Search

Context: Treatment modalities for progressive iodine-refractory poorly differentiated thyroid carcinomas are not yet well defined. Molecular targeted therapy with multikinase inhibitors has recently shown promising results, and cytotoxic chemotherapy is generally considered of low efficacy., Objective: We report the case of a 57-yr-old woman with an advanced iodine-refractory poorly differentiated thyroid cancer who was treated sequentially between October 2006 and March 2011 with two different regimens of cytotoxic chemotherapy and three lines of multikinase inhibitors., Methods: Efficacy and adverse effects of the consecutive treatment modalities, i.e. vandetanib, doxorubicin-cisplatin combination, sorafenib, paclitaxel-carboplatin combination, and sunitinib, are reported., Results: The patient presented a complete tumor response to a doxorubicin-cisplatin combination lasting 10 months and to a paclitaxel-carboplatin regimen lasting 5 months and had no or limited response to kinase inhibitors, i.e. progression after 3 months of vandetanib, progression after 4 months of sorafenib, and stable disease for 8 months with sunitinib treatment., Conclusions: When tumor progresses with kinase inhibitors, cytotoxic chemotherapy may be an alternative in selected cases of advanced iodine-refractory poorly differentiated thyroid cancer. For those rare cases, clinical management should benefit from a multidisciplinary team approach through specialized networks.

Unlabelled: The prognosis of medullary thyroid carcinoma (MTC) varies from long- to short-term survival based on such prognostic factors as serum calcitonin and carcinoembryonic antigen (CEA) doubling times (DTs). This prospective phase II multicenter trial evaluated the efficacy and safety of anti-CEA pretargeted radioimmunotherapy (pRAIT) in rapidly progressing metastatic MTC patients and also how serum biomarker DTs correlate with clinical outcome., Methods: From June 2004 to January 2008, 42 patients were treated with anti-CEA × anti-diethylenetriaminepentaacetic acid (DTPA) bispecific antibody (hMN-14 × m734) (40 mg/m(2)), followed by (131)I-di-DTPA-indium bivalent hapten (1.8 GBq/m(2)) 4-6 d later., Results: The disease control rate (durable stabilization plus objective response) was 76.2%. Grade 3-4 hematologic toxicity was observed in 54.7% of patients and myelodysplastic syndrome in 2, including 1 heavily treated previously. After pRAIT, 21 of 37 assessed patients (56.7%) showed a significant impact on DT (≥100% increase of pre-pRAIT calcitonin or CEA DT or prolonged decrease of the biomarker concentration after pRAIT). Pre-pRAIT DT and post-pRAIT DT were significant independent predictors for overall survival (OS) from pRAIT (pre-pRAIT: hazard ratio [HR], 0.46; 95% confidence interval [CI], 0.24-0.86; P = 0.016; and post-pRAIT: HR, 5.32; 95% CI, 1.63-17.36; P = 0.006) and OS from diagnosis (pre-pRAIT: HR, 0.21; 95% CI, 0.08-0.51; P = 0.001; and post-pRAIT: HR, 6.16; 95% CI, 1.81-20.98; P = 0.004)., Conclusion: pRAIT showed antitumor activity, with manageable hematologic toxicity in progressive MTC. Increased biomarker DT after treatment correlated with increased OS.

Objectives: Sperm-associated antigen 9 (SPAG9) has been suggested as a possible biomarker in several malignancies including thyroid cancer. We investigated the expression of SPAG9 mRNA in fine needle aspiration (FNA) material from papillary thyroid carcinoma (PTC) and benign thyroid nodules., Study Design: SPAG9 expression was assessed in 36 FNA samples corresponding to 16 PTC and 20 benign nodules using the original method detecting the SPAG9 transcript containing intron 21 (NCBI X91879). The presence of the BRAF V600E point mutation was also analyzed by pyrosequencing., Results: Six of 16 (38%) PTC samples were positive for X91879 SPAG9 transcript compared to 8 of 20 (40%) benign samples (p = 0.88). Out of 12 BRAF-positive PTC, 3 (25%) also expressed the SPAG9 transcript compared to 3 out of 4 BRAF-negative PTC (75%; p = 0.12)., Conclusions: The X91879 SPAG9 transcript originally described does not appear to be overexpressed in FNA material from PTC or to be clinically relevant in the diagnosis of thyroid nodules.

Background: To assess 18-fluorodeoxyglucose (FDG) bowel uptake in patients with differentiated thyroid cancer (DTC) treated with sorafenib., Findings: Visual (5-point scale) and high maximum standard uptake value (SUVmax) semi-quantitative analyses were conducted in 63 positron emission tomography (PET) studies performed in patients on sorafenib (group 1, n = 20), in a control group (group 2, n = 28) and in patients on sunitinib or vandetanib (group 3, n = 15).Moderate or high and diffuse bowel uptake (grade 4 or 5) was observed in 90% of the PET scans of group 1 versus none in group 2. Only 20% of PET scans in group 3 were scored grade 4. SUVmax values were significantly higher for all colic segments in group 1 than in group 2 (P < 0.0001) or 3 (P < 0.0004). This uptake pattern appeared rapidly (one month) and disappeared after sorafenib withdrawal., Conclusions: FDG uptake is increased in the colon of DTC patients treated by sorafenib.

Background: It is not clear whether the administration of radioiodine provides any benefit to patients with low-risk thyroid cancer after a complete surgical resection. The administration of the smallest possible amount of radioiodine would improve care., Methods: In our randomized, phase 3 trial, we compared two thyrotropin-stimulation methods (thyroid hormone withdrawal and use of recombinant human thyrotropin) and two radioiodine ((131)I) doses (i.e., administered activities) (1.1 GBq and 3.7 GBq) in a 2-by-2 design. Inclusion criteria were an age of 18 years or older; total thyroidectomy for differentiated thyroid carcinoma; tumor-node-metastasis (TNM) stage, ascertained on pathological examination (p) of a surgical specimen, of pT1 (with tumor diameter ≤1 cm) and N1 or Nx, pT1 (with tumor diameter >1 to 2 cm) and any N stage, or pT2N0; absence of distant metastasis; and no iodine contamination. Thyroid ablation was assessed 8 months after radioiodine administration by neck ultrasonography and measurement of recombinant human thyrotropin-stimulated thyroglobulin. Comparisons were based on an equivalence framework., Results: There were 752 patients enrolled between 2007 and 2010; 92% had papillary cancer. There were no unexpected serious adverse events. In the 684 patients with data that could be evaluated, ultrasonography of the neck was normal in 652 (95%), and the stimulated thyroglobulin level was 1.0 ng per milliliter or less in 621 of the 652 patients (95%) without detectable thyroglobulin antibodies. Thyroid ablation was complete in 631 of the 684 patients (92%). The ablation rate was equivalent between the (131)I doses and between the thyrotropin-stimulation methods., Conclusions: The use of recombinant human thyrotropin and low-dose (1.1 GBq) postoperative radioiodine ablation may be sufficient for the management of low-risk thyroid cancer. (Funded by the French National Cancer Institute [INCa] and the French Ministry of Health; ClinicalTrials.gov number, NCT00435851; INCa number, RECF0447.).

