Haruhiko Cho

Is Adenocarcinoma of the Esophagogastric Junction Different between Japan and Western Countries? The Incidence and Clinicopathological Features at a Japanese High-Volume Cancer Center

BackgroundWe clarified the incidence of adenocarcinoma of the esophagogastric junction (AEG) at a Japanese high-volume cancer center and its clinicopathological features between the Siewert subtypes.MethodsPatients with AEG were selected from a prospective database of gastric and esophageal tumors established by Kanagawa Cancer Center. The Siewert subtypes were determined retrospectively by examining pathological pictures of the resected specimens and by evaluating the pathology and endoscopy findings.ResultsFrom January 1986 to December 2005, 147 (4.0%) patients were determined to have AEG; 2,794 (75.8%) were diagnosed to be true gastric cancer, whereas 745 (20.2%) were true esophageal cancer. Of these 147 patients with AEG, 5 (3.4%) were classified as type I, 82 (55.8%) as type II, and 60 (40.8%) as type III tumors. The depth of tumor invasion was deeper and the nodal metastases were more frequent in type III compared with type II. The risk factors for nodal metastases included the depth and size of the tumor, but not the Siewert subtypes itself. Mediastinal nodal metastases were strongly influenced by a thoracotomy and the extent of the dissection. The pathological grade was higher in type III than in type II. Although the 5-year survival rate was significantly higher in type II than in type III tumors, the survival difference disappeared when the patients were restricted to an R0 resection, even though type III patients demonstrated a more advanced stage.ConclusionsThe proportions of AEG were strikingly different between Japan and western countries. Although each Siewert subtype had some different characteristics, nodal metastases were determined by both the tumor progression and the extent of the nodal dissection. An R0 resection was a key for the survival in AEG.

A prospective validation study to diagnose serosal invasion and nodal metastases of gastric cancer by multidetector-row CT.

BackgroundMultidetector-row CT (MDCT) may provide accurate preoperative staging of resectable gastric cancer. However, the standard methods and criteria to diagnose the T and N stages to select the patients who are good candidates for neoadjuvant chemotherapy have not been established yet.MethodsThe aim of this prospective study was to evaluate the accuracy of MDCT to diagnose the serosal invasion and nodal metastases of gastric cancer. Patients who had gastric adenocarcinoma underwent MDCT scanning using a standardized method. The T and N stage were diagnosed by prespecified criteria. The analyses were performed in the patients who had cN0–2 and M0 tumors and underwent curative gastrectomy as a primary treatment. The accuracy was calculated by comparing the results of MDCT with the histopathological findings.ResultsA total of 315 patients were analyzed. The overall diagnostic accuracy (95 % confidence interval) of T staging was 71.4 % (225 of 315, 66.2–76.1). The accuracy, sensitivity, and specificity for serosal invasion were 85.7 % (81.4–89.1), 54.5 % (42.6–66.0), and 94.0 % (90.3–96.3), respectively. The false-positive rate for serosal invasion was 6.0 % (2.9–7.7). The overall diagnostic accuracy of N staging was 75.9 % (239 of 315, 70.9–80.3). The accuracy, sensitivity, and specificity for nodal metastases were 81.3 % (76.6–85.2), 46.4 % (36.8–56.3), and 96.8 % (93.5–98.4), respectively. The false-positive rate for nodal metastases was 3.2 % (1.6–6.5 %).ConclusionsThese results suggest that MDCT provides an accurate diagnosis with high specificity and a low false-positive rate and can be used to select the patients who are candidates for preoperative chemotherapy.

Clinical Diagnosis of Metastatic Gastric Tumors: Clinicopathologic Findings and Prognosis of Nine Patients in a Single Cancer Center

The clinical features of metastatic gastric tumors (MGTs) have not been well documented. We present a clinical series of nine patients with MGTs. Among 2579 patients with gastric tumors seen between 1992 and 2001, we studied 9 (0.3%) patients with MGT according to a prospective database. The MGTs were diagnosed based on findings in the surgical or endoscopic specimen, and patients with malignant lymphoma or direct invasion from adjacent organs were excluded from the study. MGTs were detected simultaneously with the primary tumors in three and afterward in six patients at 14 to 74 months. The primary tumors included one each of squamous cell carcinoma of the esophagus, signet-ring cell carcinoma of the breast, large-cell or small-cell carcinoma of the lung, renal cell carcinoma, hepatocellular carcinoma, squamous cell or epidermoid carcinoma of the uterus, and melanoma. Multiple organ metastases were present simultaneously in six patients. Although six patients underwent gastrectomy, macroscopic eradication of gastric metastatic disease was accomplished in only four, in whom a UICC R0 resection was possible in only two. Five patients were treated by chemotherapy with no apparent survival benefit. A median survival after MGT diagnosis was 170 days (range 16-892 days) for all cases, 384 days for those who underwent gastrectomy (n = 6), and 27 days for those without active treatment (n = 3) (p = 0.002). The cause of death was multiple organ metastases in most cases. Because multiple metastases are common, the prognosis of MGT is poor even after curative resection. MGT is likely to be a preterminal event, and surgical resection may be useful only for palliation.

