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Evaluation of the clinical significance of the sentinel node concept in GI cancer has just begun. The authors' preliminary data, using intraoperative radiation techniques and the gamma probe, suggest that it is worthwhile to continue the evaluation of this procedure to determine its role in an accurate staging and a minimally invasive approach to GI cancers.
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BACKGROUND: A novel synthesized organic compound, FR167653, has been characterized as a potent suppressant of interleukin-1 and tumor necrosis factor-alpha. We designed this experimental study to evaluate the effect of FR167653 on ischemia-reperfusion injury of the rat lung. METHODS: Following general anesthesia, the left bronchus, pulmonary artery and vein were clamped for 1 hour. FR167653 was administered continuously beginning 30 minutes before the onset of ischemia and extending for 2 hours after reperfusion. Thirty-eight Wistar rats were divided into 4 groups according to the dose of FR167653 at the rate of 0.1, 0.05 and 0.025 mg/kg/hr in each group. After the optimal dose was obtained from the result of 1-week survival rate, the group with the optimal dose was compared with a control group by using such parameters as arterial oxygen saturation (SaO(2)), arterial oxygen tension (PaO(2)), cytokines, the expression of p38 MAP kinase and histologic study. RESULTS: Survival rate of the group received FR at the rate of 0.1 mg/kg/hr (FR0.1 group) was best among the 4 groups. SaO(2) levels and PaO(2) levels after 2-hour of reperfusion were significantly (p < 0.05, respectively) higher in the FR0.1 group than in the control group. After 2-hour reperfusion, IL-1 beta was lower in the FR0.1 group than in the control group, and the expression of p38 MAP kinase was reduced in the FR0.1 group compared with the control group. In histologic study after 2-hour of reperfusion, alveolar damage with edema and interstitial thickening localized along the alveolar duct were observed in the control group, whereas these findings were remarkably less evident in the FR0.1 group. CONCLUSIONS: We concluded that FR167653 ameliorates ischemia-reperfusion injury of the lung and may inhibit the production of proinflammatory cytokines by means of the inhibition of p38 MAP kinase.
BACKGROUND: Nitric oxide (NO) seems to play an important role in tissue injury during reperfusion of the lung. FK409 is the first spontaneous NO donor that increases plasma guanosine 3':5'-cyclic monophosphate. It is reported that FK409 prevented myocardial infarction following occlusion and reperfusion in rat coronary arteries. In this study, we evaluated the effects of FK409 on pulmonary ischemia-reperfusion injury in an in situ warm ischemia model of rats. METHODS: Animals were divided into 2 groups: the FK409 study group that was administered FK409 (0.4 mg/kg) before reperfusion and the control group, administered a saline vehicle only. Following a thoracotomy, the bronchus, pulmonary artery and vein were separately clamped for 1 hour. Arterial oxygen tension (PaO2), arterial oxygen saturation (SaO2), and endothelin-I (ET-I) were measured after 2 hours of reperfusion. Histologic and immunohistochemical studies were performed; polymorphonuclear neutrophils (PMNs) were counted after 2 hours of reperfusion. RESULTS: PaO2, SaO2, ET-I after 2 hours of reperfusion and the 7-day survival rate were significantly (p < 0.05) better in the FK409 group than the control group. Histologic damage was reduced in the FK409 group compared with the control group. PMN infiltration was also significantly (p < 0.05) lower in the FK409 group than in the control group. CONCLUSION: FK409 seems to protect against ischemia-reperfusion injury of the lung. This effect may be related to a homeostatic effect on pulmonary vascular beds and prevention of PMN sequestration.
BACKGROUND: Matrix metalloproteinases (MMPs), enzymes capable of degrading collagens and other extracellular matrix components, have been implicated in gastric ulcer formation. However, the effect on MMP expression of Helicobacter pylori, also implicated in these lesions, has not been studied to our knowledge. AIM: To seek links between H. pylori and MMP expression likely to affect gastric ulcer formation. After fibroblasts from human gastric wall were cocultured with H. pylori. concentrations of MMP-1 and -2 in the medium were determined by enzyme-linked immunosorbent assays. RESULTS: Whereas MMP-1 was not detected in media from fibroblasts or H. pylori culture alone, MMP-1 was detected in cocultures (P<0.01). Similar amounts of MMP-2 were detected in medium from fibroblasts cultured alone and with H. pylori. No MMP-2 production by H. pylori cultured alone was detected. CONCLUSIONS: MMP-1 appears to be important in gastric ulcer pathogenesis, and MMP-1 induction by H. pylori may impede gastric ulcer healing.