Purpose: To assess the diagnostic value of dual-phase (99m)Tc sestamibi scintigraphy with neck and thorax single-photon emission computed tomography/computed tomography (SPECT/CT) in patients with primary hyperparathyroidism, and to analyze the relationships between SPECT/CT data and serum calcium or parathyroid hormone (PTH) concentrations., Materials and Methods: (99m)Tc sestamibi scintigraphy was performed in 94 consecutive patients. Images included early and delayed planar neck images and delayed neck and thorax SPECT/CT. Scintigraphy was scored positive or negative., Results: Fifty-nine sestamibi studies (63%) were positive. SPECT/CT demonstrated a single focus in 56 patients, in usual parathyroid sites in 80% of cases and in unusual sites in the remaining 20% (retrotracheal area, 7%; intrathyroidal, 9%; mediastinum, 4%), and double foci in 3. Serum calcium values were higher in patients with a positive scintigraphy than in those with a negative scintigraphy (2.80 vs. 2.66 mmol/L, P = 0.001) with similar figures for serum PTH values (129 vs. 107 pg/mL, P = 0.0649). In patients with a measurable parathyroid adenoma on integrated CT scan (n = 43), the greatest axial diameter of the adenoma was correlated to serum calcium (r = 0.405, P < 0.0071) or PTH concentrations (r = 0.589, P < 0.0001). Fifty-four patients underwent surgery, 45 with a positive, and 9 with a negative preoperative scintigraphy, resulting in a sensitivity of 92% (95% CI: 80-98) and a specificity of 83% (95% CI: 36-100)., Conclusions: Dual-phase (99m)Tc sestamibi scintigraphy with SPECT/CT enables to identify a parathyroid adenoma in about two-thirds of patients with primary hyperparathyroidism and allows the surgeon to plan appropriate surgery. The likelihood of scintigraphy to be positive is affected by calcium or PTH concentrations.

Purpose: The prognostic value of [(18)F]fluorodeoxyglucose-positron emission tomography (PET), interpreted according to visual criteria, is a matter of debate for diffuse large B-cell lymphoma (DLBCL). Moreover, most published studies do not differentiate between patients treated with or without rituximab. We retrospectively investigated the prognostic value of PET performed in patients with DLBCL receiving chemotherapy plus rituximab. Images were interpreted both visually and by computing maximum standardized uptake value (SUV(max)) between PET performed at baseline and after two cycles of chemotherapy., Patients and Methods: One hundred twelve patients newly diagnosed with DLBCL were treated with an anthracycline-based regimen plus rituximab. A PET was performed after two cycles of treatment. PET positivity or negativity was related to progression-free survival (PFS) and overall survival (OS) using Kaplan-Meier analysis., Results: Visual analysis showed that 70 patients (62.5%) presented with a negative PET scan after two cycles of treatment. The 3-year PFS and OS rates were 84% and 88%, respectively, in patients with PET-negative results versus 47% and 62%, respectively, in patients with PET-positive results (P < .0001 and P < .003, respectively). A second analysis was performed on 85 patients by using interim PET in a quantitative approach on the basis of a ΔSUV(max) evaluation of more than 66%. The 3-year PFS was 77% for patients with PET-negative results and 37.5% for patients with PET-positive results (P = .002)., Conclusion: An early PET scan after two cycles of treatment can effectively predict the outcome in patients with DLBCL treated with rituximab and anthracycline-based chemotherapy by using either a visual or quantitative approach.

The prognostic value of interim positron emission tomography (PET) interpreted according to visual criteria is a matter of debate in diffuse large B-cell lymphoma (DLBCL). Maximal standardized uptake value reduction (ΔSUVmax) may better predict outcome. To compare the prognostic value of both methods, we analyzed PET done at baseline (PET0) and after 2 (PET2) and 4 (PET4) cycles in 85 patients with high-risk DLBCL enrolled on a prospective multicenter trial. All images were centrally reviewed and interpreted visually according to the International Harmonization Project criteria and by computing ΔSUVmax between PET0 and PET2 (ΔSUVmaxPET0-2) or PET4 (ΔSUVmaxPET0-4). Optimal cutoff to predict progression or death was 66% for ΔSUVmaxPET0-2 and 70% for ΔSUVmaxPET0-4. Outcomes did not differ significantly whether PET2 and PET4 were visually positive or negative. Inversely, ΔSUVmaxPET0-2 analysis (> 66% vs ≤ 66%) identified patients with significantly different 2-year progression-free survival (77% vs 57%; P = .0282) and overall survival (93% vs 60%; P < .0001). ΔSUVmaxPET0-4 analysis (> 70% vs ≤ 70%) seemed even more predictive for 2-year progression-free survival (83 vs 40%; P < .0001) and overall survival (94% vs 50%; P < .0001). ΔSUVmax analysis of sequential interim PET is feasible for high-risk DLBCL and better predicts outcome than visual analysis. The trial was registered at http://clinicaltrials.gov as NCT00498043.

Objective: Neck and thorax single photon emission computed tomography with computed tomography (SPECT-CT) improves the reliability of postablation (131)I whole-body scan (WBS) for differentiated thyroid cancer (DTC). The aim of this study was to assess the prognostic value for persistent or recurrent disease of postablation (131)I scintigraphy combining WBS and neck and thorax SPECT-CT with that of the previously known predictive factors., Methods: This is a single referral center prospective study with a median follow-up of 29 months. Postablation (131)I WBS and neck and thorax SPECT-CT were performed in 170 consecutive patients treated between 2006 and 2008. Stimulated serum thyroglobulin (Tg) and anti-thyroglobulin antibodies (TgAb) levels were measured. The impact on disease-free survival of age; gender; postablation (131)I scintigraphy; stimulated serum Tg level; T, N, and M status; and macroscopic lymph node involvement was assessed by univariate and multivariate analyses., Results: Persistent or recurrent disease was observed in 32 (19%) patients. In the whole group of patients, only positive WBS with SPECT-CT was related to an increased risk of persistent or recurrent disease (hazards ratio (HR)=65.21, 95% confidence interval (CI)=26.03-163.39, P<0.0001). In patients without TgAb (n=146), both positive WBS with SPECT-CT (HR=18.86, 95% CI=5.02-70.85, P<0.0001) and serum Tg level ≥58 ng/ml (HR=4.42, 95% CI=1.18-16.53, P=0.0271) were associated with an increased risk., Conclusion: In patients with DTC, the cross analysis of postablation (131)I scintigraphy with neck and thorax SPECT-CT and stimulated serum Tg level enables early assessment of the risk of persistent or recurrent disease.

Objective: Definition of a strategy for the management of thyroid differenciated carcinoma in children., Design and Setting: Retrospective cohort study from the Normandy area in France., Method: Analysis of the medical records of 13 children and adolescents (age > 15 years), presenting with thyroid differenciated carcinoma in three Normandy French hospitals from 1994 to 2006, to determine the clinical features and treatment of the disease., Results: X of the patients were male and y were female, with a mean age at presentation of 11 years. Most frequently symptom was solitary nodes in the thyroid gland (69%). Most frequent histological type was papillary cancer (92%). Size of tumor was > 4 cm in 23% of cases. Children had undergone surgery with total thyroidectomy, radio-iodine treatment and suppressive hormonotherapy. We observed 46% post surgery complications. All patients were alive and none developed a recurrence., Conclusion: Thyroid differenciated carcinoma in children and adolescents were more agressif with most frequently metastasis and recurrence than thyroid differenciated carcinoma of adults. Pronostic is good with 90% of survival at 20 years. We propose a coherent plan of treatment: 1. Thyroidectomy with cervical central lymph node dissection (group VI) completed bilateral selected head neck dissection compartments (groups IIa, III, IV) if macroscopic lymph node metastases in lateral cervical compartment. 2. Postoperative radioiodine is done in all tumor > T1N0 and completed with hormonotherapy.

