Tumor size and presence of metastases in differentiated thyroid cancer: comparing cohorts from two countries.

OBJECTIVE: Incidence of thyroid cancer varies widely, even across neighboring countries. Data on this phenomenon are largely lacking but are likely related to differences in health care systems. Therefore, we explored whether there are differences between populations from these 2 countries with respect to the relationship between tumor size and advanced disease. METHODS: We retrospectively studied 2 cohorts of adult differentiated thyroid cancer (DTC) patients from a Dutch and a German university hospital. We analyzed the presence of lymph node metastases with respect to tumor size for papillary thyroid cancer (PTC), and the presence of distant metastases for DTC, and PTC and follicular thyroid cancer (FTC) separately. RESULTS: We included 1771 DTC patients (80% PTC, 20% FTC; 24% lymph node and 8% distant metastases). For PTC, the proportion of patients with lymph node metastases was significantly higher in the Dutch than in the German population for tumors ≤ 1 cm (45% vs. 14%; P < .001). For DTC, distant metastases occurred particularly significantly more frequently in the Dutch than in the German population for tumors ≤ 2 cm (7% vs. 2%; P = .004). CONCLUSION: The presence of lymph node and distant metastases is significantly higher in pT1 DTC cases in the Dutch compared to the German cohort, which might be caused by differences in the indication for and application of diagnostic procedures eventually leading to DTC diagnosis. Our results implicate that one should be cautious when extrapolating results and guidelines from 1 country to another.

Evaluating the use of a two-step age-based cutoff for the UICC/AJCC TNM staging system in patients with papillary or follicular thyroid cancer.

BACKGROUND: The joint Union International Contre le Cancer and American Joint Committee on Cancer (UICC/AJCC) Tumor, Node, Metastasis (TNM) staging system for differentiated thyroid cancer (DTC) involves a single age cutoff as a prognostic criterion. Because a single cutoff is a dichotomization of what might be a sliding scale, using multiple age cutoffs might result into a better stage definition. The aim of our study was to investigate if using a two-step age-based cutoff would improve the TNM staging system regarding disease-specific survival (DSS). METHODS: We retrospectively studied two cohorts of adult DTC patients from The Netherlands and Germany. DSS was analyzed for papillary (PTC) and follicular thyroid cancer (FTC) separately, investigating several two-step age-based cutoffs for those with distant metastases; below lower threshold classified as stage I, between lower and upper threshold as stage II, and above upper threshold as stage IV. RESULTS: We included 3074 DTC patients (77% PTC). For PTC, an age cutoff of 45 with 50 years had the best statistical model performance, while this was 25 with 40 years for FTC. However, differences with the optimal single age cutoffs of 50 years for PTC and 40 years for FTC were small. CONCLUSIONS: The optimal two-step age-based cutoff to predict DSS is 45 with 50 years for PTC and 25 with 40 years for FTC, rather than 55 years currently used for DTC. Although these two-step age-based cutoffs were marginally better from a statistical point of view, from a clinical point of view, the recently defined optimal single age cutoffs of 50 years for PTC and 40 years for FTC might be preferable.

Finding the Optimal Age Cutoff for the UICC/AJCC TNM Staging System in Patients with Papillary or Follicular Thyroid Cancer.

Background: Differentiated thyroid cancer (DTC) is the only cancer entity for which the UICC/AJCC (Union for International Cancer Control and American Joint Committee on Cancer) TNM (tumor-node-metastasis) staging system involves an age cutoff as a prognostic criterion. However, the optimal age cutoff has not yet been determined in detail. The aim of our study was therefore to investigate the optimal age cutoff for the TNM staging system to predict disease-specific survival (DSS) with a focus on differences between patients with papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC). Methods: We retrospectively studied two large well-described cohorts of adult DTC patients from a Dutch and a German university hospital. DSS was analyzed for DTC overall, and for PTC and FTC separately, using several age cutoffs (per 5-year increment between 20 and 85 years and subsequently 1-year increments between 35 and 55 years), employing the histopathological criteria from the TNM staging system, eighth edition. Results: We included 3074 DTC patients (77% PTC and 23% FTC; mean age at diagnosis was 49 years). Median follow-up was seven years. For DTC and for PTC and FTC separately, the majority of the age cutoffs had a better statistical model performance than a model with no age cutoff. For DTC overall and for PTC, an age cutoff of 50 years had the best statistical model performance, while it was 40 years for FTC. Conclusions: In this large European population of DTC patients, when employing the histopathological criteria of the TNM system (eighth edition), the optimal age cutoff to predict DSS is 50 years rather than the 55 years currently in use. With the optimal age cutoff being 50 years for PTC and 40 years for FTC, there was a substantial difference in age cutoff for the respective histological entities. Therefore, implementation of different age cutoffs for PTC and FTC could improve the predictive value of the TNM staging system.

