Guidance for peptide vaccines for the treatment of cancer.

Recent progress in fundamental understanding of tumor immunology has opened a new avenue of cancer vaccines. Currently, the development of new cancer vaccines is a global topic and has attracted attention as one of the most important issues in Japan. There is an urgent need for the development of guidance for cancer vaccine clinical studies in order to lead to drug development. Peptide vaccines characteristically have the effect of indirectly acting against cancer through the immune system - a mechanism of action that clearly differs from anticancer drugs that exert a direct effect. Thus, the clinical development of cancer peptide vaccines should be planned and implemented based on the mechanism of action, which differs significantly from conventional anticancer drug research. The Japanese Society for Biological Therapy has created and published Guidance for peptide vaccines for the treatment of cancer as part of its mission and responsibilities towards cancer peptide vaccine development, which is now pursued globally. We welcome comments from regulators and business people as well as researchers in this area.

Coronary arterial wall disruption and intramural hematoma in a patient with coronary spastic angina.

Acute myocardial infarction is sometimes complicated in patients with coronary spastic angina. The mechanisms are known to be plaque rupture and thrombosis induced by spasm, and reduced coronary flow due to prolonged spasm. We describe the case of a 45-year-old woman with coronary spastic angina who had a complication of an acute myocardial infarction. A specimen obtained with thrombectomy was the disrupted coronary artery wall accompanied by massive intramural hemorrhage. The cause of the acute myocardial infarction was thought to be an embolism of the coronary arterial wall that was disrupted by spasm and intramural hemorrhage.

Impact of low-density lipoprotein particle size on carotid intima-media thickness in patients with type 2 diabetes mellitus.

Small low-density lipoprotein (LDL) particles and modifications to LDL such as glycation and oxidation have been linked to the pathogenesis of atherosclerosis in patients with diabetes. We investigated whether LDL particle size, or the levels of glycated LDL or malondialdehyde-modified LDL (MDA-LDL) are associated with carotid intima-media thickness (IMT) in patients with type 2 diabetes mellitus. One hundred seventy-two patients with type 2 diabetes mellitus were enrolled. Carotid IMT was measured by high-resolution ultrasound, and LDL particle size and serum glycated LDL and MDA-LDL levels were determined. The 3 variables were significantly correlated with one another. Univariate analyses defined statistically significant correlations of carotid IMT with LDL size, hemoglobin A(1c), glycated LDL, MDA-LDL, high-density lipoprotein (HDL) cholesterol, and age. The strongest association of IMT was with LDL size (r = -0.406, P < .0001), followed by that with HDL cholesterol (r = -0.225, P = .004). A stepwise multiple regression analysis revealed that LDL size and HDL cholesterol are independent predictors of carotid IMT. Neither glycated LDL nor MDA-LDL had a significant independent contribution to the severity of carotid IMT in the multivariate model. Low-density lipoprotein particle size, but not the glycated LDL or MDA-LDL level, was independently associated with carotid IMT in patients with type 2 diabetes mellitus regardless of antidiabetic and lipid-lowering medications. These results suggest that the measurement of LDL size may be more useful than quantification of modified LDLs for assessing atherosclerosis in patients with type 2 diabetes mellitus. Small LDL particles may be the most important predictor for the risk of cardiovascular disease in diabetic patients.

Impact of plasma aldosterone levels for prediction of in-stent restenosis.

Aldosterone promotes vascular smooth muscle cell proliferation and endothelial dysfunction, suggesting the contribution to in-stent restenosis (ISR). This study evaluated any relation between plasma aldosterone levels and ISR 6 months after successful coronary stenting. We enrolled 156 consecutive patients with stable angina who underwent coronary bare metal stenting. Plasma aldosterone levels and other serum markers known to influence cardiovascular events were measured in all patients at baseline. Patients with restenosis were found to have significantly higher plasma aldosterone levels than their counterparts without restenosis (162 +/- 60 vs 122 +/- 60 pg/ml, p = 0.007). On logistic regression analysis, even after adjusting for clinical, angiographic, and other confounding variables, plasma aldosterone level per 10 pg/ml (odds ratio 1.34, 95% confidence interval 1.10 to 1.63, p = 0.006) proved to be the independent predictor of ISR. The area under the receiver-operating characteristic curve for plasma aldosterone level was 0.75, and the optimal cut-off value identified by receiver-operating characteristic analysis was 141.9 pg/ml, which had a predictive accuracy of 69%. In conclusion, the present findings indicate that plasma aldosterone levels at baseline are independent predictors of ISR and may constitute a potential therapeutic target.

