A randomized phase III trial comparing S-1 versus UFT as adjuvant chemotherapy for stage II/III rectal cancer (JFMC35-C1: ACTS-RC).

BACKGROUNDS: Preventing distant recurrence and achieving local control are important challenges in rectal cancer treatment, and use of adjuvant chemotherapy has been studied. However, no phase III study comparing adjuvant chemotherapy regimens for rectal cancer has demonstrated superiority of a specific regimen. We therefore conducted a phase III study to evaluate the superiority of S-1 to tegafur-uracil (UFT), a standard adjuvant chemotherapy regimen for curatively resected stage II/III rectal cancer in Japan, in the adjuvant setting for rectal cancer. PATIENTS AND METHODS: The ACTS-RC trial was an open-label, randomized, phase III superiority trial conducted at 222 sites in Japan. Patients aged 20-80 with stage II/III rectal cancer undergoing curative surgery without preoperative therapy were randomly assigned to receive UFT (500-600 mg/day on days 1-5, followed by 2 days rest) or S-1 (80-120 mg/day on days 1-28, followed by 14 days rest) for 1 year. The primary end point was relapse-free survival (RFS), and the secondary end points were overall survival and adverse events. RESULTS: In total, 961 patients were enrolled from April 2006 to March 2009. The primary analysis was conducted in 480 assigned to receive UFT and 479 assigned to receive S-1. Five-year RFS was 61.7% [95% confidence interval (CI) 57.1% to 65.9%] for UFT and 66.4% (95% CI 61.9% to 70.5%) for S-1 [P = 0.0165, hazard ratio (HR): 0.77, 95% CI 0.63-0.96]. Five-year survival was 80.2% (95% CI 76.3% to 83.5%) for UFT and 82.0% (95% CI 78.3% to 85.2%) for S-1. The main grade 3 or higher adverse events were increased alanine aminotransferase and diarrhea (each 2.3%) in the UFT arm and anorexia, diarrhea (each 2.6%), and fatigue (2.1%) in the S-1 arm. CONCLUSION: One-year S-1 treatment is superior to UFT with respect to RFS and has therefore become a standard adjuvant chemotherapy regimen for stage II/III rectal cancer following curative resection.

S-1 as adjuvant chemotherapy for stage III colon cancer: a randomized phase III study (ACTS-CC trial).

BACKGROUND: S-1 is an oral fluoropyrimidine whose antitumor effects have been demonstrated in treating various gastrointestinal cancers, including metastatic colon cancer, when administered as monotherapy or in combination chemotherapy. We conducted a randomized phase III study investigating the efficacy of S-1 as adjuvant chemotherapy for colon cancer by evaluating its noninferiority to tegafur-uracil plus leucovorin (UFT/LV). PATIENTS AND METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive S-1 (80-120 mg/day on days 1-28 every 42 days; four courses) or UFT/LV (UFT: 300-600 mg/day and LV: 75 mg/day on days 1-28 every 35 days; five courses). The primary end point was disease-free survival (DFS) at 3 years. RESULTS: A total of 1518 patients (758 and 760 in the S-1 and UFT/LV group, respectively) were included in the full analysis set. The 3-year DFS rate was 75.5% and 72.5% in the S-1 and UFT/LV group, respectively. The stratified hazard ratio for DFS in the S-1 group compared with the UFT/LV group was 0.85 (95% confidence interval: 0.70-1.03), demonstrating the noninferiority of S-1 (noninferiority stratified log-rank test, P < 0.001). In the subgroup analysis, no significant interactions were identified between the major baseline characteristics and the treatment groups. CONCLUSION: Adjuvant chemotherapy using S-1 for stage III colon cancer was confirmed to be noninferior in DFS compared with UFT/LV. S-1 could be a new treatment option as adjuvant chemotherapy for colon cancer. CLINICALTRIALSGOV: NCT00660894.

Safety of UFT/LV and S-1 as adjuvant therapy for stage III colon cancer in phase III trial: ACTS-CC trial.

