Kagami Nagai

Surgery Plus Chemotherapy Compared With Surgery Alone for Localized Squamous Cell Carcinoma of the Thoracic Esophagus: A Japan Clinical Oncology Group Study—JCOG9204

PURPOSE We performed a multicenter randomized controlled trial to determine whether postoperative adjuvant chemotherapy improves outcome in patients with esophageal squamous cell carcinoma undergoing radical surgery. PATIENTS AND METHODS Patients undergoing transthoracic esophagectomy with lymphadenectomy between July 1992 and January 1997 at 17 institutions were randomly assigned to receive surgery alone or surgery plus chemotherapy including two courses of cisplatin (80 mg/m2 of body-surface area x 1 day) and fluorouracil (800 mg/m2 x 5 days) within 2 months after surgery. Adaptive stratification factors were institution and lymph node status (pN0 versus pN1). The primary end point was disease-free survival. RESULTS Of the 242 patients, 122 were assigned to surgery alone, and 120 to surgery plus chemotherapy. In the surgery plus chemotherapy group, 91 patients (75%) received both full courses of chemotherapy; grade 3 or 4 hematologic or nonhematologic toxicities were limited. The 5-year disease-free survival rate was 45% with surgery alone, and 55% with surgery plus chemotherapy (one-sided log-rank, P =.037). The 5-year overall survival rate was 52% and 61%, respectively (P =.13). Risk reduction by postoperative chemotherapy was remarkable in the subgroup with lymph node metastasis. CONCLUSION Postoperative adjuvant chemotherapy with cisplatin and fluorouracil is better able to prevent relapse in patients with esophageal cancer than surgery alone.

Ultra-high Magnification Endoscopic Observation of Carcinoma in situ of the Esophagus

Abstract: Super‐zooming observation of carcinoma in situ of the esophagus was achieved utilizing an ultra‐high magnification endoscope which has a 150X magnification capacity. Superficial flat and slightly depressed lesions (O‐llb and O‐llc according to the Japanese classification of esophageal cancer), usually observed as a well‐demarcated reddish patch, were revealed to be a composite of scattered red dots and a pinkish homogeneous background. Those red dots were disclosed to be intrapapillary capillary loop changes such as dilatation, meandering and caliber irregularities. These changes were never observed in normal mucosa or in the setting of esophagitis. These characteristic findings were confirmed histologically in the resected specimen.

Ultra‐high Magnification Endoscopy of the Normal Esophageal Mucosa

Abstract: The normal esophageal mucosa was observed in detail using ultra‐high magnification endoscopy (UHM endoscopy). The UHM endoscope has a magnification capacity ranging from eight to 150x. High‐quality UHM endoscopic pictures can be continuously obtained by attaching a 2‐mm depth soft distal attachment to the tip of the UHM endoscope. The vascular architecture, which extends from the submucosal vessels through the proper mucosal layer, can be continuously visualized, thereby demonstrating the characteristic fine‐vascular network pattern, and the intrapapillary capillaries in the epithelium. With UHM endoscopy, intrapapillary capillaries can be clearly demonstrated as single loop vessels which we have termed “intrapapillary loops.” These structures cannot be observed with an ordinary magnifying endoscope which is capable of only 35x magnification. We conclude that a technique for obtaining high‐resolution endoscopic pictures has been established. The images obtained are useful for elucidating the microstructure of the esophageal mucosa, especially the fine‐vascular network and the newly recognized intrapapillary loop.

Multiple Primary Cancers Associated with Esophageal Carcinoma

Abstract This study was conducted to examine the characteristics of esophageal cancers with primary synchronous or metachronous cancer in another organ. We retrospectively evaluated 744 patients who underwent esophagectomy for esophageal cancers between 1985 and 1998. The patients were divided into two groups according to whether they had multiple primary cancer (MPC) or nonmultiple primary cancer (NPC). Stage I cancer was significantly more frequent among patients with MPC than among those with NPC (P < 0.0001). Among patients with MPC, another primary cancer was found in the head and neck region in 70 (42.4%), in the stomach in 51 (30.9%), and in the colon, lung, breast, and other locations in the remaining patients. Of the 70 patients with another primary cancer in the head and neck region, 32 (45.7%) had pharyngeal cancer. Furthermore, the incidence of intraesophageal multiple cancer in the patients with primary cancer in the head and neck region was significantly higher than that in those whose other primary cancers were gastric cancer or in those with NPC (P = 0.0135, P < 0.0001). The 5-year survival rate of the patients with MPC was 51.28%, which was significantly higher than that of those with NPC (P = 0.019). In conclusion, a better knowledge of the relationships between esophageal carcinoma and cancers in other organs may lead to earlier detection of other primary cancers and improved therapeutic results.

