Patient with multiple primary carcinomas including 4 separate oral cancers: study of p53 mutations and their implications for management.
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Carcinoma, Squamous Cell↗
Biomedical subjects
Kaoru Kusama
Publications and source records attributed to Kaoru Kusama.
A community-based picture of type 2 diabetes mellitus in Vietnam.
There has been a significant increase in the prevalence of type 2 diabetes mellitus (T2DM) in Vietnam. We found that Vietnamese with T2DM had a normal body mass index (BMI), but high levels of total body fat and abdominal fat. Based on published reports together with our own findings, we believe that a sedentary lifestyle and an abundance of starchy foods and also Western style energy-rich foods are factors associated with disease. The staple food of the Vietnamese is still polished-rice which has high glycemic index values. In addition, a Westernized diet, and the chronic consumption of high-glycemic index foods together with a sedentary lifestyle result in insulin resistance and diabetes. The average BMI of T2DM patients is or= 0.90). We therefore, tentatively suggest a BMI of 23 kg/m(2) together with a WHR of 0.90 for males and 0.85 for females as new cutoff values for the risk of T2DM in Vietnamese. These findings have important implications for primary prevention because they indicate that screening and intervention should focus on high-risk populations.
Body Mass Index↗
Ultrastructural spectrum of solitary fibrous tumor: a unique perivascular tumor with alternative lines of differentiation.
Eight tumors diagnosed as solitary fibrous tumor (SFT) of the oral cavity were studied. Histologic spectrum was entirely comparable with the extrapleural SFT of other sites. One tumor had glomus tumor-like foci. Immunohistochemical results confirmed most of the previous observations, indicating characteristic expression of vimentin, CD34, bcl-2, and CD99. Factor XIIIa and alpha-smooth muscle actin were less commonly reactive and a very few cells were faintly positive for factor VIII-related antigen and Ulex europaeus agglutinin 1. All were essentially negative for S-100 protein, desmin, CD31, and CD68. In stark contrast to the conclusive immunoprofile, ultrastructural investigation of six tumors demonstrated considerable cellular heterogeneity. Other than fibroblasts, perivascular undifferentiated cells and pericytes predominated, but endothelial cells were regularly present. There was a distinctive proliferation of pericytic cells in four tumors, one of which had glomoid foci of myopericytes. The extreme increase in number of Weibel-Palade bodies occurred in voluminous capillary endothelium. Occasional single and clustered cells with consistent features of endothelium showed intracytoplasmic lumen formation. Such composite cells constituted an integral segment of richly vascularized SFT. Myofibroblastic form smooth muscle differentiation was present in only a minority of cells. From phenotypic analysis by electron microscopy, SFT may originate from a unique, perivascular multipotent mesenchyme sharing with its lineage with pericytes, fibroblasts, and infrequently, endothelium. Consequently, morphological features of SFT may become diversely varied by whether predominantly constituent cells are undifferentiated, pericytic or fibroblastic in nature.
Adult↗
Therapeutic implications of interferon regulatory factor (IRF)-1 and IRF-2 in diffusely infiltrating astrocytomas (DIA): response to interferon (IFN)-beta in glioblastoma cells and prognostic value for DIA.