A Comparison of Multimodality Treatment: Two or Four Courses of Paclitaxel plus Cisplatin or S-1 plus Cisplatin Followed by Surgery for Locally Advanced Gastric Cancer, a Randomized Phase II Trial (COMPASS)

This randomized Phase II trial compares neoadjuvant chemotherapy of two or four courses of S-1 (1 M tegafur-0.4 M gimestat-1 M ostat potassium) plus cisplatin or paclitaxel plus cisplatin by a two-by-two factorial design for patients with macroscopically resectable locally advanced gastric cancer. The primary endpoint is the 3-year overall survival. The sample size is 60-80 in a total for two hypotheses of the superiority of four courses to two courses and the superiority of paclitaxel plus cisplatin to S-1 plus cisplatin. In both arms, S-1 is strongly recommended post-operatively for at least 6 months but no adjuvant chemotherapy is permitted other than S-1 until recurrence. This trial could appraise more suitable cycles and regimen as neoadjuvant chemotherapy for gastric cancer.

Impact of plasma tissue inhibitor of metalloproteinase-1 on long-term survival in patients with gastric cancer

BackgroundThe expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) is correlated with tumor invasion and metastases.MethodsThe plasma TIMP-1 concentration was examined preoperatively in 149 patients with gastric cancer who underwent a surgical resection. The cutoff value of TIMP-1 was set at 112.5 ng/ml based on a previous report. These patients were followed up for more than 5 years prospectively.ResultsPlasma TIMP-1 was positive in 30 of the 149 patients (20.1%). The overall survival rate was 78.2% at 5 years in patients with negative plasma TIMP-1, while this rate was 26.7% at 5 years in patients with positive plasma TIMP-1. By univariate analyses, T, N, M, and R category, and TIMP-1, were significant prognosticators. Multivariate analyses demonstrated T, N, and TIMP-1 to be significant prognosticators. The survival curve was clearly separated with respect to TIMP-1.ConclusionThese results suggest that plasma TIMP-1 is a strong independent prognosticator for the long-term survival of patients with gastric cancer.

Prognostic value of extracapsular invasion and fibrotic focus in single lymph node metastasis of gastric cancer

BackgroundHistological findings of metastatic lymph nodes are important prognosticators in patients with gastric cancer. The aim of this study was to clarify the clinical significance of various pathological characteristics of the early phase of lymph node metastasis in patients with gastric cancer, by selecting patients with tumors that had single lymph node metastases, no serosal invasion, and no metastases to the peritoneum, liver, or distant organs.MethodsSeventy-eight patients were eligible and were entered in this study. These patients were subdivided according to the following histological characteristics of the one metastatic lymph node: size of the metastasis (i.e., amount of tumor cells [AT]), proliferating pattern (PP), intranodal location (IL), and the presence or absence of extracapsular invasion (ECI) and/or fibrotic focus (FF). Associations between clinicopathological factors, survival, and the nodal findings were examined.ResultsThere were no correlations between AT or PP and any clinicopathological factors. IL was significantly correlated with venous invasion and the pathological characteristics of the primary tumor. ECI and FF were observed significantly more frequently in pT2 than in pT1 cancer. Overall survival (OS) differed significantly according to depth of invasion, venous invasion, and the presence or absence of ECI or FF, although OS was not affected by AT, PP, or IL. The 10-year overall survival rates of patients with and without ECI were 50 % and 80 %, respectively, while these rates for patients with and without FF were 50 % and 79 %, respectively. Multivariate analysis revealed that ECI and FF were significant prognosticators of survival.ConclusionThese results strongly suggested that the presence of ECI or FF could affect the survival of patients with gastric cancer.

Clinical and pathological study of gastric cancer with ovarian metastasis.

