Published papers

Background. Scirrhous gastric cancer is biologically aggressive, and the prognosis is poor even with curative surgery. We compared outcomes with different therapies in order to identify prognostic factors. Methods. Records for 83 patients, who were treated between 1991 and 2004, were evaluated for survival and stage, treatment, and clinicopathological factors. Results. Cumulative 5-year overall survival was 10.2% for all 83 patients, including 27 (32.5%) patients with stage II/III disease and 56 (67.4%) with stage IV disease. The 5-year overall survival rate and median survival time for patients with stage II/III disease after curative surgery were 24.3% and 1150 days. For patients with stage IV disease, 2-year and 5-year survival rates after initial surgery were 13.7% and 0% and median survival was 250 days. In contrast, preoperative chemotherapy for advanced, unresectable disease produced 2-year and 3-year overall survival rates of 53.6% and 26.8% and medican survival was 910 days. Conclusion. Aggressive surgery alone does not seem to improve outcome, but preoperative chemotherapy might be beneficial and should be investigated further.

Background: Endoscopic classifications were reported to reflect the pathophysiology of gastric mucosa. However, relationship between gastric lesions and classifications has not been examined well. Aim: To investigate the relationship between endoscopic classifications and cancers or ulcers. Methods: In this study, 487 patients undergoing upper gastrointestinal endoscopy in Takahashi Clinic and 257 patients with early gastric cancer in Keio University Hospital were enrolled. Results: Incidence of reflux oesophagitis was higher in Helicobacter pylori-negative patients. K-form was better in the H. pylori-positive patients. Most cancers in the patients with the closed-type or reflux oesophagitis were of undifferentiated types. Incidences of ulcers were highest in C-2 and C-3 in which the borders of atrophy cross the medial oblique muscle bundle, the border circular muscle bundle or both, and 94% of ulcers in C-2 and C-3 stomach were located along the lesser curvature. Conclusion: The predominant existence of undifferentiated types in patients with reflux oesophagitis or closed-type stomach can be useful information for early diagnosis of cancers. The relationship between the Kimura-Takemoto classification and ulcer location may explain why H. pylori infection is related to ulcer formation along the lesser curvature.

Background: Endoscopic classifications were reported to reflect the pathophysiology of gastric mucosa. However, relationship between gastric lesions and classifications has not been examined well. Aim: To investigate the relationship between endoscopic classifications and cancers or ulcers. Methods: In this study, 487 patients undergoing upper gastrointestinal endoscopy in Takahashi Clinic and 257 patients with early gastric cancer in Keio University Hospital were enrolled. Results: Incidence of reflux oesophagitis was higher in Helicobacter pylori-negative patients. K-form was better in the H. pylori-positive patients. Most cancers in the patients with the closed-type or reflux oesophagitis were of undifferentiated types. Incidences of ulcers were highest in C-2 and C-3 in which the borders of atrophy cross the medial oblique muscle bundle, the border circular muscle bundle or both, and 94% of ulcers in C-2 and C-3 stomach were located along the lesser curvature. Conclusion: The predominant existence of undifferentiated types in patients with reflux oesophagitis or closed-type stomach can be useful information for early diagnosis of cancers. The relationship between the Kimura-Takemoto classification and ulcer location may explain why H. pylori infection is related to ulcer formation along the lesser curvature.

A recent development of novel anticancer agents like S-1, CPT-11 or taxanes has improved a therapeutic outcome for advanced gastric cancer, while conventional anticancer agents showed less anticancer effect against gastric cancer. The present main drug in Japan is S-1, which is easily used for outpatient with a high efficacy rate and low toxicity, also shows better effect in combination with other anticancer drugs than S-1 alone. In the present article, we demonstrated significant meaning of additional radiation therapy with anticancer drugs like S-1. With novel anticancer drugs like S-1, we will expose a clinical advantage and appropriateness for chemo-radiation therapy against gastric cancer discussed in the present references according to chemo-radiation therapy. Although chemo-radiation therapy has been recognized as one of the standard therapies for gastric cancer in Western countries, radiation therapy was selected in Japan for palliation therapy of recurrent disease or a terminal cancer to improve patients' QOL. On the other hand, we demonstrated in our trial of chemo-radiation therapy with S-1/low-dose CDDP/radiation (TSLDR), which was applied to initial treatment against highly advanced Stage IV gastric cancer and revealed the usefulness of the regimen in anticancer effect and toxicity. In addition, chemo-radiation therapy including novel anticancer agents like S-1 will be discussed based on various kinds of view points, expecting a better clinical outcome of multimodal therapies against advanced gastric cancer.

