Higher risk of death among MEN1 patients with mutations in the JunD interacting domain: a Groupe d'etude des Tumeurs Endocrines (GTE) cohort study.

Multiple endocrine neoplasia syndrome type 1 (MEN1), which is secondary to mutation of the MEN1 gene, is a rare autosomal-dominant disease that predisposes mutation carriers to endocrine tumors. Although genotype-phenotype studies have so far failed to identify any statistical correlations, some families harbor recurrent tumor patterns. The function of MENIN is unclear, but has been described through the discovery of its interacting partners. Mutations in the interacting domains of MENIN functional partners have been shown to directly alter its regulation abilities. We report on a cohort of MEN1 patients from the Groupe d'étude des Tumeurs Endocrines. Patients with a molecular diagnosis and a clinical follow-up, totaling 262 families and 806 patients, were included. Associations between mutation type, location or interacting factors of the MENIN protein and death as well as the occurrence of MEN1-related tumors were tested using a frailty Cox model to adjust for potential heterogeneity across families. Accounting for the heterogeneity across families, the overall risk of death was significantly higher when mutations affected the JunD interacting domain (adjusted HR = 1.88: 95%-CI = 1.15-3.07). Patients had a higher risk of death from cancers of the MEN1 spectrum (HR = 2.34; 95%-CI = 1.23-4.43). This genotype-phenotype correlation study confirmed the lack of direct genotype-phenotype correlations. However, patients with mutations affecting the JunD interacting domain had a higher risk of death secondary to a MEN1 tumor and should thus be considered for surgical indications, genetic counseling and follow-up.

Pulmonary metastasis of struma ovarii: a case report.

We report the case of a 42-year-old woman who presented with multiple pulmonary nodules. Surgical resection of 3 nodules revealed differentiated thyroid carcinoma. Thyroid and neck ultrasound was normal. A review of her history revealed that this patient underwent an ovarian cyst resection 15 years ago. Reexamination of pathology samples, with the help of immunohistochemical markers, concluded to a struma ovarii. Pelvic ultrasound was normal; F-18 FDG PET scan was negative. She had total thyroidectomy, with negative histology, followed by first I-131 therapy (3.9 GBq). Thyroglobuline (Tg) was elevated (3230 microg/L in hypothyroidism). The whole-body scan showed multiple foci of pulmonary I-131 uptake, a bone metastasis of third rib, and I-131 uptake in an abdominal para-aortic lymph node. At second I-131 therapy (3.8 GBq), Tg level had decreased to 14 microg/L and there was a decrease in the number of pulmonary nodular I-131 uptake, and resolution of the bone and para-aortic lymph node metastasis. At third I-131 therapy (4.9 GBq), thyroglobuline was undetectable and the whole-body scan showed no I-131 uptake. Struma ovarii is a rare ovarian tumor mostly benign. Metastasis of malignant struma ovarii are rare. Most frequent localizations are liver and peritoneum. Treatment of the malignant struma ovarii implies ovarian surgical resection, total thyroidectomy, and I-131 therapy.

Impact of fluorodihydroxyphenylalanine-18F positron emission tomography on management of adult patients with documented or occult digestive endocrine tumors.

CONTEXT AND OBJECTIVES: Fluorodihydroxyphenylalanine-(18F) (FDOPA) positron emission tomography (PET) is a recent imaging modality used to localize endocrine tumors. This study was conducted to evaluate the impact of FDOPA-PET on the management of patients referred for carcinoid or noncarcinoid digestive tumors and the clinical relevance of the treatment decisions based on this examination. METHODS AND PATIENTS: Between March 2002 and December 2006, 101 FDOPA-PET examinations were performed in 78 adult patients for follow-up of histologically documented carcinoid tumor of the ileum (23 patients) or noncarcinoid digestive tumor (26 patients) or to screen for occult digestive endocrine tumors (29 patients). More than one FDOPA-PET examination was performed in 12 patients. The impact of FDOPA PET was evaluated on a per-patient basis by means of a questionnaire completed by the referring physician, and the relevance of the treatment decision was assessed on the basis of follow-up data. RESULTS: The survey response rate was 91% (71 of 78). The overall impact rate of FDOPA-PET on patient management was 25% (18 of 71). The greatest impact was observed for carcinoid tumors (50%: 11 of 22) and was clinically relevant in every case, followed by occult endocrine tumors (16%: four of 25), and was clinically relevant in three of the four cases, and noncarcinoid tumors (13%: 3 of 22), clinically relevant in only one case. CONCLUSION: FDOPA-PET appears to be a major tool for the management of carcinoid tumors with excellent diagnostic performances and induced relevant changes in patient management. FDOPA-PET was less sensitive and less useful for the management of noncarcinoid tumors.

