Breast cancer risk among thyroid cancer survivors and the role of I-131 treatment.

BACKGROUND: Female thyroid cancer survivors are more likely to have a higher risk of breast cancer compared to the general population, and the underlying causes are yet to be understood. The potential role of I-131 treatment on this association remains controversial. METHODS: We pooled individual data of women who were treated for differentiated thyroid cancer from 1934 to 2005 in France, Italy and Sweden. Standardized incidence ratios (SIRs) for breast cancer were estimated by comparison with age, sex and calendar-year expected values of the general population in each country. We estimated breast cancer risk in relation to I-131 treatment using time-dependent Poisson models. RESULTS: Of 8475 women (mean age at diagnosis: 45 years, range 2-90 years), 335 were diagnosed with breast cancer [SIR = 1.52, 95% confidence interval (CI): 1.36-1.69] during a median follow-up time of 12.7 years since diagnosis. Overall, breast cancer risk did not differ between women treated or not with I-131 (relative risk=1.07, 95% CI 0.84-1.35). However, breast cancer risk increased with increasing cumulative I-131 activity, without significant departure from linearity (excess relative risk per 100 mCi=17%, 95% CI: 2% to 38%). The higher risk associated with a cumulative I-131 activity of ≥100 mCi and ≥400 mCi was translated into 4 (95% CI -4 to 13) and 42 (95% CI -8 to 93) excess breast cancer cases per 10,000 person-years, respectively. CONCLUSIONS: An elevated risk was observed for the highest cumulative administered activity (>=400 mCi), and a significant dose-dependent association was observed among thyroid cancer survivors who were treated with I-131. However, overall, I-131 treatment might only explain partly the increase in breast cancer risk among female thyroid cancer survivors.

Prevalence of interstitial pneumonia suggestive of COVID-19 at 18F-FDG PET/CT in oncological asymptomatic patients in a high prevalence country during pandemic period: a national multi-centric retrospective study.

PURPOSE: To assess the presence and pattern of incidental interstitial lung alterations suspicious of COVID-19 on fluorine-18-fluorodeoxyglucose positron emission tomography (PET)/computed tomography (CT) ([18F]FDG PET/CT) in asymptomatic oncological patients during the period of active COVID-19 in a country with high prevalence of the virus. METHODS: This is a multi-center retrospective observational study involving 59 Italian centers. We retrospectively reviewed the prevalence of interstitial pneumonia detected during the COVID period (between March 16 and 27, 2020) and compared to a pre-COVID period (January-February 2020) and a control time (in 2019). The diagnosis of interstitial pneumonia was done considering lung alterations of CT of PET. RESULTS: Overall, [18F]FDG PET/CT was performed on 4008 patients in the COVID period, 19,267 in the pre-COVID period, and 5513 in the control period. The rate of interstitial pneumonia suspicious for COVID-19 was significantly higher during the COVID period (7.1%) compared with that found in the pre-COVID (5.35%) and control periods (5.15%) (p < 0.001). Instead, no significant difference among pre-COVID and control periods was present. The prevalence of interstitial pneumonia detected at PET/CT was directly associated with geographic virus diffusion, with the higher rate in Northern Italy. Among 284 interstitial pneumonia detected during COVID period, 169 (59%) were FDG-avid (average SUVmax of 4.1). CONCLUSIONS: A significant increase of interstitial pneumonia incidentally detected with [18F]FDG PET/CT has been demonstrated during the COVID-19 pandemic. A majority of interstitial pneumonia were FDG-avid. Our results underlined the importance of paying attention to incidental CT findings of pneumonia detected at PET/CT, and these reports might help to recognize early COVID-19 cases guiding the subsequent management.

Evaluating 2-[18F]FDG-PET in differential diagnosis of dementia using a data-driven decision model.

