Yoshinori Hosoya

Phase II feasibility study of preoperative chemotherapy with docetaxel, cisplatin, and fluorouracil for esophageal squamous cell carcinoma

The combination of docetaxel, cisplatin, and 5‐fluorouracil (DCF) as preoperative treatment for esophageal squamous cell carcinoma (ESCC) has not been investigated. We carried out a multicenter phase II feasibility study of preoperative chemotherapy with DCF for ESCC. Patients with clinical stage II/III ESCC (International Union Against Cancer TNM classification system, 6th edition) were eligible. Chemotherapy consisted of i.v. docetaxel (70–75 mg/m2) and cisplatin (70–75 mg/m2) on day 1, and continuous infusion of fluorouracil (750 mg/m2/day) on days 1–5. Antibiotic prophylaxis on days 5–15 was mandatory. This regimen was repeated every 3 weeks with a maximum of three cycles allowed. After completion of chemotherapy, esophagectomy with extended lymphadenectomy was carried out. The primary endpoint was the completion rate of protocol treatment. Forty‐two eligible patients were enrolled. During chemotherapy, the most common grade 3 or 4 toxicities were neutropenia (83%), anorexia (7%), and stomatitis (5%). Forty‐one (98%) patients underwent surgery. The completion rate of protocol treatment was 90.5% (38/42). No treatment‐related death was observed and the incidence of operative morbidity was tolerable. According to RECIST, the overall response rate after the completion of DCF was 64.3%. Pathological complete response was achieved in 17%. The estimated 2‐year progression‐free survival and overall survival were 74.5% and 88.0%, respectively. Although these data are preliminary, preoperative DCF was well tolerated. Antitumor activity was highly promising and warrants further investigation. This trial was registered with University Hospital Medical Information Network (no. UMIN000002396).

Regulatory SNP in the RBP4 Gene Modified the Expression in Adipocytes and Associated With BMI

Retinol‐binding protein 4 (RBP4) is a recently identified adipokine that was involved in insulin resistance. RBP4 is predominantly expressed from the liver in normal metabolic state to transport retinoids throughout the body, but the exact physiological function and the regulatory mechanisms of adipocyte‐derived RBP4 have not been revealed. We conducted the genetic analysis about metabolic parameters in Japanese and Mongolian; the minor allele carriers of regulatory single‐nucleotide polymorphism (SNP −803G>A) showed significantly higher BMI in Japanese men (P = 0.009) and women (P = 0.017), and in Mongolian women (P = 0.009). Relative quantification of RBP4 transcripts in −803GA heterozygotes showed that the minor allele–linked haplotype‐derived mRNA was significantly more abundant than the transcript from major allele. RBP4 promoter assay in 3T3L1 adipocytes revealed that the minor allele increased the promoter activity double to triple and the administration of 9‐cis‐retinoic acid (RA) and 8‐bromo‐cyclic adenosine monophosphate (8‐Br‐cAMP) enhanced the activity. Multiple alignment analysis of human, mouse, rat, and cattle RBP4 promoter suggested conserved seven transcription factor binding motifs. Electrophoretic mobility shift assay showed the −803G>A SNP modulate the affinity against unidentified DNA‐binding factor, which was assumed to be a suppressive factor. These results collectively suggested that the minor allele of RBP4 regulatory SNP enhanced the expression in adipocytes, which may be associated with the adipogenesis.

Prevalence of Synchronous Colorectal Neoplasms Detected by Colonoscopy in Patients with Gastric Cancer

PurposeOur purpose was to study the characteristics of colorectal neoplasms in patients with gastric cancer (GC).MethodsThe study group comprised GC patients who underwent colonoscopy before resection of their GC. We examined the prevalence, site, and histology of colorectal neoplasms, as well as the clinicopathological features and treatment of the patients who had synchronous colorectal cancers (CRC). The logistic regression model was applied to investigate the features of the GC patients with concurrent CRC.ResultsWe studied 466 GC patients (mean age 64.5 years; 147 women, 319 men), 143 (31%) of whom had a family history of gastrointestinal cancer. Synchronous colorectal adenoma and cancer were detected in 182 (39%) and 18 (4%) patients, respectively. Among the 18 synchronous CRCs, 11 were in the early stages and 10 of these were resected endoscopically. The other eight required simultaneous open radical surgery. All the GC patients with synchronous CRC were older than 50 years. Statistical analysis did not show a significant difference between the features of the patients with and those without concurrent CRC.ConclusionsThe possibility of synchronous colorectal neoplasms in GC patients cannot be disregarded in clinical practice; however, screening of the large bowel may not be necessary in GC patients younger than 50 years.