The type and the position of HNF1A mutation modulate age at diagnosis of diabetes in patients with maturity-onset diabetes of the young (MODY)-3.

OBJECTIVE: The clinical expression of maturity-onset diabetes of the young (MODY)-3 is highly variable. This may be due to environmental and/or genetic factors, including molecular characteristics of the hepatocyte nuclear factor 1-alpha (HNF1A) gene mutation. RESEARCH DESIGN AND METHODS: We analyzed the mutations identified in 356 unrelated MODY3 patients, including 118 novel mutations, and searched for correlations between the genotype and age at diagnosis of diabetes. RESULTS: Missense mutations prevailed in the dimerization and DNA-binding domains (74%), while truncating mutations were predominant in the transactivation domain (62%). The majority (83%) of the mutations were located in exons 1- 6, thus affecting the three HNF1A isoforms. Age at diagnosis of diabetes was lower in patients with truncating mutations than in those with missense mutations (18 vs. 22 years, P = 0.005). Missense mutations affecting the dimerization/DNA-binding domains were associated with a lower age at diagnosis than those affecting the transactivation domain (20 vs. 30 years, P = 10(-4)). Patients with missense mutations affecting the three isoforms were younger at diagnosis than those with missense mutations involving one or two isoforms (P = 0.03). CONCLUSIONS: These data show that part of the variability of the clinical expression in MODY3 patients may be explained by the type and the location of HNF1A mutations. These findings should be considered in studies for the search of additional modifier genetic factors.

Bone metastases of differentiated thyroid cancer: impact of early 131I-based detection on outcome.

Bone is the second most frequent target of distant metastases in patients with differentiated thyroid cancer, and such forms carry a very poor prognosis. The impact of (131)I therapy in this setting is controversial. We describe the diagnostic circumstances and outcome of patients with bone metastases recently managed in two institutions. Among 921 consecutive thyroid cancer patients who had total thyroidectomy and (131)I ablation between January 2000 and December 2004 and who were subsequently monitored, bone metastases had been diagnosed in 16 patients. In three cases, the bone metastases were non-functioning (negative (131)I uptake) . These patients were treated with surgery and radiotherapy but progressed rapidly. The other 13 patients had functioning (positive (131)I uptake) bone metastases. In five of them, thyroid cancer was revealed by signs of distant involvement (bone pain, n = 4; dyspnea, n = 1). The bone metastases progressed in these five patients, despite local therapy and multiple courses of (131)I. The bone metastases in the remaining eight patients were discovered on the post-surgery (131)I therapy scan. Complementary radiological studies were negative except in one patient in whom one of the metastases (a 5 mm lesion of the right humerus) was visible on magnetic resonance imaging (MRI). Six of these patients showed a good response to (131)I therapy, with (131)I uptake and Tg levels becoming undetectable or showing a sharp fall. One patient refused (131)I therapy; bone metastases became visible on MRI within 1 year and the Tg level rose tenfold. The disease progressed in one patient despite (131)I therapy. Post-surgical (131)I ablation can contribute to early detection of bone metastases at a time when the Tg level may be only moderately elevated, when other radiological studies are negative, and when the disease is potentially curable by (131)I therapy.

