Alcohol consumption, smoking, and subsequent risk of colorectal cancer in middle-aged and elderly Japanese men and women: Japan Public Health Center-based prospective study.

Few studies have examined the association of alcohol consumption and cigarette smoking with colorectal cancer in Asian populations whose genetic susceptibility to these factors are different from Western populations. We investigated this association and the joint effect of these factors, and estimated the population-attributable fraction to clarify the public health impact on a Japanese population, based on a prospective study. We analyzed the 10-year (cohort I) and 7-year (cohort II) follow-up data of the Japan Public Health Center-based prospective study on cancer and cardiovascular disease, derived from 90,004 (42,540 male and 47,464 female) middle-aged and elderly Japanese. We identified 716 (457 in men and 259 in women) newly diagnosed cases of colorectal cancer. Both alcohol consumption and smoking were clearly associated with colorectal cancer in men, after adjusting for age, family history of colorectal cancer, body mass index, and physical exercise. Regular heavy drinking of 150 g/week or more of ethanol showed a statistically significant increased risk compared with nondrinkers: relative risks (RRs) were 1.4 [95% confidence interval (CI), 1.1-1.9] for 150-299 g/week and 2.1 (95% CI, 1.6-2.7) for 300 g/week or more. On the contrary, regular ethanol consumption was not associated with colorectal cancer (RR, 0.7; 95% CI, 0.4-1.1) in women. In terms of smoking, the RRs were 1.4 (95% CI, 1.1-1.8) for current smokers and 1.3 (95% CI, 0.98-1.7) for ex-smokers compared with never-smokers in men. The risk of smoking in women was similar to that in men, although not statistically significant. The colorectal cancer risk with 300 g/week or more of ethanol in current smokers was estimated at 3.0 (95% CI, 1.8-5.1) compared with nondrinkers among nonsmokers in men. Colorectal cancer attributable to alcohol consumption or smoking was estimated to be 46%. In conclusion, approximately half of the colorectal cancer cases may be preventable by tobacco and alcohol controls in middle-aged and elderly Japanese men.     

Carotid Resection and Reconstruction for Advanced Cervical Cancer

Patients with advanced cervical cancers often have direct invasion of their carotid arteries. The prognosis for these patients with nonsurgical therapy is extremely poor. Because complete tumor removal is the only therapy that can offer these patients a chance for cure, carotid resection should be performed. We performed carotid resection and reconstruction on nine patients with advanced cervical cancers. Of these patients, none suffered from severe neurologic postoperative complications such as permanent hemiplegia. Three of the nine patients have been disease free for more than 24 months. These three patients would not have survived without carotid resection. Further study will show the usefulness of carotid resection and reconstruction in decreasing the morbidity and mortality in patients with cervical cancer involving the carotid artery.     

Seven-year survivor with malignant melanoma of the anus without radical surgery

We report a case of a long-term survivor with malignant melanoma of the anus who did not undergo radical surgery. A 71-year-old woman who presented with anal bleeding and anal tumor underwent an excisional biopsy in September 1985. The biopsy specimen was a lobulated, polypoid, pigmented mass 2 cm in diameter, that had been located on the anterior wall of the anus. A satellite nodule 7 mm in diameter was found on the left wall of the anus at the level of the dentate line. Both tumors were histologically diagnosed as malignant melanoma. The primary tumor was 6 mm thick. Melanoma cells were present microscopically at the cut end of the rectum. Because of her history of ischemic heart disease, the patient rejected our recommendation that she undergo radical surgery, and received 10 courses of carboplatin 20 mg intramuscularly and OK-432 10 K.E. (Klinische Einheit) intradermally every week. A single, pigmented metastatic inguinal lymph node developed and was excised in June 1987. A recurrent tumor was detected in the rectum in October 1992, so again we recommended radical surgery. The patient rejected radical surgery again, and received 12 courses of carboplatin 10 mg intramuscularly every 2 weeks. She died of disease at home in July 1993 after surviving for 7 years and 10 months. An autopsy was not performed. This case shows that local excision of the primary lesion may be appropriate to preserve the quality of life of patients with early-stage malignant melanoma of the anus.     

