Christoph Reiners

Cancer consequences of the Chernobyl accident: 20 years on

26 April 2006 marks the 20th anniversary of the Chernobyl accident. On this occasion, the World Health Organization (WHO), within the UN Chernobyl Forum initiative, convened an Expert Group to evaluate the health impacts of Chernobyl. This paper summarises the findings relating to cancer. A dramatic increase in the incidence of thyroid cancer has been observed among those exposed to radioactive iodines in childhood and adolescence in the most contaminated territories. Iodine deficiency may have increased the risk of developing thyroid cancer following exposure to radioactive iodines, while prolonged stable iodine supplementation in the years after exposure may reduce this risk. Although increases in rates of other cancers have been reported, much of these increases appear to be due to other factors, including improvements in registration, reporting and diagnosis. Studies are few, however, and have methodological limitations. Further, because most radiation-related solid cancers continue to occur decades after exposure and because only 20 years have passed since the accident, it is too early to evaluate the full radiological impact of the accident. Apart from the large increase in thyroid cancer incidence in young people, there are at present no clearly demonstrated radiation-related increases in cancer risk. This should not, however, be interpreted to mean that no increase has in fact occurred: based on the experience of other populations exposed to ionising radiation, a small increase in the relative risk of cancer is expected, even at the low to moderate doses received. Although it is expected that epidemiological studies will have difficulty identifying such a risk, it may nevertheless translate into a substantial number of radiation-related cancer cases in the future, given the very large number of individuals exposed.

Comprehensive Clinical Assessment of 740 Cases of Surgically Treated Thyroid Cancer in Children of Belarus

Objective:A retrospective study was designed to evaluate the results of surgical treatment and follow-up data in thyroid cancer patients less than 15 years old at the time of surgery. Summary Background Data:Pediatric thyroid carcinomas have a high rate of lymph nodal and distant metastases. Risk factors for recurrences and postoperative morbidity have not been assessed yet in a representative series. Methods:The group included 740 pediatric patients with thyroid cancer. Total thyroidectomy was performed in 426 (57.6%), lobectomy in 248 (33.5%), subtotal thyroidectomy in 58 (7.8%) cases, and 8 patients (1.1%) underwent partial lobectomy. Results:The mean follow-up period was 115.8 months (range, 1.5–236.4 months). Recurrence was diagnosed in 204 cases (27.6%), including 73 local relapses (9.9%), 90 distant metastases (12.2%), and a combination of local and distant recurrences in 41 (5.5%) patients. Multivariate statistical assessment revealed the following independent parameters significantly associated with the risk of recurrent nodal disease: a young age at diagnosis, multifocal carcinomas, N1 status, and lack of neck lymph node dissection. For lung metastases, the significant risk factors were female gender, young age at diagnosis, and presence of symptoms. The observed 5- and 10-year survival for the entire group was 99.5% and 98.8%, respectively. Postoperative hypoparathyroidism was significantly associated with multifocal tumors, central compartment removal, and ipsilateral dissection. Conclusions:Total thyroidectomy followed by radioiodine therapy is an optimal treatment strategy that makes it possible to achieve a cure in a vast majority of pediatric patients with differentiated thyroid carcinomas. Risk of recurrence is strongly associated with tumor stage, extent of surgery, the young patients age, and presence of symptoms at diagnosis.

Redifferentiation Therapy with Retinoids: Therapeutic Option for Advanced Follicular and Papillary Thyroid Carcinoma

Abstract. During the course of tumor progression the differentiated morphologic and functional characteristics of differentiated thyroid carcinomas (DTC) disappear. This corresponds to more aggressive growth, metastatic spread, and loss of iodine uptake. Experimental data give strong evidence that differentiated functions of iodine metabolism can be reinduced by retinoic acids. Results of a study performed in patients with advanced DTC are presented. Twenty patients with DTC (eight follicular, seven papillary, five oxyphilic) were selected for treatment with retinoic acid 1.5 mg/kg body weight/day over 5 weeks. All patients had advanced tumor stages with prior operative and radioiodine treatment. Extensive tumor invasion, distant metastatic spread, or insufficient or no radioiodine uptake precluded any conventional therapeutic option. The aim was to assess the changes under retinoid treatment. Iodine uptake increased in eight patients (three follicular, three papillary, two oxyphilic). Thyroglobulin (TG) as parameter for tumor mass and differentiation increased in 12 (63%) patients, decreased in 6 (32%), and did not change in 1 (5%). Retinoids do have an effect on differentiation status of DTC, reinducing iodine uptake in 50% of patients. TG levels do not always parallel a response in iodine uptake.