Evaluation of an Indicator for Lymph Node Metastasis of Esophageal Squamous Cell Carcinoma Invading the Submucosal Layer

Lymph node metastasis is a major prognostic factor for esophageal squamous cell carcinoma (ESCC). In recent years, endoscopic mucosal resection (EMR) has been developed with excellent results for the treatment of the superficial ESCC. To make the EMR treatment successful, it is important to establish a good indicator to identify ESCC patients at a high risk of lymph node metastasis. In this study, we examined clinicopathological and immunohistochemical factors to investigate the factors involved in lymph node metastasis of ESCC invading to the submucosal layer (sm‐ESCC). Surgical specimens from 84 sm‐ESCC patients were examined. Among 84 sm‐ESCC patients, 33 (39.3%) had lymph node metastases. Clinicopathologically, tumor depth, lymphatic invasion and blood vessel invasion showed significant correlations with lymph node metastasis by univariate analysis. Tumor depth and lymphatic invasion showed significant correlations by multivariate analysis of these factors. Immunohistochemically, P53 accumulation was observed in 45 cases (53.6%), cyclin D1 overexpression in 25 (29.8%), and pRB in 65 (77.4%). P53 accumulation, cyclin D1 overexpression and MIB‐1 Labeling Index were significantly associated with lymph node metastasis by univariate analysis, and P53 accumulation showed a significant correlation with lymph node metastasis by multivariate analysis. Among tumor depth, lymphatic invasion and P53 accumulation, tumor depth and lymphatic invasion were significantly correlated with lymph node metastasis (P=0.0023 and P=0.0092, respectively) by multivariate analysis. These data suggest that tumor depth and lymphatic invasion can be considered as good indicators for lymph node metastasis among patients with sm‐ESCC. In addition, P53 accumulation could be helpful to identify the patients who need additional treatment after EMR.

Changes of α1‐acid glycoprotein microheterogeneity in acute inflammation stages analyzed by isoelectric focusing using serum obtained postoperatively

The relationship between variations of α1‐acid glycoprotein (orosomucoid, AGP) microheterogeneity detected from isoelectric focusing (IEF) patterns and clinical stage of acute inflammation based on serum C‐reactive protein (CRP) levels and interleukin‐6 (IL‐6) levels was investigated. Serum samples were obtained from healthy subjects, and from patients with esophageal or stomach carcinoma before and after operation. Samples without neuraminidase treatment were used for AGP microheterogeneity analysis, and samples with neuraminidase treatment for AGP heterogeneity analysis. In AGP microheterogeneity, nine bands were detected in the range of pI 3.18—3.57 in sera obtained from healthy subjects. In patients, AGP microheterogeneity changed the first day after operation; the percentage of bands surrounding pI 3.5 increased, and the highest value appeared in sera taken the first or second day after operation and then decreased quickly. These bands showed reactivity for concanavalin A (Con A). The increase in Con A‐reactive AGP occurred later than the increase in IL‐6, and occurred earlier than the increase in CRP. On the seventh day after operation, the percentage of bands around pI 3.2 increased. These bands showed the reactivity for Datura stramonium agglutinin. On the other hand, in samples with neuraminidase treatment, little change of AGP heterogeneity was observed in most samples, which did not reflect the stage of inflammation. These findings suggested that AGP microheterogeneity detection was a useful marker for the clinical stage of inflammation.

Internal Pressure of the Conduit during Endoscopy on the Day after Esophagectomy

Background: In gastrointestinal surgery, anastomosis can result in various complications. Anastomosis is evaluated using classical examinations. The most reliable one is endoscopy, which provides direct information on the anastomosis and conduit. But the influence of endoscopy on anastomosis is uncertain. Methods: The internal pressure of a graft during endoscopy was measured in 36 patients who received esophagectomy, by utilizing the decompression tube which was inserted into the graft during operation. We filled the tube with water and measured the maximum water level in a centimeter water column. All examinations were routinely performed on the day after operation, and thin endoscopes were selected for reducing the stress. Results: The internal pressure before endoscopy ranged from 6 to 20 cm H2O, and during endoscopy ranged from 9 to 27 cm H2O. The difference in the internal conduit pressure in each patient ranged from 1 to 9 cm H2O. There was no increase in complications caused by endoscopy, including anastomotic leakage. Conclusion: This study is the first to report changes in internal pressure due to the endoscope by direct measurement. The pressure gradient observed was below the physiological pressure during swallowing. These results suggest that endoscopy is a safe examination even after surgery.