Metastatic gastric cancer originating from malignant fibrous histiocytoma (MFH) is rare. To our knowledge, only nine other cases have been reported. We report the case of a 75-year-old man who underwent a distal gastrectomy for advanced gastric carcinoma, 2 years after resection of an MFH from the left side of his back. We based our preliminary diagnosis of primary advanced gastric carcinoma on the results of a preoperative biopsy specimen, which suggested either poorly differentiated adenocarcinoma or nonepithelial cell-originating malignant disease-like lymphoma. The resected stomach contained a large ulcerative tumor in the antral section, which was positive for Kp-1 and S-100 by immunohistochemical staining, confirming a pathological diagnosis of metastatic MFH of the stomach. He died of recurrence in the mediastinal space 16 months after the gastrectomy. Our analysis of this and previous cases suggests that resection may be inappropriate for patients with gastric metastasis of MFH because of the extremely high malignant potential of this tumor.

The clinical usefulness of the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) chemosensitivity test (MTT assay; MTTA) in the selection of anticancer drugs against advanced gastric cancer (AGC) was evaluated. MTTA is widely used to predict patient responses to particular drugs, allowing for the selection of appropriate chemotherapeutic drugs and the avoidance of ineffective chemotherapeutic drugs, thereby improving patient survival. Since 1989, we have accumulated MTTA efficacy data from AGC patients. In this study, the present clinical roles of MTTA and the data from 202 patients with stage III or IV gastric cancer analyzed for survival outcome following surgery, with or without postoperative chemotherapy, evaluated by MTTA, are discussed. The patients were divided into 3 groups; an adapted group found to be sensitive to chemotherapy by MTTA, a non-adapted group found to be insensitive to chemotherapy by MTTA and a group that received no chemotherapy. For stage III gastric cancer patients, the adapted group had a statistically better survival rate compared to the other groups, while for stage IV patients, there was no difference in survival rate between any of the groups. However, further classification of stage IV patients as to the presence or absence of peritoneal dissemination (P) showed that the adapted group with P showed better prognoses than the other groups with P. The analysis of data collected since 2000 revealed that the 11 patients in the taxane-adapted group, who received chemotherapeutic regimens that included taxanes and were found to be sensitive to taxanes by MTTA, demonstrated better survival than the taxane non-adapted group (n=11) (p=0.045). In conclusion, MTTA results predicted patient prognoses, based on the selection of appropriate chemotherapy.

Among multidisciplinary therapies developed for advanced esophageal cancer, neoadjuvant chemotherapy and chemoradiotherapy have been established as standard treatments. To deliver cautious follow up and intense treatment for high-risk patients, a simple and instructive biomarker for the postoperative recurrence needs to be identified. Fibrinogen, a common component of hemostasis, has been suggested to not only play an important role in cancer metastasis, but also correlate with tumor recurrence. We aim to clarify the validity of plasma fibrinogen as a marker for predicting the postoperative recurrence of esophageal squamous cell carcinoma patients who received neoadjuvant treatment. We reviewed 72 consecutive patients with esophageal squamous cell carcinoma who received neoadjuvant chemotherapy or chemoradiotherapy, followed by esophagectomy at the Keio University Hospital from 2001 to 2010. Of them, we retrospectively examined 68 patients who underwent plasma fibrinogen examination before and after neoadjuvant treatment and underwent transthoracic radical esophagectomy. We investigated patient characteristics, clinicopathological factors, neoadjuvant treatment effects, postoperative course, and plasma fibrinogen levels. We investigated pretreatment and preoperative (postneoadjuvant treatment) plasma fibrinogen levels, as well as changes in fibrinogen levels before and after neoadjuvant treatment. Patients with preoperative hyperfibrinogenemia (>350mg/dL) and patients with increased plasma fibrinogen levels during neoadjuvant treatment showed significantly shorter postoperative disease-free survival (DFS) (P=0.002 and P=0.037, respectively). Moreover, we classified these patients into three classes on the basis of their preoperative fibrinogen levels and changes in fibrinogen levels during neoadjuvant treatment. Patients who had both high preoperative plasma fibrinogen and increased fibrinogen levels showed significantly shorter DFS than others. In contrast, patients who had normal preoperative plasma fibrinogen and decreased fibrinogen levels showed significantly longer DFS. Based on this fibrinogen classification, we could differentiate between significantly favorable and poor prognosis patients group. Overall, this classification (hazard ratio=1.812, P=0.013) and the response to neoadjuvant treatment (hazard ratio=0.350, P=0.007) were found to be significant determining factors for postoperative DFS. With the validity of preoperative plasma fibrinogen levels and changes in fibrinogen levels during neoadjuvant treatment, the plasma fibrinogen level was found to be a possible biomarker for postoperative recurrence in advanced esophageal cancer patients who received neoadjuvant treatment. Moreover, plasma fibrinogen classification could be a simple and valuable predictive marker for postoperative follow up.

