Renzo Hirayama

Total colectomy, mucosal proctectomy, and ileoanal anastomosis

A safe and practical procedure for total colectomy and mucosal proctectomy with ileonal anastomosis has been developed and performed by us on 11 patients with adenomatosis coli and two patients with ulcerative colitis. The major features of the operative procedure are 1) total removal of the rectal mucosa to just above the dentate line; 2) preservation of anorectal function by a long rectal cuff procedure achieved by rectal mucosal excision from a level just below the sacral promontory, using a rectal internal stent and gauze packing techniques for rectal mucosal stripping, with, in some patients, an ileal reservoir added; and 3) prevention of pelvic sepsis by intraoperative rectal irrigation, rectal cuff drainage, and a temporary defunctioning loop ileostomy. Of six patients with at least three months of follow-up after reconstruction, each has returned to normal life, averaging two to seven semiformed stools each day. A side-to-end ileoanal anastomosis with a lowlying, loop-type ileal reservoir provided the best functional results.

A comparison of patterns of metastasis in gastric cancer by histologic type and age

Patterns of metastasis were examined in 173 autopsy cases of gastric cancer in which the primary tumor had not been resected and the death was mainly caused by growth and metastasis of the cancer. The results were compared by different histologic types as well as different age groups. From the histologic viewpoint, gastric cancer of glandular type showed preferential metastasis to the liver, whereas the nonglandular type showed a preference for peritoneal involvement and lymph node metastasis. With regard to age, peritoneal involvement was more frequently observed in younger patients for both glandular and nonglandular types. Younger patients also had a higher incidence of lymph node metastasis of gastric cancer of nonglandular type, but not for the glandular type. Regarding liver metastasis, there was no difference in incidence between different age groups.

Thymidylate synthase predictive power is overcome by irinotecan combination therapy with S-1 for gastric cancer

The predictive values of thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) gene expressions were retrospectively evaluated in patients with gastric cancer treated by a regimen containing S-1. The study population consisted of 53 patients registered into different two phase II studies for metastatic gastric cancer; 27 patients treated by S-1-alone study: 26 patients treated with S-1 combined with irinotecan (CPT-11). TS and DPD gene expressions in primary tumours were measured by the real-time reverse transcription PCR method. There was no statistical difference in DPD gene expression in terms of response in cases treated with S-1 alone and those treated with S-1 plus CPT-11. TS mRNA of responding tumours was lower than that of nonresponding ones when treated with S-1 (P<0.005). In the S-1-alone group, taking TS cutoff as the median values, the response rate in the low TS group was 50%, but only 8% in the high TS group (P<0.05). Patients with low TS gene expression survived longer than those with high TS gene expression (P<0.0001). However, there was no statistically significant difference in response rate and survival between patients with low TS tumours and those with high TS tumours, when the cutoff was taken as the median value of TS gene expression in the group treated with S-1 plus CPT-11. In conclusion, treatment effects of S-1 monotherapy for gastric cancer were determined by the status of TS gene expression, regardless of DPD gene expression. TS predictive power was overcome by CPT-11 combination therapy with S-1.

Simple combinations of 5-FU pathway genes predict the outcome of metastatic gastric cancer patients treated by S-1.

We evaluated the expression of 5‐FU pathway genes in prechemotherapeutic fresh frozen samples obtained from primary tumors to predict response and survival of 59 metastatic gastric cancer patients treated with S‐1 monotherapy as first line treatment. Five 5‐FU pathway genes, including thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), orotate phosphoribosyltransferase (OPRT), thymidine phosphorylase (TP) and uridine phosphorylase (UP), were analyzed by the quantitative real‐time reverse transcriptional PCR method. Median values of each gene were selected for cut‐off values separating high and low gene expressions. In univariate analyses, low TS, high OPRT and low TP were significantly associated with a tumor shrinkage and a long survival, whereas DPD and UP gene expressions did not correlate with response and survival. Multivariate analyses revealed that independent variables were OPRT and TS for response and TS and TP for survival. When OPRT and TS were combined, a significantly increased accuracy rate of 91.5% was seen for response. Similarly, an increased hazard ratio of 10.29 was observed for survival in patients possessing low TS and low TP, compared with those with high TS or high TP. The simple combinations of 2 genes, OPRT and TS for response and TS and TP for survival, may allow identification of gastric cancer patients who will benefit from S‐1 chemotherapy.