BACKGROUND: The Adjuvant Chemotherapy Trial of TS-1 for Colon Cancer (ACTS-CC) is a phase III trial designed to validate the non-inferiority of S-1 to UFT/leucovorin (LV) as postoperative adjuvant chemotherapy for stage III colon cancer. We report the results of a planned safety analysis. METHODS: Patients aged 20-80 years with curatively resected stage III colon cancer were randomly assigned to receive UFT/LV (UFT, 300 mg m(-2) per day as tegafur; LV, 75 mg per day on days 1-28, every 35 days, 5 courses) or S-1 (80, 100, or 120 mg per day on days 1-28, every 42 days, 4 courses). Treatment status and safety were evaluated. RESULTS: Of 1535 enrolled patients, a total of 1504 (756 allocated to S-1 and 748 to UFT/LV) were analysed. The completion rate of protocol treatment was 77% in the S-1 group and 73% in the UFT/LV group. The overall incidence of adverse events (AEs) were 80% in S-1 and 74% in UFT/LV. Stomatitis, anorexia, hyperpigmentation, and haematological toxicities were common in S-1, whereas increased alanine aminotransferase and aspartate aminotransferase were common in UFT/LV. The incidences of grade 3 AEs were 16% and 14%, respectively. CONCLUSION: Although AE profiles differed between the groups, feasibility of the protocol treatment was good. Both S-1 and UFT/LV could be safely used as adjuvant chemotherapy.

The primary structure of the rat insulin-like growth factor II gene region.

Complete nucleotide sequences of the rat insulin-like growth factor II gene region including 5' 18 kilobases (kb) up to the insulin gene, all exonic and intronic, and 3' 6 kb sequences were determined. Among these sequences several repetitive stretches became evident besides integration of type II Alu and identifier sequences. They were: (1) twelve repetitions of about 100 base pair (bp) units; (2) duplication of 60 bp units; (3) triplication of a 24 bp unit; and (4) 41-fold expansion of 12-15 bp units.

Functional analysis of multiple promoters of the rat insulin-like factor II gene.

We have characterized the multiple promoters of the rat insulin-like growth factor II (rIGFII) gene by in vivo transient expression assay using a series of deletion mutant templates. Among the four promoters (P1, P2, P3 and P6), two (P2 and P3) showed relatively strong promoter activities compared with the other two. One of the four promoters, P2, was further characterized by gel band-shift and footprinting analysis using HeLa cell nuclear extract, showing two retarded bands and at least one protected sequence stretch. The results indicated that P2 has a very simple structure like P3, and consists of no more than 141 base-pairs (bp) including a TATA box and two GC core hexanucleotides. Promoter strength shown by in vivo transient expression in different cell types failed to explain the differential employment of P2 and P3 in these cells, suggesting the involvement of other regulatory mechanisms that might operate only in the native state.

Multiple polyadenylation sites in a large 3'-most exon of the rat insulin-like growth factor II gene.

The rat insulin-like growth factor II (rIGFII) gene produces, in addition to three major mRNA species 3.6 kilobases (kb), 4.6 kb and 3.8 kb in length which represent transcripts from three independent leader-exons, multiple smaller-sized products that distribute broadly in the 1-3 kb region on Northern blots. Structural constituents of these RNAs were analyzed by hybridization with region-specific probes prepared from the entire rIGFII genome. Most of these shorter RNAs contained both 5'-untranslated and coding regions, but only parts of the 3'-untranslated region. At least nine protected sites were mapped within a single 3'-most exon E6 by S1 nuclease analysis. Some but not all of these sites were associated with the upstream polyadenylation signal, AATAAA, or its variants. Since none of the shorter subspecies contained intronic sequences, aberration in splicing is not involved in their generation. Thus, the main parts of submature materials are a collection of discrete species of RNAs, most, if not all, of which are produced by alternative polyadenylation site selection.

Identification and initial characterization of a fourth leader exon and promoter of the human IGF-II gene.

Transcription of the human insulin-like growth factor II (IGF-II) gene is regulated by activation of multiple promoters which act in a tissue-specific and development-dependent manner. Previously, we have identified three different promoters, one of which is active in adult liver tissue only, whereas the other two are active in many fetal tissues and adult non-hepatic tissues. Here we report the identification of a fourth leader exon of the human IGF-II gene indicating the presence of a fourth promoter. Transcription from this promoter yields a 5.0 kb IGF-II mRNA species, which is detected in fetal liver and leiomyosarcoma tissue.