Background. Molecular-targeted drugs are not available for esophageal squamous cell carcinoma (ESCC), which has a poor prognosis. We investigated the clinicopathological significance of epithelial cell adhesion molecule (EpCAM) expression and the utility of EpCAM as a potential therapeutic target. Methods. The relationship between EpCAM expression and clinicopathological factors was examined by immunohistochemistry in 74 patients with resectable ESCC. A total of ten ESCC cell lines were analyzed for EpCAM expression. The effects of EpCAM knockdown in TE4, TE10, and TE14 cells were examined with regard to cell proliferation and gene expression in vitro and tumor growth in vivo. The antitumor effect of catumaxomab in ESCC cell lines was examined. Results. EpCAM overexpression was associated with poor survival in ESCC patients (P = 0.026). Multivariate Cox regression analysis showed that EpCAM overexpression was a significant and independent prognostic factor for surgically treated ESCC (P = 0.004). TE4 and TE10 cells showed high EpCAM expression, in contrast to TE14. EpCAM siRNA knockdown in TE4 and TE10 cells downregulated CCND1 and CCNE2 and suppressed cell proliferation. Low EpCAM expression reduced tumorigenesis; TE4 cells initiated tumorigenesis in seven of the ten mice injected, whereas shRNA knockdown resulted in smaller tumors in two of ten mice at 6 weeks after transplantation. Concentration- and time-dependent antitumor effects of catumaxomab were observed in TE4 and TE10 cells. Conclusions. EpCAM overexpression is an independent prognostic factor for surgically treated ESCC. EpCAM contributes to cell proliferation and tumorigenesis and may be a useful therapeutic target for ESCC.

Esophagogastric junction carcinoma incidence is increasing worldwide. However, surgical strategies for this cancer remain controversial. This study aimed to clarify the optimal surgical strategy for esophagogastric junction carcinoma. We retrospectively reviewed a database of 68 consecutive patients with esophagogastric junction carcinoma [Japanese classification of gastric carcinoma (Nishi's definition): adenocarcinoma, N=53; squamous cell carcinoma, N=15] who underwent curative surgical resection at Keio University Hospital between January 2000 and September 2008. In both adenocarcinoma and squamous cell carcinoma, most lymph node metastases were located in the lesser curvature area. Mediastinal lymph node metastasis was observed in 4 patients (7.5%) with adenocarcinoma and 7 patients (46.7%) with squamous cell carcinoma. No patient presented with lymph node metastases in the pyloric region. The therapeutic value of extended lymph node dissection was 0, except for lymph node station numbers 1, 2, 3, 4sa, 7, and 110. Extended lymph node dissection in the lesser curvature area showed a high therapeutic value. The para-aortic lymph node was the most frequent nodal recurrence site. All patients with tumor centers located below the esophagogastric junction (N=37) did not develop mediastinal lymph node metastasis or recurrence. Proximal gastrectomy through a transhiatal approach may be the optimal surgical strategy for esophagogastric carcinoma. Mediastinal lymph node dissection through a thoracic approach seems unnecessary, particularly when the tumor center is located below the esophagogastric junction. To confirm the necessity of para-aortic nodal dissection, further studies are required.