Orotate Phosphoribosyltransferase Gene Polymorphism Predicts Toxicity in Patients Treated with Bolus 5-Fluorouracil Regimen

Purpose: We investigated whether the determination of orotate phosphoribosyltransferase (OPRT) and thymidylate synthase (TYMS) polymorphisms could predict the toxicity of 5-fluorouracil (5-FU) in colorectal cancer patients. Experimental Design: The determination of OPRT and TYMS genotypes were done in genomic DNA extracted from blood by PCR amplification in 69 patients treated with bolus 5-FU as adjuvant chemotherapy. Associations between these polymorphisms and toxicity were evaluated retrospectively. Results: The Ala allele in OPRT Gly213Ala polymorphism and the two tandem repeats (2R) in TYMS promoter polymorphism were associated with grade 3 to 4 neutropenia and diarrhea. The multivariate logistic regression models revealed that only TYMS promoter polymorphism had an independent value to predict grade 3 to 4 neutropenia [odds ratio, 19.2 for patients with the 2R allele compared with patients with homozygous with the three repeat (3R) alleles], whereas both OPRT and TYMS promoter polymorphisms were independent predictive factors for grade 3 to 4 diarrhea (odds ratio, 13.3 for patients with the Ala allele compared with patients in the Gly/Gly genotype and 11.1 for patients with the 2R allele compared with patients in the 3R/3R genotype). A significant difference was observed in the time to onset of severe toxicity, defined as grade 4 neutropenia and/or grade 3 to 4 gastrointestinal toxicities according to OPRT and TYMS promoter polymorphisms. Conclusion: OPRT Gly213Ala polymorphism seems to be a useful marker for predicting toxicity to bolus 5-FU chemotherapy. Prospective translational treatment trials including larger number of patients are needed to confirm our results.

Telomere shortening in gastric carcinoma with aging despite telomerase activation

Abstract In the present study, we analyzed both telomere length and telomerase activity in surgical and autopsy samples of non-neoplastic mucosa and carcinomas of the stomach. Telomere length, determined by Southern blot analysis, demonstrated progressive shortening with age in non-neoplastic gastric mucosal specimens from 38 human subjects aged between 0 and 99 years, with an average annual loss rate of 46 base pairs (bp). The mean (±SD) telomere length in 21 gastric carcinomas was 7.0 ± 1.6 × 103 base pairs (1.6 kbp). In 20 (95%) of the 21 subjects, the values were smaller than those in the non-neoplastic gastric mucosa (mean shortening 1.8 kbp), although a strong correlation was observed for the paired data (r = 0.69, P = 0.0004). Similarly, telomere lengths in carcinomas were shorter than those for intestinal metaplasia (a mean difference of 1.1 kbp). Telomerase activity, estimated using the telomeric repeat amplification protocol assay, was positive in 18 (86%) of the 21 gastric carcinomas, without significant differences among the three histological types (well, moderately, and poorly differentiated adenocarcinomas) or with sex or age. The results suggest that telomere length and possibly shortening rates vary with the individual, and that examination of both non-neoplastic mucosa and tumors is necessary to improve our understanding of the significance of telomerase in neoplasia.

Thymidylate synthase and dihydropyrimidine dehydrogenase gene expression in relation to differentiation of gastric cancer.

Thymidylate synthase (TS) and dihydropyrimidine dehydrogenase (DPD) are important enzymes of DNA de novo synthesis and the salvage pathway in cancer cells, respectively. Intratumoral TS and DPD gene expressions were evaluated to determine the correlation between the expression of the 2 genes in both normal stromal tissues and tissues with different degrees of malignant differentiation in primary gastric cancer. The study population consisted of 78 consecutive patients with advanced gastric cancer who underwent surgical treatment. Laser‐captured microdissection of malignant or normal stromal tissues was performed in formalin‐fixed, paraffin‐embedded specimens. After extraction of RNA, TS and DPD gene expressions were measured by the real‐time reverse transcriptional PCR method. Apart from degree of differentiation, TS and DPD in malignant tissue showed no correlation with clinicopathologic factors. TS in malignant tissue was higher in differentiated type cases than undifferentiated type cases (p < 0.01). However, DPD in malignant tissue of undifferentiated type cases was statistically higher than that of differentiated type cases (p < 0.05). In normal stromal tissue, neither TS nor DPD had any correlation with clinicopathologic factors. TS in malignant tissue was statistically higher than in normal stromal tissue in both differentiated and undifferentiated types (p < 0.0001). DPD in differentiated type malignant tissue was statistically lower than in normal stromal tissue (p < 0.001), but no difference was seen in undifferentiated type cases. TS and DPD gene expressions in primary gastric cancer differ according to degree of differentiation and between malignant and normal stromal tissue.

