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 adultonset 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.
Mustard gas (MG) is a mutagenic and carcinogenic alkylating agent, and is a known risk factor for occupational lung cancer. Our hypothesis is that lung cancers from MG workers contain mutations (G:C to A:T transitions) as the result of MG-produced DNA promutagenic adducts in the p53 tumor suppressor gene. We analyzed 12 primary lung cancers from Japanese MG factory workers and 12 lung cancers from non-exposed individuals. Genomic DNA was isolated from archival paraffin-embedded tissues. Exons 5-8 were amplified by polymerase chain reaction using p53-specific primers, and sequenced by dideoxy termination methods. Six out of 12 lung cancers from MG workers contained a total of eight somatic point mutations: two cases had double G:C to A:T transitions; one had a G:C to T:A transversion; one case had an A:T to G:C transition; and two cases had single base deletions. Four of the six mutated purines occurred on the non-transcribed, DNA-coding strand. Out of 12 unexposed cases, there were six single base mutations in six cancers, and no double mutations. The p53 mutational frequency in the MG-exposed cases is similar to the non-exposed controls and the usual smoking-related lung cancers reported previously. However, the distinctive double mutations (G:C to A:T transition) observed in two cases are unusual and may be related to MG exposure.
An 8-year retrospective analysis of invasive Aspergillus stomatitis in neutropenic patients with acute leukemia was performed to characterize the epidemiology and clinical features of the infection. Twelve cases of invasive Aspergillus stomatitis were identified with both clinicohistological and microbiological evidence, and the majority of cases were caused by Aspergillus flavus (10 [83%] of 12 patients). The infection was strongly suspected when a neutropenic patient developed persistent fever without a known source, symptoms of gingival pain and facial swelling, and a solitary ulcerating lesion of mucogingiva covered with a gray necrotic pseudomembrane. Aspergillus stomatitis was diagnosed a median 23 days after admission. In all 12 patients, the diagnosis was made during the period of neutropenia. Ten patients (83%) were treated with amphotericin B and surgery and survived with recovery of neutrophils. Two patients died, and disseminated aspergillosis was identified in 1 patient.
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