The presence and active transcription of three independent leader exons in the mouse insulin-like growth factor II gene.

The presence of multiple leader exons is one of the common features in the insulin-like growth factor II (IGFII) genes. Among them the 5' most exon sequence, rE1, was so far reported to be present only in the rat genome. We have found a rE1-homologous sequence in the mouse genome (mE1) and have isolated it by genomic cloning. The mE1 sequence was located in the 5' region of the IGFII gene and was considered to take an integral part in the mouse IGFII gene construction, just like in the rat gene. Overall homology between mE1 and rE1 regions was approx. 95%. The mE1 was actively transcribed in the newborn tissues and generated approx. 3.8 kb RNA species. Since the other two leader exon sequences were also active, producing 4.6 kb and 3.6 kb RNA species, respectively, transcription units of the mouse IGFII gene were, thus, composed of three leader exon systems.

Age-related glucose intolerance in hyperthyroid patients.

In an attempt to study age-related metabolic abnormalities, glucose intolerance and serum insulin were examined in normal subjects and hyperthyroid patients. For comparison, serum concentrations of thyroxine (T4), triiodothyronine (T3), and total cholesterol were also measured in normal subjects and hyperthyroid patients. Although serum T4 concentration remained unchanged, serum T3 concentration decreased significantly in an elderly group of normal subjects. Similarly, serum T4 did not change with age and serum T3 decreased slightly but progressively with age in hyperthyroid patients. In addition, serum total cholesterol concentration increased progressively with age in normal subjects. Oral glucose tolerance decreased with age in normal subjects despite the same timing, peak level attained, and total magnitude of insulin response for old and young subjects. Although the severity of hyperthyroidism decreases with age, age-related glucose intolerance was much more apparent in hyperthyroid patients because of the age-related decrease of basal concentration, the peak level attained, and the total magnitude of insulin response. It is suggested that age-related glucose intolerance is magnified by the hyperthyroid state.

Insulinotropic effects of vanadate.

Vanadium compounds are known to affect multiple membrane and cytosolic phosphoenzymes from various tissues; the most characterized effect is the inhibition of Na+-K+-ATPase. Since we previously reported that immunoreactive insulin (IRI) secretagogues tend to inhibit rat islet cation-dependent ATPases, we examined the effects of sodium vanadate on rat IRI secretion from incubated and perifused rat islets. In the presence of 2.4 mM Ca2+, vanadate (10(-3) M) induced biphasic IRI secretion with a background glucose of 100 mg/dl. In the absence of extracellular Ca2+, IRI released from incubated islets by vanadate at 100 and 300 mg/dl glucose was doubled and tripled, respectively. Furthermore, this stimulatory effect was completely abolished by known inhibitors of IRI release such as somatostatin, epinephrine, and diphenylhydantoin. Although we found the expected dose-dependent inhibition by vanadate of islet membrane Na+-K+-ATPase activity, the mechanism of action of vanadate on IRI secretion remains unknown. Vanadate probably interacts in a complex fashion with different islet phosphoenzymes and may prove to be a useful probe to further unravel the mechanisms leading to insulin secretion.

Effects of excess iodide and other anions on thyroid hormone secretion in normal or hypophysectomized rats treated with graded doses of thyroid hormone.

In order to obtain further information about the stimulatory action of excess iodide on thyroid hormone secretion in thyroxine (T4)-treated rats, experiments were performed in hypophysectomized rats, or rats treated with graded doses of T4 or triiodothyronine (T3).T3 as well as T4 played a permissive role in the production of the iodide effect in normal animals, but T3 was more effective than T4. Excess iodide stimulated thyroid hormone secretion in hypophysectomized animals, this finding being compatible with the hypothesis that, by inhibiting TSH secretion, T3 and T4 produced a condition in which excess iodide stimulated thyroid hormone secretion in intact rats. However, T4 played an additional role in thyroid hormone secretion by acting directly on the thyroid. In hypophysectomized animals, small doses of T4 stimulated thyroid hormone secretion, and this action was additive to that of excess iodide, whereas large doses of T4 were inhibitory and reduced the effectiveness of excess iodide. The stimulatory action on thyroid hormone secretion was specific for iodide and was not shared by other anions. The action of excess iodide was blocked by methimazole. We suggest that excess iodide stimulates thyroid hormone secretion by increasing intrathyroidal concentrations of cyclic AMP in the absence of TSH, and that this increase in cyclic AMP concentration is blocked by methimazole.