2-[18F]fluoro-2-deoxy-d-glucose positron emission tomography (2-[18F]FDG-PET) has an emerging supportive role in dementia diagnostic as distinctive metabolic patterns are specific for Alzheimer's disease (AD), dementia with Lewy bodies (DLB) and frontotemporal dementia (FTD). Previous studies have demonstrated that a data-driven decision model based on the disease state index (DSI) classifier supports clinicians in the differential diagnosis of dementia by using different combinations of diagnostic tests and biomarkers. Until now, this model has not included 2-[18F]FDG-PET data. The objective of the study was to evaluate 2-[18F]FDG-PET biomarkers combined with commonly used diagnostic tests in the differential diagnosis of dementia using the DSI classifier. We included data from 259 subjects diagnosed with AD, DLB, FTD, vascular dementia (VaD), and subjective cognitive decline from two independent study cohorts. We also evaluated three 2-[18F]FDG-PET biomarkers (anterior vs. posterior index (API-PET), occipital vs. temporal index, and cingulate island sign) to improve the classification accuracy for both FTD and DLB. We found that the addition of 2-[18F]FDG-PET biomarkers to cognitive tests, CSF and MRI biomarkers considerably improved the classification accuracy for all pairwise comparisons of DLB (balanced accuracies: DLB vs. AD from 64% to 77%; DLB vs. FTD from 71% to 92%; and DLB vs. VaD from 71% to 84%). The two 2-[18F]FDG-PET biomarkers, API-PET and occipital vs. temporal index, improved the accuracy for FTD and DLB, especially as compared to AD. Moreover, different combinations of diagnostic tests were valuable to differentiate specific subtypes of dementia. In conclusion, this study demonstrated that the addition of 2-[18F]FDG-PET to commonly used diagnostic tests provided complementary information that may help clinicians in diagnosing patients, particularly for differentiating between patients with FTD, DLB, and AD.

Incremental value of amyloid-PET versus CSF in the diagnosis of Alzheimer's disease.

PURPOSE: To compare the incremental diagnostic value of amyloid-PET and CSF (Aß42, tau, and phospho-tau) in AD diagnosis in patients with mild cognitive impairment (MCI) or mild dementia, in order to improve the definition of diagnostic algorithm. METHODS: Two independent dementia experts provided etiological diagnosis and relative diagnostic confidence in 71 patients on 3 rounds, based on (1) clinical, neuropsychological, and structural MRI information alone; (2) adding one biomarker (CSF amyloid and tau levels or amyloid-PET with a balanced randomized design); and (3) adding the other biomarker. RESULTS: Among patients with a pre-biomarker diagnosis of AD, negative PET induced significantly more diagnostic changes than amyloid-negative CSF at both rounds 2 (CSF 67%, PET 100%, P = 0.028) and 3 (CSF 0%; PET 78%, P < 0.001); PET induced a diagnostic confidence increase significantly higher than CSF on both rounds 2 and 3. CONCLUSIONS: Amyloid-PET should be prioritized over CSF biomarkers in the diagnostic workup of patients investigated for suspected AD, as it provides greater changes in diagnosis and diagnostic confidence. TRIAL REGISTRATION: EudraCT no.: 2014-005389-31.

Reciprocal Incremental Value of 18F-FDG-PET and Cerebrospinal Fluid Biomarkers in Mild Cognitive Impairment Patients Suspected for Alzheimer's Disease and Inconclusive First Biomarker.

BACKGROUND: In Alzheimer's disease (AD) diagnosis, both cerebrospinal fluid (CSF) biomarkers and FDG-PET sometimes give inconclusive results. OBJECTIVE: To evaluate the incremental diagnostic value of FDG-PET over CSF biomarkers, and vice versa, in patients with mild cognitive impairment (MCI) and suspected AD, in which the first biomarker resulted inconclusive. METHODS: A consecutive series of MCI patients was retrospectively selected from two Memory Clinics where, as per clinical routine, either the first biomarker choice is FDG-PET and CSF biomarkers are only used in patients with uninformative FDG-PET, or vice versa. We defined criteria of uncertainty in interpretation of FDG-PET and CSF biomarkers, according to current evidence. The final diagnosis was established according to clinical-neuropsychological follow-up of at least one year (mean 4.4±2.2). RESULTS: When CSF was used as second biomarker after FDG-PET, 14 out of 36 (39%) received informative results. Among these 14 patients, 11 (79%) were correctly classified with respect to final diagnosis, thus with a relative incremental value of CSF over FDG-PET of 30.6%. When FDG-PET was used as second biomarker, 26 out of 39 (67%) received informative results. Among these 26 patients, 15 (58%) were correctly classified by FDG-PET with respect to final diagnosis, thus with a relative incremental value over CSF of 38.5%. CONCLUSION: Our real-world data confirm the added values of FDG-PET (or CSF) in a diagnostic pathway where CSF (or FDG-PET) was used as first biomarkers in suspected AD. These findings should be replicated in larger studies with prospective enrolment according to a Phase III design.

Head-to-Head Comparison among Semi-Quantification Tools of Brain FDG-PET to Aid the Diagnosis of Prodromal Alzheimer's Disease.

