Quality of life following esophagectomy with three-field lymphadenectomy for carcinoma, focusing on its relationship to vocal cord palsy.

To clarify the quality of life of patients who underwent esophagectomy for carcinoma by right thoracotomy, laparotomy and cervical anastomosis, 116 patients who were cancer free at the time of mailing a questionnaire were analyzed. A significant decrease in vital capacity for 3 years postoperatively, as well as in the percentage of ideal body weight, between 3 and 5 years were observed in 57 patients with three-field lymphadenectomy. Patients' quality of life undergoing three-field dissection was worse than those with less radical lymphadenectomy (59 cases) in terms of the performance status and difficulty in talking at 60 months or more postoperatively. Around 20% of all patients reported severe hoarseness due to permanent recurrent nerve paralysis, resulting in poor quantity of food intake at 24 months or less postoperatively and restricted daily activity and difficulty in talking at 60 months or more after the operation. When a patient suffers from vocal cord insufficiency caused by permanent paralysis of the recurrent nerve, early treatment before discharge from the hospital should be performed to improve the quality of life of such a patient.

Clinical significance of LAMB3 and COL7A1 mRNA in esophageal squamous cell carcinoma.

AIMS: LAMB3 and COL7A1 genes code for the laminin-5beta3 chain and type VII collagen, respectively. They constitute the major components of the basement membrane zone. The aim of the current study was to clarify the clinical significance of LAMB3 and COL7A1 mRNA expression in esophageal squamous cell carcinoma (ESC). METHODS: We quantitated the expression of LAMB3 mRNA and COL7A1 mRNA in malignant esophageal tissues (T) and corresponding normal tissues (N) by real-time quantitative reverse transcription-polymerase chain reaction assays. The clinicopathologic significance of LAMB3 and COL7A1 expression was also determined. Paired T and N tissues were obtained from 66 patients who underwent curative esophagectomy. RESULTS: The expression levels of LAMB3 and COL7A1 mRNAs were higher in malignant tissues than in the corresponding normal tissues. The level of LAMB3 expression was significantly correlated with the depth of invasion and venous invasion (p=0.007 and 0.001, respectively). COL7A1 expression was significantly correlated with depth of tumor invasion and lymphatic invasion (p=0.046, 0.013, respectively). The five-year survival rate was better in the 22 patients with relatively low expression of both LAMB3 and COL7A1 in comparison with the other 44 cases (p<0.05). CONCLUSION: The evaluation of LAMB3 and COL7A1 mRNA expression is useful for predicting the malignant properties of ESC and may prove valuable in predicting the future course of the disease.

Expression of uPAR mRNA in peripheral blood is a favourite marker for metastasis in gastric cancer cases.

Urokinase-type plasminogen activator receptor (uPAR) plays a central role in the plasminogen activation cascade and participates in extracellular matrix degradation, cell migration and invasion. We evaluated the expression level of uPAR mRNA and the presence of isolated tumour cells (ITCs) in bone marrow (BM) and peripheral blood (PB) in gastric cancer patients and clarified its clinical significance. We assessed specific uPAR mRNA expression by quantitative real-time reverse transcriptase- polymerase chain reaction (RT-PCR) in BM and PB in 846 gastric cancer patients as well as three epithelial cell markers, carcinoembryonic antigen (CEA), cytokeratin (CK)-19 and CK-7. The uPAR mRNA expression in bone marrow and peripheral blood expressed significantly higher than normal controls (P<0.0001). The uPAR mRNA in BM showed concordant expression with the depth of tumour invasion, distant metastasis, and the postoperative recurrence (P=0.015, 0.044 and 0.010, respectively); whereas in PB, we observed more intimate significant association between uPAR expression and clinicopathologic variables, such as depth of tumour invasion, the distant metastasis, the venous invasion and the clinical stage (P=0.009, 0.002, 0.039 and 0.008, respectively). In addition, the uPAR mRNA expression in PB was an independent prognostic factor for distant metastasis by multivariate analysis. We disclosed that it was possible to identify high-risk patients for distant metastasis by measuring uPAR mRNA especially in peripheral blood at the timing of operation in gastric cancer patients.

CD133 expression is correlated with lymph node metastasis and vascular endothelial growth factor-C expression in pancreatic cancer.

