Human papillomavirus and p53 mutations in head and neck squamous cell carcinoma among Japanese population.

We aimed to reveal the prevalence and pattern of human papillomavirus (HPV) infection and p53 mutations among Japanese head and neck squamous cell carcinoma (HNSCC) patients in relation to clinicopathological parameters. Human papillomavirus DNA and p53 mutations were examined in 493 HNSCCs and its subset of 283 HNSCCs. Oropharyngeal carcinoma was more frequently HPV-positive than non-oropharyngeal carcinoma (34.4% vs 3.6%, P < 0.001), and HPV16 accounted for 91.1% of HPV-positive tumors. In oropharyngeal carcinoma, which showed an increasing trend of HPV prevalence over time (P < 0.001), HPV infection was inversely correlated with tobacco smoking, alcohol drinking, p53 mutations, and a disruptive mutation (P = 0.003, <0.001, <0.001, and <0.001, respectively). The prevalence of p53 mutations differed significantly between virus-unrelated HNSCC and virus-related HNSCC consisting of nasopharyngeal and HPV-positive oropharyngeal carcinomas (48.3% vs 7.1%, P < 0.001). Although p53 mutations were associated with tobacco smoking and alcohol drinking, this association disappeared in virus-unrelated HNSCC. A disruptive mutation was never found in virus-related HNSCC, whereas it was independently associated with primary site, such as the oropharynx and hypopharynx (P = 0.01 and 0.03, respectively), in virus-unrelated HNSCC. Moreover, in virus-unrelated HNSCC, G:C to T:A transversions were more frequent in ever-smokers than in never-smokers (P = 0.04), whereas G:C to A:T transitions at CpG sites were less frequent in ever-smokers than in never-smokers (P = 0.04). In conclusion, HNSCC is etiologically classified into virus-related and virus-unrelated subgroups. In virus-related HNSCC, p53 mutations are uncommon with the absence of a disruptive mutation, whereas in virus-unrelated HNSCC, p53 mutations are common, and disruptive mutagenesis of p53 is related with oropharyngeal and hypopharyngeal carcinoma.

Area Dose-Response and Radiation Origin of Childhood Thyroid Cancer in Fukushima Based on Thyroid Dose in UNSCEAR 2020/2021: High 131I Exposure Comparable to Chernobyl.

The FMU and the United Nations Scientific Committee on the Effects of Atomic Radiation (UNSCEAR) concluded that the high incidence of thyroid cancer after the Fukushima nuclear accident was not the result of radiation exposure, but rather might have been overdiagnosis based on the low thyroid dose estimated in the UNSCEAR 2020/2021 report. In this study, the origin of increased PTC in Fukushima was examined based on the thyroid dose estimated by UNSCEAR. The dose-response relationship of the incidence rate per person-years (PY) was analyzed for four areas in Fukushima prefecture via regression analysis. The linear response of the annual incidence rates to thyroid dose in the first six years showed that the dominant origin of childhood thyroid cancer was radiation exposure. Excess absolute risk (EAR) proportionally increased with thyroid dose, with an EAR/104 PY Gy of 143 (95%CI: 122, 165) in the second TUE (p < 0.001), which is approximately 50-100 times higher than the EAR/104 PY Gy ≒ 2.3 observed after the Chernobyl accident. This suggests an underestimation of the thyroid dose by UNSCEAR of approximately 1/50~1/100 compared with the thyroid dose for Chernobyl. The increased childhood thyroid cancer in Fukushima was found to arise from radioactive iodine exposure, which was comparable to that in Chernobyl.

Correction: Kato et al. Area Dose-Response and Radiation Origin of Childhood Thyroid Cancer in Fukushima Based on Thyroid Dose in UNSCEAR 2020/2021: High 131I Exposure Comparable to Chernobyl. Cancers 2023, 15, 4583.

The authors wish to revise two points in Sections 3 [...].

A rapid and easy method for the qualitative detection of intracellular deposition of inhaled nanoparticles.