BACKGROUND: The incidence of gastric carcinoma is increasing in elderly patients. It has not been determined whether surgery improves the quality of life or prolongs survival in patients older than 85 years. This study was designed to evaluate surgery as a treatment option in patients more than 85 years of age. METHODS: The records of 18 patients aged 85 to 91 years (mean 87.3 years), who underwent surgery for gastric carcinoma between 1983 and 1997 were analysed. RESULTS: Three patients had multiple lesions. A total of 21 lesions were examined. Operative procedures included distal gastrectomy (n = 12), total gastrectomy (n = 4), proximal gastrectomy (n = 1), and laparoscopic wedge resection (n = 1). Perigastric lymphadenectomy was performed in 15 patients. No lymph node dissection was performed in three patients. Postoperative complications, including delirium, respiratory dysfunction, cardiac dysfunction, anastomotic leakage, bleeding, and ileus, occurred in 11 patients. There were two hospital deaths in patients who underwent emergency surgery. Survival was neither shortened nor prolonged by surgery as determined by life table analysis. CONCLUSIONS: Surgical treatment should not be avoided based solely on the age of the patient, and quality of life in this population may be improved by surgery. Careful patient selection should include an assessment of the will to live.
Three different membrane-type matrix metalloproteinases (MT-MMPs) activate in vitro the latent form of matrix metalloproteinase-2 (MMP-2), which is one of the key proteinases in invasion and metastasis of various cancers. We examined the mRNA expression of MT1, 2, and 3-MMPs and MMP-2 in cell lines of head and neck squamous cell carcinoma (HNSCC) and quantitated the relative expression levels in human HNSCC tissues by Northern blotting. The tissue localization of MT1-MMP and MMP-2 was determined by immunohistochemistry and in situ hybridization. Their implications in clinicopathologic factors were statistically evaluated. All cell lines examined consistently expressed MT1-MMP and MMP-2, but not MT2, 3-MMP. In the clinical specimens, there was a significant correlation in coexpression of messenger of RNA (P = .0005) and colocalization by immunohistochemistry (P < .0001) for MT1-MMP and MMP-2. Relative mRNA expression levels of MT1-MMP and MMP-2 in the carcinoma tissues were significantly higher than those of the control tissues (P = .0045 and P = .0122, respectively). Both mRNA expression level and immunopositivity of MT1-MMP significantly correlated with lymph node metastasis (P = .0081 and P = .0193, respectively), which was confirmed by multivariate logistic regression analysis. Immunoreaction of MT1-MMP and its mRNA expression were observed in both carcinoma cells and stromal cells. The localization of MMP-2 closely corresponded to that of MT1-MMP. These observations suggest that MT1-MMP possesses a role as a determinant of lymph node metastasis in HNSCC, and that concurrent expression of MT1-MMP and MMP-2 are involved in progression of HNSCC.
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.
UCN-01 (7-hydroxystaurosporine) is a newly developed cell cycle inhibitor known to have several modes of action, including inhibition of cyclin-dependent kinase, induction of p21 and suppression of pRb phosphorylation. In order to test a combination therapy of UCN-01 and 5-fluorouracil (5-FU), growth inhibition of CRL 1420 (MIA PaCa-2; undifferentiated pancreatic carcinoma) by four different treatments was measured using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyl-2H-tetrazolium bromide (MTT) assay. The treatments used were UCN-01 alone, 5-FU alone, 5-FU followed by UCN-01 (5-FU/UCN-01) and UCN-01 followed by 5-FU (UCN-01/5-FU). We also assessed changes in thymidylate synthetase (TS) mRNA levels, TS activity, and 5-FU incorporation by RNA (F-RNA) for each treatment. Although treatment with UCN-01 alone, 5-FU alone, and 5-FU/UCN-01 inhibited CRL 1420 growth in a concentration-dependent manner, treatment with UCN-01/5-FU inhibited the growth of CRL 1420 synergistically at less than 1 microg/ml drug concentration. The down-regulation of TS mRNA by UCN-01 resulted in stable total TS and decreased free TS, and UCN-01/ 5-FU resulted in enhanced thymidylate synthetase inhibition rate (TSIR) compared to UCN-01 alone and 5-FU/UCN-01. This increased TSIR due to UCN-01 pretreatment was accompanied by elevated F-RNA concentrations in the UCN-01/5-FU treatment. The suppression of TS mRNA and TS activity by UCN-01 may lead to higher sensitivity of tumor cells to 5-FU and may explain the synergistic antitumor effect of UCN-01/5-FU. In conclusion, low concentrations of UCN-01 (from 0.01 to 1 microg/ml) may be clinically useful, affording low cytotoxicity of UCN-01, while enhancing the antitumor effect of 5-FU.
