for hyperparathyroidism and multiple pancreatic neuroendocrine neoplasms. Molecular analysis in the MEN1 locus at 11q13 showed loss of heterozygosity in the adrenal lesion, while kidney cancer was unrelated to MEN1 syndrome.

Hereditary hyperparathyroidism syndromes.

Primary hyperparathyroidism is a common endocrine disorder, resulting from a persistent hypercalcemia along with an inadequate secretion of parathyroid hormone. In approx 95% of cases, it occurs sporadically; rarely, it is part of familial syndromes. These inherited syndromes typically present at an earlier age than the nonheritable form and occur with equal frequencies in both sexes. The differential diagnosis is often difficult, but it is of fundamental importance for the management of patients and their family. The availability of specific genetic tests has improved the diagnostic accuracy allowing early diagnosis in asymptomatic family members. Before the advent of genetic testing, a definitive diagnosis could be made only in symptomatic cases based on clinical data and family history.

Bone and Mineral Metabolism Phenotypes in MEN1-Related and Sporadic Primary Hyperparathyroidism, before and after Parathyroidectomy.

Primary hyperparathyroidism (PHPT) is the most common endocrinopathy in multiple endocrine neoplasia type 1 (MEN1). Persistent levels of increased parathyroid hormone (PTH) result in a higher incidence of osteopenia and osteoporosis compared to the general population. Surgical removal of hyper-functioning parathyroid tissue is the therapy of choice. This retrospective study evaluated the effect of parathyroidectomy (PTX) on bone metabolism and bone mass in two series of patients with MEN1 PHPT and sporadic PHPT (sPHPT) by comparing bone metabolism-related biochemical markers and bone mineral density (BMD) before and after surgery. Our data confirmed, in a higher number of cases than in previously published studies, the efficacy of PTX, not only to rapidly restore normal levels of PTH and calcium, but also to normalize biochemical parameters of bone resorption and bone formation, and to improve spine and femur bone mass, in both MEN1 PHPT and sPHPT. Evaluation of single-patient BMD changes after surgery indicates an individual variable bone mass improvement in a great majority of MEN1 PHPT patients. In MEN1 patients, PTX is strongly suggested in the presence of increased PTH and hypercalcemia to prevent/reduce the early-onset bone mass loss and grant, in young patients, the achievement of the bone mass peak; routine monitoring of bone metabolism and bone mass should start from adolescence. Therapy with anti-fracture drugs is indicated in MEN1 patients with BMD lower than the age-matched normal values.

Multiple endocrine neoplasia type 1 (MEN1): not only inherited endocrine tumors.

MEN 1 is a rare hereditary cancer syndrome which manifests a variety of endocrine and non-endocrine neoplasms and lesions. Growing knowledge of this condition in both its molecular genetic underpinnings and its clinical implications have affected the entire spectrum of the clinical management of MEN patients. The MEN1 gene is a tumor suppressor gene, and mutations in it account for the development of the MEN1 clinical syndrome through impairment of several cell functions, such as cell proliferations, cell growth control, apoptosis, DNA replication and repair, gene expression, transcriptional machinery control, and hormone secretion. Currently, DNA testing makes possible the early identification of germline mutations in asymptomatic mutation carriers. The ever increrasing combination of genetic and clinical tools will allow early detection of MEN1-associated neoplasms, potentially improving clinical outcomes and quality of life for both affected patients and their relatives.

Biological effects of various regimes of 25-hydroxyvitamin D3 (calcidiol) administration on bone mineral metabolism in postmenopausal women.