In recent years, nanoparticle exposure risk has drawn increasing attention from the research community and the general public. However, analysis of nanoparticles is hindered by their small size, which prevents the development of methods for their detection in cells and tissues. For risk assessment of nanoparticle exposure, it is important to measure the exact amount of deposited material in pulmonary tissue. Using a nanoparticle exposure device, A/JJmsSlc mice were chronically exposed transtracheally to anatase-type titanium dioxide particles. A microscope-integrated laser Raman spectrometer was used to detect differentially stained macrophages in a pulmonary wash obtained from the mice exposed to the particles. This detection method allowed rapid and easy sample collection and qualitative analysis, and the method may be useful for conducting large-scale evaluations in workers exposed to environments heavily contaminated with nanoparticles. FROM THE CLINICAL EDITOR: This paper discusses a microscope-integrated laser Raman spectrometer method to measure the exact amount of nanoparticles deposited in pulmonary tissue. This method allows rapid sample collection, qualitative analysis, and may be useful for large-scale evaluations.

Effects of fission neutrons on human thyroid tissues maintained in SCID mice.

Morphology and function (secretion of thyroid hormone) of human thyroid tissues from Graves' disease patients are well maintained in C57BL/6J-scid mice. Serum level of thyroid hormone was reduced by fission neutrons from the nuclear reactor UTR-KINKI, and changes in thyroid hormone by fission neutrons were bigger than those by low LET radiations, X-rays and (137)Cs gamma-rays, suggesting high relative biological effectiveness (RBE; 6.5) of fission neutrons. Microarray analyses revealed that about 3% of genes showed more than 4-fold change in gene expression in the unexposed thyroid tissues against surgically resected thyroid tissues from the same patient, probably due to the difficult oxygen and nutrient supply shortly after transplantation. Dose-dependent changes in gene expression against unexposed concurrent controls were observed with increasing doses of fission neutrons (0.2-0.6Gy) and (137)Cs gamma-rays (1.0-3.0Gy) and showed high RBE (4.2). Furthermore, there were some specific genes which showed more than 4-fold change in gene expression in all the thyroid tissues exposed to higher doses of radiation, especially neutrons (0.4 and 0.6Gy), but none at lower doses (0.2Gy of neutrons and 1.0 and 2.0Gy of gamma-rays). These genes related to degeneration, regeneration, apoptosis, and transcription, respond specifically and very sensitively to neutron injury in human thyroid tissues. This is the first experimental report that fission neutrons can induce some morphological and functional disorders in human tissues, showing high RBE against gamma-ray exposure. These results are useful to evaluate the risks of fission neutrons and cosmic rays to humans.

Biological fingerprint using scout computed tomographic images for positive patient identification.

PURPOSE: Management of patient identification is an important issue that should be addressed to ensure patient safety while using modern healthcare systems. Patient identification errors can be mainly attributed to human errors or system problems. An error-tolerant system, such as a biometric system, should be able to prevent or mitigate potential misidentification occurrences. Herein, we propose the use of scout computed tomography (CT) images for biometric patient identity verification and present the quantitative accuracy outcomes of using this technique in a clinical setting. METHODS: Scout CT images acquired from routine examinations of the chest, abdomen, and pelvis were used as biological fingerprints. We evaluated the resemblance of the follow-up with the baseline image by comparing the estimates of the image characteristics using local feature extraction and matching algorithms. The verification performance was evaluated according to the receiver operating characteristic (ROC) curves, area under the ROC curves (AUC), and equal error rates (EER). The closed-set identification performance was evaluated according to the cumulative match characteristic curves and rank-one identification rates (R1). RESULTS: A total of 619 (383 males, 236 females, age range 21-92 years) patients who underwent baseline and follow-up chest-abdomen-pelvis CT scans on the same CT system were analyzed for verification and closed-set identification. The highest performances of AUC, EER, and R1 were 0.998, 1.22%, and 99.7%, respectively, in the considered evaluation range. Furthermore, to determine whether the performance decreased in the presence of metal artifacts, the patients were classified into two groups, namely scout images with (255 patients) and without (364 patients) metal artifacts, and the significance test was performed for two ROC curves using the unpaired Delong's test. No significant differences were found between the ROC performances in the presence and absence of metal artifacts when using a sufficient number of local features. Our proposed technique demonstrated that the performance was comparable to that of conventional biometrics methods when using chest, abdomen, and pelvis scout CT images. Thus, this method has the potential to discover inadequate patient information using the available chest, abdomen, and pelvis scout CT image; moreover, it can be applied widely to routine adult CT scans where no significant body structure effects due to illness or aging are present. CONCLUSIONS: Our proposed method can obtain accurate patient information available at the point-of-care and help healthcare providers verify whether a patient's identity is matched accurately. We believe the method to be a key solution for patient misidentification problems.