MEN1 gene mutations in sporadic neuroendocrine tumors of foregut derivation

Foregut‐derived neuroendocrine (NE) tumors occur sporadically or in association with multiple endocrine neoplasia type 1 (MEN1) syndrome. Thirty‐nine sporadic NE tumors of foregut derivation (six thymic, 21 bronchial, three gastric, and nine pancreatic tumors) as well as two hindgut‐derived rectal carcinoids for somatic MEN1 gene mutation were analyzed by direct sequencing analysis. Five tumors showed mutations: nonsense mutations (Q393X and R98X) in thymic and pancreatic NE tumors, respectively, a 4 b.p. deletion (357del4) in a gastric NE carcinoma, and missense mutations (D172Y and S178Y) in pancreatic NE tumors. No mutation was identified in pulmonary or rectal NE tumors. In a patient with a pancreatic NE tumor (D172Y), the corresponding germline DNA showed the same mutation, suggesting that sporadic MEN1 syndrome was masked in this case. Somatic MEN1 gene mutations and deletions may play a crucial role in the tumorigenesis of a subset of foregut‐derived NE tumors. Sporadic MEN1 syndrome may occur as a sporadic NE tumor of the pancreas.

Reliability and validity of a new scale to assess postoperative dysfunction after resection of upper gastrointestinal carcinoma

PurposeWe evaluated the purpose reliability and validity of a preliminary scale, which we developed to assess postoperative dysfunction after surgery for gastric and esophageal carcinoma.MethodsAfter interviews with 12 patients, reviews of previous studies, and discussions with experts, we identified the physical symptoms that develop after resection of upper gastrointestinal (GIT) carcinoma, and devised a preliminary scale comprised of 34 items. A questionnaire survey based on this scale was then sent to 283 patients.ResultsThe questionnaire was returned by 223 patients (78.8%), and 219 responses (98.2%) were valid. Among the 219 respondents, 168 had gastric carcinoma and 51 had esophageal carcinoma. After the elimination of scale items regarded as irrelevant based on statistical considerations and the judgment of experts, factor analysis was done. Seven factors were valid, namely, limited activity due to decreased food consumption, reflux, gastric dumping, nausea and vomiting, deglutition difficulty, pain, and difficulty with passing stools, which were often poorly formed. Scale reliability was confirmed by a Cronbach α-coefficient of 0.924. The validity of the construction of this scale was confirmed using the known-group technique based on the operative procedures performed, and the results of factorial validity.ConclusionOur preliminary scale is sufficiently reliable and valid, and will prove to be clinically useful.

Alternate-day oral therapy with TS-1 for advanced gastric cancer.

BackgroundTS-1 (1 M tegafur-0.4 M 5-chloro-2,4-dihydroxypyrimidine-1 M potassium oxonate) has a high single-agent response rate, of more than 40%, for gastric cancer; however, the recommended regimen of 4 weeks of administration interrupted by 2 weeks of drug withdrawal frequently causes adverse effects. The alternate-day dosage of pyrimidine fluoride anticancer drugs could reduce their adverse effects without compromising their effects. We attempted an alternate-day therapy with TS-1 aiming at the avoidance of adverse effects and significantly longer duration of administration.MethodsWe observed patients for clinical effects and adverse effects under alternate-day dosage of TS-1, and determined blood 5-fluorouracil (FU) levels. The judgment of clinical effects was based on the New Guidelines to Evaluate the Response to Treatment in Solid Tumors (RECIST), whereas the evaluation of adverse effects was based on the National Cancer Institute NCI-common toxicity criteria (CTC).ResultsIn 72 (78%) of 92 patients, the TS-1 regimen was converted to the alternate-day dosage because of adverse effects. Twenty patients were treated with the alternate-day dosage regimen from the start because of the fear of adverse effects. The alternate-day dosage was clinically effective, as 28 of 34 patients after relatively curative resection remained alive and free from recurrence. The median survival time of 58 patients after noncurative resection or with unresectable or recurrent cancer was 332 days. Fifty-three percent of these 58 patients achieved partial response and stable disease of more than 12 weeks’ duration. We followed time-dependent changes in blood 5-FU levels in 36 of the patients on alternate-day therapy, in whom TS-1 had been administered daily before being administered every other day. The trough level was significantly lower when TS-1 was administered on alternate days, and blood 5-FU reached a peak at sufficiently effective levels at 2 h even after administration on the alternate-day basis.ConclusionThis study demonstrated that, compared with daily administration, alternate-day administration of TS-1 reduces adverse effects, and simultaneously ensures effective blood levels and provides sufficient clinical effects.