BACKGROUND: Several automatic tools have been implemented for semi-quantitative assessment of brain [18]F-FDG-PET. OBJECTIVE: We aimed to head-to-head compare the diagnostic performance among three statistical parametric mapping (SPM)-based approaches, another voxel-based tool (i.e., PALZ), and a volumetric region of interest (VROI-SVM)-based approach, in distinguishing patients with prodromal Alzheimer's disease (pAD) from controls. METHODS: Sixty-two pAD patients (MMSE score = 27.0±1.6) and one hundred-nine healthy subjects (CTR) (MMSE score = 29.2±1.2) were enrolled in five centers of the European Alzheimer's Disease Consortium. The three SPM-based methods, based on different rationales, included 1) a cluster identified through the correlation analysis between [18]F-FDG-PET and a verbal memory test (VROI-1), 2) a VROI derived from the comparison between pAD and CTR (VROI-2), and 3) visual analysis of individual maps obtained by the comparison between each subject and CTR (SPM-Maps). The VROI-SVM approach was based on 6 VROI plus 6 VROI asymmetry values derived from the pAD versus CTR comparison thanks to support vector machine (SVM). RESULTS: The areas under the ROC curves between pAD and CTR were 0.84 for VROI-1, 0.83 for VROI-2, 0.79 for SPM maps, 0.87 for PALZ, and 0.95 for VROI-SVM. Pairwise comparisons of Youden index did not show statistically significant differences in diagnostic performance between VROI-1, VROI-2, SPM-Maps, and PALZ score whereas VROI-SVM performed significantly (p < 0.005) better than any of the other methods. CONCLUSION: The study confirms the good accuracy of [18]F-FDG-PET in discriminating healthy subjects from pAD and highlights that a non-linear, automatic VROI classifier based on SVM performs better than the voxel-based methods.

Case of posterior cortical atrophy (PCA) evolved to PCA-CBS.

A 68-year-old lawyer developed insidious disturbances in topographic orientation and apraxia. He underwent a geriatric evaluation, only documenting slight cognitive disturbances, and a 18F-fluorodeoxyglucose positron emission tomography (FDG-PET), showing mild right-lateralised frontoparietal hypometabolism. After 1 year, because of worsening in spatial orientation and the onset of dressing apraxia, he was referred to our memory clinic. The neuropsychological evaluation documented proeminent visuospatial, praxis deficits and dysgraphia. Cerebrospinal fluid biomarker analysis showed mild increase of total-τ, with normal Aß1-42, ruling out Alzheimer's disease. Progression of the right parietal hypometabolism at FDG-PET and right superior longitudinal fasciculus damage at high-field MRI revealed a probable neurodegenerative aetiology. The neurological examination disclosed then Gerstmann's and Balint's syndromes, and extrapyramidal signs later appeared, suggesting the diagnosis of posterior cortical atrophy associated with corticobasal syndrome. Genetic analysis for mutations inmicrotubule-associated protein tau (MAPT), C9orf72 and GRN genes was negative. A 1-year follow-up documented significant worsening of the cognitive and functional impairment, revealing a frank dementia.

Plasma antioxidants and brain glucose metabolism in elderly subjects with cognitive complaints.

PURPOSE: The role of oxidative stress is increasingly recognized in cognitive disorders of the elderly, notably Alzheimer's disease (AD). In these subjects brain(18)F-FDG PET is regarded as a reliable biomarker of neurodegeneration. We hypothesized that oxidative stress could play a role in impairing brain glucose utilization in elderly subjects with increasing severity of cognitive disturbance. METHODS: The study group comprised 85 subjects with cognitive disturbance of increasing degrees of severity including 23 subjects with subjective cognitive impairment (SCI), 28 patients with mild cognitive impairment and 34 patients with mild AD. In all subjects brain FDG PET was performed and plasma activities of extracellular superoxide dismutase (eSOD), catalase and glutathione peroxidase were measured. Voxel-based analysis (SPM8) was used to compare FDG PET between groups and to evaluate correlations between plasma antioxidants and glucose metabolism in the whole group of subjects, correcting for age and Mini-Mental State Examination score. RESULTS: Brain glucose metabolism progressively decreased in the bilateral posterior temporoparietal and cingulate cortices across the three groups, from SCI to mild AD. eSOD activity was positively correlated with glucose metabolism in a large area of the left temporal lobe including the superior, middle and inferior temporal gyri and the fusiform gyrus. CONCLUSION: These results suggest a role of oxidative stress in the impairment of glucose utilization in the left temporal lobe structures in elderly patients with cognitive abnormalities, including AD and conditions predisposing to AD. Further studies exploring the oxidative stress-energy metabolism axis are considered worthwhile in larger groups of these patients in order to identify pivotal pathophysiological mechanisms and innovative therapeutic opportunities.

Determining the appropriate time of execution of an I-131 post-therapy whole-body scan: comparison between early and late imaging.