Nasal NK/T-cell lymphoma: epidemiology and pathogenesis.

Nasal NK/T-cell lymphoma (NKTCL) is an uncommon disease, but usually shows a highly aggressive clinical course. The disease is much more frequent in Asian and Latin American countries than in Western countries, and is universally associated with Epstein-Barr virus (EBV) infection. Analyses of gene mutations, especially p53 and c-KIT, revealed the different frequencies by district. Epidemiological studies revealed the changes of the disease frequency in Korea during the period from 1977-1989 to 1990-1996. Case-control study showed that the exposure to pesticides and chemical solvents could be causative of NKTCL. Further studies including HLA antigen typing of patients is necessary to further clarify the disease mechanism.

Differential radiation sensitivity to morphological, functional and molecular changes of human thyroid tissues and bone marrow cells maintained in SCID mice.

Morphology and function of human organs and tissues are well maintained in the improved SCID (severe combined immunodeficient) mice for a long period (approximately 3 years). To study the radiation-induced damage on human thyroid gland, human thyroid tissues transplanted to SCID mice were consecutively exposed to X-rays or 137Cs gamma-rays at high and low dose rates for approximately 2 years. Consecutive irradiation resulted in the disappearance of follicles and significant decrease of thyroid hormone secretion. Mutations in p53 and c-kit genes were induced significantly in human thyroid tissues from old head and neck cancer patients (av. 56.8 years, 4 males) and a Graves' disease patient (20 years, male) over the dose of 24 Gy (44.7+/-5.9 Gy, mean+/-S.E) and 11 Gy (20.2+/-7.8 Gy), respectively, while mutations were not detected at lower doses nor in unexposed matched controls (p < 0.01). There were significant differences in mutation frequency in the transplanted human thyroid tissues (31 years, female) between high dose rate (1.19 Gy/min; 8 in 20 tissues) and low dose rate (0.00023 Gy/min; 0 in 14 tissues) exposures (p < 0.01). Mutations were not detected in RET, K-ras and beta-catenin genes. Expression analysis by GeneChip indicated that gene expression was also well maintained in the transplanted human thyroid tissues. However, lower doses (1 or 3 Gy) of 137Cs gamma-rays can induce changes in gene expression in the transplanted human thyroid tissues. Furthermore, fatally irradiated SCID mice could survive with human bone marrow cell transplantation. When about half of mouse bone marrows were replaced by human bone marrow cells, the human bone marrow cells showed high sensitivity to gamma-irradiation; 28.0% and 0.45% survival after 0.5 and 2.0 Gy exposures, respectively.

Analysis of p53 and Bak gene mutations in lymphoproliferative disorders developing in rheumatoid arthritis.

PURPOSE: Individuals affected by rheumatoid arthritis (RA) occasionally develop lymphoproliferative disorders (RA-LPD). To study the molecular changes underscoring the RA-LPD, mutations of p53 and Bak gene were analyzed in RA-LPD with (MTX-LPD) or without methotrexate treatment for RA (non-MTX-LPD). METHODS: Histology and immunophenotype were immunohistochemically examined in 32 cases of MTX-LPD and 21 of non-MTX-LPD. Polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) followed by direct sequencing was employed to detect the mutations of p53 and Bak gene. RESULTS: Frequency of p53 mutations in non-MTX-LPD (47.6%) was significantly higher than that in MTX-LPD (15.6%) (P < 0.05). Among the cases with non-Hodgkin's lymphoma (NHL), the largest category of RA-LPD, the frequency of p53 mutations in the non-MTX-NHL (47.6%) was significantly higher than that in the MTX-NHL (14.8%) (P < 0.05). Interval between the onset of RA and LPD development was significantly longer in LPD with p53 gene mutations (median 228 months) than that without mutations (133 months). LPD with p53 gene mutations had more advanced diseases and an unfavorable prognosis than those without mutations. CONCLUSIONS: MTX-LPD and non-MTX-LPD show similar findings in clinical characteristics, histology, EBV positive rate, and frequency of Bak gene mutations. Whereas the non-MTX-LPD is distinct from the MTX-LPD in its significantly higher p53 mutation frequency.

