Significant correlation between micrometastasis in the lymph nodes and reduced expression of E-cadherin in early gastric cancer.

BACKGROUND: E-cadherin has been recognized as an important factor associated with tumor metastasis. However, the relationship between micrometastasis in the lymph nodes and the expression of E-cadherin in the primary tumor in gastric cancer remains unclear. METHODS: Two consecutive sections of 4522 lymph nodes from 162 patients with early gastric cancer were prepared for simultaneous hematoxylin and eosin (H&E) and cytokeratin (CK) staining. Sections of primary tumors from 135 of these patients were prepared for E-cadherin immunostaining. RESULTS: The incidence of lymph node involvement was significantly increased, from 6.8% (11/162 patients) by H&E staining, to 27% (43/162 patients) by CK immunostaining (P < 0.0001). Micrometastasis in the lymph node was found in 32 of 151 (21%) patients who had no lymph node metastasis evidenced by H&E staining. Micro-lymph node metastasis was frequently found in tumors with a diameter more than 1.0 cm, of those that were poorly differentiated, deeply invaded, showed lymphatic on vascular invasion, and in those that showed reduced expression of E-cadherin. Loss of expression of E-cadherin in the primary tumor was closely correlated with micro-lymph node metastasis. Patients with tumors with micro-lymph node metastasis detected by CK immunostaining had a significantly lower 5-year survival rate (P < 0.01) than those without such metastases. CONCLUSION: Tumors more than 1.0 cm in diameter and those that exhibit poor differentiation, deep invasion (i.e., to the submucosa), lymphatic or vascular invasion, and reduced expression of E-cadherin are risk factors for lymph node metastasis in early gastric cancer. Thus, it is recommended that cancers confined to the mucosa (m-cancers) that are more than 1.0 cm in diameter should not be treated with limited surgery without lymphadenectomy.

Quantification of TECTA and DFNA5 expression in the developing mouse cochlea.

TECTA and DFNA5 are the mouse orthologues of the human deafness-associated genes TECTA and DFNA5. To determine how expression of these genes is regulated during development, relative mRNA abundance was examined in mice by non-radioactive RT-PCR. TECTA mRNA was detected on embryonic day 15 (E15), increased to its highest level on postnatal day 3 (P3) and then dramatically decreased by P15. Low levels persisted (adulthood, P45 to 67) with mean mRNA abundance after P15 less than 25% of P3 levels. DFNA5 mRNA expression was constant throughout these time points. These results imply that TECTA is transcribed at a particularly high level during tectorial membrane morphogenesis. In contrast, DFNA5 is present in both the developing and mature cochlea.

Prognostic factors in patients with advanced gastric cancer treated by noncurative resection: a multivariate analysis.

BACKGROUND/AIMS: The relationship between prognostic factors and survival time after noncurative gastric resection in patients with advanced gastric cancer was examined by a retrospective review of data on 364 patients. METHODOLOGY: There were 168 patients without metastasis to the liver or peritoneum (group A), 127 with peritoneal metastasis and no liver metastasis (group B), 50 with liver metastasis and no peritoneal metastasis (group C) and 19 with synchronous liver and peritoneal metastases (group D). Patients were primarily treated with the following 3 drugs: the fluorinated pyrimidines, cisplatin, and mitomycin C. RESULTS: Patients in group D had a very poor prognosis as compared with the other groups. Multivariate analysis using the Cox's proportional hazard model adjusted for sex, age, and other covariants indicated that lymph node metastasis, lymph node dissection, and fluorinated pyrimidines for group A, cisplatin for group B, and lymph node dissection for group C were independent prognostic factors. An analysis of patients excluding cases who died within 30 days after surgery revealed that lymph node dissection for group A, lymph node dissection and cisplatin for group B, and lymph node dissection for group C were independent prognostic factors. CONCLUSIONS: Treatment protocol specific for the residual disease may improve the survival of patients with advanced gastric cancer treated by noncurative resection.

