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Background/aim: Chemoimmunotherapy is a promising treatment for various malignant diseases. In this study, we examined whether first-line chemoimmunotherapy using adoptive immune-cell therapy was effective for metastatic colorectal cancer (mCRC)., Patients and Methods: The therapeutic efficacy and safety of the standard first-line chemoimmunotherapy with adoptive αβ T cell therapy and bevacizumab were assessed using thirty-two patients with mCRC in our hospital. Immunological status after this chemoimmunotherapy was also evaluated., Results: The response and disease control rates were 68.8% and 87.5%, respectively. Further, median progression-free and overall survival were 14.2 and 35.3 months. Immunotherapy-associated toxicity was minimal. Significant decrease in the change of monocyte number (p=0.006) and increase in the change of rate of lymphocyte-to-monocyte ratio (p=0.039) were seen in the complete response group., Conclusion: First-line chemoimmunotherapy with adoptive αβ T cell therapy may be useful for mCRC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: We aimed to investigate the efficacy of immune-cell therapy in terms of the survival of patients with neuroendocrine carcinoma of the uterine cervix (NECC), which lacks standardized therapeutic approaches., Patients and Methods: We identified 17 patients who were diagnosed as having NECC and treated with immune-cell therapy. The clinical characteristics of these patients were extracted from their records and their overall survival was measured., Results: Of the 17 patients, two patients with early-stage NECC without recurrence and three patients with less than four treatments were excluded. The median survival times from the time of diagnosis and from the initial administration of immune-cell therapy were 49.7 and 24.4 months, respectively. The overall survival rates at 1, 2, and 5 years were 63.6%, 38.2%, and 25.5%, respectively. Long-term survival was observed in the patients with distant metastases., Conclusion: The preliminary results of this retrospective study suggested the potential efficacy of immune-cell therapy for NECC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: In this retrospective study, we aimed to investigate the efficacy of immune-cell therapy using T lymphocytes activated in vitro with or without dendritic cell vaccination in combination with standard therapies in terms of the survival of patients with advanced or recurrent endometrial and cervical cancers of the uterus., Patients and Methods: A total of 187 patients with advanced or recurrent uterine cancer were enrolled in this study. The correlation between overall survival and various clinical factors was examined by univariate and multivariate analyses., Results: Univariate analysis revealed that the prognosis was improved in uterine cancer patients who received immune-cell therapy without prior chemotherapy or without distant metastasis. Multivariate analysis demonstrated that the absence of prior chemotherapy for endometrial cancer and liver/lung metastasis of cervical cancer are indications for immune-cell therapy., Conclusion: Survival benefit in uterine cancer patients could be potentially obtained by a combination of immune-cell therapy with other therapies., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Adoptive immunotherapy for cancer has evolved through development of novel technologies for generating a large number of activated killer cells, such as αβ T-cells, γδ T-cells, and natural killer cells. There has been no prospective trial of combination therapy involving adoptive immunotherapy and first-line chemotherapy for stage IV colorectal cancer. The present pilot study aimed to evaluate the safety and feasibility of combination therapy involving adoptive immunotherapy and chemotherapy for stage IV colorectal cancer (COMVI study)., Patients and Methods: The COMVI study was a prospective, single-arm pilot trial. Therapy in each 21-day treatment cycle involved XELOX (130 mg/m 2 of oxaliplatin on day 1 plus 1,000 mg/m 2 of capecitabine twice daily on days 1-14), bevacizumab (7.5 mg/kg on day 1), and αβ T-lymphocytes (over 5×10 9 on day 18) cultured ex vivo with an immobilized antibody to CD3 and interleukin-2., Results: The study included six patients (two men and four women) between June 2013 and September 2014. The median patient age was 68 years (range=55-75 years). The overall response rate was 83.3% [complete