Breast Cancer After Treatment of Differentiated Thyroid Cancer With Radioiodine in Young Females: What We Know and How to Investigate Open Questions. Review of the Literature and Results of a Multi-Registry Survey.

Published studies on the risk of radiation-induced second primary malignancy (SPM) after radioiodine treatment (RAI) of differentiated thyroid cancer (DTC) refer mainly to patients treated as middle-aged or older adults and are not easily generalizable to those treated at a younger age. Here we review available literature on the risk of breast cancer as an SPM after RAI of DTC with a focus on females undergoing such treatment in childhood, adolescence, or young adulthood. Additionally, we report the results of a preliminary international survey of patient registries from academic tertiary referral centers specializing in pediatric DTC. The survey sought to evaluate the availability of sufficient patient data for a potential international multicenter observational case-control study of females with DTC given RAI at an early age. Our literature review identified a bi-directional association of DTC and breast cancer. The general breast cancer risk in adult DTC survivors is low, ~2%, slightly higher in females than in males, but presumably lower, not higher, in those diagnosed as children or adolescents than in those diagnosed at older ages. RAI presumably does not substantially influence breast cancer risk after DTC. However, data from patients given RAI at young ages are sparse and insufficient to make definitive conclusions regarding age dependence of the risk of breast cancer as a SPM after RAI of DTC. The preliminary analysis of data from 10 thyroid cancer registries worldwide, including altogether 6,449 patients given RAI for DTC and 1,116 controls, i.e., patients not given RAI, did not show a significant increase of breast cancer incidence after RAI. However, the numbers of cases and controls were insufficient to draw statistically reliable conclusions, and the proportion of those receiving RAI at the earliest ages was too low.In conclusion, a potential international multicenter study of female patients undergoing RAI of DTC as children, adolescents, or young adults, with a sufficient sample size, is feasible. However, breast cancer screening of a larger cohort of DTC patients is not unproblematic for ethical reasons, due to the likely, at most slightly, increased risk of breast cancer post-RAI and the expected ~10% false-positivity rate which potentially produced substantial "misdiagnosis."

Changing trends of incidence and prognosis of thyroid carcinoma.

AIM: to evaluate the time trend of epidemiology of follicular cell derived thyroid cancer (TC) based on data from a well documented cancer registry. METHODS: Population based data on TC from Lower Franconia (LF), Germany, within 1981 and 2015 were analysed to estimate the regional epidemiology of TC. The incidence was assessed in 5-year-intervals for gender, histology, and tumor stage. RESULTS: Incidence of TC solely attributable to papillary TC (PTC) doubled mainly in T1- and T2-stages within the evaluation period from 4.5 to 8.7/100.000/y in females and 1.7 to 4.1/100.000/y in males. There was no significant change of follicular TC (FTC), whereas anaplastic TC (ATC) decreased in the same interval. The number of lymph-node metastases and T3-cases increased, while the frequency of T4-stage and distant metastases decreased. Increased incidences of T1- and T2-stages suggest an over-diagnosis. In contrast, increasing number of tumors at T3-stage and with lymph node involvement contradict the over-diagnosis as the only reason for rising incidence. Declining of T4-stages in spite of increasing of T3-stages and N1-cases indicates the value of timely detection and treatment of TC. In accordance, reduced incidence of advanced cancers with M1-stage and ATC cases promote our current management of TC. CONCLUSION: Timely diagnosis and adequate risk-adopted treatment of thyroid cancer reduce the frequency of high-risk cases with distant metastases and the possible protracted dedifferentiation of TC to anaplastic features. Our analyses support the management algorithm in thyroid cancer according to the recent guidelines of German Nuclear Medicine Society.