Purpose: The objective of the study was to evaluate state-of-the-art clinical PET/CT technology in performing static and dynamic imaging of several mice simultaneously., Methods: A mouse-sized phantom was imaged mimicking simultaneous imaging of three mice with computation of recovery coefficients (RCs) and spillover ratios (SORs). Fifteen mice harbouring abdominal or subcutaneous tumours were imaged on clinical PET/CT with point spread function (PSF) reconstruction after injection of [18F]fluorodeoxyglucose or [18F]fluorothymidine. Three of these mice were imaged alone and simultaneously at radial positions -5, 0 and 5 cm. The remaining 12 tumour-bearing mice were imaged in groups of 3 to establish the quantitative accuracy of PET data using ex vivo gamma counting as the reference. Finally, a dynamic scan was performed in three mice simultaneously after the injection of (68)Ga-ethylenediaminetetraacetic acid (EDTA)., Results: For typical lesion sizes of 7-8 mm phantom experiments indicated RCs of 0.42 and 0.76 for ordered subsets expectation maximization (OSEM) and PSF reconstruction, respectively. For PSF reconstruction, SOR(air) and SOR(water) were 5.3 and 7.5%, respectively. A strong correlation (r (2) = 0.97, p < 0.0001) between quantitative data obtained in mice imaged alone and simultaneously in a group of three was found following PSF reconstruction. The correlation between ex vivo counting and PET/CT data was better with PSF reconstruction (r (2) = 0.98; slope = 0.89, p < 0.0001) than without (r (2) = 0.96; slope = 0.62, p < 0.001). Valid time-activity curves of the blood pool, kidneys and bladder could be derived from (68)Ga-EDTA dynamic acquisition., Conclusion: New generation clinical PET/CT can be used for simultaneous imaging of multiple small animals in experiments requiring high throughput and where a dedicated small animal PET system is not available.

Context and Objectives: Radiation is known to be mutagenic. The present study analyses birth outcomes and the health of offspring from men previously exposed to (131) I treatment for thyroid carcinoma., Methods: Data on 493 pregnancies (356 from 173 untreated fathers, 23 from 17 patients who have undergone surgery alone and 114 from 63 fathers who received (131) I) were obtained by interviewing male patients treated for thyroid carcinoma who had not received significant external radiation to the testes. Among these pregnancies, 73 were conceived from fathers who had received more than 370 MBq., Results: The mean activity for the 114 pregnancies fathered by 63 patients was 3993 MBq leading to an estimated radiation dose of 9.2 cGy to the testes (MIRD committee coefficient). No significant differences between untreated and treated fathers were found for any adverse outcome., Conclusion: There was no evidence that exposure to radioiodine affects the outcome of subsequent pregnancies and offspring, whatever the event considered. As our study is underpowered, the question of whether testicular irradiation, fractionated or not, is linked to impaired fertility or consequences on offspring remains to be established., (© 2009 Blackwell Publishing Ltd.)

Purpose: We aimed at investigating whether early metabolic response to corticosteroid therapy may be used as a diagnostic tool to discriminate between cancer and sarcoidosis, a well-known cause of false-positive 2-deoxy-2-[F-18]fluoro-D: -glucose-positron emission tomography (FDG-PET) findings in oncology., Procedure: Two cancer patients with biopsy-proven sarcoidosis or sarcoid-like reaction had multiple thoracic FDG foci. After infectious disease had been excluded, patients received oral corticosteroids for 16 and 14 days, respectively, and underwent posttherapeutic FDG-PET examination., Results: Posttreatment PET revealed a complete metabolic response in both patients, and clinical and imaging follow-up showed no sign of cancer progression., Conclusion: Early metabolic response to systemic corticosteroid treatment may be used as a tool in the establishment of final diagnosis when sarcoidosis is suspected in a cancer patient and could be capable of differentiating cancer from sarcoidosis in the case of coexisting diseases.

Context: In patients with differentiated thyroid carcinoma, postablation (131)I scintigraphy aims to detect residual neck disease and distant metastases, usually found in lungs and bones. New hybrid single-photon emission computed tomography/computed tomography (SPECT-CT) cameras that permit functional and anatomical image fusion may improve its clinical relevance., Objective: Our objective was to test the added value of neck and thorax SPECT-spiral CT to whole-body scan (WBS) in postablation (131)I scintigraphy., Design and Setting: This was a single-referral-center prospective study with a median follow-up of 21 months., Patients and Methods: Postablation (131)I WBS and neck and thorax SPECT-CT were performed in 55 consecutive patients treated in 2006. WBS and SPECT-CT data were blindly reviewed, scored negative (benign), positive (malignant), or indeterminate and were correlated to the patient outcome., Results: At patient level, WBS and SPECT-CT were negative in 67 and 78% of patients, positive in 4 and 15%, and indeterminate in 29 and 7%, respectively. Overall, nine patients (16%) presented treatment failure (persistent or recurrent disease) 1-16 months after radioiodine ablation. In the 16 patients with indeterminate WBS, negative SPECT-CT ruled out suspicion of disease in nine of nine patients, and positive SPECT-CT confirmed malignant lesions in four of five patients. Positive SPECT-CT predicted treatment failure better than positive WBS (McNemar's test, P = 0.03)., Conclusions: This study demonstrates the complementary role of neck and thorax SPECT-CT to WBS in postablation (131)I scintigraphy. Because SPECT-CT allows one to confirm or to rule out residual disease in most cases where WBS remains indeterminate, we recommend its use when available.

Objectives: Prognostic factors for progression of benign adrenocortical adenomas (AI) remain poorly known. We assessed the usefulness of (131)I-6-beta-iodomethylnorcholesterol scintigraphy (IMS) to predict the occurrence of adrenal hyperfunction or mass enlargement., Design: Fifty-one consecutive inpatients with unilateral AI and normal 24-h urinary free cortisol (UFC) were enrolled in a multicenter observational prospective study to investigate the relationship between the scintigraphic pattern and the progression of biological abnormalities of the hypothalamo-pituitary-adrenal axis or tumor size., Results: Biochemically defined 'subclinical' Cushing's syndrome (SCS) was found at baseline in 47% of patients. Unilateral uptake (UU) was significantly associated with SCS (P<0.05). During the follow-up (4.3+/-1.6-year): 53% of patients showed unchanged hormonal evaluation, 29% displayed intermittent SCS and 18% showed definitive hormonal progression of SCS but without overt biochemical hypercortisolism. UU was associated with persistence of SCS and hormonal progression (P<0.01). In multivariate analysis, UU and impaired 1 mg dexamethasone suppression were independently associated with hormonal progression. Three patients with UU developed clinical CS despite persistently normal UFC. Tumor size increased in 10% patients and was not associated with any scintigraphic pattern., Conclusion: Evolution of SCS toward overt biochemical CS in patients with AI is a rare event during a 4-year follow-up. UU is predictive for the occurrence of SCS, its persistence and progression within the spectrum of SCS. Further studies aiming to establish the clinical consequences of SCS are needed to recommend IMS as a complementary evaluation in patients with AI and biochemical SCS.