A case of multiple hepatic peribiliary cysts which contributed to the obstructive jaundice and led to liver failure at the young man with von Recklinghausen's disease.

We treated a young man with obstructive jaundice, in whom multiple hepatic peribiliary cysts were detected at autopsy. He had been diagnosed with von Recklinghausen's disease in early childhood and had undergone surgery for a ventricular septal defect with massive blood transfusion at the age of 4 years. Examination at the age of 21 revealed prominent splenomegaly and a low platelet count. He underwent splenectomy and liver cirrhosis was confirmed by open biopsy of the liver. He was followed up at a local hospital and was admitted several times. When he was 41 years old, he was transferred to our hospital with severe jaundice and hepatic encephalopathy. Computed tomography showed marked dilation of the intrahepatic bile ducts and liver function tests showed that jaundice was mainly due to an increase of direct bilirubin. Despite endoscopic nasobiliary drainage, plasma exchange, and continuous hemodiafiltration, he died of hepatic failure after 5 days. At autopsy, multiple hepatic peribiliary cysts were found. Although peribiliary cysts have generally been considered to cause no symptoms, this report describes a patient with multiple hepatic peribiliary cysts which appear to have been responsible for the progression of obstructive jaundice.

Designing in vitro assay systems for hazard characterization. basic strategies and related technical issues.

Adverse effects of chemicals on humans are typically assessed following four steps: hazard identification, hazard characterization, exposure assessment and risk characterization. Hazard characterization is defined as the qualitative and/or quantitative evaluation of the nature of the adverse effects associated with biological, chemical and physical agents of interest. For chemical agents, hazard characterization is based on a series of in vitro and/or in vivo data obtained from mechanistic, kinetic and dose-response studies on the agent of concern, which are analyzed and integrated for extrapolation to eventually match human conditions. Thus, an accurate experimental design and the development of test methods capable of generating data relevant to hazard characterization are essential for the useful risk assessment of chemicals, including inhaled materials. It should, however, be stressed that hazard characterization has widely been limited to single chemicals. The hazard characterization of airborne mixtures therefore poses a new problem in toxicology, which calls for a novel approach to its scientific assessment. During the last three decades, a number of epidemiological and experimental studies have been conducted focusing on two kinds of inhaled complex mixtures, namely cigarette smoke and diesel exhausts. A new approach to the assessment of airborne complex mixtures may be elaborated through the appropriate, combined use of the findings of such studies. In this context, the present review article is intended to illustrate some basic strategies for and technical issues related to the hazard characterization of inhaled complex mixtures, thereby taking up representative epidemiological and experimental data from published papers on tobacco smoke.

Metastatic leiomyosarcoma of the brain manifesting as multiple hemorrhages. Case report.

A 74-year-old man presented with a rare metastatic leiomyosarcoma of the brain manifesting as subacute development of multiple cerebral hemorrhages. Cerebral angiography demonstrated no tumor staining or vascular malformation. Whole body computed tomography revealed abnormal masses in the liver, left adrenal gland, and duodenum. Histological examination of an open biopsy specimen identified the lesion as metastatic leiomyosarcoma. Whole brain irradiation controlled the intracranial lesions, but the patient's general condition progressively deteriorated and he died of pneumonia. Metastatic leiomyosarcoma is a very uncommon tumor in the central nervous system with a poor response to existing treatment options. Consequently, new approaches to the treatment of this disease are needed.

Inhibition of COX-2 prevents hypertension and proteinuria associated with a decrease of 8-iso-PGF2alpha formation in L-NAME-treated rats.