The precise mechanisms governing the direct effect of IFN-beta, including apoptosis induction, are not yet fully understood. To gain a better insight into these mechanisms, we investigated the signaling pathways focusing particularly on interferon regulatory factor 1 (IRF-1) and IRF-2 in glioblastoma cell lines. Furthermore, we attempted to determine whether or not IRF-1 and IRF-2 act as additional prognostic indicators in diffusely infiltrating astrocytomas (DIA). We first assessed the cytotoxic effects of IFN-beta based on a cell growth study and modified MTT assay, and then quantified the apoptosis using a sandwich enzyme immunoassay following IFN-beta treatment in the cell lines, U-87MG, T98G, and A-172. Subsequently, we carried out an analysis of apoptosis-related molecules as evaluated by densitometric analysis of Western blots, focusing on IRF-1 and IRF-2, and two major initiator caspases, caspase-8 and caspase-9. Furthermore, we assessed the expression of type I IFN receptor, IRF-1, and IRF-2 using immunohistochemical techniques in 63 DIA (15 of WHO grade II, 18 of grade III, and 30 of grade IV), and analyzed their impact on prognosis. An increase in apoptosis was apparent after 48 h of IFN-beta treatment (1 x 10(4) IU/ml) in T98G but not in U-87MG or A-172. IFN-beta treatment for 6 h significantly enhanced the expression of IRF-1 in all three cell lines. However, an enhanced expression of IRF-2 was observed only in the not-most-sensitive, non-apoptosis-induced U-87MG and A-172. While minimal processing of caspase-8 was noted in the three cell lines throughout the experiment, caspase-9 activation was observed in the apoptosis-detected T98G after 48 h of treatment, as indicated by a 1.33-fold increase (P=0.037). On the other hand, the IRF-1 LI and IRF-1/IRF-2 LI ratio were greater in low-grade DAI, and were negatively correlated with the histopathological grade in DIA (P=0.017 and P=0.001, respectively). Furthermore, the IRF-1/IRF-2 LI ratio was negatively correlated with the MIB-1 LI in DIA (P=0.004), and represented an independent and most powerful determinant of overall survival compared to other conventional prognostic factors (P=0.018). However, the relation was not statistically significant when only patients with high-grade DIA were assessed. Our findings suggest that up-regulation of IRF-1 and IRF-2 might be an important determinant of susceptibility to IFN-beta mediated cytotoxicity including apoptosis. Furthermore, the IRF-1/IRF-2 LI ratio may reflect the proliferative state of DIA and constitute an important prognostic marker in DIA. Thus, IRF-1 and IRF-2 could represent one of the therapeutic target sites for the regulation of cell growth in DIA.
Adult↗
Anthropometric characteristics, dietary patterns and risk of type 2 diabetes mellitus in Vietnam.
OBJECTIVE: To determine the impact of anthropometric characteristics and dietary patterns on Type 2 diabetes mellitus in Vietnam. METHODS: Data from 144 subjects (9m/39f newly diagnosed diabetics; 18m/78f control subjects) were analyzed in this case-control study. Height, weight, waist and hip circumferences and percent body fat were measured. Dietary intakes were assessed by 24-hour recall on three non-consecutive weekdays. Fasting blood samples were collected for the analysis of plasma glucose, fructosamine, protein and lipid concentrations. RESULTS: Although the body mass index (BMI, kg/m(2)) was similar between diabetic and control subjects, diabetic subjects had significantly greater percent body fat (31.1 +/- 5.8% vs. 27.7 +/- 6.2%) and waist-hip ratios (WHR, 0.91 +/- 0.07 vs. 0.86 +/- 0.08). Diabetic subjects had higher intakes of protein (p < 0.01), especially animal protein (p < 0.001), and consumed more meat (p < 0.01) than control subjects. Percent body fat and WHR were positively associated with diabetes (odds ratios [OR] 1.53 [95%CI 1.29-1.79] and 1.09 [95% CI 0.89-1.58], respectively) as were protein intake (OR 1.21 [95% CI 1.12-1.31]) and animal protein intake (OR 1.18 [95% CI 1.10-1.26]). CONCLUSIONS: This study indicates that percent body fat and WHR are risk factors associated with diabetes even when the BMI is normal. Evolving dietary patterns with increasingly more protein and meat consumption may also contribute to the deterioration of glucose metabolism among Vietnamese people.
Adipose Tissue↗
Reproducibility and validity of a food frequency questionnaire among Vietnamese in Ho Chi Minh City.