OBJECTIVE: The aim of this study was to investigate the appropriate time for performing an iodine-131 post-therapy whole-body scan (TxWBS) through a qualitative and semiquantitative analysis of early and late scans. MATERIALS AND METHODS: This study evaluated pairs of scans of 134 patients who underwent TxWBS on the third and seventh day. The scans were analyzed to evaluate sites, intensity of uptake, concordance or discordance between the scans, relationship with risk factors, and serum thyroglobulin (Tg) levels. To evaluate early and late radioiodine kinetics in thyroid remnants and metastases, 65/134 pairs of scans (48.5%) were subjected to a semiquantitative analysis. RESULTS: The early and late scans furnished concordant images in 108/134 patients (80.5%). In 10/134 patients (7.5%), early scans provided more information compared with late scans, showing lymph node and distant metastases in seven and three patients, respectively. In 16/134 patients (12%), late scans provided more data compared with early scans, with thyroid remnants and lymph node and distant metastases demonstrated in four, seven, and five patients, respectively. Negative early/positive late TxWBS results in patients were found to be significantly correlated (P=0.007) with elevated serum levels of Tg and a high-risk for recurrence (P=0.003). CONCLUSION: This study suggests that in about 20% of patients early or late TxWBS can miss the visualization of thyroid remnants or lymph node or distant metastases, which can be achieved performing both studies. High-risk patients with elevated serum Tg levels should be considered for a late TxWBS, which can demonstrate a possible metastatic involvement that was not diagnosed or that was downstaged by early TxWBS.

Targeted therapies for advanced thyroid cancer.

PURPOSE OF REVIEW: Thyroid cancer incidence has significantly increased and the majority of cases are represented by differentiated thyroid carcinomas that are characterized by a very good prognosis. Nevertheless, after initial treatment up to 15% of patients present disease persistence or relapse and those with locally advanced or metastasized cancers that do not respond to established therapies ultimately risk death. This scenario has started to change following the development of molecular targeted therapies. This review will focus on the principles behind the use of these novel therapies and on the results of the most recent clinical trials with tyrosine kinase inhibitors (TKIs) and other targeted therapies in thyroid cancer. RECENT FINDINGS: An understanding of the molecular events involved in cancer formation has prompted the development of numerous drugs that target key molecules implicated in angiogenesis and in the maintenance of the malignant phenotype of cancer cells. The results of several phase I and phase II studies and one phase III trial testing the efficacy of these drugs in advanced thyroid cancer are now available. SUMMARY: Among the tested drugs, the TKIs sorafenib for differentiated thyroid carcinoma and vandetanib and XL184 for medullary thyroid carcinoma appear very effective and have reached phase III clinical trials. Second-generation TKIs and selective kinase inhibitors are showing even more promising profiles. Improved knowledge of the targets of the different drugs, combined with molecular profiling of the tumors to treat, will allow a tailored pharmacogenomic approach.

Recombinant thyrotropin use in children and adolescents with differentiated thyroid cancer: a multicenter retrospective study.

CONTEXT: Although recombinant human TSH (rhTSH) is widely used in differentiated thyroid cancer (DTC) to aid diagnostic follow-up procedures and radioiodine thyroid remnant ablation, almost all clinical investigation was in adults. OBJECTIVE: The aim of this study was to characterize rhTSH clinical safety and peak TSH response in DTC patients 18 yr old or younger. DESIGN AND SETTING: We conducted a retrospective study involving 23 tertiary referral centers in 12 European, Asian, and Oceanian countries. PATIENTS: One hundred DTC patients (69% female, 31% male, 84% papillary, 61% N1, 18% M1) ages 4.9-18 yr at first rhTSH administration were studied. INTERVENTIONS: A total of 181 rhTSH courses were administered (range, one to eight per patient; 42% of patients received two or more courses), 92% using the approved adult regimen (one 0.9 mg im injection daily on two consecutive days), 34% including thyroid hormone withdrawal for less than 7 d ("mini-THW"). MAIN OUTCOME MEASURES: Clinical adverse event (AE) incidence, type, and severity, and peak post-rhTSH serum TSH concentrations were assessed. RESULTS: No clinical AEs occurred in 88% of rhTSH courses. Most common clinical AEs were nausea (5% of courses) and vomiting (3%). Multiple or severe AEs were rare (0.6% and 2.8% of courses, respectively); serious AEs were absent. Peak TSH concentration post-rhTSH exceeded 25 mU/liter in approximately 98% of courses. In logistic regression analyses, the rhTSH regimen, "mini-THW," peak TSH concentration, body mass index (BMI), or peak TSH concentration/unit of BMI were not associated with clinical AE occurrence. In analyses of covariance, higher BMI was associated with lower peak TSH concentrations. CONCLUSIONS: rhTSH was clinically well tolerated in pediatric DTC patients although courses preponderantly comprised the adult regimen, and repeated courses were frequent. Both the adult and reduced-dose regimens almost always sufficiently elevate TSH in children and adolescents.