Abstract.Background: The aim of this study was to determine the treatment strategy for ovarian metastases from gastric cancer, by a retrospective study of the treatment results. Methods: We reviewed the records of patients with ovarian metastases from primary gastric cancer. Ovarian metastases were found in 24 of 897 female patients with gastric cancer. Of these, 21 patients with histologically proven disease were studied. Results: Ovarian metastasis was detected before the primary gastric cancer in 1 patient, simultaneously in 6, and after in 14. Ovarian tumors were detected by computed tomography (CT) in a majority of patients (95%), while uterine tumors were detected in only 29%. Metastasis to the uterus was histologically examined in 14 tumors and confirmed in 11 tumors. All patients with positive endometrial cytology had uterine metastases. Total abdominal hysterectomy was performed with bilateral salpingo-oophorectomy in 12 patients and with unilateral resection in 2. In these 14 patients, 5 were curatively operated. In the clinical course, all patients developed multiple metastases, and patients suffered peritoneal dissemination. None survived for longer than 3 years. The median survival time after ovarian metastases (MST) was 10.3 months for all patients; 3.6 months in patients in their sixties, and 12.5 months in those in their fifties. Survival was significantly longer in patients who underwent curative resection (MST, 30.4 months) compared with those who had noncurative resection (MST, 10.3 months). Conclusion: The prognosis for ovarian metastasis of gastric cancer was poor without curative resection. Because of frequent microscopic metastases to the uterus, total hysterectomy with bilateral oophorectomy is recommended if curative resection is possible.

Indications for Staging Laparoscopy in Clinical T4M0 Gastric Cancer

BackgroundThis study was undertaken to determine the efficacy of the clinical indications for performing staging laparoscopy for locally advanced gastric cancer to detect peritoneal metastasis or positive cytology findings.MethodsThe study included 231 patients with T4 gastric cancer without hematogenous or clinically evident peritoneal metastasis. The clinicopathologic features, including T and N factors, were diagnosed by clinical staging. The relation between the clinicopathologic features and the presence of peritoneal metastasis or lavage cytology at surgery was analyzed.ResultsA total of 31 patients underwent staging laparoscopy; 200 others underwent open surgery as a primary treatment. Both peritoneal metastasis and lavage cytology were negative in 145 (62.8%) patients, whereas peritoneal metastasis or lavage cytology was positive in 86 patients (37.2%). When calculating diagnostic accuracy in the 23 patients who underwent open laparotomy after staging laparoscopy, the accuracy rate was 95.7%. A multivariate analysis showed that a tumor location involving three portions; macroscopic type 3, 4, or 5; and positive lymph node metastasis to all three is significantly correlated with either peritoneal metastasis or positive cytology. When patients had two or three factors among these three independent risk factors, peritoneal metastasis or positive cytology could be detected with 91.9% sensitivity and 46.7% positive predictive value.ConclusionsThe selection of T4 tumors based on clinically evaluable risk factors is therefore considered useful for detecting peritoneal metastasis efficiently and hence avoiding unnecessary staging laparoscopy.

A comparison of multimodality treatment: two and four courses of neoadjuvant chemotherapy using S-1/CDDP or S-1/CDDP/docetaxel followed by surgery and S-1 adjuvant chemotherapy for macroscopically resectable serosa-positive gastric cancer: a randomized phase II trial (COMPASS-D trial).

This randomized Phase II trial will compare the outcome of neoadjuvant chemotherapy using two and four courses of S-1 plus cisplatin or S-1 plus cisplatin plus docetaxel by a two-by-two factorial design for patients with macroscopically resectable serosa-positive gastric cancer. After neoadjuvant chemotherapy, patients will receive D2 gastrectomy followed by S-1 chemotherapy for 1 year postoperatively. The primary endpoint is the 3-year overall survival. The sample size is 120 for the two hypotheses: the superiority of four courses compared with two courses and the superiority of S-1 plus cisplatin plus docetaxel compared with S-1 plus cisplatin. This trial will be able to define the more suitable number of cycles and better regimen of neoadjuvant chemotherapy for gastric cancer.

Establishment of patient-derived cancer xenografts in immunodeficient NOG mice

Viable and stable human cancer cell lines and animal models combined with adequate clinical information are essential for future advances in cancer research and patient care. Conventional in vitro cancer cell lines are commonly available; however, they lack detailed information on the patient from which they originate, including disease phenotype and drug sensitivity. Patient-derived xenografts (PDX) with clinical information (so-called ‘cancer xenopatients’) are a promising advance that may accelerate the development of anticancer therapies. We established 61 PDX lines from 116 surgically removed tumor tissues inoculated subcutaneously into NOG mice (53% success rate). PDX lines were established from various types of epithelial tumors and also from sarcomas, including gastrointestinal stromal tumors and Ewing/PNET sarcomas. The metastatic tumors yielded PDX lines more effectively (65%) than the primary tumors (27%, P<0.001). In our PDX models, morphological characteristics, gene expression profiles, and genetic alteration patterns were all well preserved. In eight cases (7%), the transplantable xenografts for several generations were composed of large monotonous nonepithelial cells of human origin, revealed to be Epstein-Barr virus infection-associated lymphoproliferative lesions. Despite this, PDX linked with clinical information offer many advantages for preclinical studies investigating new anticancer drugs. The fast and efficient establishment of individual PDX may also contribute to future personalized anticancer therapies.