Gene mutation analysis of sinonasal lymphomas in Indonesia.

Sinonasal lymphomas comprise NK/T-cell (NKTCL) type and B-cell type with unique geographical development. In this study, mutations of p53, K-ras, c-kit, beta-catenin, and bak gene were analyzed using polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) followed by direct sequencing in 41 sinonasal lymphomas (27 NKTCL and 14 B-cell type) from Indonesia. In situ hybridization study with EBER-1 probe revealed that 85% of NKTCL cases were EBV positive, but none of B-cell type was EBV positive. Frequency of mutations in p53, K-ras, c-kit, beta-catenin, and bak gene was 62.9%, 0%, 11.1%, 18.5%, and 25.9%, respectively, in NKTCL, and 71.4%, 0%, 23.1%, 21.4%, and 57.1%, respectively, in B-cell cases, showing that mutation frequency in all genes was higher in B-cell than in NKTCL cases. These findings suggest that gene mutations might be the driving-force for B-cell lymphoma, whereas combined EBV infection and gene mutations contribute to NKTCL development in Indonesia.

p53, K-ras, c-kit and beta-catenin gene mutations in sinonasal NK/T-cell lymphoma in Korea and Japan.

Mutations of p53, K-ras, c-kit, and beta-catenin gene were examined in 100 cases of sinonasal NK/T-cell lymphoma (NKTCL) from Korea and Japan. Age of patients ranged from 12 to 72 (median 41.0) in Korea and 27 to 82 (median 61.0) years in Japan. Gene mutations were analyzed on paraffin-embedded specimens by PCR-SSCP followed by direct sequencing. p53 is a well-known tumor suppressor gene. c-kit gene encodes a receptor tyrosine kinase, which plays a crucial role in proliferation and differentiation of hematopoietic stem cells. Mutations of K-ras and beta-catenin are frequently observed in cancers. Thirteen of 42 (31.0%) cases from Korea and 36 of 58 (62.1%) from Japan had p53 mutations, showing significant differences in the incidence of p53 mutation between two countries. Of the Japanese cases 18 (31.0%) had mutations in exon 4, while only 3 cases (7.1%) were found in Korea cases (p<0.01 by chi2 test). K-ras, c-kit and beta-catenin mutations were also found in higher incidence in Japanese cases. In conclusion, different frequency of p53 mutations with different pattern of exon involvement and difference in age of disease onset is evident between sinonasal NKTCL in Korea and Japan.

TP53 gene mutation, an unfavorable prognostic factor for malignant lymphomas in autoimmune diseases.

OBJECTIVES: To investigate whether mutations of the TP53 tumor suppressor gene are associated with a poor prognosis in lymphoproliferative disorders (LPD) developing in patients with a history of autoimmune disease (AID). METHODS: Fifty patients, 15 males and 35 females ranging in age from 23 to 83 (median, 61) years, were examined. Rheumatoid arthritis (21 cases) is the commonest type of AID followed by systemic lupus erythematosus (10), dermatomyositis (9), progressive systemic sclerosis (4), and autoimmune hemolytic anemia (6). The interval between the diagnosis of AID and LPD ranged from 1 to 660 months (mean 42 months). Histological, immunohistological, and in situ hybridization studies revealed that 37 tumors were B cell lymphomas and 13 were T cell lymphomas with the Epstein-Barr virus genome present in the tumor cells in 24% of cases. Stage of disease was I in 15 cases, II in 5, III in 9, and IV in 21. RESULTS: Polymerase chain reaction-single strand conformation polymorphism followed by direct sequencing revealed TP53 mutations in 45.9% of B cell and 53.8% of T cell lymphomas. The follow-up study revealed an unfavorable prognosis in cases with mutations compared with those without: the 1-year survival rate was 43.5 and 73.0% in B cell and 16.7 and 50% in T cell lymphoma, respectively. CONCLUSIONS: The occurrence of a TP53 mutation is an unfavorable prognostic factor not only in B cell but also in T cell LPD in AID.

Mutations of p53, c-kit, K-ras, and beta-catenin gene in non-Hodgkin's lymphoma of adrenal gland.