We report the case of a 72-year-old man with prostate cancer, in whom Tc-99m MDP bone scintigraphy revealed a "superscan" pattern, except in a dorsal vertebra, which appeared photopenic. A low-dose SPECT/CT acquisition demonstrated that the lack of tracer uptake corresponded to a blastic lesion with no lytic component. Surprisingly, the cold vertebra appeared as an "ivory vertebra" on the CT part of the SPECT/CT acquisition. In the present case, the photopenic appearance is thought to be due to a concomitant blastic lesion and spine infarct.

Unlabelled: Radiation is known to be mutagenic. The present study updates a 10-y-old study regarding pregnancy outcome and the health of offspring of women previously exposed to radioiodine ((131)I) during thyroid carcinoma treatment, by doubling the number of pregnancies that occurred after exposure., Methods: Data on 2,673 pregnancies were obtained by interviewing female patients who were treated for thyroid carcinoma but had not received significant external radiation to the ovaries., Results: The incidence of miscarriages was 10% before any treatment for thyroid cancer; this percentage increased after surgery for thyroid cancer, both before (20%) and after (19%) (131)I treatment, with no variation according to the cumulative dose. In contrast to previously reported data, miscarriages were not significantly more frequent in women treated with radioiodine during the year before conception, not even in women who had received more than 370 MBq during that year. The incidences of stillbirths, preterm births, low birth weight, congenital malformations, and death during the first year of life were not significantly different before and after (131)I therapy. The incidences of thyroid and nonthyroid cancers were similar in children born either before or after the mother's exposure to radioiodine., Conclusion: There is no evidence that exposure to radioiodine affects the outcomes of subsequent pregnancies and offspring. The question as to whether the incidences of malformations and thyroid and nonthyroid cancers are related to gonadal irradiation remains to be established. The doubling dose is still being heatedly debated, and the value of 1 Gy as the doubling dose in humans should be reevaluated.

Objective: Whether lymph-node dissection (LND) influences the lymph-node recurrence (LNR) risk in patients with papillary thyroid cancer remains controversial. The prognostic impact of macroscopic and microscopic lymph-node involvement at diagnosis is also an unresolved issue. A retrospective study was conducted to assess the influence of various LND procedures and to search for LNR risk factors., Methods: Overall 545 patients without distant metastases prior to surgery and main tumour > or =10 mm were included. A total thyroidectomy was performed in all patients with either no LND (Group 1, n=161), bilateral LND of the central and lateral compartments (Group 2, n=181) or all other dissection modalities (Group 3, n=203). Post-operative radioiodine was given to 496 (91%) patients. The 10-year cumulative probability of LNR was assessed and a prognostic study using multivariate analysis was performed., Results: Macroscopic lymph-node metastases were present in 118 patients, 57 diagnosed before surgery and 61 only at surgery (including 81% in the central compartment). Overall, the 10-year cumulative probability of LNR was 7%. Macroscopic lymph-node metastases (P=0.001), extra-thyroidal invasion (P=0.017) and male gender (P=0.05) were independent risk factors, while bilateral LND of the central and lateral compartments was protective (P=0.028). In patients with macroscopic lymph-node metastases, the 10-year probability was lower in Group 2 than in Group 3 (10% vs 30%, P<0.01). In patients without macroscopic lymph-node metastases (n=427), no significant differences were observed between the three LND groups., Conclusions: Patients with macroscopic, but not microscopic, lymph-node involvement have a major LNR risk and need an optimal LND at primary surgery.

Context: Patients with progressive medullary thyroid carcinoma (MTC) undergo multiple imaging procedures for diagnosis of relapse and staging., Objective: Our objective was to assess the sensitivity and prognostic value of 18F-2-fluoro-2-deoxy-d-glucose (FDG) positron emission tomography (PET)/computed tomography (CT), and the imaging sensitivity of pretargeted iodine-131-radioimmunotherapy (RIT) in patients with progressive MTC., Design/setting/patients: We performed a prospective multicenter study in high-risk patients with rapidly progressing MTC enrolled in a phase-II pretargeted RIT study, as documented by short serum calcitonin (Ct) or carcinoembryonic antigen (CEA) doubling time (DT). INTERVENTIONS/MAIN OUTCOME MEASURES: Patients underwent neck-thoracic-abdominal CT, spine and pelvic magnetic resonance imaging, whole-body post-RIT immunoscintigraphy (IS) with iodine-131, and whole-body 18F-FDG-PET/CT imaging. Imaging sensitivity and the correlation between FDG uptake and biomarkers DT were evaluated., Results: A total of 33 patients with mean CEA and Ct DTs of 1.90 yr (range 0.21-8.50) and 1.52 yr (range 0.09-6.01), respectively, were evaluated. Sensitivity of FDG-PET/CT was 83% for neck, 85% for mediastinal, 75% for lung, 60% for liver, and 67% for bone metastases; overall sensitivity was 76%. Median standardized uptake value (SUVmax) was 5.23 (2.06-13.90). SUVmax correlated significantly with Ct DT (P = 0.011) and minimal DT (minimal value between CEA DT and Ct DT) (P = 0.027). Overall sensitivity of post-RIT IS, CT, and bone magnetic resonance imaging were 94, 74, and 85%, respectively., Conclusions: These results demonstrate the value of FDG-PET/CT for staging of patients with progressive MTC, especially in the neck and mediastinum, with possible prognostication by SUV quantification. Post-RIT IS was the most sensitive of the imaging modalities studied prospectively.

Aim: To evaluate the influence of CA 15-3 blood level and doubling time on diagnostic performances of 18F-FDG PET in breast cancer patients with occult recurrence., Materials and Methods: Thirty-five 18F-FDG PET examinations in 32 patients with CA 15-3 blood level above the normal range, and negative conventional imaging within 3 months before PET examination were included in this retrospective study. PET examinations were reviewed blindly by two experienced nuclear medicine physicians who were unaware of any clinical, biological or radiological information. CA 15-3 assays performed prior to the PET examinations and all using the same technique were collected and used for doubling time calculation if (1) no therapeutic modification occurred in the meantime, and (2) the delay between assays was less than 6 months., Results: Median CA 15-3 blood levels were higher in the positive PET group (100 U x ml(-1)) than in the negative group (65 U x ml(-1)) (P=0.04). The likelihood of depicting recurrence was higher in patients with a short doubling time (<180 days) (P=0.05), a CA 15-3 blood level >60 U x ml(-1) (P=0.05), and when a short doubling time was associated with a CA 15-3 blood level >60 U x ml(-1) (P=0.03)., Conclusions: The likelihood of depicting recurrence was influenced by CA 15-3 blood level and doubling time. Further studies are required to confirm that selections of patients based on those criteria could improve the sensitivity of positron emission tomography in the detection of breast cancer recurrence, particularly in the case of low CA 15-3 blood level.