Postoperative morbidity and mortality after gastrectomy for gastric carcinoma.

BACKGROUND/AIMS: Surgical technique and postoperative care for gastric cancer have significantly improved in recent years. However, whether postoperative morbidity or mortality rates after gastrectomy for gastric cancer were reduced or not in recent years was unclear. In this study, we analyzed the chronological changes of postoperative morbidity and mortality rates, and we analyzed risk factors for postoperative morbidity and mortality in patients undergoing gastrectomy for carcinomas of the stomach. METHODOLOGY: A total of 887 patients with gastric cancer were gastrectomized in our hospital between January 1985 and December 1996. The patients were divided into three groups on the basis of chronology. The first group included patients treated over the period 1985 to 1988 (n = 324); the second group, 1989 to 1992 (n = 300); and the third group, 1993 to 1996 (n = 263). Postoperative morbidity rates and mortality rates were compared among the three groups. Also, significant risk factors affecting postoperative morbidity and in-hospital mortality were analyzed by the multiple logistic regression analysis. RESULTS: Postoperative complications were detected in 95 patients (10.7%) and in-hospital mortality rate was 2.4% (21/887). Postoperative morbidity rates were 10.5%, 11%, and 10.6% in the first, second, and third groups, respectively and postoperative mortality rates were 2.5%, 2%, and 2.7%, respectively. These postoperative morbidity and mortality rates were not different between the groups (P = 0.979 and P = 0.866). The most common postoperative complication was anastomotic leakage (56/95, 58.9%). Significant risk factors affecting in-hospital mortality were Stage IV (P = 0.006) and noncurative gastric resection (P = 0.004). However, the extent of lymph node dissection, combined resection, or the existence of preoperative complications were not significant risk factors of in-hospital mortality by multiple logistic regression analysis. CONCLUSIONS: These results indicate that patients with far-advanced gastric cancer might have a high risk of postoperative mortality. In noncurative operations for patients with advanced gastric cancer, unnecessary lymph node dissection or combined resection should be avoided.

False-positive magnetic resonance image in the diagnosis of small acoustic neuroma.

A patient presented with sudden hearing loss on her first visit to our department. Gadolinium-DTPA-enhanced magnetic resonance imaging (MRI) of the posterior cranial fossa portrayed an intracanalicular tumour image (2-3 mm), and the pure tone average (PTA) and speech discrimination score (SDS) values were 65 dB and 60 per cent, respectively. Surgical intervention to remove the suspected tumour was scheduled by the translabyrinthine approach. Intracanalicular observations by the retrolabyrinthine approach revealed limited oedema on the inferior vestibular nerve with vascular dilation. The tumour image disappeared two years after the operation. Surgical findings and the post-operative course advocate that gadolinium-DTPA-enriched MRI image of an intracanalicular lesion such as arachnoiditis might produce a false-positive result.

Correlation between spontaneous apoptosis and the expression of angiogenic factors in advanced gastric adenocarcinoma.

The aim of this study was to investigate whether angiogenic factors influence the occurrence of spontaneous apoptosis in advanced gastric cancer. The apoptotic indices (AIs) of 97 tumors from 97 patients with advanced gastric cancer (pT3, pN0, pM0, Stage II) were analyzed by the terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate biotin nick end labeling (TUNEL) method. Intratumoral microvessel densities (IMVDs) of tumors stained with anti-CD34 monoclonal antibody were quantified under x 200 magnification using computer-assisted image analysis. The expressions of angiogenic factors, such as vascular endothelial growth factor (VEGF), thymidine phosphorylase (dThdPase), transforming growth factor-alpha (TGF-alpha), and p53 were analyzed immunohistochemically and compared with IMVDs and AIs. The mean IMVD of the 97 tumors was 365/mm2 (range 147-990/mm2). The mean AI of tumors was 2.1% (range 0-11.3%). A significant inverse correlation between the AIs and the IMVDs was shown (p = -0.278, P = 0.0064). The mean IMVDs of tumors with high expressions of dThdPase, TGF-alpha, or p53 were significantly higher than those of tumors with low expressions of these factors. The mean AI of tumors with high expressions of dThdPase was significantly lower than that of tumors with low expressions of dThdPase (P = 0.023). However, no significant correlations were detected between AIs and the expression levels of VEGF, TGF-alpha, or p53. In gastric cancer, dThdPase may play an important role in tumor progression by increasing microvessels and by suppressing apoptosis of cancer cells.