OBJECTIVE: Our objective was to assess the reproducibility and validity of a food frequency questionnaire (FFQ) among individuals living in Ho Chi Minh City, Vietnam. METHODS: A total of 116 food items in our FFQ were selected by ranking food items according to their contribution to the population intake of nutrients, based on multiple 24-hour recalls (24HRs) from 144 participants in July 2001. The FFQ was validated by using three 24HRs for 118 men and women in Ho Chi Minh City, Vietnam in August 2002. The reproducibility of the FFQ was assessed by repeated administration at 7 +/- 3.4 days. RESULTS: The reproducibility study showed that Spearman correlation coefficients, adjusted for energy intake, ranged from 0.47 to 0.72, and that weighted kappa values ranged from 0.42 for lipid to 0.65 for potassium. In the validation study, correlation coefficients, adjusted for energy intake, between the FFQ and the 24HRs ranged from 0.16 (calcium) to 0.45 (retinol). The proportion of subjects classified by the FFQ into the same third as determined by the 24HRs was between 42% and 62%. CONCLUSIONS: This food frequency questionnaire measured the usual intake of major nutrients for Vietnamese adults living in Ho Chi Minh City and its urban area, where dietary patterns are similar to those of the Vietnamese population.
Adult↗
Expression of hard alpha-keratins in pilomatrixoma, craniopharyngioma, and calcifying odontogenic cyst.
To examine the properties of shadow and ghost cells, 3 kinds of antibodies were raised against human hair proteins and their immunoreactivity was examined in tumors expressing those cells: pilomatrixoma, 14 cases; craniopharyngioma, 17 cases; and calcifying odontogenic cyst (COC), 14 cases. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis and Western blot analyses demonstrated that 2 polyclonal antibodies, PA-HP1 and PA-HP 2, reacted strongly with type I acidic and type II neutral/basic hard alpha-keratins. The other monoclonal antibody, MA-HP1, reacted with type II neutral/basic hard alpha-keratins. Immunohistochemical examination revealed that all 3 antibodies reacted only with the hair shaft in sections of normal skin and dermoid cyst. In all pilomatrixoma cases, 3 antibodies reacted with the cytoplasm of transitional and shadow cells but not with that of basophilic cells. Positive reactions were found only in shadow cells of all 13 adamantinomatous craniopharyngiomas. In all COCs, the antibodies reacted only with ghost cells, not with other epithelial components. Immunoreactivity for phosphothreonine, detected in hard alpha-keratins, also was found in transitional, shadow, and ghost cells. The appearance of shadow or ghost cells might represent differentiation into hair in these 3 kinds of tumors.
Animals↗
Induction of apoptosis in human salivary gland tumor cells by anti-NCAM antibody.
Neural cell adhesion molecule (NCAM) is a type of cell surface glycoprotein and a member of the immunoglobulin superfamily. It has been reported that NCAM may be associated with perineural invasion by malignant salivary gland tumors such as adenoid cystic carcinoma. We have previously demonstrated that NCAM is constitutively expressed in the human salivary gland tumor cell line HSG, in vitro. In the present study, we have aimed to clarify the hypothesis that NCAM-mediated inhibition of salivary gland tumor proliferation is caused by homophilic binding and involves the prevention of signal transduction for perineural invasion using HSG cells. NCAM mRNA and protein expression was found to decrease in a dose-dependent manner upon treatment with the anti-NCAM antibody (MAb NCAM) for 24 h. The MTT assay showed a significant reduction in the number of viable HSG cells. Confocal laser microscopy showed that HSG cells underwent apoptosis after treatment with MAb NCAM. The activation of caspases 3, 7 and 9 was observed in HSG cells after treatment with MAb NCAM, thus confirming that apoptosis was induced by the activated caspases. Apaf-1 activity was also detected in HSG cells in a dose-dependent manner after treatment with MAb NCAM. The up-regulation of TGF-beta1-mediated NCAM expression appeared to lead to the activation of homophilic NCAM binding, further accelerating HSG cell proliferation. In addition, the localization of NCAM in adenoid cystic carcinomas (ACCs) was examined using an immunohistochemical method. NCAM was slightly to moderately positive in 9 of 13 cases (69.2%) of ACC. These findings suggest that NCAM is associated not only with a cell-to-cell adhesion mechanism, but also with tumorigenesis, including growth, development and perineural invasion in human salivary gland tumors.