Introduction. It is evident from several studies that vitamin D inadequacy is widespread among women with osteoporosis across all continents regardless of season or latitude, with similar prevalence in patients treated for osteoporosis and in untreated women. These results underscore a need to improve physician and patient awareness of the importance of adequate vitamin D supplementation in postmenopausal women with osteoporosis.Materials and Methods. As the daily administration of vitamin D combined with 1 gr calcium is hampered by an insufficient patient adherence, we performed a longitudinal study in 90 randomly recruited postmenopausal women aged 65-75 years with inadequate calcium intake and circulating levels of 25-hydroxyvitamin D3 (lower than 30 ng/mL). The prevalence of secondary hyperparathyroidism (parathyroid hormone > 65 pg/mL) was 36% in the all population. The possible repercussion of oral single weekly or monthly calcidiol administration on phospho-calcium metabolism was observed after three months treatment (from April through July) with 500 mg calcium daily and with three different therapeutic regimens of calcidiol (Group I: 25 drops weekly; Group II: 50 drops monthly; and Group III: 100 drops monthly). The general baseline characteristics of the three groups were superimposable. We measured fasting morning serum 25-hydroxyvitamin D3, parathyroid hormone, calcium, phosphate, bone alkaline phosphatase, urinary deoxypyridinoline, and 24hr-calcium, - phosphate, and - creatinine.Results. The adherence to the weekly calcidiol treatment was over 80% in 90% of the patients. All three therapeutic regimens of calcidiol led to normalization of 25-hydroxyvitamin D3 after 3 months, yet with a significantly higher potency (P >0.01) of regimens I and III, when compared to Group II. Also the decrease of circulating levels of parathyroid hormone was significantly higher (P < 0.001) in Groups I and III versus Group II. No biochemically and clinically relevant adverse effects were observed at the end of the 90-day follow-up.ConclusionsIn postmenopausal women with inadequate circulating levels of 25-hydroxyvitamin D3, calcium and pulsed calcidiol supplementation normalized 25-hydroxyvitamin D3 levels and reduced circulating parathyroid hormone levels.

Multiplex gene expression profile in inflamed mucosa of patients with Crohn's disease ileal localization: A pilot study.

BACKGROUND: Crohn's disease (CD) is a complex disorder resulting from the interaction of genetic, environmental, and microbial factors. The pathogenic process may potentially affect any segment of the gastrointestinal tract, but a selective location in the terminal ileum was reported in 50% of patients. AIM: To characterize clinical sub-phenotypes (colonic and/or ileal) within the same disease, in order to identify new therapeutic targets. METHODS: 14 consecutive patients undergoing surgery for ileal CD were recruited for this study. Peripheral blood samples from each patient were collected and the main polymorphisms of the gene Card15/Nod2 (R702W, G908R, and 1007fs) were analyzed in each sample. In addition, tissue samples were taken from both the tract affected by CD and from the apparently healthy and disease-free margins (internal controls). We used a multiplex gene assay in specimens obtained from patients with ileal localization of CD to evaluate the simultaneous expression of 24 genes involved in the pathogenesis of the disease. We also processed surgery gut samples with routine light microscopy (LM) and transmission electron microscopy (TEM) techniques to evaluate their structural and ultrastructural features. RESULTS: We found a significant increase of Th17 (IL17A and IL17F, IL 23R and CCR6) and Th1 (IFN-γ) gene expression in inflamed mucosa compared to non-inflamed sites of 14 CD patients. DEFB4 and HAMP, two genes coding for antimicrobial peptides, were also strongly activated in inflamed ileal mucosa, suggesting the overwhelming stimulation of epithelial cells by commensal microbiota. IFN-γ and CCR6 were more expressed in inflamed mucosa of CD patients with ileal localization compared with patients with colonic localization suggesting a more aggressive inflammation process in this site. Morphological analysis of the epithelial lining of Lieberkün crypts disclosed enhanced release activity from goblet mucocytes, whereas the lamina propria contained numerous cells pertaining to various lines. CONCLUSION: We observed that the expression of ileal genes related to Th1 and Th17 activity is strongly activated as well as the expression of genes involved in microbiota regulation.

Role of Acupuncture in the Management of Severe Acquired Brain Injuries (sABIs).

Acupuncture therapy has been used to treat several disorders in Asian countries and its use is increasing in Western countries as well. Current literature assessed the safety and efficacy of acupuncture in the acute management and rehabilitation of patients with neurologic disorders. In this paper, the role of acupuncture in the treatment of acute severe acquired brain injuries is described, acting on neuroinflammation, intracranial oedema, oxidative stress, and neuronal regeneration. Moreover, beneficial effects of acupuncture on subacute phase and chronic outcomes have been reported in controlling the imbalance of IGF-1 hormone and in decreasing spasticity, pain, and the incidence of neurovegetative crisis. Moreover, acupuncture may have a positive action on the arousal recovery. Further work is needed to understand the effects of specific acupoints on the brain. Allegedly concurrent neurophysiological measurements (e.g., EEG) may help in studying acupuncture-related changes in central nervous system activity and determining its potential as an add-on rehabilitative treatment for patients with consciousness disorders.