An increase of plasma triiodothyronine and thyroxine after administration of dexamethasone to hypothyroid patients with Hashimoto's thyroiditis.

In an attempt to study the effect of adrenal steroids on plasma thyroid hormone concentration in patients with Hashimoto's thyroiditis, 2 mg dexamethasone was administered for 2-4 weeks to 9 patients with normal plasma TSH, 3 patients with compensatory increase of plasma TSH, and 10 patients with a marked elevation of plasma TSH. Dexamethasone depressed plasma T4, T3, and TSH and reduced thyroid size in nine euthyroid patients, whereas a similar treatment did not affect plasma T3 and T4, but reduced plasma TSH and thyroid size in three patients with compensatory increase of plasma TSH. In contrast, dexamethasone elevated plasma T3 and T4 in 10 hypothyroid patients with a marked elevation of plasma TSH. The increase of T3 was more than that of T4, suggesting preferential secretion of T3. Plasma TSH was reduced, but was still above normal after administration of dexamethasone. It is suggested that the intrathyroidal autoimmune processes inhibiting thyroid hormone synthesis are significant in patients with more severe Hashimoto's thyroiditis, and that dexamethasone stimulated hormone synthesis by depressing the autoimmune processes.

Volume of sella turcica in normal subjects and in patients with primary hypothyroidism and hyperthyroidism.

In an attempt to assess a possible relationship between pituitary size and TSH secretion, the volume of sella turcica was measured in 570 subjects, 26 primary hypothyroid patients, and 34 thyrotoxic patients. The volume of sella turcica, measured by a 3-dimensional approach, increased progressively with age until 20 years of age and was rather constant thereafter in normal subjects. In thyrotoxic patients, the volume of sella turcica was normal in spite of decreased plasma TSH concentration. In contrast, 81% of primary hypothyroid patients had an abnormal enlargement of the sella turcica. The magnitude of an increase of sella turcica inversely related with a decrease in serum T4 and T3 concentrations. On the other hand, the magnitude of an increase of sella turcica correlated well with an increase of circulating TSH. We suggest that an increase of sella turcica indirectly reflects an increase in pituitary size and TSH-secreting capacity, possibly due to hypertrophy and hyperplasia of TSH cells in primary hypothyroid patients.

Pituitary unresponsiveness to thyrotropin-releasing hormone in thyrotoxic patients during chronic anti-thyroid drug therapy and in rats previously treated with excess thyroid hormone.

In an attempt to study pituitary-thyroid feedback control in thyrotoxic patients, TRH tests were performed in 10 thyrotoxic patients who were treated for varying intervals with propylthiouracil. Plasma TSH was undetectable before and after administration of 500 mug TRH in 7 patients (euthyroid or hypothyroid) after therapy for 1 to 4 months. Also, plasma TSH was undetectable before and after TRH in 3 patients who had been euthyroid for at least 6 months. To explore this abnormality, rats were made thyrotoxic by administering large doses of thyroxine or desiccated thyroid for 3 to 28 days. Discontinuation of thyroid hormone administration was followed by a significant but temporary fall of plasma thyroxine and triiodothyronine concentration below control levels. Duration of the low plasma thyroxine and triiodothyronine concentration was longer with the prolonged administration of thyroid hormone. Despite low plasma thyroxine and triiodothyronine concentrations, plasma TSH was below normal before and after administration of TRH. This unresponsiveness of the pituitary to TRH may be comparable to that found in thyrotoxic patients receiving antithyroid drugs for a certain period. Since this pituitary unresponsiveness to TRH in rats is due to a depletion of pituitary TSH content, it is suggested that depletion of pituitary TSH in thyrotoxic patients during antithyroid therapy is the cause of pituitary unresponsiveness to TRH.

Clinical study of niceritrol on serum lipids in the treatment of hyperlipidemia.