Adrenal Metastasis from Rectal Cancer: Report of a Case

Abstract.We report a case of heterochronic adrenal metastasis from colorectal carcinoma in a 51-year-old woman. A left adrenal metastasis was found by computed tomography and magnetic resonance imaging 8 months after an anterior resection for advanced rectal carcinoma, and a left hepatectomy for a solitary liver metastasis. The level of serum carcinoembryonic antigen was still within the normal range. A left adrenalectomy was performed, and histopathological examination revealed adenocarcinoma, compatible with the rectal carcinoma resected 8 months earlier. The patient died of lung metastases 6 months after the adrenalectomy. A review of autopsy series in the world literature revealed that adrenal metastasis from colorectal cancer is not rare. Therefore, the possibility of adrenal metastasis should be considered in the follow-up of patients after primary surgery for colorectal cancer, even though the liver and lung are the main metastatic sites.

Churg-Strauss Syndrome Manifesting as Perforation of the Small Intestine: Report of a Case

We report a case of Churg-Strauss syndrome (CSS) causing perforation of the small intestine. A 51-year-old woman was admitted with an asthma attack and paralysis of both legs. Intravenous predonisolone (40 mg) was given to relieve her asthma. Laboratory data on admission showed leukocytosis with hypereosinophilia and a high level of serum IgE. Neurological examination also revealed mononeurutis multiplex. Based on these findings, we diagnosed CSS, and oral corticosteroids were continued. On the 20th day after admission, she suffered sudden abdominal pain. Abdominal X-ray showed free air in the abdomen, suggesting perforation of the gastrointestinal tract. Emergency laparotomy revealed generalized peritonitis caused by a perforated ulcer of the ileum. The resected specimens contained a perforation and multiple nonperforated ulcers with an irregular shape on the mucosal surface. Histopathological examinations revealed angiitis of the small vessels surrounded by eosinophilic infiltration and granuloma, consistent with CSS. Considering the high risk of perforation of the gastrointestinal tract, including the small intestine, during corticosteroid treatment in patients with CSS, any abdominal pain or discomfort must be investigated carefully.

Induction of thymidine phosphorylase by interferon and taxanes occurs only in human cancer cells with low thymidine phosphorylase activity

Thymidine phosphorylase (TP) regulates intracellular thymidine metabolism. It has been reported to be a prognostic factor for tumor angiogenesis and to activate some prodrugs of 5-fluorouracil (5-FU) to 5-FU. There is also evidence that TP is induced by interferons (IFNs) and xenobiotics, such as cyclophosphamide and taxanes, in experimental human cancer cells and xenografts. We investigated the induction of TP expression by IFNalpha and Paclitaxel in vitro and in vivo in human tumor cells with low and with high TP activity. TP activity in KB, NUGC-3, and KOC2S cells, which had low TP activity, was increased 2 to 4 fold by IFNalpha, but was still lower than in non-treated SHIN-3 and HRA cells, which have high TP activity. IFNalpha did not promote TP activity in SHIN-3 and HRA cells, but expression of TP mRNA increased 2 to 4 fold in response to IFNalpha in all cells tested. These results suggest that the expression of TP protein would be regulated post-transcriptionally by another factor after IFN-induced amplification of TP mRNA. A single dose of Paclitaxel to nude mice xenografted with KB and KM20C tumors, expressing low TP activity, increased TP activity about 4 to 7 fold compared to non-treated tumors. In contrast, TP expression in MX-1 and H-31 tumors was originally high and did not change by the treatment of Paclitaxel. The activities of uridine phosphorylase in all tumors used showed no changes in response to IFNalpha or Paclitaxel. We determined the level of STAT1alpha, an IFN-inducible transcription factor of the TP gene, and found that it was low in low TP expressing tumor cells and markedly increased to about 4 fold by IFN, almost reaching the level in high TP expressing cells whose STAT1alpha level was unchanged by IFN. When TP activity and STAT1alpha expression in clinically resected colorectal cancers were simultaneously measured, almost all tumors had high expression of both TP and STAT1alpha. In conclusion, our results suggest that IFN and Paclitaxel affect human cancer cells with low TP activity but not those with high TP activity and that the STAT1alpha expression may reflect TP activity, at least in experimental human cancer cells.