Should 'low-risk' thyroid cancer patients with residual thyroglobulin be re-treated with iodine 131?

OBJECTIVE: The American consensus statement on patients with low-risk thyroid cancer, published in 2003, suggests repeat (131)I therapy if the thyroglobulin value is elevated at first follow-up. We evaluated this strategy in our practice. METHODS: Among 407 patients with thyroid cancer who had total thyroidectomy and (131)I ablation between January 2000 and December 2003, 12 patients with stage I thyroid cancer (any tumour (T), any node (N), metastasis (M)0 if < 45 years or T1, N0, M0 if > 45 years), were re-treated on the basis of their thyroglobulin level at first follow-up. Mean patient age was 32.8 years. None of them had a T4 tumour. Thyroglobulin levels after thyroid hormone withdrawal 'off-T4' ranged between 4.5 and 251 ng/ml (median 8). One to four courses of 3.7 GBq (131)I were given. RESULTS: Three patients had a negative (131)I therapy scan and an uneventful course. Two patients had slight residual uptake only in the thyroid bed and negative ultrasound examination. Four patients had isolated (131)I uptake in the mediastinal region. No abnormalities were found on complementary mediastinal imaging. This finding was interpreted as benign (131)I thymic uptake. The last three patients also had mediastinal thymic uptake associated with a slight thyroid bed uptake. One patient had a gradual increase in the thyroglobulin level, and underwent resection of nonfunctioning neck lymph nodes. Thyroglobulin levels declined in all other patients. CONCLUSIONS: No distant lesions were found in a group of young 'low-risk' thyroid cancer patients given empirical (131)I therapy for residual thyroglobulin. When blind (131)I therapy shows no uptake, or uptake limited to the thymus, (131)I therapy should not be repeated. The authors also briefly discuss the hypothesis that enhanced thymus might be a source of benign thyroglobulin secretion.

Stimulation test in the follow-up of thyroid cancer: plasma rhTSH levels are dependent on body weight, not endogenously stimulated TSH values.

BACKGROUND: Stimulation testing in the first year following thyroid ablation has important prognostic value in thyroid cancer patients. Recombinant human TSH (rhTSH) is better tolerated than thyroid hormone withdrawal but provides only transient stimulation so that the TSH threshold of 30 mIU x l(-1) which defines adequate testing during thyroid hormone withdrawal is not appropriate for rhTSH stimulation. We looked at rhTSH levels after a standard two intramuscular injections of 0.9 mg rhTSH. METHODS: Plasma rhTSH levels were measured 24 h after the second injection in 143 consecutive patients. RESULTS: rhTSH levels showed large inter-patient variation (range: 44-240; mean+/-SD: 131+/-48). There was a strong inverse correlation between TSH levels and body weight (P<0.001). Levels lower than 80 mIU x l(-1) (corresponding to 1 SD below average) were recorded in 24 patients (16.8%). These patients had an average body weight of 79.7 kg, as compared to 67.9 kg for those patients with TSH levels higher than 80 mIU x l(-1). A withdrawal test in the first year after thyroid ablation was available in 64 patients. Only one patient (1.6%) had inadequate endogenous TSH stimulation, and there was no dependence of endogenous plasma TSH levels upon weight. CONCLUSION: Contrary to endogenous stimulation, TSH levels after rhTSH injection vary with body weight. The dosage of rhTSH may need to be adapted in patients with more than 80 kg body weight.

Which thyroid cancer patients need periodic stimulation tests?