The effects of niceritrol, a nicotinic acid derivative, on the levels of HDL-cholesterol (HDL-Ch) and a mixture of VLDL- and LDL-Ch (VLDL- + LDL-Ch) were studied in hyperlipidemic patients. Serum total cholesterol (sTC) and serum triglyceride (sTG) were significantly reduced during niceritrol administration. Lipoprotein electrophoresis showed that niceritrol increased the alpha:beta ratio. HDL-Ch showed a significant increase of 12.5% by the 16th week of therapy. This increase was more marked in patients with lower pre-treatment HDL-Ch levels and significant in patients whose pre-treatment sTG levels were in excess of 200 mg/dl. Females displayed higher pre-treatment HDL-Ch levels (38.5 mg/dl) than males (30.6 mg/dl). However, niceritrol increased HDL-Ch significantly in both groups. At 16 weeks, the VLDL- + LDL-Ch level showed a significant decrease of 9.2%; the HDL-Ch:VLDL + LDL-Ch and HDL-CH:sTC ratios were significantly increased throughout niceritrol administration. Niceritrol is thought to be effective in preventing the development and progression of atherosclerosis because it raises the level of anti-atherogenic HDL-Ch and lowers the level of atherogenic VLDL- + LDL-Ch.

Histologic and immunohistologic findings and prognosis of 40 cases of gastric large B-cell lymphoma.

It has been considered that gastric large B cell lymphoma mainly consists of mucosa-associated lymphoid tissue lymphoma (MALToma) with large cell transformation. However, debate continues about the cell lineage. We analyzed 61 operated cases of gastric B cell lymphoma, mainly focusing on 40 cases of diffuse large cell lymphoma (DLCL). Immunohistologically, two cases were classified as CD10-positive follicular lymphoma, 19 cases were low-grade MALToma, 11 CD10-negative DLCL with a component of low-grade MALToma (high-grade MALToma), 12 CD10-positive DLCL, and 17 CD10-negative DLCL without MALToma (pure DLCL). Lymphoepithelial lesion (LEL) was found in all -cases of high-grade MALToma, and in eight of these its invasion was confined to the mucosa and submucosa. Expression of Bcl-6 was detected in two cases of high-grade MALToma. Only two cases of CD10-positive DLCL had large cell LEL, and seven cases showed tumor invasion beyond the submucosa. All 12 cases were positive for Bcl-6, and a delicate meshwork of CD35 (Ber-MAC-DRC)-positive follicular dendritic cells was detected in eight cases. Pure DLCL of all 17 cases reached the proper muscle layer or more, and expression of Bcl-6 was detected in 10 cases. For patients with pure DLCL, overall survival was significantly (p <0.05) worse than those of high-grade MALToma and CD10-positive DLCL by Kaplan-Meier and log-rank methods. Clinical staging and Bcl-6 expression were also good prognostic factors in patients with DLCL. Three groups of gastric DLCL each had unique histologic findings, immunohistologic characteristics, and prognosis.

An insulin-like growth factor II-producing histiocytoma associated with hypoglycemia: analysis of the peptide, its gene expression, and glucose transporter isoforms.

An insulin-like growth factor II (IGF-II)-producing histiocytoma was detected in a patient presenting with the classical findings of tumor-related hypoglycemia (low serum insulin and IGF-I concentrations, glucose intolerance, and only modestly increased serum IGF-II levels). Acid-gel filtration of serum extracts showed a single peak of IGF-II immunoreactivity that emerged at the same site as the 125I-labeled human IGF-II standard. High-performance liquid chromatography (HPLC) analysis of the tumor IGF-II demonstrated that it had an identical retention time to that of recombinant human IGF-II. The tumor IGF-II content was extremely high, messenger RNA (mRNA) for IGF-II showed a 100-fold increase in expression compared with normal human liver tissue. Of special interest, a newly identified exon (hE1) was shown to be predominantly expressed in the tumor by Northern blot analysis using leader exon-specific rat IGF-II complementary DNA (cDNA) probes. Although the significance of this finding remains uncertain, this is the first evidence of a new transcription unit in the human IGF-II gene. In addition, immunoblotting showed that the levels of the glucose transporters, GLUT1 and GLUT4, in the tumor were low and undetectable, respectively. This finding makes it unlikely that increased glucose consumption by the tumor accounted for the hypoglycemia in this patient. This case report provides an interesting insight into the pathophysiology of tumor-induced hypoglycemia and new evidence of the abnormal regulation of IGF-II gene expression in human tumors.