BACKGROUND: The inhibition of nitric oxide (NO) exerts injurious effects on the cardiovascular system by several mechanisms, such as the activation of the renin-angiotensin system, oxidative stress, and inflammatory cytokines. We examined whether COX-2, an inducible isoform of cyclooxygenase, is associated with the pathogenesis observed in N(omega)-nitro-L-arginine methyl ester (L-NAME)-induced hypertensive rats. METHODS: Three groups of 8-week-old male Sprague-Dawley rats were studied (n = 6 in each group): group 1, untreated controls; group 2, treated with L-NAME (1 g/l for 3 weeks, p.o.); and group 3, L-NAME co-treated with COX-2 inhibitor NS-398 (5 mg/kg per day, i.p.). The L-NAME-induced expression of COX-2 mRNA and protein was semi-quantified in the kidneys and the thoracic aorta. Urinary excretion of the prostaglandin 6-keto PGF(1alpha), thromboxane B2 (TXB2), and prostaglandin E2 (PGE2) was measured in the three groups. Moreover, urinary excretion of 8-iso-PGF(2alpha), a potent vasoconstricting arachidonic acid metabolite acting through thromboxane A (TXA) receptor activation, proposed recently as a marker of oxidative stress, was also measured. RESULTS: L-NAME induced significant increases in systolic blood pressure (P< 0.01), urinary protein (P< 0.05), and renal excretion of 8-iso-PGF(2alpha)(P< 0.01), compared with the control. In L-NAME-treated rats, the levels of COX-2 mRNA and protein were more than 50% higher in the kidneys (P< 0.05), and six-fold higher in the thoracic aorta (P< 0.01) than in control rats. NS-398 significantly ameliorated an increase in systolic blood pressure (P< 0.01) and urinary protein (P< 0.05) induced by L-NAME. CONCLUSIONS: These data indicate that an increase in COX-2 expression might have a hypertensive effect, partly associated with 8-iso-PGF(2alpha) formation in l-NAME-treated rats.

Dissecting basilar artery aneurysm growing during long-term follow up--case report.

A 58-year-old male presented with a dissecting aneurysm of the basilar artery manifesting as dysarthria, left hemiparesis, and numbness of the left side. Angiography revealed a double lumen at the midportion of the basilar artery which was consistent with a diagnosis of dissecting basilar artery aneurysm. The patient was treated conservatively, and remained neurologically stable for a 5-year period following initial presentation, but serial magnetic resonance imaging revealed growth of the aneurysm compressing the brain stem. His condition then worsened. Computed tomography revealed obstructive hydrocephalus. Ventriculoperitoneal shunting was performed and the patient's symptoms improved. However, he died of subarachnoid hemorrhage. Autopsy showed the patient had had a type 3 "dolichoectatic dissecting aneurysm." Surgical treatment should be seriously considered for treating the patients with dissecting basilar artery aneurysm causing brain stem ischemia, especially if the aneurysm is growing. High-flow bypass and proximal occlusion may be the choice in patients with poor collateral circulations.

[Special proposal].

Various kinds organs and tissues obtained from operations and autopsies are preserved for a certain period of time after obtaining samples for histopathological examination and are later disposed of. Some of these organs and tissues are occasionally used for research or educational purposes. Although consent is usually obtained from the patient or from the family of the deceased patient before performing an operation or autopsy, the use and disposal of residual organs and tissues have been performed by clinicians or pathologists without obtaining consent from the patient or from the family of the deceased patient. Now, however, consent must be obtained after sufficient explanation to the patient or to the family of the deceased patient for the storage, use and disposal of residual organs and tissues. It must be kept in mind that residual organs and tissues are parts of a human body and that these parts belong to the patient from which they were obtained or to the family of the deceased patient. These points are important and provide an ethical basis for use and disposal of residual organs and tissues.

Rearranged anaplastic lymphoma kinase (ALK) gene in adult-onset papillary thyroid cancer amongst atomic bomb survivors.