response in two (33.3%); partial response in three (50.0%); stable disease in one (16.7%); no cases of progressive disease]. The tumor volume reduction rate was 53% (range=38.0-100%). The median progression-free and overall survival durations were 567 and 966 days, respectively. Most adverse events were mild-to-moderate in intensity, and no grade 4 adverse events occurred in the six patients. Only one patient experienced grade 3 hypertension and ileus. Immunotherapy-associated toxicity was minimal in this study., Conclusion: Combination therapy involving adoptive immunotherapy and chemotherapy for stage IV colorectal cancer is feasible and safe. Phase II prospective studies are needed to confirm the safety and efficacy of such chemoimmunotherapy., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Various types of chemoimmunotherapies for malignant tumors have been reported. However, there are few reports on hepatectomy after chemoimmunotherapy. We evaluated the safety and efficacy of hepatectomy for patients with stage IV colorectal liver metastases (CLM) after chemoimmunotherapy using activated αβ T-cells., Patients and Methods: From June 2012 to December 2016, five patients who underwent hepatectomy after receiving capecitabine and oxaliplatin (XELOX) plus bevacizumab and ex vivo-expanded αβ T-lymphocytes as first-line chemoimmunotherapy were included., Results: The median age of the five patients (two men, three women) was 61.4 (range=56-75) years. The surgical procedure was partial hepatectomy in two, laparoscopic partial hepatectomy in two, and one case of partial hepatectomy with subsegmentectomy. There was no postoperative complication of Clavien-Dindo grade 3A or higher. One patient had multiple lung metastases., Conclusion: Hepatectomy after chemoimmunotherapy using activated αβ T-cells for CLM can be performed safely., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Adoptive immunotherapy of cancer is evolving with the development of novel technologies that generate proliferation of large numbers of αβ and γδ T cells. We evaluated the safety and efficacy of the combination of adoptive immunotherapy using αβ T cells with chemotherapy for stage IV colorectal cancer (CRC)., Patients and Methods: Fifteen patients with advanced or recurrent CRC received XELOX + bevacizumab + ex vivo expanded αβ T lymphocytes as a first-line chemoimmunotherapy., Results: Median age of the 15 patients (4 men, 11 women) was 65 years (range=49-80). Median progression-free survival was 21.3 months. Response rate was 80% (complete response (CR)=26.7%, partial response (PR)=53.3%, stable disease (SD)=20% and progressive disease (PD)=0%). Most adverse events were mild to moderate regarding their intensity and immunotherapy-associated toxicity was minimal., Conclusion: Combination of adoptive αβ T cell immunotherapy with chemotherapy for stage IV CRC is feasible and safe., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: The benefits of adjuvant chemotherapy for completely resected non-small cell lung cancer (NSCLC) have been demonstrated using mainly cisplatin (CDDP)-based chemotherapeutic regimens. However, treatment-related deaths sometimes occur. Therefore, the development of a safer regimen is necessary., Patients and Methods: The patients were randomized to either carboplatin (CBDCA) area under the curve (AUC) 3 and paclitaxel (PTX) 90 mg/m(2) (PCb arm) or CBDCA (AUC3) plus gemcitabine (GEM) (1000 mg/m(2)) (GCb arm) every 2 weeks for 8 cycles after surgery. The primary endpoint was the compliance with the regimen, while the secondary endpoints were safety and toxicity., Results: A total of 75 patients were enrolled in a multi-institutional study. Twenty-one out of 39 patients (54%) in the PCb arm and 25 of 36 patients (69%) in the GCb arm completed 8 cycles, and 59% in the PCb arm and 81% in the GCb arm completed ≥6 cycles. The predominant toxicity was neutropenia. Non-hematological adverse effects were infrequent and no treatment-related death was registered. The estimated disease-free survival and overall survival at 2 years were 70.8% and 66.3% in the PCb and 91.4% and 79.1% in the GCb arm, respectively., Conclusion: This adjuvant bi-weekly scheduled chemotherapy resulted in good compliance in both arms, and the regimen was feasible, with acceptable levels of toxicity in completely resected Japanese NSCLC patients. Therefore, these regimens represent a new treatment option suitable for outpatients with completely resected NSCLC.

