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Purpose: Possible significance of sex hormone estrogen as an antitumor therapeutic arm toward esophageal squamous cell carcinoma (ESCC) cells has been suggested. The aim of the current study was to clarify the clinicopathologic significance of an immunohistochemical expression of estrogen receptors alpha and beta (ER alpha and ER beta) in ESCC., Experimental Design: Expression of ER alpha and ER beta were examined using an immunohistochemical methods in 73 paraffin-embedded sections collected from patients with ESCC who had been subjected to esophageal resection and digestive reconstruction without any preoperative induction therapy., Results: Forty-seven (64.4%) ESCCs had a positive cytoplasmic expression of ER alpha and 21 (28.8%) ESCCs had a positive nuclear expression of ER beta. Univariate analysis showed that both positive ER alpha expression (P=0.0001) and negative ER beta expression (P=0.026) were unfavorable prognostic indicators in ESCC. Moreover, multivariate analysis showed that ER alpha-positive/ER beta-negative expression (P=0.003) and progression of tumor stage (P=0.014) were found to be independent unfavorable prognostic indicators in ESCCs., Conclusions: Immunohistochemical expression of ER alpha and ER beta were found to be observed in ESCC. Positive expression of ER alpha in addition to negative expression of ER beta proved to be an unfavorable independent prognostic indicator in ESCC.

Purpose: We studied the effects of gender difference on the incidence of lung cancer and its mortality rate, which is a subject of much discussion., Methods: We examined gender difference in the clinical features of 491 men and 222 women who underwent resection of primary non-small cell lung cancer (NSCLC) between 1994 and 2004., Results: The histological types of cancer were adenocarcinoma in 249 (51%) of the men and 182 (82%) of the women, and squamous cell carcinoma in 182 (37%) of the men and 27 (12%) of the women. The incidence of adenocarcinoma was significantly higher in the women. The proportion of stage IA disease was significantly higher in the women than in the men (45% vs 29%, respectively). The 5-year overall survival rates were 50% in the men and 63% in the women. In a multivariate analysis, gender difference was an independent prognostic factor; however, when death as a result of unrelated disease was excluded, there was no significant difference in prognosis., Conclusion: Although the higher incidences of adenocarcinoma and stage IA cancer contributed to the good results of surgery in women, the low incidence of death attributed to diseases other than lung cancer was a major reason for their better prognosis.

Background: Lung cancer tissues are often infiltrated by B lymphocytes, but it is not clear whether these infiltrations represent tumor-specific immune response or a nonspecific reaction., Materials and Methods: The serological analysis of recombinant cDNA expression libraries (SEREX) were previously modified using a severe combined immunodeficient (SCID) mice model engrafted with fresh human lung cancer. Here, a panel of antigens recognized by tumor-infiltrating B lymphocytes (TIB) in human lung cancer were characterized., Results: The modified SEREX analysis identified 22 distinct antigens in a large cell carcinoma of the lung. Sequence analysis and real time-PCR analysis showed that 55% of isolated antigens were overexpressed in tumor tissues and 9% had mutation., Conclusion: The results of this study indicate that the humoral immune response of TIB in lung cancer patients can be detected in the xenotransplanted SCID mouse model and our modification shows high sensitivity and specificity for identification of tumor antigens.

Background: Tumor-infiltrating B lymphocytes (TIB) are often observed in lung cancer. The role of TIB in tumor growth has not been well investigated., Materials and Methods: Forty-four surgically-resected human lung cancer tissues were xenotransplanted into SCID mice. Their blood was collected and the volume of the transplanted tumors was measured regularly. The correlations between the IgG titer in the sera and the growth of the transplanted tumors according to the clinicopathological variables were examined., Results: Human IgG production from TIB was observed in the all xenotransplanted mice. Twenty-seven out of the 44 tumors regressed gradually. The average serum human IgG level of the tumor regressors (n = 10) was significantly higher than that of the progressors (n = 9) in squamous cell carcinoma (p = 0.02), while there was no significant difference in the other histological groups., Conclusion: IgG produced by TIB might play a crucial role in preventing tumor growth in squamous cell carcinoma.