Although CD133 has been shown to be a marker for cancer stem cells in various tumours, its expression in pancreatic cancer has not yet been clinically reported. In this study, we investigated the relationship between CD133 expression and clinicopathological factors in pancreatic cancer. Pancreatic head carcinoma specimens from 80 patients who underwent surgical resection were immunohistochemically assessed for CD133, vascular endothelial growth factor (VEGF)-C, CXCR4, CD34, Ki-67, and cytokeratin (CK) expressions. Sixty percentage (48/80) of specimens were CD133-positive, with less than 15% cells per specimen expressing the marker. CD133-positive cells were found at the peripheral site of adenocarcinoma glandular structures and were negative for CK. There was a significant correlation between CD133 expression and clinicopathological factors, including histological type, lymphatic invasion, and lymph node metastasis (P=0.0215, 0.0023, and 0.0024, respectively). Vascular endothelial growth factor-C expression was also significantly correlated with CD133 expression (P=0.0002). Consequently, the 5-year survival rate of CD133-positive patients was significantly lower than that of CD133-negative patients (P=0.0002) and multivariate analysis revealed that CD133 expression was an independent prognostic factor (P=0.0103). These results suggest that CD133 expression in pancreatic cancer was significantly associated with lymphatic metastasis, VEGF-C expression, and prognosis.

Cyclooxygenase-2 expression is related to prognosis in patients with esophageal squamous cell carcinoma.

AIM: Esophageal carcinoma is one of the most aggressive malignancies. Many studies have examined various biological factors associated with the malignant potential of esophageal carcinoma. Cyclooxygenase (COX)-2 is overexpressed in various types of human malignancies, including esophageal carcinomas. Although some groups have described COX-2 expression in esophageal adenocarcinoma, few studies have reported COX-2 expression in esophageal squamous cell carcinoma (ESCC). METHODS: We immunohistochemically investigated relationships between COX-2 overexpression in surgical specimens of primary tumors in 228 patients with ESCC. Relationships between COX-2 expression and clinicopathological factors, including prognosis, were analyzed. COX-2 expressions were classified into 4 criteria: Score 0, no staining; Score 1, <10% staining; Score 2, 10-90% staining; and Score 3, >90% staining. RESULTS: Scores of COX-2 immunoreactivity in 228 patients were as follows: Score 0, 21 of 228; Score 1, 71of 228; Score 2, 117 of 228; and Score 3, 19 of 228, respectively. COX-2 expression was significantly correlated with depth of invasion and tumor stage (p=0.03 and p=0.04, respectively). The 5-year survival rate of patients decreased significantly with increased expression of COX-2 (p=0.005). Multivariate regression analysis indicated COX-2 expression as an independent prognostic factor for ESCC. CONCLUSIONS: COX-2 overexpression was significantly correlated with depth of invasion, tumor stage and survival in ESCC. Evaluation of COX-2 expression should be useful for determining tumor properties, including prognosis, in patients with ESCC.

Acceleration of primary liver tumor growth rate in embolized hepatic lobe after portal vein embolization.

BACKGROUND: Portal vein embolization (PVE) is now widely accepted as a useful preoperative procedure in selected patients undergoing extended hepatectomy. However, the effect of PVE on the growth of liver tumors has not been fully elucidated. PURPOSE: To retrospectively evaluate the effects of PVE on the growth of liver tumors in the embolized lobes. MATERIAL AND METHODS: Eight patients with a primary liver tumor, six hepatocellular carcinomas (HCC) and two cholangiocellular carcinomas (CCC), were studied. The growth rates of the tumors in the embolized lobes and non-embolized liver parenchyma were calculated using the computed tomography (CT) volume values at the time of tumor identification, and before and after PVE. RESULT: The median tumor growth rate was 0.59 cm(3)/day (range 0.22-6.01 cm(3)/day) before PVE and 2.37 cm(3)/day (range 0.29-13.97 cm(3)/day) after PVE (P = 0.018). The tumor growth acceleration ratios ranged from 1.50 to 7.46 (median 2.65) in the six HCCs, and were 1.00 and 1.32 in the two CCCs. There was no apparent correlation between the tumor growth rate after PVE and the growth rate of non-embolized liver parenchyma (median 6.00 cm(3)/day, range 1.24-11.0 cm(3)/day). CONCLUSION: Liver tumor growth in an embolized lobe accelerates after PVE, in patients with HCC.