Background: Adjuvant chemotherapy improves the prognosis of patients with non-small cell lung cancer (NSCLC) after a complete resection despite unacceptable toxicity and low compliance., Methods: A total of 67 patients were enrolled in a multi-institutional study. The patients received chemotherapy with carboplatin (CBDCA) area under the curve of 3 and paclitaxel (PTX) 90 mg/m(2) every 2 weeks for six cycles after surgery., Results: Fifty patients (74.6%) completed all cycles of therapy. The presence of grade 3 and 4 toxicities of neutropenia were 13.4, and 3.0%, respectively. Non-haematological adverse effects were infrequent and no treatment-related death was registered. The estimated disease-free survival and overall survival at 2 years were 89.0% and 88.8%, respectively., Conclusion: A bi-weekly schedule of CBDCA and PTX as adjuvant chemotherapy showed an acceptable toxicity and favourable feasibility in Japanese NSCLC patients after complete tumor resection. Consequently, it is desirable to validate this regimen in a future randomized clinical trial.

Background: This study analysed the humoral immune response in asbestos exposed lung cancer patients to identify new surrogate markers of the carcinogenic risk in populations exposed to asbestos., Methods and Results: A serological analysis identified five distinct antigens reactive with IgG derived from a lung cancer patient with high asbestos exposure. In one of the isolated antigens, quantitative RT-PCR indicated that annexin A2 (AnxA2) was overexpressed in lung cancer tissues and normal lung from patients with high asbestos exposure. Antibody against AnxA2 was detected in 9/15 (60%) of lung cancer patients with high asbestos exposure; however, in only 1/12 (8%) of lung cancer patients with low asbestos exposure. AnxA2 was also overexpressed in malignant mesothelioma cells, and the antibody was also positive in 8/15 (53%) of patients with malignant mesothelioma., Conclusion: The antibody titer against AnxA2 may be a potentially useful new diagnostic surrogate marker for asbestos-related lung cancer and malignant mesothelioma.

Subsets of non-small cell lung cancer (NSCLC) patients who carry activating somatic mutations of the epidermal growth factor receptor (EGFR) have demonstrated an increased probability of obtaining objective responses to the receptor tyrosine kinase inhibitors (TKIs), gefitinib and erlotinib. However, a substantial proportion of the cases with somatic mutations, which suggest sensitivity to gefitinib, are primary resistant to it. A primary resistant case of lung adenocarcinoma that was found to carry both delE746-A750 and a G796A mutation in the EGFR is reported. In vitro, a stable clone of cells bearing the G796A mutation was approximately 50,000-fold less sensitive to gefitinib in comparison to cells carrying the delE746-A750 mutant EGFR. This study suggests that screening tumour samples for a range of EGFR mutations may improve our ability to identify the patients most likely to benefit from EFGR TKIs.

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: p53 is mutated in about 50% of various malignant diseases including lung cancer. The p53 family consists of p53, p73 and p63. Although transactivating protein isoforms display p53-like functions, the deltaNp73 or deltaNp63 isoforms act toward p53 in a dominantly negative way. The aim of this study was to detect p53, deltaNp73 and deltaNp63 expressions in lung cancer and to evaluate the relationship between the expression levels of the proteins and the prognosis of patients with resectable lung cancer., Materials and Methods: Immunohistochemistry was employed to analyze the protein expression of p53, deltaNp73 and deltaNp63 in paraffin-embedded tumor samples from 132 well-characterized lung cancer patients. The correlation among the expression levels of p53, deltaNp73 and deltaNp63, clinical variables and survival outcome was analyzed., Results: Positive expressions of p53, deltaNp73 and deltaNp63 were detected in the tumor cells in 52, 77 and 44 of the 132 patients, respectively (39.4%, 58.3% and 33.3%) with lung cancer. The incidence of p53 positive expression was 54.5% and 27.6% in patients with squamous cell carcinoma and adenocarcinoma, respectively (p = 0.03). The incidence of a positive expression of deltaNp73 was 64.5% and 43.6% in male and female patients, respectively (p = 0.03). The incidence of deltaNp63 positive expression was 68.2% and 15.8% in the patients with squamous cell carcinoma and adenocarcinoma, respectively (p < 0.0001). The expressions of p53 and deltaNp63 were not found to significantly affect survival. However, lung cancer patients with a positive deltaNp73 expression had a poorer prognosis than those with a negative deltaNp73 expression. In addition, multivariate analysis indicated that a positive expression of deltaNp73 was a significantly independent factor for predicting a poor prognosis (p < 0.0001, risk ratio = 3.38)., Conclusion: Clinical evidence that the p53 family is frequently overexpressed in lung cancer specimens, especially deltaNp63 in squamous cell carcinoma, was provided. The expression of deltaNp73 may be a useful marker for predicting a poor prognosis in resectable lung cancer. Understanding how groups of lung cancer cell genes are coordinately expressed in response to physiological, immunological and micro-environmental stimuli remains an important goal. A better understanding of the gene expression profiles of tumors may help to identify molecular targets, such as deltaNp73, for effective therapy.

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.

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.