Background: Both alcohol consumption and cigarette smoking are risk factors for esophageal cancer. The purpose of this study was to clarify whether the fragile histidine triad (FHIT) is their target gene in esophageal carcinogenesis as well as in multicentric carcinogenesis., Patients and Methods: The expression of FHIT was immunohistochemically examined in the squamous cell carcinoma as well as in the normal esophageal epithelium of 55 cases with esophageal cancer., Results: The median drinking indices (DIs) were 546 and 1092 (p<0.01) in cases with positive FHIT expression and those with a diminished expression in the esophageal epithelium, respectively. Furthermore, the incidences of intra-esophageal multiple cancer were 44% and 13%, respectively (p<0.05). Regarding the expression in cancer lesions, the median DIs were 280 and 721 in positive and diminished cases, respectively (p=0.081)., Conclusion: A loss of FHIT expression is associated not only with alcohol-induced esophageal carcinogenesis, but also with multicentric carcinogenesis.

p53R2 plays a crucial role in supplying dNTPs for DNA repair. The expression of p53R2 is induced by DNA-damaging agents in a p53-dependent manner and p53R2 translocates to the nucleus upon DNA damage. Immunohistochemistry was used to analyze the protein expression of p53R2 in paraffin-embedded tumor samples from 130 well-characterized non-small cell lung cancer (NSCLC) patients and the expression level of p53R2, clinical variables and survival outcome were compared. A positive expression of p53R2 was detected in the cytoplasm of tumor cells in 61 of the 130 patients (46.2%) with NSCLC. The positive ratio was significantly higher in the patients with pathological stage II/III, pathological T3-4 and pathological N1-3 than in those with stage I, T1-2 and N0, respectively. No significant difference was observed between the p53R2 expression and the gender, age at operation, histological type or p53 expression. Though our findings do not support that the p53R2 immunocytochemical marker alone plays an important prognostic role in NSCLC, the DNA repair pathway mediated by p53R2 may be responsible for controlling the growth of lung cancer.

Alcohol consumption is a risk factor for esophageal cancer. Acetaldehyde, a highly toxic intermediate produced from ethanol, is converted to acetic acid mainly by aldehyde dehydrogenase 2 (ALDH2) in the metabolic pathway of ethanol. Fifty percent of Japanese have inactive ALDH2 due to genetic polymorphism, which is considered to be a risk factor associated with esophageal cancer. In our previous study, we have demonstrated that ALDH2 is expressed in the esophagus with a considerable variation among individuals. In this study, we further investigated the expression of ALDH2 in esophagus and its relationship with risk factors of esophageal cancer. Tissue specimens resected from 51 patients with esophageal cancer were analyzed by immunohistochemistry using ALDH2-antibody. The immuno-staining of ALDH2 in the esophageal epithelium was compared with both the drinking habit and the occurrence of flushing that is closely associated with the ALDH2 deficiency. ALDH2 was not detectable in 8 (16%) among 51 specimens. All of the 8 patients were non- or light-drinkers but not heavy-drinkers. Among 18 patients showing the high level ALDH2 expression in the esophagus, 15 patients (83%) were heavy-drinkers. Although the relationship between the ALDH2 deficiency and drinking habit is not clear, the patients with ALDH2 deficiency tend to be non- or light drinkers while heavy-drinkers tend to have the active form of ALDH2. These results suggest that both inactive and active forms of ALDH2 are induced in the esophagus by heavy drinking and also support a hypothesis that ALDH2 deficiency might be a high-risk factor of esophageal cancer for the individuals having a heavy-drinking habit. To our knowledge, this is the first study demonstrating the induction of ALDH2 in the esophagus by ethanol consumption.

