Koichiro Kumai

Curative Laparoscopic Surgery for Early Gastric Cancer: Five Years Experience

Sixty-one patients who were diagnosed with mucosal gastric cancer have been successfully treated with two laparoscopic techniques at our institute from March 1992 to March 1997. One is laparoscopic wedge resection of the stomach using a lesion-lifting method for lesions of the anterior wall, the lesser curvature, and the greater curvature of the stomach. The other is laparoscopic intragastric mucosal resection for lesions of the posterior wall of the stomach and near the cardia or the pylorus. Indications are as follows: (1) preoperatively diagnosed mucosal cancer; (2) <25 mm diameter elevated lesions; and (3) <15 mm diameter depressed lesions without ulcer formation. Patients were discharged in 4 to 8 days uneventfully. There was no major complication or mortality. The resected specimens had sufficient surgical margins horizontally (16 +/- 5 and 8 +/- 4 mm, respectively) and vertically. In one patient histologic examination revealed slight tumor infiltration into the submucosal layer with lymphatic invasion. He underwent gastrectomy with lymph node dissection 1 month after surgery. Otherwise, histologic examination revealed curative surgery. All patients in the series have survived during the 4- to 65-month follow-up period. There have been two recurrences in the series, both of which were found near the staple line 2 years after the initial surgery and were still mucosal lesions. They were successfully treated by open gastrectomy and laser irradiation. A separate early gastric cancer was found 2 years after the initial surgery in one patient, who then underwent curative open gastrectomy. In conclusion, if the patients are selected properly, these laparoscopic procedures are curative, minimally invasive treatment for early gastric cancer.

Laparoscopic wedge resection of gastric submucosal tumors.

Minimally invasive surgery has revolutionized the treatment of gastrointestinal tumors. Submucosal tumors (SMTs) of the stomach can be resected using laparoscopic techniques. Between 1993 and 1997, laparoscopic wedge resection was performed in 34 patients with an SMT of the stomach. The tumors ranged from 8 to 60 mm in diameter. All surgical margins were clear. The average operative time was 131 minutes. Most of the patients began eating on the first postoperative day and were discharged within 5 to 7 days. Histopathologic examination of the tumors showed gastrointestinal stromal tumor (n = 14), ectopic pancreas (n = 7), leiomyosarcoma (n = 4), schwannoma (n = 3), carcinoid (n = 2), leiomyoma (n = 2), an inflammatory lesion caused by parasites (n = 1), and cyst (n = 1). No recurrences were observed over the 5-year follow-up period. A solid SMT of the stomach larger than 20 mm in diameter can be treated using laparoscopic wedge resection.

Minimally invasive surgery for gastric cancer--toward a confluence of two major streams: a review.

The minimalization of therapeutic invasiveness in order to preserve quality of life (QOL) is a major topic in the management of early gastric cancer. After laparoscopic surgery for gastric cancer was introduced by Kitano et al. in 1991, an enthusiasm to develop laparoscopic procedures has grown steadily. In the initial phase, early gastric cancer limited to the mucosal layer with no risk of lymph node metastasis was treated by laparoscopic wedge resection or intragastric mucosal resection. Since technical and instrumental advances in endoscopic treatment were achieved by gastroenterologists, these cases can be managed by intraluminal endoscopic approaches. The attention of surgeons then shifted to more radical procedures such as laparoscopic gastrectomy with lymph node dissection, which is comparable to open surgery and can be indicated even in advanced cancer. Although this paradigm shift has already been realized in the field of colorectal surgery, we must pay attention to the particular biological nature of gastric cancer in terms of the potential of peritoneal dissemination. While early-phase recovery after surgery has been improved by laparoscopic surgery, preservation of late-phase QOL by function-preserving surgery is also essential in this regard; therefore, the sentinel node (SN) concept has been a much-discussed topic in gastric cancer surgery to approach this aspect. Recently, the validity of the SN concept has been demonstrated by a number of single institutional studies, and prospective multicenter trials are currently ongoing. Theoretically, various types of function-preserving surgery could be applied in cases of early gastric cancer with negative SNs as less invasive surgery to improve long-term QOL. Although we still have to solve several remaining issues in the treatment of gastric cancers, a confluence of these two major streams, laparoscopic surgery and sentinel node navigation surgery, would enable us to apply a novel individualized minimally invasive approach, both in terms of degree of incisional access and extent of function preservation.

