Shunji Morita

Genetic polymorphisms of drug‐metabolizing enzymes and susceptibility to head‐and‐neck squamous‐cell carcinoma

We have investigated the association between the polymorphisms of drug‐metabolizing enzymes and susceptibility to head‐and‐neck squamous‐cell carcinoma (HNSCC). PCR‐based analysis was performed on 145 Japanese patients and 164 healthy Japanese controls to determine genotypes of polymorphisms in CYP1A1, CYP2E1, GSTM1, GSTP1, and NAT2. Patients and controls were compared by multivariate analysis. The CYP1A1 Val/Val genotype was seen more frequently in patients than in controls [odds ratio (OR) 4.1, p = 0.038). The frequency of the slow plus intermediate NAT2 genotypes was also higher in patients (OR 2.0, p = 0.039). When we analyzed the distributions of the genotypes in 69 laryngeal and 45 pharyngeal cancer patients, laryngeal cancer patients had a higher frequency of NAT2 slow or intermediate genotype (OR 2.7, p = 0.011) and GSTP1 AA genotype (OR 2.4, p = 0.047) than controls. Pharyngeal cancer patients had a higher frequency of the CYP1A1 Val/Val genotype than controls (OR 5.7, p = 0.034), suggesting that different organs may be responsive to different chemicals from the environment. Furthermore, 23 patients who developed multiple cancers (HNSCC plus other) were compared with 115 patients with HNSCC alone. There was no significant difference in the polymorphisms between the 2 groups, though excessive alcohol consumption (more than 50 g/day of ethanol) appeared to be a risk factor for multiple cancers (p = 0.053). Int. J. Cancer 80:685–688, 1999.

CYP1A1 CYP2E1 and GSTM1 polymorphisms are not associated with susceptibility to squamous-cell carcinoma of the esophagus

We investigated the genetic polymorphisms of CYPIAI, CYP2EI and GSTMI in Japanese esophageal cancer patients (n = 53) with a histological diagnosis of squamous‐cell carcinoma, to determine whether susceptibility to esophageal cancer is associated with these polymorphisms. There were no significant differences in the frequency distribution of any one of the 3 polymorphisms between esophageal cancer patients and 132 healthy Japanese controls. The genotype distributions in tobacco smokers or alcohol drinkers were also quite similar for male patients and male controls. The age at onset of esophageal cancer was also similar for patients with any genotype of the 3 polymorphisms. We conclude that the 3 polymorphisms are unlikely to be associated with esophageal cancer susceptibility. Int. J. Cancer 71:192–195, 1997.

Association between genetic polymorphisms of glutathione S‐transferase P1 and N‐acetyltransferase 2 and susceptibility to squamous‐cell carcinoma of the esophagus

We examined the effect of genetic polymorphisms of phase‐II enzymes, glutathione S‐transferase P1 (GSTP1) and N‐acetyltransferase2 (NAT2) on susceptibility to esophageal squamous‐cell carcinoma. To determine the genotypes of the 2 polymorphisms, PCR‐based analysis was performed on samples from 66 Japanese patients who had been histologically diagnosed as having esophageal squamous‐cell carcinoma, and 164 healthy Japanese controls. The frequency of the AA genotype of GSTP1 was significantly higher in esophageal‐cancer patients than in the controls according to logistic‐regression analysis (92% of the patients and 68% of the controls; odds ratio (OR), 8.0; p = 0.0013). Also, more patients had the slow and intermediate acetylator genotypes of NAT2 than the controls (15% and 38% vs. 10% and 32% respectively; OR of the slow acetylator genotype, 4.2; p = 0.032; OR of the slow plus intermediate acetylator genotypes, 2.9; p = 0.015). Polymorphisms of GSTP1 and NAT2 may serve as genetic biomarkers for predicting susceptibility to esophageal squamous‐cell carcinoma. Int. J. Cancer (Pred. Oncol.) 79:517–520, 1998.© 1998 Wiley‐Liss, Inc.

does Serum Ca19-9 Play a Practical Role in the Management of Patients With Colorectal Cancer?