Cystic parathyroid glands in MEN1: A rare entity?

Approximately 300 cases of sporadic parathyroid cyst (PCs) have been reported to date. Only two cases have been described in MEN1 so far. Detection by imaging could be challenging, especially in multiglandular primary hyperparathyroidism (HPT) and clinical outcome could be different. During the period 1990-2014, 71 MEN1 patients were operated for primary hyperparathyroidism in our centre. We report three cases of PCs in MEN1 patients affected by HPT, who underwent a total or subtotal parathyroidectomy with transcervical thymectomy. In our series, all three patients had an unsatisfactory postoperative course, at variance with the high percentage (over 90 %) of long-term success in MEN1 patients operated at our centre. One patient affected by cystic degeneration of all the four parathyroid glands reported persistent hypoparathyroidism, despite autografts of parathyroid tissue. For the other two cases, surgery failed to cure hyperparathyroidism, perhaps because of the presence of undetected ectopic parathyroid tissue. In the context of a multiglandular disease such as MEN1 syndrome, PCs seem rare but our experience shows about a 4 % incidence. Furthermore their presence, even in expert hands, could affect the preoperative identification of the parathyroid glands due to the difficult differential diagnosis between PC and other cystic lesions of the neck, and intraoperative detection of the glands as well as the postoperative outcome.

Crohn's Colitis: Development of a multiplex gene expression assay comparing mRNA levels of susceptibility genes.

Crohn's disease (CD) is a multifactorial immunologically mediated disease. In this study we explored, for the first time, the efficacy of the Multiplex Gene Assay technology for detecting mRNA expression profile of 24 selected CD related genes in endoscopic biopsies and surgical specimens from CD patients with colonic localization of the disease. The polymorphisms of genes most frequently associated with CD were also analysed in DNA samples from the same patients. The analysis of endoscopic samples showed increased expression of 7 genes in inflamed mucosa compared to non-inflamed mucosa and suggests the activation of the autophagy process and of a Th17 adaptive response. The analysis of surgical specimens showed increased expression of 16 genes in inflamed tissue compared to non-inflamed internal controls and revealed the activation of immune-adaptive Th17 response in association with a Th1 response. Furthermore, an increased expression of genes involved in ionic transport and signal transduction was found in inflamed mucosa compared to non-inflamed internal controls. This study confirms the activation of Th17 and Th1 adaptive-immune response also in colonic CD. It should be stressed that these responses have been disclosed in biopsy tissue, while only Th17 differentiation is revealed in endoscopic tissue. Interestingly, the polymorphisms analysis revealed that a homozygous genotype is associated to a more complicated clinical course.

Peripheral quantitative computed tomography (pQCT) for the assessment of bone strength in most of bone affecting conditions in developmental age: a review.

Peripheral quantitative computed tomography provides an automatical scan analysis of trabecular and cortical bone compartments, calculating not only their bone mineral density (BMD), but also bone geometrical parameters, such as marrow and cortical Cross-Sectional Area (CSA), Cortical Thickness (CoTh), both periosteal and endosteal circumference, as well as biomechanical parameters like Cross-Sectional Moment of Inertia (CSMI), a measure of bending, polar moment of inertia, indicating bone strength in torsion, and Strength Strain Index (SSI). Also CSA of muscle and fat can be extracted. Muscles, which are thought to stimulate bones to adapt their geometry and mineral content, are determinant to preserve or increase bone strength; thus, pQCT provides an evaluation of the functional 'muscle-bone unit', defined as BMC/muscle CSA ratio. This functional approach to bone densitometry can establish if bone strength is normally adapted to the muscle force, and if muscle force is adequate for body size, providing more detailed insights to targeted strategies for the prevention and treatment of bone fragility. The present paper offers an extensive review of technical features of pQCT and its possible clinical application in the diagnostic of bone status as well as in the monitoring of the skeleton's health follow-up.