The ability of certain chemicals to mimic the effects of natural steroid hormones and their potential to disrupt the delicate balance of the endocrine system in animals has attracted much interest in recent years. Alkylphenolic chemicals have been reported to be weakly estrogenic. Estrogen receptor (ER) binding is primarily the result of interaction of the receptor with both a phenolic residue, and a hydrophobic pharmacophore. We have prepared and screened various phenols having a bulky 4-alkyl group, which may interact hydrophobically with the receptor, for estrogenic activity by using a previously described reporter gene assay employing COS-1 cells transfected with rat ER alpha-expression plasmid and an appropriate reporter plasmid. Some of the tested compounds, such as 4-(1-adamantyl)phenol and 4-cycloalkylphenols, exhibited much more potent activity than the typical estrogenic alkylphenol, 4-tert-octylphenol.
Various types of carcinoma cells have been shown to escape immune recognition by constitutive resistance to Fas receptor (Fas)-mediated apoptosis. The purpose of this study was to examine the sensitivity to Fas-mediated apoptosis of human head and neck squamous cell carcinoma (HNSCC) cells. We applied an anti-Fas monoclonal antibody (CH11) to HNSCC cell lines and monitored their cell death. All three HNSCC cell lines examined expressed Fas protein but not Fas-ligand mRNA. CH11 did not induce cell death (CH11-resistant) in any of the three HNSCC cell lines examined. Treatment with actinomycin D (ActD) converted the phenotypes of the CH11-resistant HNSCC cell lines from CH11-resistant to CH11-sensitive, suggesting that the resistance to CH11-induced apoptosis was dependent on RNA synthesis. Western blot analysis did not show any differences in expression of Bcl-2 between the non-treated and ActD-treated HNSCC cell lines. Expression of Bcl-XL, on the other hand, was greatly reduced in the ActD-treated HNSCC cell lines, implying that Fas signaling in the CH11-resistant HNSCC cell lines might be regulated by an Bcl-XL-inhibitable step.
Although the sentinel node concept has been validated and clinically applied to breast cancer and malignant melanoma, its clinical significance in other solid tumors has not been thoroughly investigated. With regard to gastrointestinal (GI) cancers in particular, our surgeons have been cautious because of the high frequency of skip metastasis and the complicated lymphatic system in the GI tract. We would like to emphasize that so-called skip metastasis has been defined according to anatomic classification of regional lymph nodes and that the lymphatic drainage route must be patient or lesion specific. To test the validity and feasibility of this concept in GI cancers, we have established a radio-guided intraoperative sentinel node navigation system using preoperative endoscopic submucosal injection of radioactive tracer followed by intra-operative gamma-probing. In 131 patients with GI cancers (esophagus: 22, stomach: 71, colorectum: 38), the detection rate of sentinel nades was 91% and overall diagnostic accuracy of lymph node metastasis by sentinel node status was 97%. Initial results suggest further investigation of this procedure as an accurate staging and a minimally invasive approach to early GI cancers.
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.
Five human cancer cell lines (MKN 45, HT-29, WiDr, PAN-3-JCK, and CRL 1420) were used to evaluate the antitumor spectrum of UCN-01, which suppressed the growth of these digestive cancer cell lines. A human pancreatic cancer xenograft (CRL 1420) and breast cancer xenograft (MX-1) were used to determine their sensitivity to UCN-01, in nude mice. UCN-01 significantly suppressed the tumor growth of CRL 1420 at a dose of 10 mg/kg in a schedule of (qd x 5) x 2, but was ineffective for MX-1. While p21 protein expression was induced by UCN-01 in both CRL 1420 and MX-1, an accumulation of dephosphorylated ppRb was observed only in CRL 1420, resulting in G1 block as detected by flow cytometric analysis. The CDK 2 activity of MX-1 was almost 6 times higher than that of CRL 1420, which might account for the resistance of MX-1 to UCN-01 in spite of the induction of p21 in this strain. We conclude that the determinant of sensitivity to UCN-01 lies in the balance of CDK 2 kinase activity and p21 protein induction.