Clinicopathological study of lymph‐node metastasis in 1389 patients with early gastric cancer: Assessment of indications for endoscopic resection

BACKGROUND:  The endoscopic resection of early gastric cancers (EGC) is a standard technique in Japan and is increasingly used throughout the world. Further experience in the treatment of EGC and a clearer delineation of the factors related to lymph‐node metastasis would permit a more accurate assessment of endoscopic resection.

Minimum Leakage Rate (0.5%) of Stapled Esophagojejunostomy with Sacrifice of a Small Part of the Jejunum after Total Gastrectomy in 390 Consecutive Patients

Background: The development of new surgical instruments and devices has facilitated the performance of esophagojejunostomy after total gastrectomy. However, total prevention of dehiscence of anastomoses remains difficult. We introduced a new procedure for esophagojejunostomy using a circular stapler, requiring sacrifice of only a small part of the jejunum. Methods: The study group comprised 390 consecutive patients who underwent reconstruction by Roux-en-Y esophagojejunostomy, performed with a circular stapler, sacrificing a small part of the jejunum after total gastrectomy. We assessed anastomotic leakage and anastomotic stenosis after surgery. Results: Only 2 patients (0.5%) had leakage and 4 (1.0%) had anastomotic stenosis after reconstruction. All the patients were cured by conservative therapy. Conclusions: Esophagojejunostomy performed with a circular stapler after total gastrectomy, with sacrifice of only a small part of the jejunum, is a useful and easy procedure, with a leakage rate of 0.5%.

Gastric Schwannoma Sonographic Findings

Schwannomas, known as neurinomas and neurilemmomas, are benign, slow-growing neoplasms originating in any nerve that has a Schwann cell sheath. They rarely occur in the digestive tract, but when they do, the most common site is the stomach, 1 , 2 and they represent 0.2% of all gastric tumors. 1 Among 150 gastric submucosal tumors (G-SMTs), only 6 gastric schwannomas (4%) have been found. 3 Because gastric schwannomas are usually covered by intact mucosa and principally involve the submucosa and muscularis propria, 1 - 3 they are categorized as G-SMTs. Although conventional procedures, such as a barium meal and an endoscopic study, are important in the initial evaluation of a G-SMT, they cannot provide enough information in the differential diagnosis of a G-SMT. Cross-sectional imaging findings, such as magnetic resonance imaging4 and transabdominal sonography, may be useful in the detection and characterization of a G-SMT and its relationship with surrounding organs. We describe here the sonographic findings of gastric schwannoma in a 65-year-old patient. To our knowledge, no previous case reported included sonographic documentation.

Comparison of alternate-day versus consecutive-day treatment with S-1: assessment of tumor growth inhibition and toxicity reduction in gastric cancer cell lines in vitro and in vivo

BackgroundThe toxic effects of S-1 can lead to discontinuation of treatment. Strategies for reducing toxicity without compromising therapeutic effectiveness are required.MethodsWe used the human gastric cancer cell lines MKN28 and MKN45 to examine such strategies in vitro. The cell lines were treated with three different regimens, given on alternate days (alternate-day) or on consecutive days (consecutive-day). On consecutive days, treatment A provided the same total dose as the alternate-day treatment, and treatment B was given for the same number of days as the alternate-day treatment. A fourth group served as control. In vitro, the relative inhibition (RI) of tumor growth by 5-fluorouracil was calculated using the 2-(2-methyl-4-nitrophenyl)-3-(4-nitrophyl)-5-2, 4-disulfophenyl)-2H-tetrazolium (WST-8) method. We also carried out an in vivo experiment in which tumor-bearing nude mice (BALBc/nu-nu) were used to examine the antitumor activity of S-1. Leukocyte counts and gastrointestinal mucosal injury were compared in mice that received alternate-day and consecutive-day treatments.ResultsIn vitro, for MKN28, the RI was 22.9% for alternate-day, 34.1% for consecutive-day A, and 37.7% for consecutive-day B treatments. For MKN45, the RI was 51.1% for alternate-day, 52.2% for consecutive-day A, and 50.5% for consecutive-day B treatments. In vivo, for MKN28, the treated groups showed higher inhibition than the control, and inhibition of tumor growth was higher with alternate-day than with consecutive-day treatment. The RI was significantly higher with alternate-day (49.3%) than with consecutive-day treatment (16.2%; P < 0.05). For MKN45, the RI was greater than 50% in both treated groups. With consecutive-day treatment, 5 of the 14 mice used died during treatment. Leukocyte counts were lower in the mice with consecutive-day than with alternate-day treatment, or control. Atrophic changes and inflammatory cell infiltration of the small intestinal mucosa were severe after consecutive-day, but minimal after alternate-day treatment.ConclusionExperimentally, alternate-day treatment with S-1 is equivalent to consecutive-day treatment in terms of RI of tumor growth, with lower toxicity.