Background: Post-esophagectomy complications have an extremely poor prognosis. Recently, polymyxin B-direct hemoperfusion (PMX-DHP) therapy using a polymyxin B-immobilized fiber column was reported to be beneficial in gram-negative and/or gram-positive bacterial sepsis. The present retrospective study investigated the effectiveness and safety of PMX-DHP therapy in severe sepsis or septic shock after esophagectomy. Methods: Fifteen severe sepsis or septic shock patients were included. Seven (four, pneumonia; two, anastomotic leakage; and one, reconstructed colon necrosis) patients received 2-5 h of PMX-DHP therapy (PMX-DHP therapy group), whereas 8 (three, pneumonia; three, anastomotic leakage; and two, gastric tube necrosis) received conventional therapy (control group). Results: Length of stay in the intensive care unit (ICU) was significantly shorter in the PMX-DHP therapy group than in the conventional therapy group (P = 0.040). In the comparison of pre- and post-PMX-DHP therapy groups, the total Sequential Organ Failure Assessment (SOFA) score, respiratory system score, and P/F ratio improved (P = 0.0027, P = 0.025, and P = 0.0087, respectively) in the post-PMX-DHP therapy group. In the comparison of conventional and PMX-DHP therapy groups, the variations in the total SOFA score, respiratory system score, and P/F ratio improved (P = 0.019, P = 0.0063, and P = 0.0015, respectively) in the PMX-DHP therapy group. Moreover, the respiratory system score was lower (P = 0.0062) in the PMX-DHP therapy group at the time of discharge from the ICU. No adverse effects were observed during the course of PMX-DHP therapy. Conclusions: PMX-DHP therapy was safe and effective in improving respiratory and general conditions of patients with severe sepsis and septic shock after esophagectomy and decreased the length of stay in the ICU.

Background. When pathological diagnosis following endoscopic resection (ER) for early gastric cancer (EGC) suggests probable lymph node metastasis, additional surgery with lymphadenectomy should be performed. The sentinel node (SN) concept has yet to be applied to tumors following ER. The aim of this study was to evaluate the feasibility of SN navigation surgery for such tumors. Methods. Forty patients diagnosed with EGC lesions <4 cm in diameter underwent gastrectomy with SN mapping following ER. A technetium-99 m tin colloid solution and a dye were injected into the submucosal layer around the post-ER scar in all four abdominal quadrants. We then compared the SN distribution and metastases among the patients who underwent ER and controls (n = 192). Results. SNs were identifiable in all patients, and the mean number of SNs per case was 4.9. The location of the SN basin was similar in the patients who underwent ER and the controls. One patient (3 %) whose primary tumor had invaded the submucosal layer had a metastatic SN. The median time from ER to surgery was 73 days. No postoperative recurrence was observed in any patient over a median follow-up of 1,023 days. Conclusions. Our findings suggest that the SN basin is not greatly affected by ER. The SN concept could be suitable for tumors following ER, but conventional gastrectomy with lymphadenectomy involving the SN basin should be used at present.

Background: Brain metastasis from esophageal carcinoma is uncommon. The aims of this study were to assess the frequency of brain metastasis from esophageal carcinoma, describe treatment modalities and their outcomes, and determine predictors of survival. Methods: Between 2004 and 2012, 680 patients with esophageal carcinoma were registered at Keio University Hospital, Tokyo, Japan. Of these patients, 16 (2.3 %) were diagnosed with brain metastasis. We reviewed their medical records and performed statistical analyses. Results: The median survival after diagnosis of brain metastasis was 5.0 months (95 % CI 1.2-8.7 months). The only statistically significant baseline characteristic that predicted worse survival from brain metastasis was the onset form of brain metastasis (p = 0.01). At the onset of brain metastasis, the median survival from brain metastasis was 13.0 months (95 % CI 0.0-31.0 months) in patients without extracranial metastasis and 2.0 months (95 % CI 0.0-4.3 months) in patients with extracranial metastasis (p = 0.01). Conclusions: Approximately 2 % patients with esophageal carcinoma were diagnosed with brain metastasis. The prognosis of brain metastasis is extremely poor, but long-term survival may be expected with intensive treatment for brain metastasis when the first metastatic site is the brain.