Pharmacokinetics of intraoperative intrapleural cisplatin chemotherapy of various osmolarities in cases of esophageal cancer.

Intraoperative intrapleural (i.pl.) cisplatin (CDDP) treatment during thoracotomy was performed for esophageal cancers. Three patients underwent isotonic (308 mOsm/l) CDDP treatment. Hypotonic CDDP treatments with a 154 mOsm/l solution and a 62 mOsm/l solution were administered to 4 and 9 patients, respectively. The maximum concentrations (Cmax) of both total and filterable platinum in the plasma after injection of the hypotonic solution were significantly higher than those after injection of the isotonic solution. The area under the curve of concentration versus time (AUC) of the plasma of the 62 mOsm/l solution was significantly higher than that of the 154 mOsm/l and isotonic solution. Although higher levels of the Cmax may increase side-effects, the hypotonic condition of the i.pl. fluid and increased AUC in the plasma may escalate the accumulation of platinum in i.pl. cancer cells. These results suggest that hypotonic i.pl. CDDP is tolerable and may be useful for treatment of the incipient phase of pleural carcinomatosis and for prophylaxis of postoperative recurrence.

Prediction of survival period for patients with postoperative recurrence after curative resection for advanced gastric carcinoma.

BACKGROUND/AIMS: Although many studies have attempted to clarify the prognostic indicators for gastric carcinoma, there have been few studies regarding the factors that correlate with the survival period of patients with postoperative recurrence. METHODOLOGY: Among 504 advanced gastric adenocarcinoma patients who had undergone curative gastrectomy, 188 patients who had died of recurrence were used in this study. RESULTS: Univariate analysis indicated that age, the presence of lymph node metastasis and blood vessel invasion, the number of positive lymph nodes, and gastrectomy significantly correlated with the survival period. Multivariate analysis indicated that the length of the survival period was independently influenced by the number of positive lymph nodes and blood vessel invasion. The survival time of patients with less than 3 positive lymph nodes and no accompanying blood vessel invasion was significantly longer than that of other patients. CONCLUSIONS: The number of positive lymph nodes and the presence of blood vessel invasion are the most important factors predicting the survival period of patients with postoperative recurrence after curative resection for advanced gastric carcinoma.

Bax expression as a prognostic marker of postoperative chemoradiotherapy for patients with esophageal cancer.

Postoperative chemoradiotherapy was introduced to improve the survival of patients with esophageal squamous cell carcinoma (ESCC). However, considerable number of patients still die of cancer recurrence despite curative operation plus chemoradiotherapy. This indicates that some ESCCs are chemoradio-resistant. To prevent unnecessary treatment and to improve the effect of post-operative adjuvant therapy, it seems to be important to investigate biological markers of chemoradio-sensitivity in ESCC. Loss of Bax expression has been reported to be associated with poor response to chemotherapy in breast cancer, and Bax promotes apoptosis in cells. Abnormal expression of Bax may play an important role in chemoradio-sensitivity in malignant tumors. In this study, we retrospectively investigated the prognostic significance of the expressions of Bax and p53 in patients with ESCC. Immunoreactivities of Bax and p53 were evaluated in 141 surgically resected ESCC by using monoclonal antibodies. Prognoses of 141 patients with or without postoperative chemoradiotherapy were compared among groups with high and low expressions of Bax or p53. High immunoreactivities of Bax and p53 were detected in 49 cases (33.1%) and in 70 cases (47.3%), respectively. Loss of Bax expression was detected more frequently in p53-positive tumors. Bax expression correlated with favorable prognosis (P=0.016) in 57 patients with postoperative chemoradiotherapy. However, in 84 patients without adjuvant therapy, the prognostic significance of Bax was minimal. Moreover, in patients with or without postoperative chemoradiotherapy, p53 expression did not correlate with the prognosis. Bax expression may be a good marker for chemoradio-sensitivity in patients with ESCC.