Transcription factor Y-box-binding protein 1 (YB-1), which binds to the inverted CCAAT box, is not only involved in the transcription of various genes, but also in cell proliferation and DNA repair. The aim of this study was to detect YB-1 and p53 expression and their relationship to proliferating cell nuclear antigen (PCNA) in non-small cell lung cancer (NSCLC) using immunohistochemical (IHC) staining, and to evaluate the relationship between their expression levels and the prognosis of patients with NSCLC. Positive expressions of YB-1, p53 and PCNA were detected in NSCLC cells in 43 (45.7%), 33 (35.0%) and 45 (47.9%) out of 94 patients, respectively. No significant differences were observed between YB-1 expression and the patients' gender, age at surgery, pathological stage, pathological T status, pathological N status, or pathological M status. The mean PCNA-labelling index (LI) for cells was 40.7+/-2.6. Also, a significant correlation between YB-1 and PCNA-LI was found (p<0.01), but none was found between p53 expression and PCNA. The positive expression of YB-1 was associated with squamous cell carcinoma and large cell carcinoma, compared with adenocarcinomas (p<0.01), and higher levels of PCNA-LI were associated with large cell carcinoma compared with adenocarcinomas and squamous cell carcinoma (p<0.01). These results suggest that YB-1 expression is correlated with PCNA expression in NSCLC. In addition, the DNA repair pathway and tumor proliferation mediated by YB-1 linking to PCNA may be responsible for controlling the growth of NSCLC.

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.

Now that the human genome has been sequenced, we consider that combinations of 3 to 10 million polymorphic loci scattered throughout the genome contribute to individual differences. Genetic polymorphism analysis is useful for the made-to-order medical treatment of patients and the prevention of disease onset in normal healthy individuals. Individually-tailored disease prevention based on findings such as genetic polymorphism analysis results can be grasped by the concept of evidence-based prevention (EBP). In this paper we outline cytochrome P450 (CYP) 1A1 and 2E1 polymorphism-related differences in metabolic activation of carcinogens in relation to the risk of lung cancer, and explain single nucleotide polymorphism (SNP). We also compare the reports to date on SNP types in CYP1A1 and CYP2E1 in relation to the risk of lung cancer with our study results, examine survival rates of lung cancer patients by CYP1A1 or CYP2E1 genotype and discuss the applicability of SNP research to EBP.

Unlabelled: Serum copper (Cu), zinc (Zn) the Cu/Zn ratio (Cu/Zn) and selenium (Se) were evaluated in 84 patients with non-small cell lung cancer (NSCLC) before surgery. Serum carcinoembryonic antigen (CEA), squamous cell carcinoma antigen (SCC) and sialyl Lewis X-i antigen (SLX) levels were also determined in the same cases. The cut-off values of Cu, Zn and Se were established to create two categories with equal numbers of patients. We investigated the clinical and prognostic usefulness of assays of serum trace elements (Cu, Zn, Cu/Zn and Se) and compared levels of serum trace elements and serum tumor markers (CEA, SCC and SLX) in NSCLC patients. Furthermore, we evaluated the usefulness of serum trace elements, when compared with tumor markers, in assessing prognosis for NSCLC., In Conclusion: (1) a preoperative increase in Cu/Zn level predicted tumor progression more effectively than changes in Cu or Zn levels; (2) Se levels seemed to vary with age, but there was no relationship between Se level and disease stage; (3) the measurement of Cu/Zn was useful for assessing both prognosis and extent of the disease in NSCLC patients, similar to the measurement of serum tumor markers such as CEA; and (4) the measurement of the Cu/Zn had prognostic significance, but was inferior to disease stage in predicting outcome. Cu and Zn in serum are storable and the determination of Cu/Zn level is so simple and inexpensive that it can be helpful in determining clinical stages and predicting the prognoses of NSCLC patients.