The Treatment of Differentiated Thyroid Cancer in Children: Emphasis on Surgical Approach and Radioactive Iodine Therapy

Pediatric thyroid cancer is a rare disease with an excellent prognosis. Compared with adults, epithelial-derived differentiated thyroid cancer (DTC), which includes papillary and follicular thyroid cancer, presents at more advanced stages in children and is associated with higher rates of recurrence. Because of its uncommon occurrence, randomized trials have not been applied to test best-care options in children. Even in adults that have a 10-fold or higher incidence of thyroid cancer than children, few prospective trials have been executed to compare treatment approaches. We recognize that treatment recommendations have changed over the past few decades and will continue to do so. Respecting the aggressiveness of pediatric thyroid cancer, high recurrence rates, and the problems associated with decades of long-term follow-up, a premium should be placed on treatments that minimize risk of recurrence and the adverse effects of treatments and facilitate follow-up. We recommend that total thyroidectomy and central compartment lymph node dissection is the surgical procedure of choice for children with DTC if it can be performed by a high-volume thyroid surgeon. We recommend radioactive iodine therapy for remnant ablation or residual disease for most children with DTC. We recommend long-term follow-up because disease can recur decades after initial diagnosis and therapy. Considering the complexity of DTC management and the potential complications associated with therapy, it is essential that pediatric DTC be managed by physicians with expertise in this area.

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.

Changing trends of incidence and prognosis of thyroid carcinoma in lower Franconia, Germany, from 1981-1995.

BACKGROUND A population-based registry (PBR) in Lower Frankonia in southern Germany was conducted to evaluate the changes of incidence and prognosis of thyroid carcinoma (TC) in this area. METHODS The study comprised 476 patients with differentiated thyroid carcinoma (DTC) from Lower Franconia (1.3 x 10(6) inhabitants) registered between 1981 and 1995 at the Regional Tumor Center. The incidence was assessed with respect to gender, age, histology, tumor stage, lymph node involvement and distant metastases in 5-year intervals (1981-1985, 1986-1990, and 1991-1995). RESULTS An increasing rate of papillary thyroid carcinoma PTC and a decreasing rate of follicular thyroid carcinoma (FTC) were observed over the three time periods (1981-1985, 1986-1990, and 1991-1995). The overall incidence revealed no significant change with time for both females from 3.22 to 3.25 and 3.73 and males (1.07 to 1.54 and 1.69) between the three time periods. There was a significant improvement in outcome of patients with DTC with respect to life expectancy. CONCLUSIONS Iodine prophylaxis does influence the distribution of the histologic types of thyroid cancer and leads to an increase in the ratio of papillary versus follicular carcinoma. Our study supports the hypothesis that the benefits of correcting iodine deficency outweigh the risks of iodine supplementation.

Sorafenib-Induced Hypothyroidism Is Associated with Increased Type 3 Deiodination

BACKGROUND Therapy with tyrosine kinase inhibitors is associated with thyroid dysfunction. Decreased serum thyroid hormone levels during tyrosine kinase inhibitors are also observed in athyreotic patients with thyroid carcinoma. We therefore hypothesized that tyrosine kinase inhibitors may influence thyroid hormone metabolism. AIM The aim was to study the effects of sorafenib therapy on serum thyroid hormone concentrations and iodothyronine deiodination in athyreotic patients. DESIGN The design included a prospective open, single-center, single-arm 26-wk study. METHODS We measured serum thyroxine (T4), free T4, 3,5,3-triiodothyronine (T3), free T3, reverse T3 (rT3), and TSH concentrations at baseline and after 26 wk in 21 patients with progressive nonmedullary thyroid carcinoma treated with sorafenib. Ratios of T3/T4 and T3/rT3, which are independent of substrate availability and reflect iodothyronine deiodination, were calculated. RESULTS Serum free T4 and T3 levels, adjusted for levothyroxine dose per kilogram body weight, decreased by 11 and 18%, respectively, whereas TSH levels increased. The serum T3/T4 and T3/rT3 ratios decreased by 18 and 22%, respectively, which is compatible with increased type 3 deiodination. CONCLUSIONS Sorafenib enhances T4 and T3 metabolism, which is probably caused by increased type 3 deiodination.

Follow-Up of Low-Risk Differentiated Thyroid Cancer Patients Who Underwent Radioiodine Ablation of Postsurgical Thyroid Remnants after Either Recombinant Human Thyrotropin or Thyroid Hormone Withdrawal

BACKGROUND We previously demonstrated comparable thyroid remnant ablation rates in postoperative low-risk thyroid cancer patients prepared for administration of 3.7GBq (131)I (100 mCi) after recombinant human (rh) TSH during T(4) (L-T4) therapy vs. withholding L-T4 (euthyroid vs. hypothyroid groups). We now compared the outcomes of these patients 3.7 yr later. PATIENTS AND METHODS Fifty-one of the 63 original patients (28 euthyroid, 23 hypothyroid) participated. Forty-eight received rhTSH and serum thyroglobulin (Tg) sampling. A (131)I whole-body scan was performed in 43 patients, and successful ablation was defined by criteria from the previous study. Based on the criterion of uptake less than 0.1% in thyroid bed, 100% (43 of 43) remained ablated. When no visible uptake instead was used, five patients (four euthyroid, one hypothyroid) had minimal visible activity. When the TSH-stimulated Tg criterion was used, only two of 45 (one euthyroid, one hypothyroid) had a stimulated Tg level greater than 2 ng/ml. RESULTS No patient in either group died, and no patient declared disease free had sustained tumor recurrence. Nine (four euthyroid, five hypothyroid) had received additional (131)I between the original and current studies due to detectable Tg or imaging evidence of disease; with follow-up, all now had a negative rhTSH-stimulated whole-body scan and seven (three euthyroid, four hypothyroid) had a stimulated serum Tg less than 2 ng/ml. CONCLUSIONS In conclusion, after a median 3.7 yr, low-risk thyroid cancer patients prepared for postoperative remnant ablation either with rhTSH or after L-T4 withdrawal were confirmed to have had their thyroid remnants ablated and to have comparable rates of tumor recurrence and persistence.