BACKGROUND: We previously noted that among atomic bomb survivors (ABS), the relative frequency of cases of adult papillary thyroid cancer (PTC) with chromosomal rearrangements (mainly RET/PTC) was significantly greater in those with relatively higher radiation exposure than those with lower radiation exposure. In contrast, the frequency of PTC cases with point mutations (mainly BRAF(V600E)) was significantly lower in patients with relatively higher radiation exposure than those with lower radiation exposure. We also found that among ABS, the frequency of PTC cases with no detectable gene alterations in RET, neurotrophic tyrosine kinase receptor 1 (NTRK1), BRAF, or RAS was significantly higher in patients with relatively higher radiation exposure than those with lower radiation exposure. However, in ABS with PTC, the relationship between the presence of the anaplastic lymphoma kinase (ALK) gene fused with other gene partners and radiation exposure has received little study. In this study, we tested the hypothesis that the relative frequency of rearranged ALK in ABS with PTC, and with no detectable gene alterations in RET, NTRK1, BRAF, or RAS, would be greater in those having relatively higher radiation exposures. METHODS: The 105 subjects in the study were drawn from the Life Span Study cohort of ABS of Hiroshima and Nagasaki who were diagnosed with PTC between 1956 and 1993. Seventy-nine were exposed (>0 mGy), and 26 were not exposed to A-bomb radiation. In the 25 ABS with PTC, and with no detectable gene alterations in RET, NTRK1, BRAF, or RAS, we examined archival, formalin-fixed, paraffin-embedded PTC specimens for rearrangement of ALK using reverse transcription-polymerase chain reaction and 5' rapid amplification of cDNA ends (5' RACE). RESULTS: We found rearranged ALK in 10 of 19 radiation-exposed PTC cases, but none among 6 patients with PTC with no radiation exposure. In addition, solid/trabecular-like architecture in PTC was closely associated with ALK rearrangements, being observed in 6 of 10 PTC cases with ALK rearrangements versus 2 of 15 cases with no ALK rearrangements. The six radiation-exposed cases of PTC harboring both ALK rearrangements and solid/trabecular-like architecture were associated with higher radiation doses and younger ages at the time of the A-bombing and at diagnosis compared to the other 19 PTC with no detectable gene alterations. CONCLUSION: Our findings suggest that ALK rearrangements are involved in the development of radiation-induced adult-onset PTC.

Foundation and progress of Japanese society of toxicologic pathology*.

The Japanese Society of Toxicologic Pathology (JSTP) has a differing conceptual framework from the Japanese Society of Pathology (JSP) and Japanese Society of Toxicology (JST) and was founded in 1985 by the leadership of late Dr. Yasukazu Nishiyama with the cooperation of several founding members and the support of JSP. The aim of the JSTP is to improve the human and animal health using an interdisciplinary scientific approach based on pathology and toxicology. In its development as a professional society, the JSTP has established society rules and activities. The JSTP has grown in terms of membership and financial aspects and is now recognized not only domestically but also internationally as a well-organized scientific society. To maintain the high professional standard and visibility of JSTP, we here provide the historical background of the society as a basis for current members to contribute to the continued improvement of our scientific organization.

Sirolimus-eluting stent implantation for ostial stenosis of left main coronary artery after Bentall operation in aortitis syndrome.

We describe a 66-year-old woman with aortitis syndrome, successfully treated with percutaneous coronary intervention using sirolimus-eluting stent (SES) for ostial stenosis of left main coronary artery after Bentall operation. At one-year follow-up, she had no evidence of restenosis and no clinical events. Stent implantation with SES may be useful for ostial left main coronary stenosis after Bentall operation in selected patients with aortitis syndrome.

Improved method for analysis of RNA present in long-term preserved thyroid cancer tissue of atomic bomb survivors.

BACKGROUND: Since many thyroid cancer tissue samples from atomic bomb (A-bomb) survivors have been preserved for several decades as unbuffered formalin-fixed, paraffin-embedded specimens, molecular oncological analysis of such archival specimens is indispensable for clarifying the mechanisms of thyroid carcinogenesis in A-bomb survivors. Although RET gene rearrangements are the most important targets, it is a difficult task to examine all of the 13 known types of RET gene rearrangements with the use of the limited quantity of RNA that has been extracted from invaluable paraffin-embedded tissue specimens of A-bomb survivors. In this study, we established an improved 5' rapid amplification of cDNA ends (RACE) method using a small amount of RNA extracted from archival thyroid cancer tissue specimens. METHODS: Three archival thyroid cancer tissue specimens from three different patients were used as in-house controls to determine the conditions for an improved switching mechanism at 5' end of RNA transcript (SMART) RACE method; one tissue specimen with RET/PTC1 rearrangement and one with RET/PTC3 rearrangement were used as positive samples. One other specimen, used as a negative sample, revealed no detectable expression of the RET gene tyrosine kinase domain. RESULTS: We established a 5' RACE method using an amount of RNA as small as 10 ng extracted from long-term preserved, unbuffered formalin-fixed, paraffin-embedded thyroid cancer tissue by application of SMART technology. This improved SMART RACE method not only identified common RET gene rearrangements, but also isolated a clone containing a 93-bp insert of rare RTE/PTC8 in RNA extracted from formalin-fixed, paraffin-embedded thyroid cancer specimens from one A-bomb survivor who had been exposed to a high radiation dose. In addition, in the papillary thyroid cancer of another high-dose A-bomb survivor, this method detected one novel type of RET gene rearrangement whose partner gene is acyl coenzyme A binding domain 5, located on chromosome 10p. CONCLUSION: We conclude that our improved SMART RACE method is expected to prove useful in molecular analyses using archival formalin-fixed, paraffin-embedded tissue samples of limited quantity.