The aim of this study was to assess the prevalence, prognostic factors, and long-term outcome of tall cell variant (TCV) in comparison with the conventional forms of papillary thyroid carcinoma (PTC). A total of 945 patients with thyroid cancer were treated and followed up from 1960 to 1998. Pathologic review was performed in 778 patients (84%) of the cohort. Of these, 674 had PTC: 503 (74%) had conventional form (CF); 56 (8%), TCV; and 155 (17%), other variants of PTC. Tall cell variant was associated with tumors of larger size (P < .001), bilaterality (P < .02), multifocality (P < .04), and extrathyroidal invasion (P < .001). Treatment was similar in both groups, but neck dissection was performed more frequently in patients with TCV (P < .04). The 10-year overall and event-free survival rates were, respectively, 90% and 85% in the CF versus 79% and 67% in the TCV group (P < .001). Histologic subtype did not have an effect on clinical outcome after multivariate analysis, the most relevant factors being age, involved nodes, or the "Metastasis, Age, Completeness, Invasion, Size" classification after multivariate analysis. In this large cohort of patients, TCV represents 8.3% of PTC, and it is a more aggressive form of PTC than CF because of the higher stage and increased grade.

The prognostic value of fluorodeoxyglucose positron emission tomography (FDG-PET) and gallium-67 scan (GS) performed early after chemotherapy was assessed in 40 patients with newly diagnosed aggressive lymphoma. FDG-PET and GS were performed before and after three cycles of CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) or two cycles of ACVBP (doxorubicin, cyclophosphamide, vindesine, bleomycin, prednisone), with or without rituximab. Thirty-five patients had diffuse large B-cell lymphoma (DLBCL), two had mantle-cell lymphoma and three had T-cell lymphoma. Four patients relapsed despite early negative FDG-PET and GS including all three patients with T-cell lymphoma. Nine patients stayed in remission despite positive FDG-PET and/or GS of whom five showed moderate intensity residual bone uptake. Seven of these nine early false positives had a negative exam at the end of treatment. In patients with DLBCL, the 2-year event-free survival was 85% for negative versus 30% for positive FDG-PET patients (P = 0.003) whereas it was 78% for negative versus 33% for positive GS patients (P = 0.018). Sensitivity, specificity and diagnostic accuracy of FDG-PET and GS were not significantly different: 90% versus 70%, 76 versus 80% and 80 versus 77%, respectively. We conclude that both FDG-PET and GS are valuable tools to early predict outcome in patients with DLBCL.

Purpose: No effective therapy is currently available for the management of patients with metastatic medullary thyroid carcinoma (MTC). The efficacy of pretargeted radioimmunotherapy (pRAIT) with bispecific monoclonal antibody (BsMAb) and a iodine-131 (131I) -labeled bivalent hapten is evaluated., Patients and Methods: Twenty-nine patients with advanced, progressive MTC, as documented by short serum calcitonin doubling times (Ct DTs), received an anti-carcinoembryonic antigen (CEA)/anti-diethylenetriamine pentaacetic acid (DTPA) -indium BsMAb, followed 4 days later by a 131I-labeled bivalent hapten. Overall survival (OS) was compared with 39 contemporaneous untreated MTC patients with comparable prognostic indicators., Results: OS was significantly longer in high-risk, treated patients (Ct DT < 2 years) than in high-risk, untreated patients (median OS, 110 v 61 months; P < .030). Forty-seven percent of patients, defined as biologic responders by a more than 100% increase in CtDT, experienced significantly longer survival than nonresponders (median OS, 159 v 109 months; P < .035) and untreated patients (median OS, 159 v 61 months; P < .010). Treated patients with bone/bone-marrow disease had a longer survival than patients without such involvement (10-year OS, 83% v 14%; P < .023). Toxicity was mainly hematologic and related to bone/bone-marrow tumor spread., Conclusion: pRAIT against CEA induced long-term disease stabilization and a significantly longer survival in high-risk patients with Ct DTs less than 2 years, compared with similarly high-risk, untreated patients. Ct DT and bone-marrow involvement appear to be prognostic indicators in MTC patients who undergo pRAIT.

Aim: Positron emission tomography (PET) using fluorine-18 fluorodeoxyglucose (FDG) can be performed using a dedicated PET scanner (PET-I) or a dual-head coincidence gamma camera (CGC-I). The aim of this study was to comparatively assess the impact of PET-I and CGC-I on clinical management in cancer patients., Methods: From November 2000 to November 2002, PET-I and CGC-I were performed at an interval of 2 days in 151 patients with colorectal cancer (n=40), breast cancer (n=28), thyroid cancer (n=23), lung tumors (n=22), germ cell tumors (n=14), unknown primary cancer (n=7) and other cancers (n=17). PET-I and CGC-I were interpreted independently with knowledge of conventional imaging (CI). In June 2003, theoretical management, e.g. treatment modality/ies and treatment intent (curative or palliative), after CI, PET-I and CGC-I were stated during multidisciplinary sessions and were a posteriori considered as appropriate or inappropriate using pathological and follow-up data., Results: The theoretical management proposed after PET-I and after CGC-I was similar in 112/151 (74%; 95% CI: 66-81%) patients. In 125 assessable patients, theoretical management after PET-I was appropriate in 86% (95% CI: 79-92%), significantly higher (P=0.0033) than after CGC-I (70%; 95% CI: 62-78%). Both proportions were also higher than after CI (46%; 95% CI: 37-56%), (P<0.0001). A similar trend for higher proportions of appropriate management after PET-I than after CGC-I was observed for each tumor localization., Conclusions: The clinical impact of PET-I is superior to that of CGC-I in a large series of cancer patients. Although CGC-I could be considered as an acceptable alternative, PET-I remains the standard and should preferably equip nuclear medicine departments.

Purpose: In thyroid cancer patients, radioiodine treatment has been shown to be associated with an increased risk of colon carcinoma. The aim of this study in thyroid cancer patients was to evaluate the role of familial factors in the risk of colorectal cancer and their potential interaction with radioiodine exposure., Methods and Materials: We performed a case-control study on 15 colorectal cancer patients and 76 matched control subjects, nested in a cohort of 3708 thyroid cancer patients treated between 1933 and 1998. For each patient, the radiation dose delivered to the colon by radioiodine was estimated by use of standard tables. In those who received external radiation therapy, the average radiation doses delivered to the colon and rectum were estimated by use of DOS&#95;Eg software. A complete familial history was obtained by face-to-face interviews, and a familial index was defined to evaluate the degree of familial aggregation., Results: The risk of colorectal cancer increased with familial aggregation of colorectal cancer (p = 0.02). After adjustment for the radiation dose delivered to the colon and rectum, the risk of colorectal cancer was 2.8-fold higher (95% CI, 1.0-8.0) for patients with at least one relative affected by colorectal cancer than for patients without such a family history (p = 0.05). The radiation dose delivered to the colon and rectum by (131)I and external radiation therapy was associated with an increase of risk near the significance threshold (p = 0.1). No significant interaction was found between radiation dose and having an affected relative (p = 0.9)., Conclusions: The role of familial background in the risk of colorectal cancer following a differentiated thyroid carcinoma appears to increase with the radiation dose delivered to the colon and rectum. However, the study population was small and no interaction was found between these two factors.