Antibodies↗
Dibenzo[A,L]pyrene-induced genotoxic and carcinogenic responses are dramatically suppressed in aryl hydrocarbon receptor-deficient mice.
Dibenzo[a,l]pyrene (DB[a,l]P), a notorious air pollutant, is the most powerful carcinogenic polycyclic aromatic hydrocarbon (PAH) ever tested. Although the carcinogenicity of PAH may be primarily mediated by the aryl hydrocarbon receptor (AhR), the in vivo role of AhR in skin carcinogenesis remains to be defined. In this context, we investigated the genotoxic and carcinogenic responses of the AhR-deficient mouse skin to DB[a,l]P. A single painting resulted in a striking epidermal hyperplasia in AhR+/+ mice but not in AhR-/- mice. Bromodeoxyuridine-labeling index and accumulation of p53 protein in epidermal cells of AhR+/+ mice were 8- and 33-fold higher than those of AhR-/- mice, respectively. 32P-Postlabeling assay for DB[a,l]P-DNA adducts displayed a 2-fold increase in the AhR+/+ mouse skin. After DB[a,l]P exposure, AhR-/- mice arranged a nearly 60% reduction in the induction of epidermal cytochrome P450 (CYP)1A1, but CYP1B1 was constitutively expressed in both genotypes of mice, irrespective of DB[a,l]P treatment. As compared with AhR+/+ mice, AhR-/- mice had both significantly lower incidence (100% vs. 33%) and multiplicity (2.7 vs. 0.46) of skin tumors by the complete carcinogenesis study. These observations indicate that a reduced tumor yield in AhR-/- mice may be secondary to reduction of inducible CYP1A1 activation and subsequent DNA adduction. It is evident from our continuous work that although AhR is likely to play a central role in epidermal proliferation and possibly neoplastic transformation, the relative importance of AhR for carcinogenesis may be different among PAH examined.
Administration, Cutaneous↗
Skin and salivary gland carcinogenicity of 7,12-dimethylbenz[a]anthracene is equivalent in the presence or absence of aryl hydrocarbon receptor.
7,12-Dimethylbenz[a]anthracene (DMBA) is a well-known polycyclic aromatic hydrocarbon (PAH) that causes a variety of tumors in exposed animals. Although PAH carcinogenicity is primarily mediated by the aryl hydrocarbon receptor (AhR) through induction of P450, it is not precisely determined whether AhR regulates the DMBA carcinogenesis in vivo. In this context, we examined the frequency of DMBA-induced tumors and the expressions of mRNAs of P450-CYP1 subfamily and microsomal epoxide hydrolase (mEH) in the skin and submandibular gland using AhR-deficient mice. After DMBA exposure, AhR-/- and AhR+/+ mice showed the same tumor incidences and latency. CYP1A1 was absent in these tissues but was slightly induced in DMBA-treated AhR+/+ mice. In AhR-/- and AhR+/+ mice, constitutive expression of CYP1B1 was evident at equivalent levels, whereas CYP1A2 was not detectable, irrespective of DMBA treatment. mEH was expressed in both tissues of all animals. Collectively, the constitutive levels of CYP1B1 and mEH in the skin and submandibular gland maintain DMBA response in these tissues of AhR-/- mice.
Animals↗
An apparent radiation-induced carcinoma of the parotid gland following treatment for adenoid cystic carcinoma of the sublingual gland: a case report.
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Carcinoma↗
Difficulty in predicting biological behavior of peripheral ameloblastoma.