Clinical significance of midkine expression in pancreatic head carcinoma.

Midkine (MK) is a heparin-binding growth factor and a product of a retinoic acid-responsive gene. Midkine is overexpressed in many carcinomas and thought to play an important role in carcinogenesis. However, no studies have been focussed on the role of MK in pancreatic carcinoma. This study sought to evaluate the clinical significance of MK expression in pancreatic head carcinoma, including the relationship between immunohistochemical expression and clinicopathologic factors such as prognosis. Immunohistochemical expression of MK and CD34 was evaluated in pancreatic head carcinoma specimens from 75 patients who underwent surgical resection. Midkine was expressed in 53.3% of patients. Midkine expression was significantly correlated with venous invasion, microvessel density, and liver metastasis (P=0.0063, 0.0025, and 0.0153, respectively). The 5-year survival rate was significantly lower for patients positive for MK vs patients negative for MK (P=0.0073). Multivariate analysis revealed that MK expression was an independent prognostic factor (P=0.0033). This is the first report of an association between MK expression and pancreatic head carcinoma. Midkine may play an important role in the progression of pancreatic head carcinoma, and evaluation of MK expression is useful for predicting malignant properties of pancreatic head carcinoma.

Phase-I trial of oral fluoropyrimidine anticancer agent (S-1) with concurrent radiotherapy in patients with unresectable pancreatic cancer.

In this phase-I trial, we evaluated the safety of S-1, a novel oral fluoropyrimidine anticancer agent, combined with external-beam radiotherapy (EBRT) to determine the maximum-tolerated dose and dose-limiting toxicity (DLT) in unresectable pancreatic cancer patients. Patients had histologically proven unresectable locally advanced or metastatic pancreatic cancer. S-1 was administered orally twice daily. External-beam radiotherapy was delivered in fractions of 1.25 Gy x 2 per day, totalling 50 Gy per 40 fractions for 4 weeks. S-1 was given at five dose levels: 60 mg m(-2) day(-1) on days 1-7 and 15-21 (level 1), 1-14 (level 2), and 1-21 (level 3a) and 80 mg m(-2) day(-1) on days 1-21 (level 3b) and 1-28 (level 4). We studied 17 patients: dose levels 1 (four patients), 2 (four patients), 3a (three patients), 3b (three patients), and 4 (three patients). One patient in level 1 (grade 3 vomiting) and two patients in level 4 (grade 4 neutropenia and grade 3 anorexia) showed DLT. No DLT was seen for levels 2, 3a, and 3b. Clinical effects by computed tomography included 5 partial responses (35%), 11 cases of stable disease, and one case of progressive disease. CA19-9 levels of less than half the starting values were observed in 8 of 16 (50%) patients. S-1 at a dose of 80 mg m(-2) day(-1) given on days 1-21 is safe and recommended for phase-II study in patients with locally advanced and unresectable pancreatic cancer when given with EBRT.

Isolated tumour cells in blood and E-cadherin expression in oesophageal squamous cell cancer.

BACKGROUND: Patients with oesophageal squamous cell carcinoma have a high rate of recurrence, even after curative resection. The aim of this study was to examine the correlation between the presence of isolated tumour cells (ITCs) in the blood and recurrence, and between the presence of ITCs and E-cadherin expression in the primary tumour in these patients. METHODS: Blood samples obtained immediately before and after resection in 125 patients with oesophageal squamous cell carcinoma were examined by real-time reverse transcription-polymerase chain reaction using carcinoembryonic antigen mRNA. Blood samples from 28 healthy volunteers and 42 patients with benign diseases were used as controls. RESULTS: Seventy-seven patients (61.6 per cent) were ITC positive. ITC positivity correlated significantly with tumour depth, lymph node metastasis, stage, lymphatic invasion and venous invasion. Multivariable analysis revealed that tumour depth and ITC positivity were independent factors for a shortened haematogenous disease-free interval. A significant correlation was found between ITC positivity and reduced E-cadherin expression in the primary tumour (P < 0.001). ITC-positive patients with preserved E-cadherin expression had a longer disease-free interval (P = 0.016), haematogenous disease-free interval (P = 0.020) and overall survival (P = 0.004) than those with reduced E-cadherin expression. CONCLUSION: Examination of ITCs in the blood is useful for predicting haematogenous recurrence in patients with oesophageal squamous cell carcinoma.