We have applied two different laparoscopic surgical techniques for early gastric cancer and have successfully treated 111 patients since March 1992. The indications are: 1) preoperative diagnosis of mucosal cancer; 2) lesion size of < 25 mm if the protruding type; and 3) lesion size < 15 mm and UI (-) if the depressed type. The first technique is laparoscopic wedge resection of the stomach using a lesion-lifting method (n = 93). The gastric wall around the cancerous lesion is exposed laparoscopically. The abdominal wall and gastric wall in the vicinity of the lesion are pierced using a 12-G sheathed needle. A small metal rod with a fine wire is introduced into the stomach through the outer sheath. By retracting the metal rod, the lesion can be lifted precisely (i.e., lesion-lifting method). Wedge resection at a sufficient distance from the metal rod is carried out using an endoscopic stapler. The second technique is referred to as laparoscopic intragastric mucosal resection (n = 18). Three balloon trocars are placed in the stomach laparoscopically. The stomach is then insufflated with CO2, and surgical instruments are introduced. The mucosal and submucosal layers around the lesion are resected with sufficient surgical margins. The selection of the laparoscopic technique depends on the site of the cancerous lesion. In our series of 111 patients, sufficient horizontal (mean 15 +/- 5 mm and 8 +/- 4 mm, respectively, using the first and second technique) and vertical surgical margins were achieved. There was no mortality and no major complications in patients undergoing either surgical technique. There have been two recurrences, both mucosal lesions found 2 years after the initial surgery, which were successfully treated with gastrectomy and laser irradiation. All patients have survived for 3 to 96 months, and there has been no trocar site recurrence. In conclusion, these laparoscopic procedures are curative and minimally invasive treatments for early gastric cancer.
Seven patients with pulmonary carcinoid including three with typical carcinoid and four with atypical carcinoid were reported. There were 3 males and 4 females, with an age range of 37 to 80 years. All patients with typical carcinoid had pathological stage I. Of the patients with atypical carcinoid, one patient had stage I, two stage IIIA and one stage IIIB. All but two patients underwent lobectomy and mediastinal lymph node dissection. Bronchoplastic operation or right pneumonectomy were performed in the two patients. All but one patient underwent absolute or relative curative operation. Only one patient died on the 4th postoperative day. One patient with atypical carcinoid died of cancer recurrence 4 years after surgery. One patient died of breast cancer. One patient underwent surgery for metachronous multiple lung cancer, and he is doing well without recurrence. In conclusion, a limited operation is thought to be acceptable only in patients with typical carcinoid in a peripheral lesion without lymph node metastasis. Lobectomy and mediastinal lymph node dissection is necessary for the atypical carcinoid case.
We conducted a validation of the treatment of satellite nodules in the UICC TNM classification of 1997. Over the past 17 years (1981 to 1997), 29 patients underwent complete pulmonary resection for primary lung cancer accompanied by satellite nodules in the same lobe as the primary. All these patients were categorized as stage IIIB according to the current staging system. The five-year survival rate of all patients was 40% and the figure was unduly better for stage IIIB patients. The three-year survival rate of 20 patients having lymphatic involvement were 18%, but those of 9 patients without it was 89%. Outcome was significantly influenced on their presence or absence of lymph node metastases. The current staging system for patients with satellite lesions in the same lobe appears to be unacceptable because they provide the different influences on prognosis and selecting treatment modality according to the N status.
In evaluations of adjuvant chemotherapy with oral anticancer agents, compliance in taking the drug as prescribed (compliance), adverse reactions, and feasibility are important factors in setting the dose. A weekday-on/weekend-off schedule, in which 600 mg/day of UFT was taken for 5 consecutive days and not taken on the following 2 days, was carried out as a postoperative adjuvant chemotherapy for one year in 87 patients with colorectal cancer who had undergone potentially curative resection. The prescribed dose and the dose of ingestion confirmed by physician interview were both highly consistent with the dose of ingestion according to the patients' self reports, with consistency rates of more than 94% for both. Relative performance (RP) yielded a value of 0.72, and individual dose intensity (IDI) yielded 0.8 on average. Female gender, low body weight, and low body surface area were factors that negatively affected feasibility. None of the adverse reactions was serious. Based on the feasibility and adverse reactions, the dosage of UFT should be set according to the body surface area at 375-425 mg/m2/day. When this schedule is used as one arm of a controlled study, it is suggested that the dose should be decided with 400 mg/m2 as a guideline.