Concerns remain over the risk of cancer following differentiated thyroid carcinoma and its causes. Iodine-131 ((131)I) and external irradiation are known to have potential carcinogenic effects. Thyroid carcinoma is a polygenic disease which may be associated with other malignancies. We investigated the incidence of second cancer and its aetiology in a cohort of 875 patients (146 men, 729 women) with differentiated thyroid carcinoma originating from Basse-Normandie, France. Cancer incidence was compared with that of the general population of the Département du Calvados matched for age, gender and period. The cumulative proportion of second cancer was estimated using the life-table method. Factors that correlated with the risk of second cancer were studied using the Cox model. After a median follow-up of 8 years, 58 second cancers had been observed. Compared with general population incidence rates, there was an overall increased risk of second cancer in women [standardised incidence ratio (SIR)=1.52; P<0.01], but not in men (SIR=1.27; P>0.20). Increased risk related to cancers of the genitourinary tract (SIR=3.31; P<0.001), and particularly to cancer of the kidney (SIR=7.02; P<0.01). Multivariate analysis showed that age above 40 years (P<0.01) and a history of previous primary cancer (P<0.001) correlated with risk. In contrast, neither cervical irradiation nor cumulative activity of (131)I was related to the risk. These data confirm that women with differentiated thyroid carcinoma are at risk of developing a second cancer of the genitourinary tract and kidney. Only age and medical history of primary cancer before thyroid carcinoma are risk factors for second cancer. Common environmental or genetic factors as well as long-term carcinogenic effects of primary cancer therapy should be considered.

Sixty-one heterozygotes harboring the germline V804L mutation of the RET protooncogene were identified in five independent families. A total of 31 subjects underwent surgery. Histology identified C cell hyperplasia in 30 cases, isolated in 12 and associated with medullary thyroid carcinoma (MTC) in 18. Six patients with MTC had lymph node metastases. Among the 14 patients with basal detectable calcitonin (CT) level, 12 had MTC and 2 had isolated C cell hyperplasia. In most individuals carrying 804 RET mutation, C cell disease displayed late onset and an indolent course; a pentagastrin test was negative in the majority of heterozygotes during the first 2 decades and was positive in only half of them during the third and fourth decades of life. Interestingly, concomitant somatic M918T was detected in a 12-yr-old girl with MTC and was likely to be responsible for both the early clinical appearance and the aggressiveness of the disease. Our data show that in these gene carriers, surgery may be postponed to the fourth decade of life or until the pentagastrin stimulation test becomes positive. Indeed, our data should be confirmed on a larger series of V804L carriers, but may offer a balanced strategy to keep under control and prevent development of the full disease phenotype.

The usefulness and complementarity of gallium (67Ga) scintigraphy and computed tomography (CT) in the management of patients with lymphoma have been extensively demonstrated. Owing to a lack of anatomical landmarks and physiological distribution of the tracer, precise localisation of abnormalities on 67Ga scintigraphy can be difficult. As fusion imaging techniques between single-photon emission tomography (SPET) and CT have been developed recently, we investigated whether use of CT/67Ga SPET fusion imaging could help in the interpretation of 67Ga scintigraphy. From November 1999 to May 2001, 52 consecutive fusion studies were performed in 38 patients [22 patients with Hodgkin's disease (HD) and 16 patients with non-Hodgkin's lymphoma (NHL)] as part of pre-treatment staging (n=13), treatment evaluation (n=20) or evaluation of suspected recurrence (n=19). 67Ga scintigraphy was carried out 2 and 6 days following the injection of 185-220 MBq 67Ga citrate. On day 2, 67Ga SPET and CT were performed, focussing on the chest and/or the abdomen/pelvis. Data from each imaging method were co-registered using external markers. 67Ga scintigraphy and CT were initially interpreted independently by nuclear medicine physicians and radiologists. CT/67Ga SPET fusion studies were then jointly interpreted and both practitioners indicated when fusion provided additional information in comparison with CT and 67Ga SPET alone. Image fusion was considered to be of benefit in 12/52 (23%) studies which were performed for initial staging (n=4), treatment evaluation (n=4) or evaluation of suspected recurrence (n=4). In these cases, image fusion allowed either confirmation and/or localisation of pathological gallium uptake (n=10) or detection of lesions not visible on CT scan (n=2). Fusion was relevant for discrimination between osseous lesions and lymph node involvement adjacent to bone, especially in the thoracic and lumbar spine and pelvis. In the abdomen and pelvis, fusion helped to differentiate physiological bowel elimination from abnormal uptake, and assisted in precisely locating uptake in neighbouring viscera of the left hypochondrium, including the spleen, left liver lobe, coeliac area, stomach wall and even the splenic flexure. At the thoracic level, fusion also proved useful for demonstrating clearly the relationships of abnormal foci to the pleura, hepatic dome, mediastinum, ribs or thoracic spine. Clinical management was altered by fusion imaging in one patient (chemotherapy was given instead of radiotherapy) and was potentially affected in three other patients (in that, in conjunction with other factors, the results of fusion imaging had an influence on the decision regarding use of irradiation and especially the treatment volume). In conclusion, CT/67Ga SPET fusion imaging allowed precise localisation of gallium uptake and correct attribution to the involved viscera, thereby altering the diagnosis in 20%-25% of studies in comparison with CT and 67Ga SPET analyses alone. CT/67Ga SPET fusion therefore appears valuable in facilitating the interpretation of 67Ga scintigraphy and we recommend its use in patients with lymphoma when CT and 67Ga scintigraphy are planned.

The clinical impact of gallium-67 scintigraphy before and after therapy for lymphoma remains controversial. The aims of this study were: (1) to compare the staging of lymphoma by 67Ga scintigraphy only with staging by clinical examination and conventional imaging (CI), and (2) to analyse the clinical relevance of both 67Ga imaging and CI after treatment. From March 1995 to November 1998, 86 67Ga scintigraphy studies were performed in 62 patients with Hodgkin's disease (n=52) or non-Hodgkin's lymphoma (n=10). 67Ga scintigraphy was performed at diagnosis (n=44) or after therapy (n=42) using 185-220 MBq 67Ga citrate and planar and single-photon emission tomography (SPET) studies. Treatment comprised radiotherapy, chemotherapy or combined modalities. CI included plain chest radiography, computed tomography (CT) of the chest and abdomen/pelvis, ultrasound of the abdomen, lymphography, bone marrow biopsy and, when necessary, magnetic resonance imaging (MRI) and bone scintigraphy. For individual suspected sites of disease before treatment, complete agreement between clinical examination and CI on the one hand and 67Ga scintigraphy on the other hand was observed in 25/44 patients (57%; 95% confidence interval 41%-72%). Clinical examination and CI showed more sites than did 67Ga scintigraphy in 12/44 patients (27%) and 67Ga imaging demonstrated more sites than CI in 6/44 patients (11%). The clinical stage of the disease as assessed using 67Ga scintigraphy only was in agreement with that using all diagnostic procedures in 34/44 patients (77%; 95% confidence interval 62%-89%). Compared with CI staging, 67Ga scintigraphy downstaged seven patients (16%) and upstaged three (7%). 67Ga scintigraphy downstaged mainly because of the limited value of the technique below the diaphragm and upstaged owing to the good sensitivity in the lung. After therapy, both CI and 67Ga scintigraphy were normal in 11 patients. All but one of these patients were in complete remission after a median follow-up of 31 months. In contrast, radiological residual mass was observed in 31/42 patients. 67Ga imaging was normal in 22/31 (71%); 17 of these 22 patients, including nine with a large residual mass (> or =2 cm), were in complete remission after a median follow-up of 32 months, while four suffered relapses 8-45 months later. The cause of death remained unknown in one patient. 67Ga scintigraphy showed abnormal uptake in 9 of the 31 patients with a large residual mass. Active disease was demonstrated in eight patients and one patient was in complete remission 30 months thereafter. Our data show that 67Ga imaging cannot replace CI in initial staging but can demonstrate additional individual sites of disease in more than 10% of patients and can lead to clinical upstaging with potential prognostic and therapeutic consequences. After therapy, 67Ga scintigraphy has a clinical impact when radiological abnormalities persist because it can either avoid unnecessary complementary treatment or confirm the need to change treatment modalities.