Randomized controlled study on preoperative chemoradiotherapy followed by surgery versus surgery alone for esophageal squamous cell cancer in a single institution.

The purpose of the present study was to compare the clinical results between preoperative chemoradiotherapy followed by surgery (CRT group) and surgery alone (Surgery group) by a randomized controlled study. Twenty-two patients were assigned to the CRT group and 23 to the Surgery group. A total radiation dose of 40 Gy was applied and in the same period, intravenous chemotherapy was performed using cisplatin (7 mg over 2 h) and 5-fluorouracil (5-FU; 350 mg over 24 h). Surgical treatment was performed in 20 patients in the CRT group except for two patients with bone metastasis after CRT. According to histological effects of primary tumors, the number of patient with Grades 1, 2 and 3 was 11, 7 and 3, respectively. Frequency of lymphatic and venous invasion was significantly lower in the CRT group than in the Surgery group. The 5-year survival rate was 57% in the CRT group and 41% in the Surgery group (P = 0.58). According to the histological effect in the CRT group, 5-year survival was 30% for Grade 1, 83% for Grade 2 and 100% for Grade 3 (P = 0.0069). This randomized trial did not demonstrate a statistically significant survival difference between the CRT group and the Surgery group.

Expression of osteopontin in oesophageal squamous cell carcinoma.

Osteopontin is a multifunctional 34 kDa extracellular matrix protein with a cell-binding domain. It is involved cell adhesion and cell migration and is therefore considered to influence tumorigenesis and/or metastasis. The purpose of the present study was to evaluate the clinical significance of Osteopontin expression in oesophageal squamous cell carcinoma (ESCC). In the present study, we immunohistochemically investigated the relationship between Osteopontin expression and clinicopathological factors including prognosis in surgical specimens of primary tumours in 175 patients with ESCC. Osteopontin was expressed in 48% of 175 patients. Osteopontin expression was significantly correlated with lymph node metastasis, lymphatic invasion, and stage (P=0.0015, 0.037 and 0.033, respectively). Tumours with expressing Osteopontin exhibited more lymph node metastasis, lymphatic invasion and advanced stage than the tumour with negative Osteopontin expression. Five-year survival rate was better in patients with negative Osteopontin expression than in those with positive Osteopontin expression (P=0.035). However, multivariate analysis revealed that Osteopontin expression was not an independent prognostic factor. As our findings suggest that Osteopontin may play an important role in progress of ESCC, the evaluation of Osteopontin expression is useful for predicting the malignant properties of ESCC.

The role of salvage surgery for recurrence of esophageal squamous cell cancer.

AIM: A consensus treatment strategy for recurrent esophageal squamous cell cancer (ESCC) has not been established. The purpose of the present study was to analyse the mode of recurrence, and evaluate the role of surgical salvage treatment in recurrence of ESCC. METHODS: Recurrence was detected in 131 of 367 consecutive patients with ESCC. We retrospectively analysed the mode of recurrence and treatment for recurrence. Recurrence was divided into four types; lymph node, hematogeneous, mixed and local. Treatments were classified into four groups; chemotherapy alone (C group), radiation therapy +/- chemotherapy (R group), surgery +/- other therapy (S group), and no therapy (N group). RESULTS: Of the 131 recurrences, the number of patients with lymph node, hematogeneous, mixed and local recurrence was 43, 44, 40 and 4, respectively. The number of patients in the C, R, S, N groups was 35, 35, 24 and 37, respectively. Of the 24 patients who received surgical treatment for recurrence, the number of patients with lymph node, hematogeneous, mixed and local recurrence was 11, 6, 6 and 1, respectively. The number of lesions in hematogeneous recurrence was 2 or less. The survival rate from recurrence to death in the C, R, S and N groups was 0, 3.9, 6.7 and 0%, respectively. A statistically significant difference was found in these groups (p < 0.0001). CONCLUSIONS: Salvage surgery is one of the useful treatment tools for resectable metastatic lesions. In such cases, the number of lesions, recurrent sites and effectiveness of chemotherapy and/or radiotherapy should be carefully evaluated.