Background: The p63 gene is present as two isoforms, namely TAp63 and deltaNp63. The biological role of deltaNp63 in the progression of esophageal cancer is still controversial., Patients and Methods: The expression of deltaNp63, as well as that of p63, was immunohistochemically examined in 61 resected specimens of squamous cell carcinoma of the esophagus., Results: The incidences of a positive deltaNp63 expression were 32 and 64% in carcinomas with and without adventitial invasion, respectively, and 37 and 65% in those with and without lymph node metastasis, respectively (p<0.05). The prognosis was significantly better in the positive deltaNp63 group than in the negative group (p<0.01). However, a multivariate analysis revealed deltaNp63 not to be an independent prognostic factor. Regarding p63, diminished expression was more frequently observed in advanced carcinomas, however, there were no statistically significant differences., Conclusion: The impaired deltaNp63 reflects the progression of squamous cell carcinoma of the esophagus.

In breast cancer, cytochrome P450 (CYP) metabolizes both endogenous substrates (i.e. estradiol) and exogenous substrates (i.e. anticancer drugs), which is associated not only with tumor development and progression but also with efficacy of cancer treatment. Therefore, we examined the expression of CYPs (CYP2A6, CYP1B1 and CYP3A) and p53 in specimens from 34 Japanese patients with breast cancer by immunohistochemistry. The expression of CYP3A was not detected in the 34 cases. CYP2A6 was detected only in one specimen (2.9%). Twenty-eight specimens (82.4%) showed positive signals for CYP1B1 expression. Eight of 34 (23.5%) were positive for p53 expression. Positive rate of CYP1B1 in stage I disease (100%) was statistically higher than that in stage II - IV disease (70.0%). Positive rate of p53 was 21.4% (6/28) in CYP1B1-positive cases and 33.3% (2/6) in CYP1B1-negative cases. There was no significant relationship between CYP1B1 expression and p53 expression. In conclusion, the expression of CYP3A in breast cancer may be less frequent in Japanese population although the expression of CYP3A has been reported in 20% of breast cancer in Caucasian, suggesting that the CYP3A expression in breast cancer may be dependent on ethnic groups. Since CYP3A is involved in the conversion of tamoxifen to its metabolites, the variation of the CYP3A expression in breast cancer tissues among ethnic groups might cause differences in the efficacy of tamoxifen.

Not only serum tumor markers, such as carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and carbohydrate antigen (CA) 125, but also serum growth factors have been examined to evaluate tumor stages and to predict the recurrence and metastasis in patients with non-small cell lung cancer (NSCLC) (1-5). In recent years, the analysis of the genome and proteome has advanced remarkably. An array of molecular genetic tumor markers (MGTMs) have been identified based on the biological characterization of tumors, such as tumor development, growth, invasion and metastasis. Molecular genetic tumor marker research has also entered a new era, since comprehensive gene profile analysis using cDNA microarrays and comprehensive protein expression analysis using proteomics technology have been developed. On the other hand, the frequency of lung cancer patients with which various tumor markers are associated is increasing in Japan (6-8). This paper reviews MGTMs characteristic of lung cancer and clarifies the clinical usefulness and applications of MGTM for cancer treatment.

Surgically resected specimens of 13 carcinoid tumors of the lung including nine typical carcinoids and four atypical carcinoids, and eight salivary gland type carcinomas (six mucoepidermoid carcinomas and two adenoid cystic carcinomas) were analyzed regarding p53 expression, loss of heterozygosity (LOH) in chromosome 3p, 9p, and K-ras mutation. The overexpression of p53 was identified in four atypical carcinoid tumors, one mucoepidermoid carcinoma, and one adenoid cystic carcinoma, however, none of typical carcinoids showed p53 immunoreactivity. LOH in 3p14 was demonstrated in three of seven informative cases in all tumors. LOH in 9p was demonstrated in two of five informative cases in all tumors. Two of three cases with LOH at 3p14 had a poor prognosis, one of which also had LOH at 9p. No mutation of the K-ras gene was observed in any of these tumors. These data thus indicate that p53 overexpression might distinguish atypical carcinoid tumors from typical tumors and might therefore be useful as an adjunct modality in the differential diagnosis of pulmonary carcinoid tumors. The presence of LOH at 3p14 or 9p may thus help to identify lung cancer patients with a poor prognosis.