Surgery in MEN 2A Patients Older Than 5 Years with Micro-MTC: Outcome at Long-term Follow-up.

In multiple endocrine neoplasia syndrome type 2A (MEN 2A), early total thyroidectomy (TT; performed before the age of 5 years) is the best option to prevent medullary thyroid carcinoma (MTC) development, but the management of MEN 2A patients diagnosed after childhood is still under debate. Seventeen consecutive patients diagnosed with MEN 2A after the age of 5 years (mean age, 23.3 years) with a pathologic diagnosis of micro-MTC without nodal involvement were enrolled. All patients underwent TT with thymectomy and central compartment lymph node dissection. During surgery, parathyroid tissue removal occurred in 14 patients. No major postoperative complications nor persistent hypoparathyroidism was observed. After a mean follow-up of 16.6 years, no patient developed primary hyperparathyroidism or disease recurrence. Even if TT is recommended before the age of 5, when MEN 2A diagnosis is performed after this age in micro-MTC without nodal involvement, TT with thymectomy and central compartment lymphadenectomy can provide good oncologic and functional results.

Ventricular fibrillation resulting from electrolyte imbalance reveals vipoma in MEN1 syndrome.

Sporadic VIPoma is an exceedingly rare tumor with an annual incidence of 1:10 million people worldwide, yet it is described in approximately 5 % of MEN1 patients. The majority of VIPomas are malignant and radical surgery is the best therapeutic option. A 58-year-old man presented with cardiocirculatory arrest due to ventricular fibrillation. The patient had a 3-month history of epigastric pain with diarrhea. After reanimation, laboratory data revealed severe hypokalemia and hypercalcemia. Further investigations showed hyperparathyroidism, left adrenal adenoma and pituitary microprolactinoma and genetic diagnosis of MEN1 syndrome was made. Abdominal computed tomography revealed a 45 × 30 mm mass of the pancreatic head and two hepatic lesions, which proved to be neuroendocrine after 68 Ga PET and needle biopsy. Vasoactive intestinal peptide (VIP) serum level had increased. Subsequently the patient underwent pylorus-preserving pancreaticoduodenectomy and hepatic resection. Intraoperative VIP returned to normal values. Histopathology confirmed a pancreatic VIPoma metastatic to the liver. The postoperative course was unremarkable and the patient is well with no evidence of disease at a 48 months follow-up. Even in case of anusual presentation, when two or more main clinical findings of MEN1 related tumors are present, unrespectively to the presence of MEN1 mutation, MEN1 syndrome should be suspected. Surgery in MEN1 pancreatic neuroendocrine tumors is indicated both to treat symptoms and to avoid oncological progression even in advanced cases.

Massive intrathoracic lipoma in men1 syndrome.

INTRODUCTION: The multiple endocrine neoplasia type 1 (MEN1) is a rare autosomal dominant syndrome characterized by the onset of hyperparathyroidism, gastroenteropancreatic neuroendocrine tumors and pituitary lesions. PRESENTATION OF CASE: This appears to be the first described case of a massive intrathoracic lipoma in MEN1. The patient was affected with primary hyperparathyroidism treated with a total parathyroidectomy followed by a distal pancreatectomy for insulinoma. At follow-up, the computed tomography showed a massive lesion on the left emithorax suggestive of a lipoma. At the onset of a mild dyspnea we decided to perform the surgical excision of the mass obtaining a complete relief of the symptoms. DISCUSSION: This case is evidence of the importance of a strict follow-up of such patients. CONCLUSION: Lipomas are the most frequent benign soft tissue tumors. They are usually sporadic but are sometimes related to hereditary syndromes. Intrathoracic localizations are rare and can arise mainly in the mediastinum, bronchus or lung. The diagnosis is often incidental; despite preoperative imaging will accurately show the features of the lesions, it is impossible obtain an accurate diagnosis-hence, the treatment of choice remains the surgical excision.

A multidisciplinary approach to desmoid tumors. When intra-abdominal fibromatosis degenerates into an abscess, which is the right treatment?