Malignant lymphoma of the adrenal gland is a rare disease, usually with diffuse large cell morphology and B-cell immunophenotype, and often associated with Epstein-Barr virus infection. In this study, mutations of p53, c-kit, K-ras, and beta-catenin gene were analyzed in 17 cases (13 males and four females with ages ranging from 25 to 84 years) of such lymphomas by polymerase chain reaction-single strand conformation polymorphism followed by direct sequencing. Selected exons in each gene, representing hot spots, were analyzed. All 44 mutations detected were single-nucleotide substitutions and 33 were missense mutations. Nineteen mutations were detected in exon 5 and / or 7 of the p53 gene in nine of 17 cases (52.9%) and 21 in exon 11 and / or 17 of the c-kit gene in 10 of 14 cases (71.4%). Bilateral adrenal lesions in one case who had not received any adjuvant therapy showed different mutational patterns of the p53 and c-kit genes, suggesting different clonal evolution of lymphoma between the left and right sides. Mutation at codon 13 of the K-ras gene was detected in one of 14 cases (7.1%), and in exon 3 of the beta-catenin gene in three of 12 cases (25%). All but one mutation were transition mutations, indicating that some endogenous mutagens act in lymphomagenesis in the adrenal gland. Our results suggest that p53 and c-kit gene mutations might play a role in adrenal lymphomagenesis.

Gene mutations in lymphoproliferative disorders of T and NK/T cell phenotypes developing in renal transplant patients.

Post-transplantation lymphoproliferative disorder (PT-LPD) is characterized by lymphoid proliferation after organ or bone marrow transplantation. In Western countries, most cases of PT-LPD are B-cell-derived and Epstein-Barr virus-associated, in which alterations of c-myc, p53, and N-ras genes might play a role in disease progression. In Japan, PT-LPD of T- and NK/T-cell types are not uncommon in renal transplant patients. Mutations of p53 (exons 4 through 8), K-ras (exons 1 and 2), c-kit (exons 11 and 17), and beta-catenin genes (exon 3) in 12 cases of these diseases were analyzed by PCR single strand conformation polymorphism and then by direct sequencing. p53 gene mutations were detected in 5 of 5 cases of peripheral T-cell lymphoma, 3 (60%) of 5 cases of adult T-cell leukemia/lymphoma, and 1 of 2 cases of NK/T cell lymphoma. Twenty-five percent of T and NK/T cell lymphomas showed K-ras mutations. Mutations of c-kit and beta-catenin genes were found in 33% of cases. Among a total of 42 substitution mutations, 40 were transitions with involvement of CpG sites in 20 to 30% of cases. Most cases had at least one mutation that changed an amino acid, which might have provided the selection pressure for expansion. These findings suggested that p53 gene mutations might play a central role in development of peripheral T-cell lymphoma including adult T-cell leukemia/lymphoma in renal transplant patients.

Analysis of p53, K-ras, c-kit, and beta-catenin gene mutations in sinonasal NK/T cell lymphoma in northeast district of China.

Recently we reported the different frequencies of p53 and c-kit gene mutations among sinonasal NK/T cell lymphoma (NKTCL) in Korea, north China (Beijing), and Japan, suggesting some racial, environmental, or life-style differences as a possible cause of nasal tumorigenesis. In this study, gene mutations in p53, c-kit, K-ras, and beta-catenin gene were analyzed by polymerase chain reaction (PCR)-single strand conformation polymorphism (SSCP) followed by direct sequencing in 20 cases of sinonasal NKTCL from northeast China (Shen Yang). Age of patients ranged from 5 to 63 (median, 40.0) years. p53 gene mutations were found in eight of 20 cases (40%), with exon 4 involvement in 10% of cases. The majority was missense mutations and G:C to A:T transition was predominant. The frequency of the c-kit and K-ras gene mutations was low (5%), while that of the beta-catenin gene was six of 20 cases (30%). From these findings, it is concluded that nasal NKTCL in northeast China shared common features with that in Korea in the younger onset of disease compared to that in Japan and lower frequency of p53 gene mutations with infrequent exon 4 involvement compared to that in Japan and north China. These differences might be caused by migration of susceptible populations or some environmental confounding factors.