Pleomorphic (spindle/giant cell) carcinoma (PC) is one subset of large cell carcinoma. It is well known that PC patients have a poor survival rate. This report describes a 68-year-old man with PC. The patient's tumor had a massive pleural effusion. A left lower lobectomy and partial resection of the left diaphragm, peritoneum, and parietal pleura were performed to remove the tumor. Numerous asbestos particles were found in the left lower lobe. This is the first reported case of PC which may have been caused by asbestos particles. Further investigation is needed into whether asbestos exposure causes PC.

Functional studies using freshly isolated tumor-infiltrating B lymphocytes(TIB) are difficult to perform and interpret. Here we document a novel function of TIB using fresh human lung cancer tissues engrafted in SCID mice; they are at activated state and produce tumor-specific antibodies in tumor microenvironment: (a) TIB engrafted in SCID mice produced human IgG; (b) IgG derived from TIB highly bound intracellular and membrane-bound antigens of autologous cancer cells; and (c) less recognition of autoantigens expressed on normal lymphocytes by IgG derived from TIB compared with IgG from the serum of the patient. On the basis of the novel findings presented in this study, we modified the original serological analysis of antigens by recombinant cDNA expression cloning design in a patient with lung cancer who expressed unusually favorable clinical evolution and analyzed humoral immunity against identified mutated p53 antigen. This study provides the first demonstration that antibodies derived from TIB recognize tumor antigens by serological analysis of antigens by recombinant cDNA expression cloning methodology and circulating anti-p53 antibodies in sera derived from TIB in tumor microenvironment. Our approach using TIB may allow the identification of key antigens in the humoral cancer-related immune system.

Background: In order to investigate host defense against solid tumors, valuable information could be provided by ex-vivo analyses of functional immune cells in tumor tissues. However, available sources of fresh tumor-infiltrating T cells (TIL) are usually very limited, and it is often difficult to establish TIL lines. In this study, we analyzed the phenotypic and functional characteristics of TIL, using an immortalized cell line prepared by cotransfection of human c-myc and c-Ha-ras., Methods: A human T-cell line was established by cotransfecting c-Ha-ras and c-myc oncogenes to T lymphocytes freshly isolated from human lung large-cell carcinoma tissue. The phenotypes were assessed by flow cytometry. T-cell receptor (TCR) V alpha- and beta-usage was analyzed by polymerase chain reaction (PCR) and Southern blot. Cytotoxic activity against autologous and allogeneic tumor cell lines was examined by standard 51Cr-release cytotoxicity assays. Cytokine production by the established T-cell line, 904-T1, in response to stimulation by autologous tumor cells was assayed by using an enzyme-linked immunosorbent assay., Results: 904-T1 (CD3+, CD8+, CD56+, CD16-, CD161-, TCR V alpha 9, 13, and V beta 1, 5) displayed a broad range of MHC-nonrestricted tumoricidal activity against various human tumor cell lines, but did not lyse autologous B cells transformed by Epstein-Barr virus. The cytotoxicity of 904-T1 was not mediated by a T-cell antigen receptor or by Fas-ligand, but by perforin-based cytolytic pathways, and was enhanced by interleukin (IL)-12. 904-T1 cells produced large amounts of interferon (IFN)-gamma, but not tumor necrosis factor (TNF)-alpha or IL-4 in response to autologous tumor cells, and produced high levels of IFN-gamma and TNF-alpha, and a substantial level of IL-4 following stimulation with anti-CD3 monoclonal antibody., Conclusions: Our results suggest that 904-T1 cells were natural killer T (NKT)-like cells with regard to their non-specific killing, cytokine repertoire, and sensitivity to IL-12, although the repertoire of the TCR variable region was not compatible with that of NKT cells.