The time point of completion thyroidectomy has no prognostic impact in patients with differentiated thyroid cancer.

BACKGROUND: After partial resection of the thyroid gland, a second operation referred to as "completion thyroidectomy" may be required if histopathological analysis indicates the presence of differentiated thyroid cancer (DTC). Although there is little evidence, it is assumed that the time point of completion thyroidectomy is not critical for oncological prognosis of patients with DTC. We assessed whether patients with total thyroidectomy (TTx) in a two-step procedure have an equal long-term prognosis with regard to disease-specific survival (DSS) compared to patients immediately undergoing total thyroidectomy in a one-step procedure. METHODS: A database study using the Würzburg thyroid cancer database with 2258 patients with pT1a-pT4b tumours DTC who were operated between 1980 and 2016 was carried out. RESULTS: A total of 277 patients with papillary microcarcinoma pT1aN0M0 were treated by hemithyroidectomy. TTx as one-step procedure was performed in 1114 patients compared to 867 with TTx as a two-step procedure. Patients with papillary thyroid cancer more frequently had a TTx as one-step procedure than follicular thyroid cancer patients (59.4% vs 47%; P < 0.001). Compared to a one-step thyroidectomy, overall complication rate was not different compared to patients undergoing a single operation. Multivariate analysis showed that the presence of distant metastases, T-stage and age at diagnosis were the only independent determinants for DTC-specific survival, regardless of a one- or two-time thyroidectomy. CONCLUSION: The present study on the largest of such patient collectives provides evidence that a delayed completion operation does not affect DSS in DTC, nor does it lead to a significant increase in complication rates.

Low or Undetectable Basal Thyroglobulin Levels Obviate the Need for Neck Ultrasound in Differentiated Thyroid Cancer Patients After Total Thyroidectomy and 131I Ablation.

BACKGROUND: Neck ultrasound (NUS) is currently seen as a main component of follow-up of differentiated thyroid cancer (DTC) and is usually performed regardless of non-stimulated thyroglobulin (Tg) levels. The aim of this study was to determine whether there is a clinical benefit from such a routine NUS in DTC patients. METHODS: A retrospective database study was conducted of 3176 cervical ultrasound exams performed in 773 patients between June 15, 1996, and July 1, 2012. The accuracy of ultrasound results was assessed based on the results of further diagnostic and/or therapeutic procedures within six months of a particular ultrasound. RESULTS: A total of 2199 NUS exams were classified as true negative, 216 as true positive, 692 as false positive in 339 (43.9%) individual patients, 170 of whom were low risk, and 69 as false negative. Thus, overall sensitivity, specificity, positive predictive value, negative predictive value, and accuracy [confidence interval] were 75.8% [70.1-81.5%], 76.1% [74.3-77.8%], 23.8% [18.1-29.5%], 97.0 [96.2-97.7%], and 76.0% [74.3-77.7%], respectively. No significant differences were found between low- and high-risk patients. There were no significant differences between patients with an undetectable and a low detectable (<1 µg/L) Tg level. However, these two groups both showed significantly lower positive predictive value and higher negative predictive value than patients with a Tg ≥1 µg/L. From January 2007 onwards, true-positive and false-negative neck ultrasounds were no longer observed in patients with Tg <1 µg/L. CONCLUSION: After total thyroidectomy and 131I ablation, neck ultrasound should be reserved only for anti-Tg antibody negative patients with a Tg level of ≥1 µg/L.

The effects of the Union for International Cancer Control/American Joint Committee on Cancer Tumour, Node, Metastasis system version 8 on staging of differentiated thyroid cancer: a comparison to version 7.