Papillary microcarcinoma of the thyroid among atomic bomb survivors: tumor characteristics and radiation risk.

BACKGROUND: : Radiation exposure is an established cause of clinical thyroid cancer, but little is known about radiation effects on papillary microcarcinoma (PMC) of the thyroid, a relatively common subclinical thyroid malignancy. Because the incidence of these small thyroid cancers has been increasing, it is important to better understand them and their relation to radiation. METHODS: : PMCs were identified in a subset of 7659 members of the Life Span Study of atomic bomb survivors who had archived autopsy or surgical materials. We conducted a pathology review of these specimens and evaluated the histological features of the tumors and the association between PMCs and thyroid radiation dose. RESULTS: : From 1958 to 1995, 458 PMCs were detected among 313 study subjects. The majority of cancers exhibited pathologic features of papillary thyroid cancers. Overall, 81% of the PMCs were of the sclerosing variant and 91% were nonencapsulated, psammoma bodies that occurred in 13% and calcification was observed in 23%. Over 95% had papillary or papillary-follicular architecture and most displayed nuclear overlap, clear nuclei, and nuclear grooves. Several of these features increased with increasing tumor size, but no association was found with radiation dose. A significant radiation-dose response was found for the prevalence of PMCs (estimated excess odds ratio/Gy = 0.57; 95% confidence interval, 0.01-1.55), with the excess risk observed primarily among women. CONCLUSIONS: : Exposure to low-to-moderate doses of ionizing radiation appears to increase the risk of thyroid PMCs, even when exposure occurs during adulthood. Cancer 2010. (c) 2010 American Cancer Society.

Scientific basis for risk analysis of food-related substances with particular reference to health effects on children.

Based on the advance of toxicology and related sciences, a regulatory regime for the safety of chemicals related to daily life has been rapidly established. Especially for the food-related substances, the process of risk analysis has facilitated the collaboration by all the players including consumers toward the security of their safety. On the other hand, except for pharmaceuticals, science-based decisions and governmental actions on safety issues have not always gained confidence of the public. One of the reasons was the inadequacy in the way of use of scientific knowledge, or in other words, inappropriateness of decision making by "the regulatory science". Regulatory science is a science to warrant the decision making processes for governmental acts (Mitsuru Uchiyama). In the case of chemical safety, it can be redefined as a theoretical concept to complements the uncertainty of scientific knowledge for the decision of governmental acts that is adequate in both scientific and social ways. Therefore, the regulatory science is an indispensable discipline to effectively apply risk analysis. Here, the significance of the regulatory science for the hazard assessment of the chemicals, especially for children is described. In the past, the hazard effects of chemicals have been assessed for adults. Recently, however, the importance of the assessment for children has gained international emphases. Not only for pharmaceuticals, but for food-related substances, the acceptable daily intake (ADI) and tolerable daily intake (TDI) are often set differently for adults and children. The child-specific responses against chemicals are related not only to the physiological factors such as body weight, basal metabolism, but also rapid growth of the body with developmental status of various organs. General knowledge on these issues will be discussed mainly referring the World Health Organization (WHO) documents. Although the cutting edge technology backs up the development of toxicology, it would appear that it is reaching a turning point from technology-centrism to look toward the direction for contribution to society from the stand point of regulatory science.

RET/PTC rearrangements preferentially occurred in papillary thyroid cancer among atomic bomb survivors exposed to high radiation dose.