Combined resection of invaded organs in patients with T4 gastric carcinoma.

BACKGROUND: To understand the efficacy of gastrectomy combined with the resection of other organs and to refine the indications for this type of surgery, the records of 156 patients with carcinoma of the stomach directly invading adjacent organs or structures (T4 gastric carcinoma) were analyzed retrospectively. METHODS: The patients were divided into three groups, as follows: in group A, curative resection was performed by the combined resection of invaded organs or structures; in group B, although combined resection was performed, curative resection could not be performed because of the extent of lymph node metastasis, liver metastasis, and/or peritoneal metastasis; in group C, combined resection was not performed. RESULTS: In patients with peritoneal or liver metastasis, there was no significant difference in prognosis among the three groups. In patients without peritoneal and liver metastasis, the prognosis of group A was significantly better than that of group B or group C, irrespective of the extent of lymph node metastasis or the number of invaded organs. In these group A patients, the 5-year survival rates of those with localized tumors and no lymph node metastasis, those with localized tumors and lymph node metastasis, those with infiltrating tumors and no lymph node metastasis, and those with infiltrating tumors and lymph node metastasis were 100%, 56.2%, 57.1%, and 13.6%, respectively. CONCLUSIONS: Combined resection of involved organs should be carried out with curative intent in patients with localized gastric cancer or infiltrating gastric cancer without lymph node metastasis.

Limited operation for patients with T1 esophageal cancer.

BACKGROUND/AIMS: Transhiatal esophagectomy without thoracotomy has been introduced as a minimally invasive operation to prevent postoperative complications in patients with relatively early-stage esophageal cancer who have preoperative pulmonary or cardiovascular complications or who are in a high age bracket. However, this procedure for patients with esophageal cancer remains controversial, especially as regards curative surgery because complete intrathoracic lymphadenectomy cannot be performed in this operation. Thus, cancer recurrence after this operation has been considered to be high. To evaluate the benefits of this less invasive surgery for patients with T1 esophageal cancer, the prognoses of patients who underwent transhiatal esophagectomy without thoracotomy were compared with those of patients who underwent traditional esophagectomy with thoracotomy. METHODS: Between 1989 and 1998, 33 patients with T1 esophageal cancer were operated on in our hospital. We introduced transhiatal esophagectomy without thoracotomy in 19 patients who were over 70 years old or who had preoperative complications (transhiatal group). The remaining 14 patients were treated with the transthoracic procedure (transthoracic group). These 33 patients were followed up at our hospital until the end of 1999. The postoperative complications and prognoses in the two groups were compared. RESULTS: We were able to reduce the operation time using the transhiatal procedure. Even though no significant difference was detected, there were fewer postoperative pulmonary complications with this procedure (11%) than with the transthoracic procedure (21%). The incidences of in-hospital mortality did not differ between the two groups. Cancer recurrence was detected in 5 of 19 patients (26%) in the transhiatal group and in 5 of 14 patients (36%) in the transthoracic group; no difference was observed (P=0.562). The 5-year survival rate (58%) of the transhiatal group was no different from that of the transthoracic group (62%, P=0.69). CONCLUSIONS: Complete intrathoracic lymphadenectomy cannot be performed along with transhiatal esophagectomy; however, the prognoses of patients who were treated with this procedure were no different from those of patients who were treated with transthoracic esophagectomy. Thus, transhiatal esophagectomy without thoracotomy might be a justifiable operation for compromised patients with T1 esophageal cancer.

Combined analysis of p53 and retinoblastoma protein expressions in esophageal cancer.