Plasticity of central monoaminergic systems during aging]

The locus coeruleus (LC), located within the caudal pontine central gray, is composed of noradrenaline-containing neurons. The axons of these neurons form extensive collateral branches that project widely to many brain sites. The function of the LC is still unclear at present, however, LC neurons are known to exhibit marked axonal regeneration and sprouting in response to brain damage. We investigated the age-related changes in noradrenergic innervations of the frontal cortex, using in vivo electrophysiological techniques and immunohistochemistry. While noradrenergic innervations gradually decreased with age in the frontal cortex, a high degree of sprouting occurred in the LC axon terminals in middle age. Neither the electrophysiological properties of LC neurons nor NA levels in the frontal cortex changed with age. These findings suggested that the LC neurons preserve a strong capacity to remodel their axon terminals even in the aging brain. Exogenous brain-derived neurotrophic factor (BDNF) infusion caused a marked increase in the density of noradrenergic axon in the aged brain, but no trophic action of BDNF was observed in the young or middle-aged brain. The result suggests that BDNF is necessary for the maintenance of noradrenergic innervations in the aged brain.     

Mutations of the epidermal growth factor receptor gene predict prolonged survival after gefitinib treatment in patients with non-small-cell lung cancer with postoperative recurrence.

PURPOSE: To evaluate the relationship between mutations of the epidermal growth factor receptor (EGFR) gene and the effectiveness of gefitinib treatment in patients with recurrent lung cancer after pulmonary resection. PATIENTS AND METHODS: We sequenced exons 18-21 of the EGFR gene using total RNA extracted from 59 patients with lung cancer who were treated with gefitinib for recurrent lung cancer. Gefitinib effectiveness was evaluated by both imaging studies and change in serum carcinoembryonic antigen (CEA) levels. RESULTS: EGFR mutations were found in 33 patients (56%). Of these mutations, 17 were deletions around codons 746-750 and 15 were point mutations (12 at codon 858, three at other codons), and one was an insertion. EGFR mutations were significantly more prevalent in females, adenocarcinoma, and never-smokers. Gefitinib treatment resulted in tumor shrinkage and/or CEA decrease to less than half of the baseline level in 26 patients, tumor growth and/or CEA elevation in 24 patients, and gefitinib effect was not assessable in nine patients. Female, never-smoking patients with adenocarcinoma tended to respond better to gefitinib treatment. Gefitinib was effective in 24 of 29 patients with EGFR mutations, compared with two of 21 patients without mutations (P < .0001). Of note, del746-750 might be superior to L858R mutations for prediction of gefitinib response. Patients with EGFR mutations survived for a longer period than those without the mutations after initiation of gefitinib treatment (P = .0053). CONCLUSION: EGFR mutations were a good predictor of clinical benefit of gefitinib in this setting.     

Down-regulation of LATS1 and LATS2 mRNA expression by promoter hypermethylation and its association with biologically aggressive phenotype in human breast cancers.

PURPOSE: LATS1 and LATS2 are tumor suppressor genes implicated in the regulation of cell cycle. Methylation status of the promoter regions of these genes as well as its correlation with their mRNA levels were studied in human breast cancers. Correlation of LATS1 and LATS2 mRNA levels with clinicopathologic characteristics of breast tumors were also studied. EXPERIMENTAL DESIGN: Methylation status of promoter regions of LATS1 and LATS2 was studied by a methylation-specific PCR and mRNA expression levels of LATS1 and LATS2 were determined by a real-time PCR assay in 30 breast cancers. In addition, correlation of LATS1 and LATS2 mRNA levels with clinicopathologic characteristics was studied in 117 breast cancers. RESULTS: Methylation-specific PCR showed that of 30 tumors, LATS1 promoter region was hypermethylated in 17 tumors (56.7%) and LATS2 promoter region was hypermethylated in 15 (50.0%) tumors. LATS1 mRNA levels in breast tumors with hypermethylation (2.15 +/- 0.37, mean +/- SE) were significantly (P < 0.01) lower than those without hypermethylation (6.09 +/- 1.38), and LATS2 mRNA levels in breast tumors with hypermethylation (1.42 +/- 0.66) were also significantly (P < 0.01) lower than those without hypermethylation (3.10 +/- 1.00). The decreased expression of LATS1 or LATS2 mRNA was significantly associated with a large tumor size, high lymph node metastasis, and estrogen receptor and progesterone receptor negativity. Furthermore, the decreased expression of LATS1 mRNA, but not LATS2 mRNA, was significantly (P < 0.05) associated with a poor prognosis. CONCLUSIONS: Hypermethylation of the promoter regions of LATS1 and LATS2 likely plays an important role in the down-regulation of their mRNA levels in breast cancers, and breast cancers with a decreased expression of LATS1 or LATS2 mRNA levels have a biologically aggressive phenotype.     