OBJECTIVE: To assess the changes resulting from the changes from UICC/AJCC TNM version 7 to version 8 and to subsequently determine whether TNM version 8 is an improvement compared to previous iterations of the TNM system and other staging systems for differentiated thyroid cancer (DTC) with regard to prognostic power. DESIGN: Database study of DTC patients treated in our centre between 1978 up to and including 1 July 2014. Results were compared to our previous comparison of prognostic systems using the same data set. PATIENTS: 2257 DTC patients. MEASUREMENTS: Staging in accordance with TNM 7 and TNM 8. Thyroid cancer-specific mortality; comparison was based on p-values of univariate Cox regression analyses as well as analysis of the proportion of variance explained (PVE). RESULTS: There is a redistribution from stage 3 to lower stages affecting 206 (9.1%) patients. DTC-related mortality according to Kaplan-Meier for younger and older patients in TNM 7 had a slightly lower prognostic power than that in accordance with TNM 8 (P = 8.0 10-16 and P = 1.5 10-21 , respectively). Overall staging is lower in 627/2257 (27.8%) patients. PVE (TNM 7: 0.29; TNM 8: 0.28) and the P-value of Cox regressions (TNM 7: P = 7.1*10-52 ; TNM 8: P = 3.9*10-49 ) for TNM version 8 are marginally lower than that for TNM version 7, but still better than for any other DTC staging system. CONCLUSION: TNM 8 results in a marked downstaging of patients compared to TNM 7. Although some changes, like the change in age boundary, appear to be associated with an improvement in prognostic power, the overall effect of the changes does not improve the predictive power compared to TNM 7.

Only a Rapid Complete Biochemical Remission After 131I-Therapy is Associated with an Unimpaired Life Expectancy in Differentiated Thyroid Cancer.

The objective of the work was to investigate the relationship between thyroglobulin doubling time (TgDT) as a marker of speed of response to 131I-therapy and the differentiated thyroid cancer (DTC) recurrence rate, DTC specific mortality rate, and relative survival rate in a DTC population followed over a long period of time after 131I-therapy. From our database, data of 1354 patients were reviewed. TgDT could be calculated in 174 patients, however, 376 patients did not have sufficient Tg values available for TgDT calculation and 804 patients reached biochemical remission before a sufficient number of Tg measurements for TgDT calculation was acquired. Main outcome measures were recurrence-free, DTC specific, and relative survival rates. In patients<45 years, TgDT in multivariate analysis was identified as the solitary significant determinant of DTC specific and relative survival. In patients≥45 years of age at diagnosis, TgDT is an independent, but not the only determinant of recurrence free, DTC specific, and relative survival. Importantly, in this age group life expectancy is normal in patients reaching rapid biochemical remission (i. e., before TgDT can be calculated); it was reduced in patients with a negative TgDT, which normally is deemed a marker of response to therapy. Only DTC patients with a rapid biochemical remission have a very good prognosis with a normal life expectancy. If no rapid biochemical remission occurs, both biochemically progressive disease and a slower biochemical remission of disease are associated with a reduced prognosis, especially in older DTC patients.

Tumour stage distribution and survival of malignant melanoma in Germany 2002-2011.

BACKGROUND: Over the past two decades, there has been a rising trend in malignant melanoma incidence worldwide. In 2008, Germany introduced a nationwide skin cancer screening program starting at age 35. The aims of this study were to analyse the distribution of malignant melanoma tumour stages over time, as well as demographic and regional differences in stage distribution and survival of melanoma patients. METHODS: Pooled data from 61 895 malignant melanoma patients diagnosed between 2002 and 2011 and documented in 28 German population-based and hospital-based clinical cancer registries were analysed using descriptive methods, joinpoint regression, logistic regression and relative survival. RESULTS: The number of annually documented cases increased by 53.2% between 2002 (N = 4 779) and 2011 (N = 7 320). There was a statistically significant continuous positive trend in the proportion of stage UICC I cases diagnosed between 2002 and 2011, compared to a negative trend for stage UICC II. No trends were found for stages UICC III and IV respectively. Age (OR 0.97, 95% CI 0.97-0.97), sex (OR 1.18, 95% CI 1.11-1.25), date of diagnosis (OR 1.05, 95% CI 1.04-1.06), 'diagnosis during screening' (OR 3.24, 95% CI 2.50-4.19) and place of residence (OR 1.23, 95% CI 1.16-1.30) had a statistically significant influence on the tumour stage at diagnosis. The overall 5-year relative survival for invasive cases was 83.4% (95% CI 82.8-83.9%). CONCLUSIONS: No distinct changes in the distribution of malignant melanoma tumour stages among those aged 35 and older were seen that could be directly attributed to the introduction of skin cancer screening in 2008.