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Ameloblastoma↗
Detection of photodynamic therapy-induced early apoptosis in human salivary gland tumor cells in vitro and in a mouse tumor model.
We studied the detection of apoptosis of malignant human salivary gland tumor cells induced by photodynamic therapy (PDT) using the photosensitizer mono-L-aspartyl chlorin e6 (NPe6) in vitro and in vivo in mice receiving transplanted human salivary gland tumor (HSG) cells. An immunohistocytochemical method using a monoclonal antibody (MoAb), M30, which reacts with the product resulting from the cleavage of cytokeratin (CK) 18 by activated caspase, was applied to detect the apoptosis of HSG cells induced by PDT. Significant amounts of immunoreactive products were observed in the cytoplasm of HSG cells after PDT. In vitro, M30-positive cells increased from 2 h after PDT, increased rapidly from 8 h and reached a peak 24 h after PDT. In vivo, a peak of early apoptosis was confirmed two hours after PDT. In comparison with DNA fragmentation detected by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) method, the destroyed tumor cells were observed sporadically 24 h after PDT. These results suggest that immunohistocytochemical staining with the MoAb M30 may be useful for detecting early apoptosis induced by PDT. Futhermore, PDT using NPe6 is effective in inducing apoptosis of HSG cells at an early stage, which suggests the possibility of the therapy being ideal for treatment of human malignant neoplasms.
Animals↗
Comparative ultrastructural and immunohistochemical study of perineurioma and neurofibroma of the oral mucosa.
In the course of assessing the cellular composition of intraoral neurofibroma (NF), we encountered a unique gingival tumor of putative perineurial (PN) origin. The lesion showed the ordinary light microscopic NF pattern, but the ultrastructural features of well-differentiated PN cells as well as an epithelial membrane antigen (EMA)-positive, S-100 protein-negative immunoprofile confirmed the diagnosis of soft tissue perineurioma (STP). In our small series of NF, there were three ultrastructural subtypes: Type I (common Schwann cell type), Type II (NF with a high content of PN cells) and Type III (predominantly fibroblastic NF), although inhomogeneous and overlapping assembly of cellular elements. A significant number of tumor cells in Type II showed the substantial reactivity for EMA, whereas many CD34-positive cells were noted in Type III. The present results confirm previous findings that PN lineage is an important constituent in the formation of NF and reinforce the value of electron microscopy in the diagnosis of peripheral nerve sheath tumors.
Biomarkers, Tumor↗
Myxolipomatous pleomorphic adenoma: an unusual oral presentation.
The first case of a myxoid variant of lipomatous pleomorphic adenoma arising in the intraoral minor salivary gland is presented. A well-encapsulated tumor was composed almost entirely of myxolipomatous tissue with honeycomb-like spindled cellular areas, which contained only a scant glandular element. Immunohistochemistry confirmed the myoepithelial nature of spindle cells intimately admixed with mucoadipose component. We propose the term myxolipomatous pleomorphic adenoma for this peculiar lesion.
Adenoma, Pleomorphic↗
Expression of RCAS1 and its function in human squamous cell carcinoma of the oral cavity.
Receptor-binding cancer antigen expressed on SiSo cells (RCAS1) is a recently discovered human tumor-associated antigen expressed in a wide variety of cancer tissues. It has been suggested that tumor cells evade from immune surveillance by expression of RCAS1. We investigated whether RCAS1 is expressed in human oral squamous cell carcinomas (HOSCCs) or HOSCC (HSC-2, -3, -4, Ca9-22 and KB) cells and whether tumor cells expressing RCAS1, induce apoptosis in its receptor-positive cells, peripheral blood lymphocytes (PBLs). RCAS1 transcripts and proteins were detected in five HOSCC cell types. Immunohistochemical examinations revealed that RCAS1 was slightly to moderately positive in 32 of 40 cases (80%) of HOSCCs. Furthermore, the frequency of RCAS1 expression in HOSCC increased with advancing tumor stage according to the pTNM system. Confocal laser microscopy and DNA fragmentation assay showed that PBLs, which were stimulated with IL-2, underwent apoptosis by co-culturing with KB cells. It was also confirmed by Western dot blotting that soluble RCAS1 is secreted into culture supernatants of KB cells. The apoptotic tumor-infiltrating lymphocytes (TILs) were detected around RCAS1-positive tumor cells in HOSCCs by TUNEL method. These results suggest that RCAS1 expression might be associated with progression of oral tumors and offer a possible mechanism for oral cancer immune escape.