In vivo growth regulation by cytokine in breast cancer cells showing an estradiol-inhibitive response in vitro.

The rates of the stimulative, insensitive, and inhibitive responses to 10(-2) nM E2 in sixty clinical breast cancer cases were 24.2%, 45.2%, and 30.6%, respectively. We then examined the expression of mRNAs of such cytokines as TNF-alpha, TGF-alpha, EGF, and TGF-beta, in cancer tissue specimens from these three different groups. In MCF-7 showing an E2-stimulative response, the expression of mRNAs of both TNF-alpha and TGF-alpha were suppressed by 10(-2) nM E2, but these same expressions in KSE-1 showing an E2 stimulative response were enhanced by E2. The mRNA expression of TGF-beta in these two cell lines was suppressed by 10(-2) nM E2, but that of EGF was enhanced. In clinical cases showing an E2-inhibitive response, the mRNA expression ratio of TNF-alpha/TGF-beta was above 2.5, but under 2.5 in E2-uninhibitive response cases. The mRNA expression ratio of TGF-alpha/TGF-beta was over 1.8 in the E2-inhibitive responsive cases, but under 1.8 in the E2-uninhibitive response cases. The mRNA expression ratio of EGF/TGF-beta did not show any regular tendency in three groups showing a different E2-response in vitro. Based on in vitro results and mRNA expression in clinical cases, the cytokine expression for E2-inhibitive cancer cells differed from those of E2-stimulative and -insensitive cells. Therefore, E2-inhibitive cancer cells are thus considered to possibly possess a characteristic growth regulation which is different from that for E2-uninhibitive cancer cells.

Surgical treatment for advanced gastric cancer.

BACKGROUND/AIMS: We herein report on the clinicopathological factors related to the unresectability of far advanced gastric cancer and the prognostic effect of gastrectomy on these cases. MATERIAL AND METHODS: There are four main prognostic factors for advanced gastric cancer including 1) peritoneal dissemination, 2) hepatic metastasis, 3) lymph node involvement and 4) invasion to adjacent organs. RESULTS: The rate of unresectability was high in the cases demonstrating both histologically undifferentiated type cancer and cancers located in the lower third of the stomach. It was difficult to resect the main tumor based on an increase in the factors regulating the macroscopical stage. The rate of unresectability tended to be higher in cancers with peritoneal dissemination or invasion to adjacent organs. The pancreas was the most frequently invaded organ. accounting for the unresectability of the disease. The prognosis for cases with unresected gastric cancers was poor and all died within 2 years of the operation. In addition, the prognosis for cases with Stage IV gastric cancer, demonstrating either 1 or 2 factors, improved after gastrectomy while no such improvement was seen in cases with 3 or 4 factors. CONCLUSIONS: To improve prognosis, gastrectomy should be performed when a patient has far advanced gastric cancer but only demonstrates 1 or 2 of the above 4 factors.

Retrospective study on the effects of lipiodolization before a potentially curative hepatectomy for colorectal liver metastases: long-term results of a pilot study.

BACKGROUND/AIMS: Lipiodolization, a selective regional cancer chemotherapeutic modality using lipiodol plus anticancer drugs, can prolong the survival time of patients with unresectable liver cancer. A preliminary study was conducted with adjuvant lipiodolization before a potentially curative hepatectomy for patients with metachronous colorectal liver metastases. The ultimate aim of this study was to improve the long-term survival after hepatectomy. METHODOLOGY: Twenty-one consecutive patients with colorectal hepatic metastases were included in this study. Seven patients underwent preoperative lipiodolization, while the remaining 14 patients did not receive any preoperative adjuvant therapy. The clinicopathological features and prognoses of these patients were investigated. The median follow-up period after a curative hepatectomy was 56 months. RESULTS: The clinicopathological factors did not differ markedly between the 2 groups. However, the cumulative survival rate of the 7 patients receiving preoperative lipiodolization was significantly (P < 0.05) better than that in those not receiving any preoperative treatment. CONCLUSIONS: Based on the above encouraging findings, we therefore propose that a prospective randomized trial should be carried out to confirm the beneficial effects of our adjuvant chemotherapeutic modality on patient survival following a curative hepatectomy for the patients with colorectal liver metastases.