Malignancies after mitoxantrone for multiple sclerosis: A retrospective cohort study.

OBJECTIVE: To assess the therapy-related risk of malignancies in mitoxantrone-treated patients with multiple sclerosis. METHODS: This retrospective observational cohort study included all mitoxantrone-treated patients with multiple sclerosis seen at our department between 1994 and 2007. We collected follow-up information on medically confirmed malignancies, life status, and cause of death, as of 2010. Malignancy rates were compared to the German national cancer registry matched for sex, age, and year of occurrence. RESULTS: Follow-up was completed in 676 of 677 identified patients. Median follow-up time was 8.7 years (interquartile range 6.8-11.2), corresponding to 6,220 person-years. Median cumulative mitoxantrone dose was 79.0 mg/m(2) (interquartile range 50.8-102.4). Thirty-seven patients (5.5%) were diagnosed with a malignancy after mitoxantrone initiation, revealing a standardized incidence ratio of 1.50 (95% confidence interval [CI] 1.05-2.08). Entities included breast cancer (n = 9), colorectal cancer (n = 7), acute myeloid leukemia (n = 4, 0.6%), and others (each entity n = 1 or 2). The standardized incidence ratio of colorectal cancer was 2.98 (95% CI 1.20-6.14) and of acute myeloid leukemia 10.44 (95% CI 3.39-24.36). It was not increased for other entities including breast cancer. Multivariate Cox regression identified higher age at treatment initiation but neither cumulative mitoxantrone dose (>75 vs ≤75 mg/m(2)) nor treatment with other immunosuppressive drugs or sex as a risk factor. Fifty-five patients had died, among them 12 of a malignancy and 43 reportedly of other causes. CONCLUSIONS: While the overall incidence of malignancies was only mildly increased, the risk of leukemia and colorectal cancer was heightened. If confirmed, posttherapy colonoscopy could become advisable.

Endogenous TSH levels at the time of 131I ablation do not influence ablation success, recurrence-free survival or differentiated thyroid cancer-related mortality.

PURPOSE: Based on a single older study it is established dogma that TSH levels should be ≥30 mU/l at the time of postoperative 131I ablation in differentiated thyroid cancer (DTC) patients. We sought to determine whether endogenous TSH levels, i.e. after levothyroxine withdrawal, at the time of ablation influence ablation success rates, recurrence-free survival and DTC-related mortality. METHODS: A total of 1,873 patients without distant metastases referred for postoperative adjuvant 131I therapy were retrospectively included from 1991 onwards. Successful ablation was defined as stimulated Tg <1 µg/l. RESULTS: Age, gender and the presence of lymph node metastases were independent determinants of TSH levels at the time of ablation. TSH levels were not significantly related to ablation success rates (p = 0.34), recurrence-free survival (p = 0.29) or DTC -elated mortality (p = 0.82), but established risk factors such as T-stage, lymph node metastases and age were. Ablation was successful in 230 of 275 patients (83.6 %) with TSH <30 mU/l and in 1,359 of 1,598 patients (85.0 %) with TSH ≥30 mU/l. The difference was not significant (p = 0.55). Of the whole group of 1,873 patients, 21 had recurrent disease. There were no significant differences in recurrence rates between patients with TSH <30 mU/l and TSH ≥30 mU/l (p = 0.16). Ten of the 1,873 patients died of DTC. There were no significant differences in DTC-specific survival between patients with TSH <30 mU/l and TSH ≥30 mU/l (p = 0.53). CONCLUSION: The precise endogenous TSH levels at the time of 131I ablation are not related to the ablation success rates, recurrence free survival and DTC related mortality. The established dogma that TSH levels need to be ≥30 mU/l at the time of 131I ablation can be discarded.

The TNM system (version 7) is the most accurate staging system for the prediction of loss of life expectancy in differentiated thyroid cancer.