Lymphatic invasion using D2-40 monoclonal antibody and its relationship to lymph node micrometastasis in pN0 gastric cancer.

The monoclonal antibody D2-40 is a specific lymphatic endothelial markers and D2-40 staining have been applicable to evaluate lymphatic invasion in various malignant neoplasms. In the present study, we investigated lymph node micrometastasis determined by immunohistochemistry (IHC) and reverse transcription-polymerase chain reaction (RT-PCR) in all dissected lymph nodes obtained from 80 patients with node-negative gastric cancer, and analysed the relationship between micrometastasis and clinicopathological findings including lymphatic invasion of the resected primary tumour using D2-40 immunohistochemical staining. The incidence of micrometastasis determined by IHC and RT-PCR was 11.3% (nine out of 80) and 31.3% (25 out of 80), respectively. Although haematoxylin-eosin (HE) staining revealed lymphatic invasion in 11.3% (nine out of 80) of patients, D2-40 staining uncovered new invasion in 23.8% (19 out of 80) of patients. In the diagnosis of HE and D2-40 staining, the incidence of micrometastasis was significantly higher in patients with lymphatic invasion than in those without lymphatic invasion (P=0.0150 and P<0.0001, respectively). Micrometastasis correlated more closely with D2-40 than with HE staining. We demonstrated a high incidence of micrometastasis and lymphatic invasion and a correlation between them even in pN0 gastric cancer. When planning less invasive treatment, the presence of such occult cancer cells should be considered.

MUC4 expression is a novel prognostic factor in patients with invasive ductal carcinoma of the pancreas.

BACKGROUND: Many patients with invasive ductal carcinoma of the pancreas (IDC) have a poor outcome. MUC4 expression has been implicated as a marker for diagnosis and progression of IDC, but there are no studies of the relation between MUC4 expression and patient prognosis in IDC. AIMS: To investigate the prognostic significance of MUC4 expression in IDC. METHODS: The expression profiles of MUC4, ErbB2, p27, and MUC1 were investigated in IDC tissues from 135 patients by means of immunohistochemistry. RESULTS: MUC4 was expressed in 43 of the 135 patients with IDC (31.9%). The survival of 21 patients with high MUC4 expression (>20% of neoplastic cells stained) was significantly worse than that of the 114 patients with low MUC4 expression (<20% of neoplastic cells stained) (p = 0.0043). Univariate analysis showed that high MUC4 expression (p = 0.0061), large primary tumour status (>T2) (p = 0.0436), distant metastasis (p = 0.0383), lymphatic invasion (p = 0.0243), and surgical margins (p = 0.0333) were significant risk factors affecting the outcome of patients with IDC. Backward stepwise multivariate analysis showed that MUC4 expression (p = 0.0121), lymph node metastasis (p = 0.0245), and lymphatic invasion (p = 0.0239) were significant independent risk factors. ErbB2, p27, and MUC1 were not independent risk factors. CONCLUSIONS: This study shows that MUC4 expression in IDC is a new independent factor for poor prognosis and predicts the outcome of patients with IDC.

Detection of sentinel nodes and micrometastases using radioisotope navigation and immunohistochemistry in patients with gastric cancer.

BACKGROUND: Patients with early gastric cancer may be treated by minimally invasive surgery. This study investigated the value of sentinel node (SN) navigation surgery, including detection of micrometastases, in patients with clinical (c) T1 and T2 gastric cancer. METHODS: The day before surgery (99m)Tc-radiolabelled tin colloid was injected submucosally near the tumour. After resecting the stomach, radioisotope uptake in all dissected lymph nodes was measured during and after surgery. Micrometastasis was detected immunohistochemically using an anticytokeratin antibody. RESULTS: SNs were identified in 99 of 104 patients. The rate of identification of SNs in patients with cT1 and cT2 tumours, excluding three technical failures, was 99 and 95 per cent respectively. Lymph node metastases and/or micrometastases were found in 28 patients (15 cT1 and 13 cT2). In the 15 patients with cT1 tumours, at least one SN contained metastasis and/or micrometastasis. For cT1 tumours, the sensitivity and accuracy of detecting SNs were both 100 per cent. Six patients with cT2 tumours had false-negative results. CONCLUSION: SN navigation surgery appears to be clinically useful only for cT1 tumours. Based on SN results, the extent of lymphadenectomy may be reduced in patients with early gastric cancer.