Introduction: The purpose of this study was to establish the clinicopathological significance of circulating tumor cells (CTCs) in patients with advanced or recurrent esophageal cancer who received either chemotherapy or chemoradiotherapy.Methods: CTCs from 38 patients with advanced or recurrent esophageal cancer were quantified using the CellSearch system before and approximately 3–5 weeks after the initiation of a new line of chemotherapy or chemoradiotherapy. The correlation between CTC counts and clinicopathological variables was examined.Results: Of the 38 patients, 15 (39 %) had recurrent esophageal cancer, and 23 patients (61 %) had primary advanced esophageal cancer. The mean age was 63 years (range 43–87 years). One patient (2.6 %) had a complete response to treatment, 16 (42.1 %) had a partial response, 12 (31.6 %) showed stable disease, and nine (23.7 %) showed signs of progressive disease. The overall survival of patients with ≥2 CTCs was significantly shorter than that of patients with <2 CTCs both at baseline and at first follow-up (p = 0.047 and p = 0.011, respectively). Significant correlation was found between the change in CTC counts and the response to treatment (p = 0.036). The overall survival in patients with ≥2 CTCs both at baseline and at first follow-up was significantly shorter than patients with <2 CTCs both at baseline and at first follow-up (p = 0.002). Patients with a reduction rate in the CTC value <80 % experienced significantly shorter survival than patients with a reduction rate of ≥80 % (p = 0.035). The CTC counts at first follow-up served as an independent prognostic factor (p = 0.011).Conclusions: Our results suggest that measuring the number of CTCs in patients with advanced or recurrent esophageal cancer can be useful for predicting the survival of patients and for monitoring the response to cancer treatments.

We report a case of peritoneal cancer dissemination with Type 4 gastric cancer, successfully treated with combination chemotherapy with TS-1. The patient was a 59-year-old female, who complained of abdominal distension with pain, weight loss, and poor appetite. She was diagnosed as unresectable Type 4 gastric cancer, T3N2MOHOP1CY1M0, Stage IV with massive ascites (cytology: Class V). After 2 courses of combined chemotherapy with TS-1 and cisplatin (CDDP), primary tumor reduction was confirmed and no cancer cells were detected from a pathological investigation with biopsied specimens by endoscopy. As additional therapy for remained ascites, intraperitoneal administration of paclitaxel and docetaxel was performed, resulting in a remarkable decrease of ascites with cytological disappearance of cancer cells. The patients underwent total gastrectomy with lymph node dissection, pathological diagnosis of primary site and lymph nodes showed grade 2 effect, and no cancer cells were detected in ascites and peritoneum, microscopically. While she died of peritoneal recurrence after the surgery, the case suggested the clinical advantage of controlling the advanced cancer-bearing state by combination chemotherapy with TS-1, instead of surgery.

We aim to clarify beneficial effect of pre-operative radiation with chemotherapy in highly advanced gastric cancer patients, evaluating histological response, toxicity and patients' quality of life (QOL). We used pre-operative radiation with S-1 and low-dose cisplatin to treat 8 patients with highly advanced gastric cancer (clinical stage IV) in a pilot study. Clinical staging after therapy showed 5 PRs (partial response), 2 NCs (no change), and 1 PD (partial disease) following evaluation of the primary tumor and suspicious metastatic lesions in the lymph nodes, esophagus, liver, and peritoneum, for a response rate of 62.5% (5/8 cases). Of 8 patients, 6 underwent surgery, and 2 of these 6 patients had a histologically complete response (grade 3 effect) and 3 patients had a partial response (grade 2 effect), suggesting that a high histological response (5/6 cases; 83.3%) is expected by the chemoradiation. The survival analysis showed that 5 out of the 8 patients died within 10 months after initiating therapy, while 3 patients are alive without recurrence at 15, 18, and 30 months after therapy, suggesting a relatively good outcome for clinical stage IV gastric cancer. All cases showed grade 2-4 bone marrow suppression toxicity and/or grade 0-2 gastrointestinal toxicity, while 5 out of 8 patients (62.5%) showed improvement in appetite loss at the end of the therapy, indicating that the patients' quality of life (QOL) was preserved. Chemoradiation may be a powerful regimen for obtaining histological response with tolerable toxicity and improved QOL in highly advanced gastric cancer patients.