Laparoscopic wedge resection of the stomach for early gastric cancer using a lesion-lifting method

Thirty-eight patients with early gastric cancer have been successfully treated by laparoscopic wedge resection of the stomach in our institute since March 1992. Our indication of the surgery is as follows: 1) preoperatively diagnosed mucosal cancer, 2) < 25 mm, if the lesion is elevated type, and 3) < 15 mm and no ulcer scar, if the lesion is depressed type. After laparoscopic exposure of the gastric wall around a cancerous lesion, a sheathed needle was inserted into the stomach through the abdominal wall at the vicinity of the lesion under gastroscopy guidance. A small metal rod was introduced into the stomach near the lesion through the outer sheath. While the lesion was lifted up precisely with the support of the metal rod, wedge resection of the stomach was performed using an endoscopic stapler (lesion-lifting method). Perigastric lymph nodes could be also resected when necessary. There was no intraoperative and postoperative complication, and no mortality. The patients were discharged within 5 days after surgery uneventfully. The resected specimens were 50 to 110 mm in diameter, and there was a sufficient surgical margin (16 +/- 5mm). All patients have survived during the 2 to 60 months follow-up period. There has been one recurrence and one separate occurence of early gastric cancer in the series, which were curatively treated by gastrectomy. Advantages of the surgery are as follows: 1) it is minimally invasive, 2) most of the stomach is preserved, 3) a sufficient surgical margin can be obtained, and 4) a detailed histologic examination is feasible. If the indication is selected properly, this laparoscopic surgery can be a curative and minimally invasive treatment for early gastric cancer.

Dihydropyrimidine dehydrogenase and messenger RNA levels in gastric cancer: possible predictor for sensitivity to 5-fluorouracil.

We investigated the correlation between tumor sensitivity to 5‐fluorouracil (5‐FU) and enzymatic activities of thymidylate synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) in human gastric cancer specimens. Forty‐one patients with advanced gastric cancer gave informed consent and were enrolled in the study. Biopsy specimens of gastric cancer were obtained preoperatively through gastrofiberscopy and used to determine TS and DPD messenger RNA (mRNA) levels. TS and DPD enzyme activity and mRNA levels were also measured in resected tumor tissue samples obtained after surgical resection. TS and DPD activity were measured using the TS‐binding assay and a radioenzymatic assay, respectively, while mRNA levels were measured by semi‐quantitative reverse transcription‐polymerase chain reaction (RT‐PCR), with co‐amplification of glyceraldehyde‐3‐phosphate dehydrogenase (GAPDH) as an internal standard. 5‐FU sensitivity of resected tumor specimens was measured by the tetrazolium‐based colorimetric assay (MTT assay). Both TS and DPD mRNA levels correlated well between biopsied and resected tumor specimens. A statistically significant correlation was also observed between mRNA levels in biopsied specimens and enzymatic activities in resected specimens. DPD levels significantly correlated with 5‐FU sensitivity, such that high DPD activity and high DPD mRNA levels resulted in low sensitivity to 5‐FU. In contrast, no correlation was observed between TS activity or TS mRNA levels and 5‐FU sensitivity. We conclude that tumor DPD mRNA level, as assessed from biopsy specimens obtained by gastrofiberscopy, may be a useful indicator in predicting tumor sensitivity to 5‐FU in patients with gastric cancer.

Interim Results of Sentinel Node Biopsy during Laparoscopic Gastrectomy: Possible Role in Function-Preserving Surgery for Early Cancer

IntroductionIntraoperative detection of sentinel nodes (SNs) has been used clinically to predict regional lymph node (LN) metastasis in patients with breast cancer and malignant melanoma. Intraoperative lymphatic mapping and SN biopsy can potentially be combined with minimally invasive surgery. However, few reports have demonstrated the validity of SN biopsy during laparoscopic gastrectomy. The aim of this study was to investigate the feasibility and accuracy of laparoscopic lymphatic mapping in predicting LN status in patients with gastric cancer.MethodsA total of 35 patients with gastric cancer diagnosed preoperatively as T1, N0 were enrolled. Endoscopic injection of technetium-99m-radiolabeled tin colloid was completed 16 hours before surgery, and radioactive SNs were identified with a gamma probe intraoperatively. Isosulfan blue dye was injected endoscopically during the operation. Laparoscopy-assisted gastrectomy with LN dissection was performed. All resected LNs were evaluated by routine pathology examination.ResultsSNs were detected in 33 (94.3%) of 35 patients. The mean number of SNs was 3.9, and the diagnostic accuracy according to SN status was 97.0% (32/33), as one patient with a false-negative result was observed. The patient with the false-negative specimen was finally diagnosed as having advanced gastric cancer with invasion into the proper muscular layer and severe lymphatic vessel invasion, causing destruction of normal lymphatic flow by the tumor.ConclusionsRadio-guided SN mapping during laparoscopic gastrectomy is an accurate diagnostic tool for detecting lymph node metastasis in patients with early-stage gastric cancer. Validation of this method requires further studies on technical issues, including indications, tracers, methods of lymph node retrieval, and diagnostic modalities of metastasis.

Intraoperative lymphatic mapping and sentinel lymph node sampling in esophageal and gastric cancer.