Adult↗
p53 haploinsufficiency profoundly accelerates the onset of tongue tumors in mice lacking the xeroderma pigmentosum group A gene.
Mice lacking the xeroderma pigmentosum group A gene (XPA-/- mice), which have a complete deficiency in nucleotide excision repair (NER), are highly predisposed to tongue squamous cell carcinoma (SCC) when exposed to 4-nitroquinoline 1-oxide (4NQO). To explore the effects of the interaction of the NER machinery with p53 in oral tumorigenesis, we generated an XPA-/- mouse strain carrying mutant alleles for p53. This mouse model of 4NQO carcinogenesis demonstrated that despite the same tumor frequency, XPA-/-p53+/- mice reached 100% SCC incidence at 25 weeks compared with 50 weeks for XPA-/-p53+/+ littermates. XPA-/-p53-/- mice succumbed to spontaneous thymic lymphomas before the development of tongue tumors (before 13 weeks of age). SCC originated in XPA-/-p53+/- mice maintained the p53+/- genotype and the retained wild-type p53 allele appeared to be structurally intact. Only one of 20 XPA-/-p53+/+ SCC showed a missense mutation of p53. Collectively, the accelerated tongue tumor growth may be a consequence of haploinsufficiency but not of mutation of p53 in the context of NER deficiency.
4-Nitroquinoline-1-oxide↗
Telomerase activity in pituitary adenomas: significance of telomerase expression in predicting pituitary adenoma recurrence.
Clinical and histopathological evaluations are inadequate for assessing biological aggressiveness and regrowth potential in benign pituitary adenomas. To develop reliable and prognostically informative means of predicting behavior remains an intractable problem. Telomerase, a reverse transcriptase that extends telomere length, may facilitate tumorigenesis and tumor immortality. In the present study, we investigated the telomerase activity of pituitary adenomas, and attempted to assess the value of telomerase expression for predicting their clinical course. In total, 31 (30 patients) benign pituitary adenoma samples including 8 recurrent adenomas were studied. Telomerase expression was evaluated by polymerase chain reaction (PCR)-based telomeric repeat amplification protocol (TRAP) assay and telomerase activity levels were quantitated by improved PCR enzyme-linked immunosorbent assay (ELISA). The data were analyzed in relation to clinical course which was reviewed at 4-5.5 years (median follow-up time, 52.5 months) after surgery. The relative values of the telomerase expression for predicting the clinical course were compared with the MIB-1 antigen-based proliferative cell index (PCI) and p53 immunoreactivity which have recently been suggested to correlate with aggressive behavior in pituitary adenomas. Overall, telomerase expression was detected in 13% of the adenomas (4 tumor tissues, 3 patients). These adenomas comprised large, invasive, and functioning adenomas. The number of telomerase-positive adenomas was small; however, the PCI was higher in cases with telomerase expression (4 tumor tissues; mean, 4.2 +/- 2.4%) than in those without it (27 tumor tissues; 1.4 +/- 1.3%) (p = 0.01). One tumor with detectable telomerase expression, which did not undergo additional pharmacological or radiotherapeutic intervention after first surgery, recurred rapidly despite gross total surgical resection, although the PCI of both the primary and recurrent adenomas was not high. Detection of telomerase expression may represent an additional useful means of identifying aggressive behavior, complementing the histopathological evaluation of benign-appearing pituitary adenomas.
Adenoma↗