A major early event in papillary thyroid carcinogenesis is constitutive activation of the mitogen-activated protein kinase signaling pathway caused by alterations of a single gene, typically rearrangements of the RET and NTRK1 genes or point mutations in the BRAF and RAS genes. In childhood papillary thyroid cancer, regardless of history of radiation exposure, RET/PTC rearrangements are a major event. Conversely, in adult-onset papillary thyroid cancer among the general population, the most common molecular event is BRAF(V600E) point mutation, not RET/PTC rearrangements. To clarify which gene alteration, chromosome aberration, or point mutation preferentially occurs in radiation-associated adult-onset papillary thyroid cancer, we have performed molecular analyses on RET/PTC rearrangements and BRAF(V600E) mutation in 71 papillary thyroid cancer cases among atomic bomb survivors (including 21 cases not exposed to atomic bomb radiation), in relation to radiation dose as well as time elapsed since atomic bomb radiation exposure. RET/PTC rearrangements showed significantly increased frequency with increased radiation dose (P(trend) = 0.002). In contrast, BRAF(V600E) mutation was less frequent in cases exposed to higher radiation dose (P(trend) < 0.001). Papillary thyroid cancer subjects harboring RET/PTC rearrangements developed this cancer earlier than did cases with BRAF(V600E) mutation (P = 0.03). These findings were confirmed by multivariate logistic regression analysis. These results suggest that RET/PTC rearrangements play an important role in radiation-associated thyroid carcinogenesis.

A case-control study in Hiroshima and Nagasaki examining non-radiation risk factors for thyroid cancer.

BACKGROUND: Because little is known about the etiology of thyroid cancer in Japan, we conducted a case-control study of thyroid cancer and lifestyle and other risk factors. The present report focuses on medical history, family history, smoking and alcohol drinking, and their interactions with radiation exposure. METHODS: Thyroid cancer cases reported to the Hiroshima and Nagasaki tumor registries during 1970-1986 were histologically reviewed by pathologists. For each of 362 cases with papillary or follicular adenocarcinoma diagnosed at <75 years of age, one control without cancer matched on city, sex, year of birth, and atomic-bomb radiation exposure was selected from the Life Span Study cohort or the offspring cohort. The cohort subjects were residents of Hiroshima and Nagasaki with or without atomic-bomb radiation exposure. Information on risk factors was obtained through a pre-structured interview carried out in 1986-1988. RESULTS: Analysis using conditional logistic regression showed history of goiter or thyroid nodule and family history of cancer to be significantly associated with an increased odds ratio for thyroid cancer. Smoking and alcohol drinking were significantly and independently associated with a reduced odds ratio. Interaction between smoking and alcohol drinking was not evident based on either an additive model or a multiplicative model. Radiation exposure did not significantly modify the associations between these factors and thyroid cancer risk. CONCLUSION: History of goiter/nodule and family history of cancer were risk factors for thyroid cancer. Smoking and alcohol drinking were independently associated with reduced risk. Self-reported retrospective information presents some limitations in interpretation of the data.

The presence of BRAF point mutation in adult papillary thyroid carcinomas from atomic bomb survivors correlates with radiation dose.

In papillary thyroid carcinogenesis, the constitutively activated mitogen-activated protein (MAP) kinase signaling pathway caused by a genetic alteration such as RET/PTC rearrangement or mutation of RAS and BRAF genes, is thought to be a major early event. Among these, the recently identified BRAF(V600E) mutation has been found at high frequency in adult patients with papillary thyroid carcinoma (PTC). However, the association between this mutation and radiation exposure in adult PTC is still unknown. In this study, we examined the BRAF(V600E) mutation in 64 PTCs among adult atomic bomb survivors in Hiroshima, Japan, comprising 17 nonexposed (0 mGy) and 47 exposed patients who developed the carcinoma after the bombing, and assessed the association of BRAF(V600E) mutation with clinico-pathological and epidemiological variables. The median radiation dose in PTCs with the BRAF(V600E) mutation was significantly lower than that without the mutation (18.5 vs.156.9 mGy, Wilcoxon rank-sum test, P=0.022). A significant difference was found in the median latency period (years elapsed from atomic bombing to diagnosis) between exposed patients with and without BRAF(V600E) mutation (29 vs. 21 yr, Wilcoxon rank-sum test, P=0.014). These findings were further confirmed by logistic regression analysis with BRAF(V600E) mutation status as a dependent variable and taking into account possible interactions between the variables. We found that the log-transformed radiation dose and latency period were independently associated with the BRAF(V600E) mutation (P=0.039 and P=0.010, respectively). These results suggest that involvement of BRAF mutation in thyroid carcinogenesis in exposed people may differ from that in the nonexposed people.