BACKGROUND: p53 gene mutation and abnormal p53 protein expression, also loss of the retinoblastoma gene and protein expression are frequently associated with esophageal squamous cell carcinoma (ESCC). Recently, the prognostic significance of the combined analysis of p53 protein and retinoblastoma protein (pRB) has been reported in non-small cell lung cancer. However, in ESCC, the prognostic significance of the combined analysis of these proteins remains unclear. In this study, we immunohistochemically analyzed the p53 protein and pRB expressions in surgically resected ESCC, and we evaluated the prognostic significance of the combination of these proteins. METHODS: We analyzed p53 protein and pRB expressions immunohistochemically in 191 surgically resected ESCC cases. Overexpression of p53 and loss of pRB were considered abnormal. RESULTS: Overexpression of p53 protein was detected in 79 patients (41%) and decreased pRB nuclear staining occurred in 82 (43%). The Kaplan-Meier survival curve showed that absence of pRB expression was significantly associated with shortened survival (p = 0.001), whereas expression of p53 was not significantly associated with survival. Moreover, p53 and pRB status individually were not independent prognostic factors in multivariate survival analysis. With respect to pRB and p53, the tumors could be grouped into four categories: p53-/pRB+ (31%); p53-/pRB- (27%); p53+/pRB+ (26%); and p53+/pRB- (16%). Favorable prognosis was observed in patients with p53-/pRB+ tumors. Multivariate analysis showed p53-/pRB+ status to be an independent prognostic factor. CONCLUSIONS: The combination of p53 protein loss and pRB expression was associated with good prognosis in patients with ESCC.

Cisplatin combined with prostaglandin E1 chemotherapy in rat peritoneal carcinomatosis.

Cisplatin intraperitoneal (i.p.) chemotherapy is frequently performed for patients with peritoneal carcinomatosis. However, cisplatin penetrates only the surface of the peritoneal tumor and has serious side effects on renal cells. Thus, cisplatin i.p. chemotherapy had been limited to use for these patients. Prostaglandin E1 (PGE1) has been used for reducing the toxic effects of anticancer drugs because of its cytoprotective effects and has been reported to enhance tumoricidal activity of anticancer drugs. In our study, the effects of PGE1 on the rat peritoneal carcinomatosis model treated with cisplatin i.p. chemotherapy were evaluated. Cisplatin (5 mg/kg) was given in an i.p. administration to 70 tumor-free rats. PGE1 was administered to 35 rats through the tail vein at an infusion rate of 0.1 microg/kg/min (1 ml/hr), and the remaining 35 rats were injected with physiological saline. Forty rats were given an i.p. injection of 1 x 10(7) AH100B cells. Ten days after injection, cisplatin (5 mg/kg) was administered with PGE1 to 20 and the remaining 20 were injected with physiological saline. The accumulation of platinum in the tissues and apoptotic renal cells were analyzed. The maximum concentrations of platinum in the kidneys of PGE1 untreated rats (tumor-free: 10.11 microg/g; tumor-bearing: 11.45 microg/g) did not differ from those of platinum in the kidneys of PGE1-treated rats (tumor-free: 10.28 microg/g; tumor-bearing: 13.28 microg/g). The number of apoptotic renal cells was significantly reduced by PGE1 administration in both tumor-free and tumor-bearing rats. Moreover, PGE1 increased the maximum platinum concentration in tumor masses (5.31 microg/g) of the treated group compared with that in tumor mass of the control group (2.72 microg/g, p = 0.009). These results indicate that PGE1 may increase the anticancer effect of cisplatin by increasing tumor platinum concentration and may reduce the chance of cisplatin-induced renal failure. Intraperitoneal cisplatin chemotherapy combined with PGE1 treatment may have a therapeutic benefit for patients with peritoneal carcinomatosis.

Nuclear profiles of cancer cells reveal the metastatic potential of gastric cancer.

