Cutaneous and systemic plasmacytosis vs. cutaneous plasmacytic castleman disease: review and speculations about pathogenesis

Cutaneous and systemic plasmacytosis (C/SP), human herpes virus-8 (HHV8), negative multicentric plasmacytic Castleman disease (MPCD), and idiopathic plasmacytic lymphadenopathy are polyclonal plasma cell proliferations of unknown etiology that predominantly affect Asian individuals. Herein, we present our experience with a Vietnamese man with typical C/SP limited to the skin but, after 10 years, may have developed perirenal involvement, and with a white man with human immunodeficiency virus and HHV8 negative MPCD with involvement of skin, lymph nodes, and kidneys at presentation, and who later succumbed to gastric carcinoma. Based on a review of the literature, we suggest that C/SP, cutaneous MPCD, and idiopathic plasmacytic lymphadenopathy with skin involvement are part of a continuum rather than distinct entities and, as such, may be regarded as variants of HHV8-negative MPCD. Although the majority of patients with C/SP run a chronic benign course, special attention should be given to monitoring for pulmonary and renal involvement. We hypothesize that long-lived plasma cells originate and survive in the environment of the skin akin to other stromal "survival" niches due to the local production of interleukin 6 and that such patients might respond to agents that interfere with interleukin-6 activity.     

Gimeracil, an inhibitor of dihydropyrimidine dehydrogenase, inhibits the early step in homologous recombination

Gimeracil (5-chloro-2, 4-dihydroxypyridine) is an inhibitor of dihydropyrimidine dehydrogenase (DPYD), which degrades pyrimidine including 5-fluorouracil in the blood. Gimeracil was originally added to an oral fluoropyrimidine derivative S-1 to yield prolonged 5-fluorouracil concentrations in serum and tumor tissues. We have already reported that gimeracil had radiosensitizing effects by partially inhibiting homologous recombination (HR) in the repair of DNA double strand breaks. We investigated the mechanisms of gimeracil radiosensitization. Comet assay and radiation-induced focus formation of various kinds of proteins involved in HR was carried out. siRNA for DPYD were transfected to HeLa cells to investigate the target protein for radiosensitization with gimeracil. SCneo assay was carried out to examine whether DPYD depletion by siRNA inhibited HR repair of DNA double strand breaks. Tail moments in neutral comet assay increased in gimeracil-treated cells. Gimeracil restrained the formation of foci of Rad51 and replication protein A (RPA), whereas it increased the number of foci of Nbs1, Mre11, Rad50, and FancD2. When HeLa cells were transfected with the DPYD siRNA before irradiation, the cells became more radiosensitive. The degree of radiosensitization by transfection of DPYD siRNA was similar to that of gimeracil. Gimeracil did not sensitize DPYD-depleted cells. Depletion of DPYD by siRNA significantly reduced the frequency of neopositive clones in SCneo assay. Gimeracil partially inhibits the early step in HR. It was found that DPYD is the target protein for radiosensitization by gimeracil. The inhibitors of DPYD, such as gimeracil, could enhance the efficacy of radiotherapy through partial suppression of HR-mediated DNA repair.     

Effects of depletion of dihydropyrimidine dehydrogenase on focus formation and RPA phosphorylation

Gimeracil, an inhibitor of dihydropyrimidine dehydrogenase (DPYD), partially inhibits homologous recombination (HR) repair and has a radiosensitizing effect as well as enhanced sensitivity to Camptothecin (CPT). DPYD is the target protein for radiosensitization by Gimeracil. We investigated the mechanisms of sensitization of radiation and CPT by DPYD inhibition using DLD-1 cells treated with siRNA for DPYD. We investigated the focus formation of various kinds of proteins involved in HR and examined the phosphorylation of RPA by irradiation using Western blot analysis. DPYD depletion by siRNA significantly restrained the formation of radiation-induced foci of Rad51 and RPA, whereas it increased the number of foci of NBS1. The numbers of colocalization of NBS1 and RPA foci in DPYD-depleted cells after radiation were significantly smaller than in the control cells. These results suggest that DPYD depletion is attributable to decreased single-stranded DNA generated by the Mre11/Rad50/NBS1 complex-dependent resection of DNA double-strand break ends. The phosphorylation of RPA by irradiation was partially suppressed in DPYD-depleted cells, suggesting that DPYD depletion may partially inhibit DNA repair with HR by suppressing phosphorylation of RPA. DPYD depletion showed a radiosensitizing effect as well as enhanced sensitivity to CPT. The radiosensitizing effect of DPYD depletion plus CPT was the additive effect of DPYD depletion and CPT. DPYD depletion did not have a cell-killing effect, suggesting that DPYD depletion may not be so toxic. Considering these results, the combination of CPT and drugs that inhibit DPYD may prove useful for radiotherapy as a method of radiosensitization.     

Impact of smoking habit on medical care use and its costs: a prospective observation of National Health Insurance beneficiaries in Japan.

BACKGROUND: To quantify excess medical use associated with smoking, a large prospective cohort study is needed. The authors examined the impact of smoking on medical care use in a large population-based cohort with an accurate data collecting system in Japan. METHOD: The data were derived from a 30-month prospective cohort study of 43,408 National Health Insurance beneficiaries aged 40--79 years living in a rural Japanese community. The smoking habit of beneficiaries was assessed in a baseline survey at the end of 1994. Medical care use and its costs were monitored by linkage with the National Health Insurance claim history files since January 1995. RESULTS: Male smokers incurred 11% more medical costs (after adjustment for age, physical functioning status, alcohol consumption, body mass index and average time spent walking) than 'never smokers' but for female smokers and never smokers the costs were almost the same. This difference was mainly attributable to increased use of inpatient medical care among smokers, especially in males, where per month cost of inpatient care was 33% higher in smokers. Age-group specific analysis in men showed that excess mortality and excess medical cost ratio for smokers peaked in those aged 60--69 years. CONCLUSIONS: Smokers consume excess medical care. Among the population aged 45 years and over, about 4% of total medical costs were attributable to smoking. To pursue both better health and lower medical costs for the nation, a comprehensive programme to reduce tobacco use is needed.     

Comparison of characteristics between frequent participants and non-participants in screening program for stomach cancer.

To clarify the differences in characteristics between participants and non-participants in the screening program for stomach cancer, life-style and medical histories were compared among 20, 169 subjects who lived in an urban area (Sendai) and a rural area (Wakuya and Tajiri) in Miyagi Prefecture, Japan. All subjects were classified into three groups according to the frequency of participation in the screening program during the last 5 years; i.e., frequent participating group (FPG) for 4 or 5 times, reference group (RG) for 1-3 times and non-participating group (NPG) for 0 times. Subjects in the FPG consumed more milk and green-yellow vegetable whereas those in the NPG consumed less these foods. The age-adjusted proportions of present smokers were higher in the NPG but lower in the FPG significantly. The proportions of subjects who had parental histories of all cancers and stomach cancer and past history of gastro-duodenal ulcer were higher in the FPG and lower in the NPG. To control influences among the variables a stepwise multiple regression analysis was done, and it revealed that smoking and parental history of cancers were strong predictors to explain the frequency of participation.