Endoscopic quadrantectomy for breast cancer with sentinel lymph node navigation via a small axillary incision.

A great deal of clinical experience has firmly established the concept of the sentinel lymph node (SN) in breast cancer. SN biopsy allows treatment without axillary lymphadenectomy and has made it possible to perform a surgical intervention via just a small skin incision. In partial resection of the breast (quadrantectomy), we use a double retractor to form a workspace under the skin via a small axillary incision. Resection does not require a large incision even in cases in which the cancer lesion is located in the upper inner or lower inner quadrant of the breast, as the endoscope allows the surgeon to see the workspace formed by the double retractors.

The predictive value of p53, p53R2, and p21 for the effect of chemoradiation therapy on oesophageal squamous cell carcinoma.

The p53 family regulates cell-cycle arrest, triggers apoptosis or is involved in repair of DNA damage. In the present study, we analysed the expression of some p53 family proteins and their responses to chemoradiation therapy (CRT) in cases of oesophageal squamous cell carcinoma (ESCC). We immunohistochemically investigated the relationship between p53, p53R2, and p21 expression in biopsy specimens of untreated primary tumours and their clinical and histological responses to CRT in 62 patients with ESCC. Chemoradiation therapy consisted of 5-fluorouracil plus cisplatin and 40 Gy of radiation. The rates of clinical and histological responses (complete or partial) to CRT were 71.0% (clinical) and 52.8% (histological). The rate of positive expression was 43.5% for p53, 37.1% for p53R2, and 54.8% for p21 expression. Statistically significant correlations were found between p53 or p53R2 expression and favourable response to CRT (P=0.0001 or 0.041 clinical, P=0.016 or 0.0018 histological, respectively). Furthermore, in p53-negative tumours, CRT was more effective in tumours with p53R2 negative expression than those with p53R2 positive expression (P=0.0014). We demonstrated that the negative expression of p53 and p53R2 expression was closely related to the effect of CRT and should predict the CRT outcome in patients with ESCC.

Quantitative c-erbB-2 but not c-erbB-1 mRNA expression is a promising marker to predict minor histopathologic response to neoadjuvant radiochemotherapy in oesophageal cancer.

We examined the potential of quantitative epidermal growth factor receptor (EGFR, synonym: c-erbB-1) and c-erbB-2 (synonym: HER2/neu) mRNA expression to predict minor or major histopathologic response to neoadjuvant radiochemotherapy (cis-platinum, 5-FU, 36 Gy), followed by radical surgical resection, in patients with oesophageal cancer. Tissue samples were collected by endoscopic biopsy prior to treatment. RNA was isolated from biopsies and quantitative real-time reverse transcriptase-polymerase chain reaction assays were performed to determine c-erbB-1 and c-erbB-2 mRNA expression. Relative expression (tumour/paired normal tissue ratio standardised for beta-actin) was calculated for EGFR and c-erbB-2 mRNA. Expression levels were correlated with the objective histopathologic response in resected specimens. Histomorphologic regression was defined as major response when resected specimens contained less than 10% of residual vital tumour cells, or in case a pathologically complete response was achieved. Expression of c-erbB-1 mRNA was not associated with the degree of histomorphological response. In contrast, the relative expression levels of c-erbB-2 mRNA >1 were not associated with major histopathologic responses (sensitivity 41.6%, specificity 100%), and 10 out of 36 (28%) patients could be unequivocally identified, whose tumours did not respond well to the delivered neoadjuvant radiochemotherapy (P<0.01). Quantitative expression levels of c-erbB-2, but not c-erbB-1 mRNA, in pretreatment biopsies appear to predict minor histopathologic response to our neoadjuvant radiochemotherapy protocol. This test could be used to prevent expensive, non effective and potentially harmful therapies in approximately one-fourth of our patients, and leads to a more individualised type of combined modality treatment.