OBJECTIVE: Many prognostic systems have been developed for differentiated thyroid cancer. It is unclear which one of these performs 'best'. Our aim was to compare staging systems applicable to our patient database to identify which best predicts DTC-related loss of life expectancy and DTC-specific mortality. DESIGN: Database study of patients with DTC treated in our centre between 1978 (earliest available data) up to and including 1 July 2014. All were staged in accordance with the AMES, Clinical Class, Memorial Sloan Kettering, Ohio State University, TNM versions 5 and 6/7, University of Alabama, University of Münster and qTNM systems. PATIENTS: A total of 2257 patients with differentiated thyroid cancer. MEASUREMENTS: Loss of life expectancy expressed as relative survival and thyroid cancer-specific mortality. Comparison was based on P values of univariate Cox regression analyses as well as analysis of the proportion of variance explained (PVE). RESULTS: Median available follow-up time was 7·2 years (range: 0-35·1 years). Three hundred and twenty-seven patients died, 149 of whom died of DTC. Version 7 of the TNM system was best for predicting DTC-related mortality (P = 7·1 × 10-52 ; PVE = 0·296), followed by TNM version 5 (P = 6·7 × 10-44 ; PVE = 0·255). For prediction of loss of life expectancy, version 7 of the TNM system was also best, closely followed by the Clinical Class system (P both < 2 × 10-16 ). CONCLUSIONS: The UICC/AJCC TNM system version 7 outperforms other prognostic classification systems based on extent of disease at the start of treatment both for prediction of differentiated thyroid cancer-related death and for prediction of loss life expectancy.

Determinants of successful ablation and complete remission after total thyroidectomy and ¹³¹I therapy of paediatric differentiated thyroid cancer.

PURPOSE: In adult differentiated thyroid cancer (DTC) patients, successful ablation and the number of (131)I therapies needed carry a prognostic significance. The goal was to assess the prognosis of DTC in children and adolescents treated in our centre in relation to the number of treatments needed and to establish the determinants of both complete remission (CR) and successful ablation. METHODS: Seventy-six DTC patients <21 years of age at diagnosis were included. Recurrence and death rates, rates of CR (=negative stimulated thyroglobulin, negative neck ultrasound and negative (131)I whole-body scintigraphy) and successful ablation (=CR after initial (131)I therapy) were studied. RESULTS: No patients died of DTC. Seven patients were treated by surgery alone and did not show signs of recurrence during follow-up. Of the 69 patients also treated with (131)I therapy, 47 patients achieved CR, 25 of whom had successful ablation. In multivariate analysis, female gender and the absence of distant metastases were independent determinants of a higher CR rate. Female gender, lower T stage and higher (131)I activity (successful ablation, median activity 3.1 GBq, unsuccessful ablation 2.6 GBq) were determinants of a higher rate of successful ablation. After (131)I therapy no patient showed recurrence after reaching CR or disease progression if CR was not reached. CONCLUSION: In our paediatric DTC population prognosis is extremely good with no deaths or recurrences occurring regardless of the number of (131)I therapies needed or whether CR was reached. The determinants of CR and successful ablation can be used to optimize the chance of therapy success.

Long-term survival in differentiated thyroid cancer is worse after low-activity initial post-surgical 131I therapy in both high- and low-risk patients.

CONTEXT: Recent trial results have revived interest in low-activity initial (131)I therapy (RIT) of differentiated thyroid cancer (DTC). OBJECTIVE: This study sought to compare different initial (131)I activities for outcome. DESIGN AND SETTING: A database study was performed in a University hospital. PATIENTS: 1298 DTC patients were included (698 low risk, 434 high risk M0, and 136 M1), grouped according to ablation activity (I, ≤ 2000 MBq [54 mCi]; II, 2000-3000 MBq [54-81 mCi]; and III, >3000 MBq [81 mCi]), subdivided by age (<45 and ≥ 45 y at diagnosis). MAIN OUTCOME MEASURES: Complete remission (CR, defined as thyroglobulin [Tg] below functional sensitivity combined with visually negative (131)I diagnostic whole-body scintigraphy), recurrence, DTC-specific mortality, and relative survival rates were studied. RESULTS: Low-risk patients: In patients <45 years, a lower median cumulative activity was required to achieve CR in group III (3590 MBq) than in groups I (8050 MBq) and II (6300 MBq). In patients at least 45 years of age, DTC-specific mortality was significantly higher in group I than in groups II and III (15-y: 16.1 ± 7.7%, 0.8 ± 0.8%, and 7.2 ± 5.5%, respectively; P = .004). High-risk M0 patients: In patients at least 45 years of age, the recurrence rate (15-y: 44.4 ± 16.6%, 24.1 ± 7.6%, and 8.6 ± 3.9%; P = .001) and DTC-specific mortality (15-y: 51.8 ± 15.8%, 13.2 ± 4.4%, and 9.5 ± 3.7%; P = .004) were significantly higher in group I than in groups II and III. M1 patients: There were no significant differences in survival results between different activity groups in either age category. CONCLUSION: Before adopting low initial activity RIT for, especially older, low-risk patients, results of long-term followup should be regarded critically. Low-activity RIT in older, high-risk patients is not to be recommended.