INTRODUCTION: Desmoid tumors are rare benign tumors that originates in the fibrous sheath or musculo-aponeurotic structure. Histologically benign, they tends to invade locally and to be recurrent. PRESENTATION OF CASE: We report a rare case of an intra-abdominal desmoid tumor in a patient affected by familial adenomatous polyposis, which degenerated into abscess. Male, 38 years, was hospitalized for abdominal pain, bowel obstruction and fever. The computed tomography showed a big dishomogeneous mass occupying the whole mesentery with internal massive liquefaction. The mass extended from the epigastrium for 13cm up to L3. On the right mesogastric side a solid, thick mass of about 2cm, with a length of 4.5cm, was identified; it was not cleavable from the wall and from some of the loops. We decided to perform a computed tomography-guided percutaneous drainage. Two hundred ml of purulent necrotic material was aspirated, and washing with antibiotic solution was carried out. Cytological examination of fluid drainage showed histiocytes and neutrophils. At follow-up, the patient's clinical condition had improved. An abdominal ultrasound showed a substantial reduction in the diameter of the mass. DISCUSSION: Diagnosis and treatment of desmoids tumor in patients with familial adenomatous polyposis may be difficult, especially when desmoids are located intra-abdominally and in the mesentery. Seldom will desmoid tumors be complicated by abscess formation. CONCLUSION: The management of desmoids tumors is not easy and the choice of the best treatment may be difficult due to the different possible anatomical presentations.

Surgical approach in patients with hyperparathyroidism in multiple endocrine neoplasia type 1: total versus partial parathyroidectomy.

Usually, primary hyperparathyroidism is the first endocrinopathy to be diagnosed in patients with multiple endocrine neoplasia type 1, and is also the most common one. The timing of the surgery and strategy in multiple endocrine neoplasia type 1/hyperparathyroidism are still under debate. The aims of surgery are to: 1) correct hypercalcemia, thus preventing persistent or recurrent hyperparathyroidism; 2) avoid persistent hypoparathyroidism; and 3) facilitate the surgical treatment of possible recurrences. Currently, two types of surgical approach are indicated: 1) subtotal parathyroidectomy with removal of at least 3-3 K glands; and 2) total parathyroidectomy with grafting of autologous parathyroid tissue. Transcervical thymectomy must be performed with both of these procedures. Unsuccessful surgical treatment of hyperparathyroidism is more frequently observed in multiple endocrine neoplasia type 1 than in sporadic hyperparathyroidism. The recurrence rate is strongly influenced by: 1) the lack of a pre-operative multiple endocrine neoplasia type 1 diagnosis; 2) the surgeon's experience; 3) the timing of surgery; 4) the possibility of performing intra-operative confirmation (histologic examination, rapid parathyroid hormone assay) of the curative potential of the surgical procedure; and, 5) the surgical strategy. Persistent hyperparathyroidism seems to be more frequent after subtotal parathyroidectomy than after total parathyroidectomy with autologous graft of parathyroid tissue. Conversely, recurrent hyperparathyroidism has a similar frequency in the two surgical strategies. To plan further operations, it is very helpful to know all the available data about previous surgery and to undertake accurate identification of the site of recurrence.

Molecular diagnosis of parathyroid carcinoma: a reality in the near future.

INTRODUCTION: Parathyroid carcinoma (PC) is a rare endocrine malignancy that still suffers from a problem of delayed clinical diagnosis. Consequently, it usually is not recognized preoperatively and often is not conclusively identified during the operation either. AREAS COVERED: The role played by parafibromin in the development of PC, representing an important advance in understanding the pathogenesis of this malignancy, is discussed. Through a careful search of the international literature, using "parathyroid carcinoma", "molecular genetics of parathyroid carcinoma" and "parathyroid tumorigenesis" as key words, other less mentioned molecular mechanisms are reappraised as potential molecular markers of PC; we also discuss their potential role in 20 parathyroid outgrowths. Finally, both the major efforts and the limitations of reported molecular diagnostic techniques and diagnostic markers are considered. EXPERT OPINION: Currently, several critical issues still need to be addressed, such as the lack of: i) common criteria for the histopathological diagnosis of parathyroid malignancy and ii) timely appropriated preoperative diagnosis of PC. The latter issue would be of fundamental importance to assist the surgeon in performing a complete resection of all carcinomatous tissue at the time of the initial surgery, allowing for the greatest likelihood of a cure.