American Association of Clinical Endocrinologists and Associazione Medici Endocrinologi medical guidelines for clinical practice for the diagnosis and management of thyroid nodules.

Thyroid nodules are common and are frequently benign. Current data suggest that the prevalence of palpable thyroid nodules is 3% to 7% in North America; the prevalence is as high as 50% based on ultrasonography (US) or autopsy data. The introduction of sensitive thyrotropin (thyroid-stimulating hormone or TSH) assays, the widespread application of fine-needle aspiration (FNA) biopsy, and the availability of high-resolution US have substantially improved the management of thyroid nodules. This document was prepared as a collaborative effort between the American Association of Clinical Endocrinologists (AACE) and the Associazione Medici Endocrinologi (AME). Most Task Force members are members of AACE. We have used the AACE protocol for clinical practice guidelines, with rating of available evidence, linking the guidelines to the strength of recommendations. Key observations include the following. Although most patients with thyroid nodules are asymptomatic, occasionally patients complain of dysphagia, dysphonia, pressure, pain, or symptoms of hyperthyroidism or hypothyroidism. Absence of symptoms does not rule out a malignant lesion; thus, it is important to review risk factors for malignant disease. Thyroid US should not be performed as a screening test. All patients with a palpable thyroid nodule, however, should undergo US examination. US-guided FNA (US-FNA) is recommended for nodules > or = 10 mm; US-FNA is suggested for nodules < 10 mm only if clinical information or US features are suspicious. Thyroid FNA is reliable and safe, and smears should be interpreted by an experienced pathologist. Patients with benign thyroid nodules should undergo follow-up, and malignant or suspicious nodules should be treated surgically. A radioisotope scan of the thyroid is useful if the TSH level is low or suppressed. Measurement of serum TSH is the best initial laboratory test of thyroid function and should be followed by measurement of free thyroxine if the TSH value is low and of thyroid peroxidase antibody if the TSH value is high. Percutaneous ethanol injection is useful in the treatment of cystic thyroid lesions; large,symptomatic goiters may be treated surgically or with radioiodine. Routine measurement of serum calcitonin is not recommended. Suggestions for thyroid nodule management during pregnancy are presented. We believe that these guidelines will be useful to clinical endocrinologists, endocrine surgeons, pediatricians, and internists whose practices include management of patients with thyroid disorders. These guidelines are thorough and practical, and they offer reasoned and balanced recommendations based on the best available evidence.

Are there disadvantages in administering 131I ablation therapy in patients with differentiated thyroid carcinoma without a preablative diagnostic 131I whole-body scan?

OBJECTIVE: To evaluate the risk of performing inappropriate (131)I ablative therapies for thyroid carcinoma in patients lacking thyroid remnants or metastases, using a strategy of treatment without a preliminary iodine-131 diagnostic whole-body scan (DxWBS). DESIGN: Retrospective evaluation of post-therapy whole-body scans to assess the prevalence of thyroid remnants or metastases after total thyroidectomy. Comparison of (131)I uptake test and thyroglobulin (Tg) off levothyroxine (L-T4) performed before therapy with post-therapy scans, in order to evaluate the ability to predict inappropriate treatments. PATIENTS: A group of 875 consecutive patients with previous total or near-total thyroidectomy for differentiated thyroid carcinoma underwent (131)I ablative therapy without a preliminary (131)I-DxWBS. All patients were clinically free of distant metastases and macroscopic residual tumour. MEASUREMENTS: Whole-body scans were performed 2-5 days after the treatment as gold standard for thyroid remnants and metastases; 24-h (131)I quantitative neck uptake test and Tg off L-T4 were performed before (131)I therapy. RESULTS: The majority of patients (94%) were found to have thyroid remnants or metastases at post-therapy scans, in most cases (91.2%) with detectable Tg off L-T4 and positive 24-h neck uptake. 14 patients (1.6%) with tiny lymph-node metastases positive at post-therapy scans showed undetectable Tg off L-T4. In 30 patients (3.6%) faint positive post-therapy images for thyroid remnants have been classified as false-positive results on the basis of both negative 24-h neck uptake and undetectable Tg off L-T4. CONCLUSIONS: This study confirms that most patients have residual thyroid tissue after total thyroidectomy and that it seems reasonable to omit routine diagnostic whole-body scans before (131)I treatment with clinical, managerial and economic advantages.