CIP2A influences survival in colon cancer and is critical for maintaining Myc expression.

The cancerous inhibitor of protein phosphatase 2A (CIP2A) is an oncogenic factor that stabilises the c-Myc protein. CIP2A is overexpressed in several tumours, and expression levels are an independent marker for long-term outcome. To determine whether CIP2A expression is elevated in colon cancer and whether it might serve as a prognostic marker for survival, we analysed CIP2A mRNA expression by real-time PCR in 104 colon cancer samples. CIP2A mRNA was overexpressed in colon cancer samples and CIP2A expression levels correlated significantly with tumour stage. We found that CIP2A serves as an independent prognostic marker for disease-free and overall survival. Further, we investigated CIP2A-dependent effects on levels of c-Myc, Akt and on cell proliferation in three colon cancer cell lines by silencing CIP2A using small interfering (si) and short hairpin (sh) RNAs. Depletion of CIP2A substantially inhibited growth of colon cell lines and reduced c-Myc levels without affecting expression or function of the upstream regulatory kinase, Akt. Expression of CIP2A was found to be dependent on MAPK activity, linking elevated c-Myc expression to deregulated signal transduction in colon cancer.

Life expectancy is reduced in differentiated thyroid cancer patients ≥ 45 years old with extensive local tumor invasion, lateral lymph node, or distant metastases at diagnosis and normal in all other DTC patients.

OBJECTIVE: Differentiated thyroid carcinoma (DTC) generally has a good prognosis. As yet, however, it is unclear whether life expectancy is reduced in these patients and, if so, to what extent. The aim of this study was to determine how the all-cause mortality rate in DTC patients compares to that of the general population. DESIGN: A prospective database study was conducted. PATIENTS: The study included 2011 DTC patients treated in our hospital from 1980-2011. All patients received total thyroidectomy with subsequent (131)I ablation, except for those with an isolated papillary microcarcinoma. Survival data for the general German population were obtained from the German Federal Statistics Agency and matched to our DTC population for age and sex. RESULTS: Patients who were at least 45 yr old at diagnosis and had extensive perithyroidal invasion (UICC/AJCC TNM system, 7th edition, stages IVa and IVb), lateral cervical lymph node metastases (TNM stage IVa), or distant metastases (TNM stage IVc) showed a clearly reduced life expectancy [relative cumulative survival rate (observed:expected) for stage IVc after 20 yr, 0.295; 95% confidence interval, 0.033-0.556]. In patients over 60 yr of age at diagnosis, the loss of life expectancy was (much) greater than for those aged 45-59 yr in all groups. Life expectancy was not reduced in patients with TNM stages I, II, or III (86% of patients). CONCLUSION: Life expectancy is not significantly reduced in 86% of DTC patients; only patients at least 45 yr old with extensive local invasion, lateral lymph node metastases, and/or distant metastases (TNM stages IVa, IVb, and IVc) at diagnosis showed a clearly lower life expectancy.

Impact of moderate vs stringent TSH suppression on survival in advanced differentiated thyroid carcinoma.