PURPOSE: CA19-9 is often used in combination with carcinoembryonic antigen to manage patients with colorectal cancer, even though there is insufficient evidence to support this use of CA19-9. Carcinoembryonic antigen, by contrast, has been regarded as a better indicator of poor prognosis and recurrence. The purpose of this study is to clarify whether CA19-9 is, in fact, a useful marker in the management of colorectal cancer patients by comparing it with carcinoembryonic antigen. METHODS: A retrospective investigation was done for a consecutive series of 155 patients with colorectal adenocarcinoma who underwent potentially curative surgery between 1995 and 1999. Excluded were patients with postoperative assays performed less than three times for either carcinoembryonic antigen or CA19-9 and those who had developed secondary cancers. Data from 118 patients were analyzed in terms of prediction of prognosis and detection of recurrences. RESULTS: The sensitivities of preoperative CA19-9 and carcinoembryonic antigen were 29.8 percent and 45.3 percent, respectively. In the univariate analysis of preoperative carcinoembryonic antigen and CA19-9 assays in 114 patients, high carcinoembryonic antigen level was significantly associated with poor prognosis (P = 0.0090 by log-rank test). We could not find a significant association between preoperative CA19-9 abnormality and survival (P = 0.12). Multivariate analysis of preoperative factors indicated significance in TNM stage (P = 0.0094) and tumor location (P = 0.036) but in neither carcinoembryonic antigen (P = 0.061) nor CA19-9 (P = 0.22). Among 40 patients with recurrences, postoperative elevations of tumor markers were seen in 19 cases for CA19-9 and in 37 for carcinoembryonic antigen throughout the follow-up periods. Sensitivity, specificity, positive predictive value, and negative predictive value were 0.48, 0.88, 0.68, and 0.77, respectively, for CA19-9, and 0.93, 0.88, 0.80, and 0.96, respectively, for carcinoembryonic antigen. In patients with recurrences, the initial postoperative elevation of tumor markers was seen earlier than the detection of recurrence in 68.4 percent of those with CA19-9 elevation and in 67.6 percent of those with carcinoembryonic antigen elevation. There was only one patient with recurrence who had CA19-9 elevation without carcinoembryonic antigen elevation, while 19 recurrent patients had carcinoembryonic antigen elevation without CA19-9 elevation. Multivariate analysis showed a significant risk of carcinoembryonic antigen elevation against recurrence with an odds ratio of 32.0 (P < 0.0001), in contrast to an insignificant association of CA19-9 elevation (P = 0.23). CONCLUSION: We could not find clinical significance to support the use of CA19-9 to predict the prognosis and detect recurrence of colorectal cancer. Because of this, we do not recommend routine use of CA19-9 in staging and surveillance of colorectal cancer patients.

The Significance of the Intraoperative Repeated Dosing of Antimicrobials for Preventing Surgical Wound Infection in Colorectal Surgery

PurposeIt is widely accepted that antimicrobial prophylaxis is useful for the prevention of surgical wound infection, especially in colorectal surgery. While many reports support the finding that the first dose should be administered immediately before surgery, there is less evidence concerning the ideal timing for the second dose. The purpose of this study is to examine the significance of intraoperative repeated dosing.MethodsA surgical series of 131 patients with primary colorectal cancer was retrospectively analyzed for 14 parameters, including the protocols of antimicrobial administration to determine the clinical risk factors for surgical wound infection.ResultsThe overall surgical wound infection rate of the 131 patients was 16.0% (21/131). When the operation finished within 4 h after the first dose (n = 29), wound infection was observed in only one patient (3.4%). In a prolonged operation exceeding 4 h after the first dose, the surgical wound infection rates were 8.5% and 26.5%, respectively, for those with (n = 47) and without (n = 49) intraoperative repeated dosing, which were significantly different based on both a univariate analysis (P = 0.031) and a multivariate analysis (P = 0.0079).ConclusionIntraoperative repeated antimicrobial dosing is therefore recommended to prevent the surgical wound infection for prolonged colorectal surgery.

Association of metabolic gene polymorphisms with tobacco consumption in healthy controls.

Polymorphisms in genes that encode for metabolic enzymes have been associated with variations in enzyme activity between individuals. Such variations could be associated with differences in individual exposure to carcinogens that are metabolized by these genes. In this study, we examine the association between polymorphisms in several metabolic genes and the consumption of tobacco in a large sample of healthy individuals. The database of the International Collaborative Study on Genetic Susceptibility to Environmental Carcinogens was used. All the individuals who were controls from the case‐control studies included in the data set with information on smoking habits and on genetic polymorphisms were selected (n = 20,938). Sufficient information was available on the following genes that are involved in the metabolism of tobacco smoke constituents: CYP1A1, GSTM1, GSTT1, NAT2 and GSTP1. None of the tested genes was clearly associated with smoking behavior. Information on smoking dose, available for a subset of subjects, showed no effect of metabolic gene polymorphisms on the amount of smoking. No association between polymorphisms in the genes studied and tobacco consumption was observed; therefore, no effect of these genes on smoking behavior should be expected.

Combination antiemetic therapy with aprepitant/fosaprepitant in patients with colorectal cancer receiving oxaliplatin-based chemotherapy (SENRI trial): a multicentre, randomised, controlled phase 3 trial.