PURPOSE: Recurrences are frequent in thyroid cancer patients and long-term follow-up is therefore necessary. We evaluated the yield of rhTSH stimulation in three groups of patients, classified according to the UICC/TNM risk stratification and the results of first follow-up testing. METHODS: The study population comprised 129 patients referred for rhTSH testing. All had undergone first follow-up testing after thyroid hormone withdrawal (off-T4) within 1 year of 131I ablation. Negative first follow-up testing was defined as Tg <2 ng/ml and no neck uptake on 131I diagnostic whole-body scan. Seventy-five patients had stage I thyroid cancer and negative first follow-up testing (group A), 19 had stage I disease and positive first follow-up testing (group B), and 35 had stage II-IV disease (group C). RhTSH stimulation was performed an average of 6 years after first follow-up testing. RESULTS: 131I diagnostic scanning after rhTSH was negative in all 75 group A patients. Only one group A patient had detectable Tg after rhTSH injection (1.5 ng/ml), but Tg had also been detected at baseline in this patient (1.45 ng/ml). Given the absence of a response to stimulation, suggesting an interference, Tg was reassessed with a different technique and proved to be undetectable (<0.1 ng/ml). Stimulation with rhTSH in group B showed residual Tg in seven patients and residual 131I uptake in the thyroid bed in two patients, but none of these patients had signs of disease progression. Five group C patients (14%) had a positive rhTSH test result, and this was suggestive of disease progression in at least two cases. CONCLUSION: The first follow-up testing is essential for prognostic classification after 131I ablation of thyroid cancer. In stage I patients, undetectable Tg and negative 131I scan 1 year after ablation define a large population of subjects who have a very low risk of recurrence and who do not require further stimulation tests. In contrast, periodic rhTSH stimulation tests appear useful in higher-risk patients.

[PET in thyroid cancers]. / La TEP dans le cancer de la glande thyroïde.

FDG PET can detect thyroid cancer in patients referred for exploration of a different cancer. Because of its lack of specificity, however, this modality is not indicated for examination of thyroid nodules: ultrasonography and fine needle biopsy with cytology allow histological diagnosis, which can be completed by iodine-123 scintigraphy when an autonomous nodule is suspected. No information is currently available about the utility of FDG PET in preoperative staging. In follow-up of patients undergoing thyroidectomy for adenocarcinoma, FDG PET is useful for detecting recurrence in cases where serum thyroglobulin levels rise and iodine-131 scintigraphy is negative: surgical resection may be appropriate. Nonetheless FDG PET should be performed more widely and earlier: the initial presence of foci positive for FDG is a major predictor of shorter survival, and most cancer lesions take up either iodine or FDG. In follow-up of medullary carcinoma, FDG PET detects residual tissue better than any other scintigraphic procedures, especially when serum levels of CEA (carcinoembryonic antigen) are rising rapidly. FDOPA PET seems to have better sensitivity than FDG-PET and may be useful in occult recurrence, as three case reports indicate.

Completion pancreatectomy for postoperative peritonitis after pancreaticoduodenectomy: early and late outcome.

HYPOTHESIS: Completion pancreatectomy in patients with pancreatic leakage associated with postoperative peritonitis after pancreaticoduodenectomy is a viable salvage procedure. DESIGN: Retrospective analysis from a cohort of consecutive patients admitted between January 1, 1989, and December 31, 1999, for postoperative peritonitis originating from pancreaticojejunostomy leakage. SETTING: Tertiary referral center with surgical intensive care unit specializing in the treatment of intra-abdominal sepsis. PATIENTS: Eight consecutive patients with postoperative peritonitis originating from pancreaticojejunostomy after pancreaticoduodenectomy, with a mean Acute Physiology and Chronic Health Evaluation II score of 18.6. We excluded patients with pancreatic fistulas or abscesses amenable to percutaneous drainage or other conservative treatment. INTERVENTION: Completion pancreatectomy. MAIN OUTCOME MEASURES: Mortality, morbidity, and long-term outcome, which was assessed by interview. RESULTS: Three patients died in the postoperative period: 2 required early reoperation during the postoperative period and died of hemorrhage and sepsis, and 1 died of multiorgan failure without reoperation. Recurrence of carcinoma was responsible for late death of 2 other patients. CONCLUSIONS: Postoperative peritonitis after pancreaticoduodenectomy still has high mortality; however, completion pancreatectomy may represent the only means to achieve source control of infection in cases of postoperative peritonitis.