Age, sex, and grip strength determine architectural bone parameters assessed by peripheral quantitative computed tomography (pQCT) at the human radius

The purpose of this study was to estimate the relation of some noninvasively derived mechanical characteristics of radial bone including architectural parameters for bone strength to grip strength and muscle cross-section. Sixty-three males between 21 and 78yr of age and 101 females between 18 and 80yr of age were measured at the nondominant forearm using peripheral quantitative computed tomography (pQCT). We assessed the integral bone mineral density (BMD(I)) and content (BMC(I)) by pQCT at the distal and at the mid-shaft radius. Integral bone area (Area(I)), cortical thickness (C-th), and a newly proposed index for bone strength; the stress-strain index (SSI) were also calculated. The dynamometrically measured maximum grip strength was taken as a mechanical loading parameter and muscle cross-section as a substitute for it. Sex, grip strength, BMC(I) and BMD(I) (distal radius) were identified in a multiple regression analysis to significantly predict bone strength as expressed by SSI, after adjusting for all other independent variables, including age and sex (p<0.0001). Grip strength was closest related to age, sex, BMD(I) and SSI(p) of the distal radius. The cross-sectional area of muscle was not significantly determining the grip strength within the analysis model. In conclusion, our results suggested that architectural parameters at the distal radius were better related to grip strength than to cross-sectional muscle area in both males and females. Maximum muscle strength as estimated by grip strength might be a stronger determinant of mechanical characteristics of bones as compared with cross-sectional muscle area.

In Vivo Formation of γ-H2AX and 53BP1 DNA Repair Foci in Blood Cells After Radioiodine Therapy of Differentiated Thyroid Cancer

DNA double-strand breaks (DSBs) are critical cellular lesions that can result from ionizing radiation exposure. A marker for DSB formation is the phosphorylated form of the histone H2 variant H2AX (γ-H2AX). DSBs also attract the damage sensor p53-binding protein 1 (53BP1) to the DSB-containing chromatin, because 53BP1 associates with the DSB-surrounding chromatin. We studied the induction, persistence, and disappearance of radiation-induced γ-H2AX and 53BP1 foci after the first 131I therapy of patients with differentiated thyroid carcinoma, a model for protracted, continuous, internal whole-body irradiation. Methods: Twenty-six patients (7 men, 19 women; mean age ± SD, 42 ± 13 y) underwent posttherapeutic blood dosimetry according to the standard operating procedure of the European Association of Nuclear Medicine, including peripheral blood sampling and external dose rate measurements at 2–144 h after administration of 131I for thyroid remnant ablation. The mean time curves of dose accumulation and dose rate to the blood were compared with the mean γ-H2AX and 53BP1 foci counts over the same period in samples of mononuclear peripheral blood leukocytes. Results: The mean absorbed dose to the blood in 24 patients evaluable for physical dosimetry was 0.31 ± 0.10 Gy (minimum, 0.17 Gy; maximum, 0.57 Gy). After 24 h, the mean daily dose increment was less than 0.05 Gy. The excess focus counts per nucleus—that is, nuclear foci in excess of the low background count—peaked at 2 h after radioiodine administration (median excess foci for γ-H2AX [n = 21 patients], 0.227, and for 53BP1 [n = 19 patients], 0.235) and progressively declined thereafter. Significantly elevated numbers of excess focus counts per nucleus (median excess foci for γ-H2AX [n = 8 patients], 0.054, and for 53BP1 [n = 6 patients], 0.046) still were present at 120–144 h after therapy. Because the rate of occurrence of radiation-induced focus counts per nucleus per absorbed dose varied considerably among patients, a dose–response relationship could not be established for this series as a whole. The number of excess radiation-induced focus counts per nucleus per absorbed dose rate increased with time, potentially indicating a slower rate of DNA repair or, alternatively, a higher de novo rate of focus formation. The values over time of both radiation-induced DSB markers correlated closely (r2 = 0.973). Conclusion: Radiation-induced γ-H2AX and 53BP1 nuclear foci are useful markers for detecting radiation exposure after radionuclide incorporation, even for absorbed doses to the blood below 20 mGy.