Nuclear profiles have been reported as useful prognostic predictors in various cancers. Data from computerized morphometry are objective and can be quickly derived using conventional microscopic analysis, but image analysis of nuclear features has only rarely been applied to investigations of gastric cancer. The aim of this study was to evaluate the correlation between one of these morphological nuclear features and the clinicopathological parameters in patients with gastric cancer. The morphometric nuclear feature (nuclear area) was analysed in 400 patients with gastric cancer. In each case, 300 cancer nuclei on routine haematoxylin and eosin-stained slides were analysed through the use of a computer-assisted image analysis system which traced the nuclear profiles (magnificationx400) on a computer monitor. The morphometric data were compared with the patients' clinicopathological status and survival rate. The mean nuclear area (NA) of cancer cells from 400 cases of gastric cancer was 47.2 microm(2). The NAs of cancer cells from tumours with microvessel invasion (lymphatic or venous invasion), lymph node metastasis or hepatic metastasis at the time of operation were significantly larger than those of cancer cells from tumours without such invasion or metastases. Cytokeratin (CK) immunostaining was performed on 2577 lymph nodes from 91 patients with advanced gastric cancer (pT3, pN0, pM0, stage II) to detect micrometastases. CK-positive lymph nodes were detected in 350 of 2577 lymph nodes (13. 6%) and in 62 of 91 patients (68.1%). The mean NA of cancer cells from 62 tumours with micrometastases (44 microm(2)) was larger than that of cancer cells from 29 tumours without micrometastases (38.8 microm(2), p=0.043), and a significant positive correlation was detected between the NAs of cancer cells from 91 tumours and the number of micrometastatic lymph nodes of 91 patients (rho=0.278, p=0. 008). Cancer cells with large NA correlated strongly with haematogenous and lymph node recurrence or relapse after gastrectomy and the NA of cancer cells was identified as an independent prognostic factor in gastric cancer. Nuclear morphometry is an objective, reproducible, and technically uncomplicated procedure. The NA of cancer cells correlates closely with the metastatic potential of gastric cancer. Nuclear morphometry may therefore be useful for the selection of patients who are at risk of haematogenous or lymph node metastatic recurrence after surgery.

Pharmacokinetics of hypotonic cisplatin chemotherapy administered into the peritoneal and the pleural cavities in experimental model.

The pharmacokinetics of intraperitoneal (i.p.) and intrapleural (i.pl.) hypotonic cisplatin (CDDP) were compared under the same experimental conditions. The same dose of CDDP was administered in hypotonic (62 mOsm/L) and isotonic (308 mOsm/L) solutions to the peritoneal and pleural cavities of Ehrlich carcinoma cell bearing mice. The intracellular amount of platinum increased for more than 60 minutes after an i.pl. injection of the hypotonic solution of CDDP, whereas it increased for up to 30 minutes after an i.p. injection. Although hypotonic conditions augmented the amount of platinum taken-up by Ehrlich cells, the amount was significantly greater in the pleural cavity than in the peritoneal cavity. In Donryu rats, the levels of platinum in the i.p. and i.pl. fluids decreased rapidly after injection of hypotonic solution as compared with isotonic solution. The extent of this decrease was greater in the peritoneal cavity than in the pleural cavity. In the hypotonic condition, the area under the curve of concentration versus time (AUC) for platinum of i.pl. fluid was greater than that of i.p. fluid. When i.p. and i.pl. hypotonic CDDP were administered, the osmolarity of the fluid returned rapidly to the isotonic level, with equilibration in 30 or 180 minutes respectively. The lower osmolarity continued for a longer duration in the pleural cavity than in the peritoneal cavity. These results indicate that the pleural cavity may require a smaller amount of CDDP to achieve the same effect on intracellular uptake of platinum than the peritoneal cavity.

[Awake pronation of surgical patients with cervical spinal lesions].