Y box-binding protein-1 (YB-1), a member of the DNA binding protein family, interacts with inverted CCAAT boxes (Y-boxes). Y-boxes are located on the promoter of numerous genes, such as DNA topoisomerase IIalpha (Topo IIalpha), proliferating cell nuclear antigen (PCNA) and multidrug resistance 1 (MDR1). In this study, we used immunohistochemical (IHC) staining to detect YB-1 expression in 59 lung cancer tissues and to evaluate whether YB-1 expression was associated with the expression of YB-1 target genes such as Topo IIalpha, PCNA and MDR1 in human lung carcinoma. Twenty-eight out of 59 cases (47.5%) were stained positive for YB-1 in the cytoplasm, while 30 out of 59 cases (50.8%) were positive for PCNA in the nuclei. Topo IIalpha-positive cells were detected in 16 out of 59 cases (27.1%). Eight out of 59 cases (13.6%) had greater than 5% P-gp positive cells expression. There was a significant correlation between the YB-1 and Topo IIalpha expression in small cell lung cancer (SCLC) (p=0.0242). YB-1 expression also correlated with PCNA expression in non-small cell lung cancer (NSCLC) (p=0.0001). Higher levels of YB-1 expression were associated with T3-4 and Stage III-IV tumors in adenocarcinomas (p=0.0072; p=0.0168). In contrast, no relationship was found between YB-1 expression and P-gp expression. Our study suggests that YB-1 expression correlates with Topo IIalpha and PCNA expression in lung cancer.

We examined p53 protein expression, proliferating cell nuclear antigen (PCNA), and argyrophilic nuclear organizer regions (AgNOR), in 102 patients with surgically-treated non-small cell lung cancer (NSCLC). p53 positive cases with DO-1 were defined when more than 10% of the tumor cell nuclei were stained. Mean AgNOR count and PCNA LI were 2.80 and 40.7 and there were no significant differences of AgNOR count and PCNA LI between p53 positive and negative cases. We assessed the relationship between the p53 immunoreactivity and various clinical or pathological parameters. p53 positive rate of stage III disease (46.3%) was significantly higher than that of stage II disease (28.6%). The p53 positive rate of squamous cell carcinoma (42.1%) tended to be higher than that of adenocarcinoma (33.9%). In the survival curves of patients with NSCLC according to the p53 immunoreactivity, there was no significant difference between p53 positive and negative cases. Eight potential prognostic parameters (p53 immunoreactivity, AgNOR count, PCNA LI, sex, age, year of operation, histology, and stage) were also estimated, using univariate and multivariate analysis. In univariate analysis, PCNA LI and AgNOR count, and stage were significantly related to shortened survival. In multivariate analysis, PCNA LI, Age, and stage were independently associated with shortened survival of NSCLC patients. PCNA staining may be more useful than p53 and AgNOR staining in assessing the aggressiveness of surgically-treated NSCLC, although the most useful clinical prognostic parameter should be achieved by the combined analysis of several prognostic indicators.

We determined the polymorphic N-acetyltransferase 2 (NAT2) genotype of 124 patients with non-small-cell lung cancer (NSCLC) and 376 control subjects using a PCR-based assay. The slow acetylator genotype was present in 17 (14%) of 124 NSCLC patients and in 40 (11%) of 376 control subjects. The relative risk of slow acetylators compared with rapid acetylators in patients with adenocarcinoma was 2.01 (p = 0.05). This trend was more marked when the analysis was confined to patients under the age of 65 (relative risk, 2.7; p = 0.03). No such trend was identified in patients with squamous cell carcinoma. We also determined the incidence of p53 gene mutations to investigate the possibility of a link between this gene mutation and N-acetylation polymorphism. There was no significant association between p53 gene mutations and NAT2 polymorphism in the overall NSCLC group. However, the incidence of p53 mutations in adenocarcinoma patients under the age of 65 who had the slow acetylator genotype was 63% compared with 38% in patients with the rapid or intermediate acetylator genotype. These findings suggest that the slow acetylator phenotype may be linked to the impaired metabolism of a carcinogen that predisposes individuals to p53 gene mutations, and thus may be associated with an increased risk of pulmonary adenocarcinoma.

The distribution of cytochrome P450 2E1 (CYP2E1) genetic polymorphism was compared in 126 patients with non-small cell lung cancer (NSCLC) and 612 control subjects by PCR-based assay. Incidence of C type (c2/c2) of CYP2E1 polymorphism in the patients with squamous cell carcinoma (9.4%) was significantly higher than that in healthy controls (4.1%) or in the patients with adenocarcinoma (2.7%) within the Japanese population. The relative risk (95% confidence limit) of C type compared with A and B type in patients with squamous cell carcinoma was 2.45 (0.92-6.48). The incidence of p53 gene mutation was studied in an association with CYP2E1 polymorphism. When all the NSCLC patients were considered, the incidence of p53 mutations in type C (85.7%) was significantly higher than that of A and B type (32.8%). It is suggested that C type of CYP2E1 may define individuals at an increased risk of squamous cell carcinoma through the impaired metabolism of a certain carcinogen which predisposes to p53 gene mutation.