OBJECTIVES: To assess (i) the influence of Thyrotropin (TSH) suppression at a level of <0·1 mU/l and (ii) whether FT3 and FT4 levels have a prognostic significance independently of TSH values with regard to survival in patients with differentiated thyroid carcinoma (DTC) and distant metastases. PATIENTS AND METHODS: In a retrospective patient chart study, we reviewed survival in 157 DTC patients with distant metastases treated between September 1985 and 1 July 2010. Patients with at least three available FT3 and FT4 values during TSH suppression were eligible. RESULTS: Fifty-three of 157 patients died from DTC. DTC-specific survival was significantly better in patients with a median TSH level ≤0·1 mU/l (median survival 15·8 years) than those with a non-suppressed TSH level (median survival 7·1 years; P < 0·001). However, there was no further improvement in survival caused by TSH suppression to a level ≤ 0·03 mU/l (P = 0·24). FT3 and FT4 levels were also significantly associated with poorer survival; of these, only the prognostic value of FT3 was independent from that of TSH levels. CONCLUSION: The care of patients with DTC and distant metastases is like walking an endocrinological tightrope: non-suppressed TSH levels, that is, >0·1 mU/l, are associated with an impaired prognosis. There is, however, no prognostic benefit from suppressing TSH to levels lower than 0·1 mU/l. On the contrary, an improvement in prognosis might be achieved by keeping FT3 levels as low as possible.

The absorbed dose to the blood is a better predictor of ablation success than the administered 131I activity in thyroid cancer patients.

PURPOSE: The residence time of (131)I in the blood is likely to be a measure of the amount of (131)I that is available for uptake by thyroid remnant tissue and thus the radiation absorbed dose to the target tissue in (131)I ablation of patients with differentiated thyroid cancer (DTC). This hypothesis was tested in an investigation on the dependence of the success rate of radioiodine remnant ablation on the radiation absorbed dose to the blood (BD) as a surrogate for the amount of (131)I available for iodine-avid tissue uptake. METHODS: This retrospective study included 449 DTC patients who received post-operative (131)I ablation in our centre in the period from 1993 to 2007 and who returned to us for diagnostic whole-body scintigraphy. The BD was calculated based on external dose rate measurements using gamma probes positioned in the ceiling. Success of ablation was defined as a negative diagnostic (131)I whole-body scan and undetectable thyroglobulin levels at 6 months follow-up. RESULTS: Ablation was successful in 56.6% of the patients. The rate of successful ablation correlated significantly with BD but not with the administered activity. Patients with blood doses exceeding 350 mGy (n = 144) had a significantly higher probability for successful ablation (63.9%) than the others (n = 305, ablation rate 53.1%, p = 0.03). In contrast, no significant dependence of the ablation rate on the administered activity was observed. CONCLUSION: The BD is a more powerful predictor of ablation success than the administered activity.

No survival difference after successful (131)I ablation between patients with initially low-risk and high-risk differentiated thyroid cancer.

PURPOSE: To compare disease-specific survival and recurrence-free survival (RFS) after successful (131)I ablation in patients with differentiated thyroid carcinoma (DTC) between those defined before ablation as low-risk and those defined as high-risk according to the European Thyroid Association 2006 consensus statement. METHODS: Retrospective data from three university hospitals were pooled. Of 2009 consecutive patients receiving ablation, 509 were identified as successfully ablated based on both undetectable stimulated serum thyroglobulin in the absence of antithyroglobulin antibodies and a negative diagnostic whole-body scan in a follow-up examination conducted 8.1+/-4.6 months after ablation. Of these 509 patients, 169 were defined as high-risk. RESULTS: After a mean follow-up of 81+/-64 months (range 4-306 months), only three patients had died of DTC, rendering assessment of disease-specific survival differences impossible. Of the 509 patients, 12 (2.4%) developed a recurrence a mean 35 months (range 12-59 months) after ablation. RFS for the duration of follow-up was 96.6% according to the Kaplan-Meier method. RFS did not differ between high-risk and low-risk patients (p=0.68). RFS differed slightly but significantly between those with papillary and those with follicular thyroid carcinoma (p=0.03) and between those aged 45 years at diagnosis (p=0.018). CONCLUSION: After (near) total thyroidectomy and successful (131)I ablation, RFS does not differ between patients classified as high-risk and those classified as low-risk based on TNM stage at diagnosis. Consequently, the follow-up protocol should be determined on the basis of the result of initial treatment rather than on the initial tumour classification.