Positioning of patients with cervical spinal lesions under general anesthesia may lead to serious neurological complications. The authors attempted awake pronation in eighteen patients to minimize the risks. In all patients, cervical instability or cervical spinal cord compression was diagnosed, and posterior fusion or laminoplasty under general anesthesia was planned. Naso-tracheal intubation was performed by broncho-fiberoptic scope under topical anesthesia and light sedation. After tracheal intubation, pronation was completed while patients were still awake. Twelve patients could change their position almost by themselves, and needed only a little assistance of the medical staff. After the patients settled in appropriate position, general anesthesia was induced. Neurological status was assessed before and after the intubation, and just before the induction of general anesthesia, to prove the absence of complications. Operations were accomplished without major troubles in all patients. During post anesthetic interviews, eight patients had memory of the positioning, but none of them had any complaints about the procedure. Awake pronation may be useful to minimize the risk of neurological complications related to positioning of surgical patients, and also need less assistance by medical staff.

Prognostic benefit of extended radical lymphadenectomy for patients with gastric cancer.

BACKGROUND: The therapeutic value of extensive gastric lymphadenectomy in gastric cancer is controversial. We retrospectively investigated the effect of extended lymphadenectomy on survival in 882 patients with gastric cancer. MATERIALS AND METHODS: From 882 patients who underwent gastrectomy, D0 or D1 lymphadenectomy was performed on 137 patients, D2 lymphadenectomy on 524 and D3 lymphadenectomy on 221. Curative gastrectomy was performed on 771 patients and the 5-year survival rate of patients had undergone D0 or D1 lymphadenectomy (D1 group) and that of patients who had undergone D2 lymphadenectomy (D2 group) was compared with that of patients had undergone D3 lymphadenectomy (D3 group). RESULTS: In each stage, the 5-year survival rates of patients who had undergone curative operations (n = 771) were compared among the D1, D2 and D3 groups. The 5-year survival rates were as follows: Stage I: n = 510, 89.3% (D1 group: n = 91, 85.8%; D2 group: n = 384, 90.3%; D3 group: n = 35, 88.1%; p = 0.539), Stage II: n = 83, 77.8% (D2 group: n = 35, 82.7%; D3 group: n = 48, 74.3%; p = 0.601), Stage III: n = 133, 50.2% (D2 group: n = 46, 39%; D3 group: n = 87, 56.1%; p = 0.027), Stage IV: n = 45, 8.9% (D2 group: n = 10, 0%; D3 group: n = 35, 11.4%; p = 0.588). Postoperative complications were detected in 10.4% of the cases and the in-hospital mortality rate was 2.4%. The postoperative morbidity rate of the D3 group (15.8%) was significantly higher than that of the other groups (D1 group: 7.3% and D2 group: 9%; p = 0.008). However, the in-hospital mortality rate of the D3 group (1.4%) was not different from that of the other groups (D1 group: 3.7% and D2 group: 2.5%; p = 0.374). CONCLUSION: These results indicate that D3 lymphadenectomy might be performed as safely as D1 or D2 lymphadenectomy on patients with gastric cancer. In addition, D3 lymphadenectomy might provide a survival benefit for patients with Stage III or Stage IV gastric cancer.

Nuclear accumulation of p53 protein in gastric cancer strongly correlates with enlargement of nuclear area of cancer cells.

The nuclear area (NA) of cancer cells have been reported to be a useful prognostic indicator in various tumors. However, this image analysis of cancer nucleus has only rarely been applied to gastric adenocarcinoma. Moreover, it remains to be shown what types of biological factors influence this nuclear feature. In this study, we analyzed the area of cancer nuclei in tumors from 97 patients with advanced gastric cancer (t3, n0, stage II) by using hematoxylin and eosin stained slides with a computer-assisted image-analysis system. The morphometric data were compared with clinicopathological and biological status of the tumors. The mean NA of 50 tumors with venous invasion (50 microm2) was significantly larger than that of 47 tumors without venous invasion (38 microm2, p<0.0001). There was a significant correlation between the NAs of cancer cells and the p53 labeling indices of tumors (p=0.0012) and Ki-67 labeling indices of tumors (p=0.0324). However, no significant correlation was detected between the NAs of cancer cells and other factors, such as, tumor size, DNA ploidy pattern, expression of vascular endothelial growth factor (VEGF), or microvessel density of tumors. The five-year survival rate of 49 patients with large nuclear area (NA > or =41 microm2, 63%) was significantly lower than that of 48 patients with small nuclear area (NA <41 microm2, 78%, p=0.043). Data from computerized morphometry are objective and can be obtained rapidly by conventional microscopic analysis. The NA of cancer cells in advanced gastric cancer appears to predict the ability to invade the microvessels in the gastric wall. This nuclear morphological feature strongly correlated with p53 accumulation in the nuclei of gastric adenocarcinoma.