The toxicity and therapeutic efficacy of escalating doses of anti-carcinoembryonic antigen x anti-N alpha-(diethylenetriamine-N,N,N',N''-tetraacetic acid)-In bispecific monoclonal antibody (F6-734) and iodine 131-labeled bivalent hapten were determined in a Phase I/II trial. A total of 26 patients with recurrences of medullary thyroid cancer documented by imaging and a rise in serum thyrocalcitonin were enrolled. Twenty to 50 mg of F6-734 and 40-100 mCi of 131I-hapten were injected 4 days apart. Quantitative scintigraphy was performed after the second injection for dosimetry estimations in eight cases. Clinical, biological, and morphological follow-up was carried out for 1 year after treatment. The mean percentage of injected activity per gram of tumor at the time of maximum uptake was 0.08% (range, 0.003-0.26%). The tumor biological half-life ranged from 3 to 95 days, and tumor doses ranged from 2.91 to 184 cGy/mCi. The estimated tumor-to-nontumor dose ratios were 43.8 x 53.4, 29.6 x 35.3, 10.9 x 13.6, and 8.4 x 10.0 for total body, red marrow, liver, and kidney, respectively. Grade III/IV hematological toxicity was observed in seven patients, most of them with bone metastases. Among the 17 evaluable patients, 4 pain reliefs, 5 minor tumor responses, and 4 biological responses with decrease of thyrocalcitonin were observed. Nine patients developed human anti-mouse antibody. Dose-limiting toxicity was hematological, and maximum tolerated activity was 48 mCi/m2 in this group of patients, most of whom had suspected bone marrow involvement. The therapeutic responses observed in patients mainly with a small tumor burden are encouraging for the performance of a Phase II trial with minimal residual disease.

Adrenal scintigraphy with 131I-6 beta-iodomethyl-19-noncholesterol requires well-prepared patients. Its interpretation requires trained observers with good knowledge of adrenal physiology and adrenal diseases. This multidisciplinary cooperative work was conducted by endocrinologists, nuclear medicine physicians and surgeons, in order to help physicians to optimize indications and practical implementation of this scintigraphy, which has constraints and pitfalls but is very informative.

Unlabelled: The purpose of this study was to estimate the dose delivered to tumor targets and normal tissues after two-step injection of an anti-CEA/anti-DTPA-In (F6-734) bispecific antibody and a 131I-labeled di-DTPA in-TL bivalent hapten in patients with medullary thyroid carcinoma (MTC) and small-cell lung cancer (SCLC)., Methods: Five patients with persistent disease or recurrences of MTC and five patients with primary SCLC or relapse were studied. In a first step, 0.1 to 0.3 mg/kg of F6-734 bispecific antibody was injected intravenously. Four days later, 6 nmole (5.8 to 9.8 mCi) of 131I-labeled di-DTPA in-TL bivalent hapten were injected. Quantitative imaging was performed during one week after the second injection., Results: All 5 patients with MTC showed positive immunoscintigraphy (IS). In the smallest visualized and resected tumor (0.8 g), the fraction of injected activity per gram (% ID/g) was 0.1% at Day 3. IS was positive in 4 of the 5 patients with SCLC. The volume of the smallest visualized SCLC tumor was estimated at 11 +/- 2 ml, and tumor uptake was about 0.009% ID/g. Tumor dose estimates ranged from 4.2 to 174 cGy/mCi in patients with MTC and from 1.7 to 8 cGy/mCi in patients with SCLC., Conclusion: High absorbed dose values were calculated for small MTC recurrences. For SCLC recurrences the values were smaller but in the same range as those obtained by other investigators with the one-step technique in lymphoma.

Objective: Most incidentally discovered adrenal tumours ('incidentaloma') are benign adrenocortical adenomas. It has been suggested that 131I-6 beta-iodomethylnorcholesterol (IMC) scan could specify the degree of functional autonomy of such adenomas depending on whether they prevent contralateral adrenal tracer uptake. Our purpose was to examine this hypothesis in a correlated scintigraphic and endocrine study., Design: Prospective study evaluating the prevalence of unilateral IMC uptake (tumour uptake with no visualization of the contralateral adrenal gland) and bilateral uptake (uptake in both the tumoral and the contralateral adrenal glands) in patients with unilateral incidentaloma. Comparison of adrenocortical function and of IMC scan after dexamethasone (DXM) in the two scintigraphic groups thus defined., Patients: Thirty-five patients with a unilateral mass highly suggestive of benign adrenocortical adenoma on CT scan., Measurements: The IMC scan was performed in basal conditions (baseline scan) and after DXM (suppression scan). Adrenocortical function assessment included basal measurements of 11-deoxycortisol, 17 alpha-hydroxyprogesterone (17-OHP), dehydroepiandrosterone sulphate (DHEAS), plasma cortisol and ACTH, urinary free cortisol (UFC), overnight and low-dose DXM suppression test, and CRH test., Results: The baseline scan showed 16 patients (46%) with unilateral uptake (group A) and 19 (54%) with bilateral uptake (group B). Patients in group A exhibited lower ACTH values at 0800h (P = 0.05) and higher cortisol values after an overnight DXM suppression test (P = 0.02), than did patients in group B. In addition, 3 patients in group A failed the overnight and the low-dose DXM suppression tests. Adrenal masses were larger in group A than group B (P = 0.04) and an inverse correlation was found in the whole population between tumour size and ACTH value at 0800h (P = 0.05). On the suppression scan performed in 14 patients (7 in each group), patients in group A continued to exhibit unilateral tumour uptake and bilateral uptake was suppressed in 72% of patients in group B. An adrenal mass was removed in 3 patients of group A with confirmed benign adrenocortical adenomas. In the post-surgical period, the contralateral gland was again visualized in a baseline scan and the hormonal evaluation returned to the normal range., Conclusion: Unilateral 131I-6 beta-iodomethylnorcholesterol tumour uptake is a frequent feature in benign adrenocortical adenomas. Hormonal data and scintigraphic profiles obtained after dexamethasone, as well as hormonoscintigraphic changes observed after surgery, provide evidence that unilateral uptake is related to functioning adenomas with various degrees of autononomy and suggest that the 131I-6 beta-iodomethylnorcholesterol scan could be a valuable tool for screening 'subclinical' Cushing's adenomas.