Recent studies for SN mapping of esophageal and gastric carcinoma show that the SN concept is valid even for upper GI cancers with multidirectional and complicated lymphatic flow. The relatively high incidence of anatomic skip metastasis can be attributed to aberrant distribution of SNs. An individualized and minimally invasive surgical approach can be applicable to management of esophageal and gastric carcinoma based on SN status. Although there are several issues to be resolved, this novel procedure has the potential for great benefit to improve quality control in the treatment of upper GI cancer. Well-designed clinical trials of lymphatic mapping for upper GI cancer will be essential to determine whether this technique is widely applicable in the management of these tumors.

Possible chemoresistance-related genes for gastric cancer detected by cDNA microarray

To identify chemoresistance‐related genes of gastric cancer, we utilized cDNA microarray technology. Thirty‐five gastric cancer specimens surgically resected at our institute between 1998 and 1999 were studied for quantification of expression of 6300 genes by means of oligonucleotide microarray methods, and the results were evaluated in comparison with the chemoresistance of the specimens, which was determined by MTT (tetrazolium‐based 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetrazolium bromide) assay. Inhibition rates (IR) were determined for cisplatin (DDP), 5‐fluorouracil (5‐FU), mitomycin C or doxorubicin. IR of 60% or more was regarded as sensitive to each agent, and IR of less than 40% was defined as resistant. Clustering was successfully completed for DDP, resulting in selection of 23 candidates as DDP‐resistance‐related genes, including vascular permeability factor, 2 membrane transporting subunits, and retinoblastoma‐binding protein‐1. In addition, further selection of DDP‐resistance‐related genes was performed according to these criteria: 1) Expression of the gene can be detected in more than 70% of resistant tumors. 2) Expression can be detected in less than 30% of sensitive tumors. 3) Expression in tumors is more than twice that of normal mucosa in more than 50% of specimens. Then, metallothionein‐IG and heparin‐binding epidermal growth factor‐like growth factor (HB‐EGF) were identified as candidate DDP‐resistance‐related genes. When known DDP‐resistance‐related genes were analyzed according to the MTT assay result, families of glutathione‐S‐transferase and cydooxygenase‐2 genes were also evaluated as resistance‐related genes. For 5‐FU resistance, dihydropyrimidine dehydrogenase and HB‐EGF‐like growth factor genes were also suggested to be resistance‐related genes. The present study demonstrated that oligonucleotide microarrays can provide information regarding chemoresistance factors in cancer. (Cancer Sci 2003; 94: 355–359)

The citrus flavonoid, nobiletin, inhibits peritoneal dissemination of human gastric carcinoma in SCID mice.

The flavonoid nobiletin (5,6,7,8,3′,4′–hexamethoxyflavone), found in Citrus depressa Rutaceae, a popular citrus fruit in Okinawa, Japan, reportedly inhibits the production of pro–matrix metallo–proteinase (proMMP)–l, 3, and 9 in rabbit synovial fibroblasts in vitro. In the present study, we demonstrated the inhibitory effects of nobiletin on the proliferation of the cancer cell line, TMK–1, and its production of MMPs. In the SCID mouse model, we found that nobiletin inhibited the formation of peritoneal dissemination nodules from TMK–1. The enzymatic activity of MMP–9 expressed in culture medium obtained from a co–culture of TMK–1 and mouse fibroblastic cells was inhibited by nobiletin in a concentration–dependent manner. In the SCID mouse model, total weight of dissemination nodules was significantly lower in the treated group compared with the vehicle control group (0.07 g vs. 0.78 g, P=0.0059). The total number of dissemination nodules was also significantly lower than in the vehicle control group (7.5 vs. 69.3/body, P=0.0001). These results suggest that nobiletin may be a candidate anti–metastatic drug for prevention of peritoneal dissemination of gastric cancer.

Surgical Management of Gastric Leiomyosarcoma: Evaluation of the Propriety of Laparoscopic Wedge Resection

Abstract. Laparoscopic surgery has been applied to malignant gastric tumors. To evaluate the propriety of laparoscopic wedge resection for gastric leiomyosarcoma it is necessary to question whether lymph node dissection is necessary for the surgical management of gastric leiomyosarcoma. A retrospective study on open surgery cases of gastric leiomyosarcoma was performed to address this issue. The clinical records of 28 patients with gastric leiomyosarcoma who had had surgery were examined. The patients who underwent open surgery were divided into a systematic lymph node dissection (SLND) group (n= 9) and a nondissection (non-D) group (n= 19). No patient had lymph node metastasis at the time of operation or recurrence, and statistical analysis showed no difference between the SLND and non-D groups in terms of survival rates. These data suggest that SLND might not be necessary for the surgical management of gastric leiomyosarcoma and that laparoscopic wedge resection of the stomach can be considered a first-line treatment for gastric leiomyosarcoma.