Prevalence of Barrett's esophagus in Japan

Norman Barrett originally described two special conditions, namely, a congenital short esophagus with an intrathoracic gastric columnar lining and congenital gastric heterotropia in the esophagus with ulceration. Thereafter, these conditions began to be known as “Barretts esophagus.” It is an acquired condition of esophageal columnar metaplasia following chronic gastroesophageal reflux, and the classical Barretts esophagus has been defined as having a circumferential columnar metaplasia spreading minimally 3 cm or more upward from the esophagogastric junction, because the esophagogastric junction still tends to be difficult to recognize precisely. Recently, from the point of view of adenocarcinogenesis of the esophagus, the term and concept of short-segment Barretts esophagus (SSBE) as a developing condition of the classical Barretts esophagus and the confirmation of intestinal metaplasia has been required; however, the definition of Barretts esophagus still remains controversial. In Japan, although the prevalence of short-segment Barretts esophagus has been reported to vary considerably, from 1% to 52%, the prevalence of long-segment Barretts esophagus (LSBE) tends to range from 0% to 2%, which is a quite lower rate than that observed in Western countries. The great difference in the prevalence of SSBE is caused by the differences in the criteria of the esophagogastric junction and the definition concerning the necessity of intestinal metaplasia. A universally accepted definition of Barretts esophagus is thus needed to accurately determine its actual prevalence.

CPT‐11 May Provide Therapeutic Efficacy for Esophageal Squamous Cell Cancer and the Effects Correlate with the Level of DNA Topoisomerase I Protein

CPT‐11 is a potent anti‐cancer drug and a specific inhibitor of DNA topoisomerase I (Topo I). In this study, we aim to evaluate the effects of CPT‐11 on esophageal squamous cell cancers (ESCC) and to determine the correlation between the effects and the levels of Topo I expression. We examined the growth‐inhibitory effect caused by SN‐38, an active metabolite of CPT‐11, in 14 human ESCC cell lines established from 10 primary and 4 metastatic lesions. CPT‐11 was considered effective against 5 cell lines from primary lesions and one from metastatic lesions, and thus may show therapeutic efficacy against both primary and metastatic ESCC tumors. Although Topo I mRNA levels in these 14 ESCC cell lines, as quantitated by northern blot analysis, showed no correlation with the IC50 values, Topo I protein levels, as quantitated by western blot analysis, showed an inverse correlation with the IC50 values. Topo I protein levels could be an indicator of sensitivity to CPT‐11. We also determined Topo I protein levels in 40 ESCC tumors and matched normal mucosae. Thirty‐four tumors showed 1.2‐22.3‐fold increases in Topo I levels. Two patients receiving pre‐operative chemotherapy and one receiving radiotherapy exhibited increased Topo I protein levels in their tumor lesions. It appeared that CPT‐11 could provide selective therapeutic efficacy against ESCC tumors. CPT‐11 may be effective for the treatment of metastatic ESCC tumors and as a second‐line anti‐cancer drug for ESCC.

Subcutaneous reconstruction using ileocolon with preserved ileocolic vessels following esophagectomy or in esophageal bypass operation.

Background: When forming an esophageal substitute with an ileocolon in esophageal reconstruction with cervical anastomosis, the ileocolic vessels should be divided in many cases and this may be followed by the occurrence of poor blood circulation in the pulled-up substitute. Methods: Twenty-two consecutive esophageal reconstructions using an all-main-vessel-preserving ileocolon had been performed in the past 4 years and we evaluated the usefulness of this surgical modality. Results: In every case, the extension length of the ileocolon was sufficient for esophageal reconstruction. There were no serious surgical complications concerning the esophageal substitutes such as necrosis of the pulled-up ileocolon. Conclusions: Although it was thought that the surgical techniques shown here were possible only in selected patients, successful esophageal reconstructions were achieved with this new concept in 22 consecutive patients with various backgrounds. The procedures shown here are not new; however, the concept of using the all-main-vessel-preserving ileocolon as an esophageal substitute for every patient requiring esophageal reconstruction is new.