Insulinoma is a rare tumour reported in 10 cases during pregnancy. In most cases, hypoglycaemia occurred during the first trimester and no fetal malformations were noted. We report a new clinical case of insulinoma diagnosed at 6 weeks of amenorrhoea in a 25-year-old woman. Surgery performed at 17 weeks of amenorrhoea confirmed the presence of a 7 mm diameter endocrine tumour in the head of the pancreas and led to a cure. The pregnancy continued without complications, and at 35 weeks the patient gave birth to a 3.5 kg infant with no malformation. This case was investigated in terms of a possible physiopathological cause of insulinoma during pregnancy. There is good evidence that insulin secretion increases rapidly from the beginning of pregnancy because of beta-cell proliferation and enhanced beta-cell sensitivity to glucose stimulus as a result of hormonal changes, i.e., prolactin and/or placental lactogen secretion. Moreover, some studies have suggested that insulin sensitivity is enhanced during early pregnancy. Taken together, these phenomena may explain why insulinoma occurs early during pregnancy. Although repeated hypoglycaemia has caused teratogenic effects in animal models, no fetal malformation has been described in previous reports of insulinoma during pregnancy, whether cured or not. This is in agreement with prospective studies in insulin-treated pregnant diabetic women showing no correlation between hypoglycaemia and malformations. These results are encouraging with respect to such pregnancies which, however, require careful supervision.

The acute insulin response to i.v. glucose (AIRG) was evaluated in 344 first-degree relatives of patients with Type 1 diabetes. In 318 relatives aged 3 to 48 years without islet cell antibody and insulin autoantibody, correlations (p < 0.0006) were found between age and fasting insulinaemia, fasting glycaemia, or AIRG, with a peak during puberty. Assuming that these relatives without islet cells and insulin auto-antibodies have a low risk of developing Type 1 diabetes, we provided a "standard age-related chart" for AIRG with a "low" AIRG defined as a value below the 1st percentile for each pubertal stage. Using these cut-off points, predictive characteristics of a low AIRG for progression towards diabetes within 6 years were analysed. Four relatives developed diabetes and one displayed impaired oral glucose tolerance. Four out of these 5 subjects had islet cell and insulin auto-antibodies, but the other one was negative for these markers. Three of these 5 subjects had low AIRG at entry (30, 24 and 1 months before diabetes, respectively). The two others displayed a steady progressive decline (p < 0.02) of age-related during the follow-up before impaired oral glucose tolerance and diabetes appeared (rate of decline: 15 microU/ml/year). Thus, independently of the presence of islet cell antibodies, the predictive value of a low age-related AIRG during the follow-up is greater than the single low AIRG at entry.(ABSTRACT TRUNCATED AT 250 WORDS)

The increased binding in vitro of CD3 CD4 T-lymphocytes from type 1 (insulin-dependent) diabetic patients to beta-cell membrane antigens compared to lymphocytes from control subjects was previously shown to be a marker of cell-mediated immunity, called diabetic rosettes. In the present study diabetic rosettes were detected in some subjects at risk for type 1 diabetes (first degree relatives of type 1 diabetic patients or nondiabetic subjects with previous transient hyperglycaemia). The mean number of lymphocytes adherent to beta-cells (beta-CL) was significantly higher in subjects at risk for type 1 diabetes than in age- and sex-matched control blood bank donors (P less than 10(-6]. This number of beta-CL was higher in type 1 diabetic patients than in subjects at risk (P less than 10(-6], and one-way analysis of variance by rank (Kruskal-Wallis) revealed that the three populations (controls, diabetics, and risk subjects) were different in terms of beta-CL values (P less than 0.001). The percentage of subjects at risk that had a positive test (arbitrarily defined as a beta-CL value higher than the 95th percentile of 228 controls) was 20%. No difference was observed between the two subgroups of subjects at risk in terms of either mean +/- SEM of beta-CL or percentages of individuals with a positive test. These diabetic rosettes were slightly associated with acute insulin response to iv glucose lower than the 5th percentile of controls (immunoreactive insulin at 1 +/- 3 min, 250 pmol/L; by chi 2, P = 0.04) and with HLA DR 3/4 heterozygosity (by chi 2, P = 0.04). They were not associated with islet cell antibodies (regardless of the threshold for positivity, expressed in Juvenile Diabetes Foundation units), insulin autoantibodies, activated (HLA DR+) T-lymphocytes, or sex. A statistical association was detected between HLA DR 3/4 heterozygosity and a low acute insulin response to iv glucose (by chi 2, P less than 0.003). The preliminary (2-yr) longitudinal follow-up revealed that out of five islet cell antibody-positive subjects who progressed to type 1 diabetes, three displayed beta-CL values higher than the 90th percentile of controls. Diabetic rosettes could, thus, be detected in some individuals at risk for type 1 diabetes as a marker of cell-mediated immunity.

The authors have previously described a marker of cell-mediated, called "diabetic rosettes", revealed by the increased binding of CD3 CD4 lymphocytes from type I diabetic patients to beta-cell membrane antigens, as compared to lymphocytes from control subjects. In the present study, they have detected such "diabetic rosettes" in some subjects at risk for type I diabetes. The mean value of lymphocytes adhering to beta (RINm5F)-cells (beta-CL) was statistically higher in those subjects at risk than in control blood bank donors (p = 0.003). When a positive test was arbitrarily defined as a value of beta-CL higher than the 95th percentile of controls, 20 p. cent of the subjects at risk were classified as beta-CL+. No difference was observed between two subgroups of subjects at risk: first degree relatives of type I diabetic patients, and non-diabetic subjects with transient hyperglycaemia. "Diabetic rosettes" were associated with HLA DR 3/4 heterozygosity (p less than 0.04) and with a "low" acute insulin release to IV glucose (p = 0.05). They were not associated with islet-cell antibodies, insulin autoantibodies, or "activated" (HLA DR+) T-lymphocytes. The authors suggest that "diabetic rosettes" represent a marker of cellular immunity in some subjects at risk for type I diabetes.

To analyze the inter- and intra-individual variability of acute insulin response to intravenous glucose (AIRG), 41 healthy volunteers underwent an intravenous glucose tolerance test (IVGTT) and 29 of them a second IVGTT 1 to 9 months later. Basal glycemic, insulin (IRI), and C-peptide values were similar for both IVGTTs. Different indices were used to estimate AIRG. A great inter-individual variability of AIRG (CV around 60%) was detected. AIRGs were not statistically different between the two IVGTTs, and the within-subject variation was fair at the group level (CVs approximately 30%). However, individual coefficients of variation ranged from 2 to 60% between the two tests. Moreover, subjects considered as "low" responders during test 1, returned to "normal" values during test 2. Conversely, other subjects dropped to a "low" response in IVGTT 2. Insulin peak (IRI max) occurred between 1 and 3 minutes after glucose infusion in 85% of the control population, but time points of IRI max were different for 45% of the population between the two IVGTTs. These results suggest that AIRG during IVGTTs are reproducible at the group level, but that AIRG has to be interpreted with caution in individual early detection of pre-insulin-dependent diabetes mellitus because inter- and intra-individual variability could be high even for some normal subjects.