Identification of the HLA-Cw*0702-restricted tumor-associated antigen recognized by a CTL clone from a lung cancer patient.

PURPOSE: A large number of tumor-associated antigens have been used in vaccination trials for mainly melanomas. Our purpose of this study is to identify a novel tumor antigen useful for immunotherapy of lung cancer patients. EXPERIMENTAL DESIGN: Analysis of an autologous tumor-specific CTL clone F2a that was established from regional lymph node lymphocytes of a patient with lung cancer (A904) by a mixed lymphocyte-tumor cell culture. RESULTS: F2a recognized and killed autologous tumor cells (A904L), whereas it did not respond to autologous EBV-transformed B cells, phytohemagglutinin-blastoid T cells, and K562 cells. cDNA clone 31.2 was isolated by using cDNA expression cloning method as a gene encoding antigen. This gene was identical to the reported gene whose function was unknown. The antigen encoded by the cDNA was recognized by the CTL in a HLA-Cw*0702-restricted manner. Furthermore, a 9-mer peptide at positions 659 to 685 in cDNA clone 31.2 was identified as a novel epitope peptide. The CTL recognized some allogeneic cancer cell lines with HLA-Cw*0702 as well as some HLA-Cw*0702-negative cell lines when transfected with HLA-Cw*0702, thus indicating that the identified antigen was a cross-reactive antigen. CONCLUSIONS: Although exact mechanism to process the encoded protein and present the antigen in the context of HLA class I remains to be elucidated, the CTL recognized some of tumor cells in the context of HLA-Cw*0702 but did not recognize a variety of normal cells and also autologous EBV-transformed B cells. These results indicated that the antigen identified in this study may therefore be a possible target of tumor-specific immunotherapy for lung cancer patients.     

Highly sensitive detection of melanoma at an early stage based on the increased serum secreted protein acidic and rich in cysteine and glypican-3 levels.

PURPOSE: There are no available tumor markers detecting primary melanoma at an early stage. The identification of such serum markers would be of significant benefit for an early diagnosis of melanoma. We recently identified glypican-3 (GPC3) as a novel tumor marker but could diagnose only 40% of melanomas. Thereby, we focused out attention on secreted protein acidic and rich in cysteine (SPARC) overexpressed in melanoma as another candidate for tumor marker. EXPERIMENTAL DESIGN: Secreted SPARC protein was quantified using ELISA in the sera from 109 melanoma patients, five patients with large congenital melanocytic nevus, 61 age-matched healthy donors, and 13 disease-free patients after undergoing a surgical removal. We also quantified GPC3 and 5-S-cysteinyldopa in the same serum samples and compared these markers for their diagnostic value. RESULTS: The serum SPARC concentrations in melanoma patients were greater than those in healthy donors (P = 0.001). When we fixed a cutoff value at the mean concentration plus 2 SD of the healthy donors, the serum SPARC was found to have increased in the sera of 36 of the 109 (33%) melanoma patients, whereas there were three (4.9%) false-positive cases of 61 healthy donors. Surprisingly, 19 of 36 patients showing increased SPARC levels were in stages 0 to II. The serum SPARC level decreased under the cutoff level in 10 of 13 patients after surgical removal. Using SPARC and GPC3 in combination thus enabled us to diagnose 47 of 75 (66.2%) melanoma patients at an early stage (0-II). CONCLUSIONS: SPARC or its combination with GPC3 is thus considered a potentially useful tumor marker, especially for melanoma at an early stage.