Clinical significance of retinoblastoma protein (pRB) expression in esophageal squamous cell carcinoma.

BACKGROUND AND OBJECTIVES: The goal was to evaluate the clinicopathological significance of retinoblastoma gene product (pRB) expression in esophageal squamous cell carcinoma. METHODS: We investigated abnormal pRB expression in tumors in 191 patients using an immunohistochemical method in conjunction with anti-RB protein antibody. Surgically resected esophageal squamous cell carcinomas were examined by immunohistochemical analysis for altered pRB expression. RESULTS: Decreased pRB nuclear staining indicating loss of RB function occurred in 82 (43%) of the cases studied. The incidence of decreased pRB expression was higher in tumors with invasion to the adventitia (50%) than in tumors without invasion to the adventitia (33%, P = 0.0188). In addition, the incidence of decreased pRB expression was higher in tumors with lymph node metastasis (50%) than in those without (34%, P = 0.0346). The 3-year survival rates of 82 patients who had tumors with decreased pRB expression (30%) was significantly lower than that of 109 patients who had tumors with normal pRB expression (52%, P = 0.0032). However, in the multivariate survival analysis, pRB expression was not an independent prognostic factor for patients with esophageal squamous cell carcinoma. CONCLUSIONS: Abnormal pRB expression appears to be closely associated with tumor development. However, the existence of tumors with hyperphosphorylated RB protein (inactivated form) in pRB-positive tumors, such as those in the present study, should be considered. Thus, discrimination of this hyperphosphorylated form of RB protein from the unphosphorylated RB protein is needed.

Micrometastasis in lymph nodes and microinvasion of the muscularis propria in primary lesions of submucosal gastric cancer.

BACKGROUND: It is important to clarify the clinicopathologic characteristics of micrometastasis in lymph nodes and microinvasion in primary lesions for the treatment options with regard to submucosal gastric cancer. METHODS: We examined 1945 lymph nodes and 68 primary tumors resected from 79 patients with submucosal gastric cancer. Two consecutive sections were prepared for simultaneous staining with ordinary hematoxylin and eosin and immunostaining with anticytokeratin antibody (CAM 5.2), respectively. RESULTS: The incidence of nodal involvement in 79 patients with submucosal gastric cancer increased from 13% (10/79 patients) by hematoxylin and eosin staining to 34% (27/79 patients) by cytokeratin immunostaining. Micrometastases in the lymph nodes were found in 17 of 69 patients (25%), with cancer-free nodes examined by hematoxylin and eosin. Microinvasion to the muscularis propria was found in 11 of 68 patients (16%) who were histologically diagnosed with submucosal gastric cancer. Survival analysis demonstrated a lesser 5-year survival in the patients with micrometastasis in lymph nodes (82%) and with microinvasion to muscularis propria (73%). A high incidence of nodal involvement was found in submucosal cancers of large size (> 2 cm; 43%), a depressed type (48%), lymphatic invasion (73%), and deeper submucosal invasion (submucosal 3, 53%). A higher incidence of microinvasion was found with the diffuse-type carcinoma (33%). CONCLUSIONS: Cytokeratin immunostaining is useful for detecting micrometastasis and microinvasion in submucosal gastric cancer. Tumor size, macroscopic type, lymphatic invasion, and the depth of submucosal invasion are strongly associated with lymph node involvement.