INTRODUCTION The oral neurokinin-1 antagonist aprepitant is recommended in several guidelines for preventing chemotherapy-induced nausea & vomiting (CINV) due to highly emetogenic cancer chemotherapy. Little is known about the feasibility and safety of aprepitant in patients treated with oxaliplatin. METHODS In this multicentre, open label, randomised, phase 3 trial, we recruited patients with colorectal cancer who underwent an oxaliplatin-based chemotherapy. Patients were centrally randomised in a 1:1 ratio to the control group (5-HT3-receptor antagonist+dexamethasone) or aprepitant group (5-HT3-receptor antagonist+dexamethasone+aprepitant or fosaprepitant) in the first course. All patients were treated with aprepitant/fosaprepitant therapy in the second course. The primary end-point was the proportion of patients with no emesis. RESULTS A total of 413 patients entered this clinical trial from 25 centres in Japan. Significantly more patients in the aprepitant group achieved no vomiting overall and delayed phase than those in the control group (95.7% versus 83.6%, and 95.7% versus 84.7%, respectively). The aprepitant group also had statistically significantly higher percentages of no significant nausea, complete response and complete protection than the control group overall. In the control group, the percentages of no vomiting were higher in the second cycle than in the first cycle. The incidence of vomiting occurred day 7 or later was significantly higher in the control group compared with the aprepitant group. Other adverse events were not significant between the groups. CONCLUSION The aprepitant therapy was more effective than the control therapy for prevention of CINV in colorectal cancer patients receiving an oxaliplatin-based regimen.

Modulation of circadian expression of D‐site binding protein by the schedule of parenteral nutrition in rat liver

The aim of this study was to investigate the changes in the circadian rhythm of the expression of liver‐specific genes caused by different schedules of parenteral nutrition (PN). Rats received PN continuously throughout the day or intermittently during the night or day for 7 days. They were examined for gene expression of D‐site binding protein (DBP), albumin, and cytochrome P450 cholesterol 7α‐hydroxylase (CYP7) in the liver. The nocturnal PN group showed circadian expression of DBP messenger RNA (mRNA) and protein with a peak at 10 PM, in the same manner as the control rats receiving normal chow feeding. However, the diurnal PN group showed inverted expression of DBP mRNA and protein with a peak at 10 AM. CYP7 mRNA levels exhibited good synchronization with the levels of DBP mRNA in all groups, whereas albumin mRNA levels did not show such synchronization. Gel mobility‐shift assay disclosed that the binding activity of the nuclear extracts to the CYP7 gene promoter was changed by the PN schedule in accordance with the expression of CYP7 mRNA. The PN schedule modulates the circadian rhythm of DBP expression and may have an effect on hepatic bile acid formation through transcriptional regulation of the CYP7 gene.

Changes of liver-enriched nuclear transcription factors for albumin gene in starvation in rats.

The regulatory mechanism of albumin gene transcription was examined using male Donryu rats (7 wk old) starved for 1 or 3 d. At the designated times, the rats were sacrificed to harvest the liver and to measure the serum albumin level. Neither the serum albumin nor the albumin messenger RNA (mRNA) level showed a significant change for these starvation periods. Among nuclear factors binding to the D site of albumin gene promoter, the CCAAT/enhancer binding protein alpha (C/EBP alpha) mRNA level showed a decrease and the D site binding protein (DBP) mRNA level tended to decrease after 3 d of starvation. In contrast, the C/EBP beta mRNA level showed a significant increase at day 1. As a B site binding nuclear factor, the hepatocyte nuclear factor 1 (HNF-1) mRNA level significantly increased at day 1. Gel mobility-shift analysis combined with Western immunoblotting confirmed the presence of D site binding proteins composed of DBP and C/EBP alpha and beta in both groups subjected to oral feeding and to 3-d starvation, though quantitative analysis could not be done. In conclusion, the nuclear transcription factors binding to the albumin gene promoter undergo regulatory changes during 3 d of starvation, whereas there is no significant decrease in the albumin mRNA level.

Outcomes in Colorectal Surgeon-driven Management of Obstructing Colorectal Cancers

BACKGROUND:Emergency surgery for obstructing colorectal cancer is associated with high mortality and morbidity rates. OBJECTIVE:The purpose of this study was to assess outcomes of emergency surgery for obstructing colorectal cancer in a single hospital, where care was primarily provided by colorectal surgeons. DESIGN:This was a retrospective cohort study. SETTINGS:The study was conducted at the Toyonaka Municipal Hospital. PATIENTS:The study included 208 consecutive patients who underwent emergency surgery for obstructing colorectal cancer between 1998 and 2013. MAIN OUTCOME MEASURES:Surgical outcomes, including mortality and morbidity, were evaluated. RESULTS:The obstructing cancers involved the right colon, left colon, and rectum in 78, 97, and 33 of the included patients. Many patients had poor performance indicators, such as age ≥75 years (42%), ASA score of III or more (38%), stage IV colorectal cancer (39%), obstructive colitis (12%), and perforation or penetration (9.6%). Colorectal surgeons performed the operations in all but 5 of the patients. Primary resection and anastomosis were accomplished in 96%, 70%, and 27% of cases involving the right colon, left colon, and rectum. Intraoperative colonic irrigation (n = 32), manual colonic decompression (n = 11), and subtotal or total colorectal resection (n = 34) were performed before left-sided anastomoses. Anastomotic leak was reported in only 2 patients. The in-hospital mortality and morbidity rates were 1.3% and 34.0%. LIMITATIONS:This study was a retrospective analysis of data from a single hospital. CONCLUSIONS:Surgical outcome analysis for obstructing colorectal cancers managed by specialized colorectal surgeons demonstrates low mortality and morbidity rates. Therefore, we concluded that our management of this condition is safe and feasible.