Yoshihiro Nabeya

Clinical significance of serum vascular endothelial growth factor in esophageal squamous cell carcinoma.

Vascular endothelial growth factor (VEGF) is a potent inducer of angiogenesis in malignant tumors. An increased in the serum VEGF concentration (S‐VEGF) has been found in patients with various solid tumors and appears to be correlated with tumor burden. The objective of the current study was to determine the correlation between pretreatment S‐VEGF and clinicopathologic features in patients with esophageal squamous cell carcinoma.

Serum p53 antibody is a useful tumor marker in superficial esophageal squamous cell carcinoma

Patients with superficial (mucosal or submucosal) esophageal carcinoma (SEC) have significantly better survival rates than patients with advanced carcinoma. Some patients with advanced esophageal carcinoma have been reported to test positive for serum p53 antibodies (Abs). Because very few patients with superficial carcinoma have been examined, the aim of this study was to evaluate the clinical significance of serum p53‐Abs in patients with superficial esophageal squamous cell carcinoma (SESCC).

Preoperative serum midkine concentration is a prognostic marker for esophageal squamous cell carcinoma

High preoperative serum midkine concentration is associated with poor survival in patients with esophageal cancer, even after radical surgery, and thus may have prognostic value. Midkine (MK), a heparin‐binding growth factor, is expressed in numerous cancer tissues, and serum MK (S‐MK) concentrations are increased in patients with various neoplasms. The aim of this study is to evaluate the clinical significance of S‐MK in patients with esophageal squamous cell cancer (SCC). S‐MK was measured by enzyme‐linked immunosorbent assay in 135 healthy controls, 16 patients with benign esophageal disease, and 93 patients with primary esophageal SCC before surgery. The serum concentrations of carcinoembryonic antigen (CEA), SCC antigen (SCC‐Ag), and cytokeratin 19 fragment (CYFRA21–1) were also evaluated. All patients with esophageal SCC underwent radical esophagec‐tomy. Tumor MK expression was assessed by immunohistochemistry in 14 fresh tumor specimens. To determine whether S‐MK is of value as a prognostic factor, the authors conducted a survival analysis using Coxs proportional hazards model. S‐MK values in patients with esophageal SCC were significantly higher than those in healthy controls (417±342 pg/ml vs. 154±76 pg/ml, P<0.001). Using 300 pg/ml as the cut‐off value (representing the mean +2 standard deviations of the S‐MK of healthy controls), 61% of patients with esophageal SCC were classified as positive. MK expression by the tumor was significantly associated with high level of S‐MK. High S‐MK (≥300 pg/ml) was associated with tumor size, immunoreactivity and poor survival. Multivariate analysis indicated that S‐MK was an independent prognostic factor. S‐MK may be a useful tumor marker for esophageal SCC. Increased preoperative S‐MK in patients with esophageal SCC is associated with poor survival.

Impact of the Number and Extent of Positive Lymph Nodes in 200 Patients with Thoracic Esophageal Squamous Cell Carcinoma after Three-field Lymph Node Dissection

BackgroundSubtotal esophagectomy with three-field lymph node dissection (3FLD) has been reported to improve survival in patients with thoracic esophageal squamous cell carcinoma (SCC). The purpose of this study was to evaluate the prognostic impact of the extent and number of positive lymph nodes for long-term survival of patients who underwent 3FLD.MethodsFrom January 1983 to December 2002, a total of 200 patients with thoracic esophageal SCC underwent 3FLD without any neoadjuvant therapy. The prognostic impact of the extent and number of positive lymph nodes was evaluated by both univariate and multivariate analysis.ResultsThe extent of positive nodes associated with a 5-year survival were as follows: none, 69%; one-field, 50%; two-field, 29%; and three-field, 11%. The number of positive nodes associated with 5-year survival were as follows: single node, 65%; two-nodes, 51%; and more than three-nodes, 20%. Among patients with cervical lymphatic spreading, patients with upper tumors showed significantly better survival than patients with lower tumors (P = 0.036). Multivariate analysis indicated that number of positive nodes and the abdominal node status were independent prognostic factors among lymph node status.ConclusionsTogether, number and extent of positive lymph nodes can be considered an independent predictor of a high risk of recurrence. Although cervical lymphatic spreading was risk factor for worse survival, patients with upper tumors may have survival benefit after cervical lymph node dissection.

Phase I/II adenoviral p53 gene therapy for chemoradiation resistant advanced esophageal squamous cell carcinoma

We investigated the feasibility, safety, biological activity and therapeutic efficacy of adenovirus‐mediated p53 gene transfer in patients with chemoradiation resistant advanced esophageal carcinoma. Eligible patients were not surgical candidates and had measurable, advanced squamous cell carcinoma of the esophagus that was resistant to chemoradiation therapy. On a 28‐day cycle, intratumoral injections of Ad5CMV‐p53 (INGN 201; ADVEXIN®) were administered on days 1 and 3 at four dose levels (10 × 1011 particles to 25 × 1011 particles) and treated for up to five cycles. Ten patients received a total of 26 cycles with no dose‐limiting toxicity. Administration of multiple courses was feasible and well‐tolerated. Local tumor responses revealed stable disease in nine cases and progressive disease in one case. The overall responses were stable in six and progressive in four cases. Using polymerase chain reaction (PCR) analyses, gene transfer and p53 specific transgene expression were detected in tumor biopsy tissue from all patients. mRNA levels of p53, p21 and MDM2 increased in all but one case. Three patients showed absence of disease upon repeat biopsies. Substantial improvement in swallowing was observed in one patient with stenotic lesions. Intratumoral injection of Ad5CMV‐p53 is safe, feasible and biologically active when administered in multiple doses to patients with esophageal cancer. Observations from this study indicate that this treatment results in local antitumor effects in chemoradiation resistant esophageal squamous cell carcinoma. (Cancer Sci 2006; 97)

Apparent diffusion coefficient correlation with oesophageal tumour stroma and angiogenesis

AbstractObjectiveBecause diffusion-weighted imaging (DWI) can predict the prognosis of patients with oesophageal squamous cell carcinoma (ESCC), we hypothesised that apparent diffusion coefficient (ADC) values might be correlated with the collagen content and tumour angiogenesis. The purpose of this study was to determine the correlation between ADC values of ESCC before treatment and oesophageal tumour stroma and angiogenesis.MethodsSeventeen patients with ESCC were enrolled. The ADC values were calculated from the DWI score. Seventeen patients who had undergone oesophagectomy were analysed for tumour stroma, vascular endothelial growth factor (VEGF) and CD34. Tissue collagen was stained with azocarmine and aniline blue to quantitatively analyse the extracellular matrix in cancer stroma. Tissues were stained with VEGF and CD34 to analyse the angiogenesis.ResultsThe ADC values decreased with stromal collagen growth. We found a negative correlation between the tumour ADC and the amount of stromal collagen (r = −0.729, P = 0.001), i.e. the ADC values decreased with growth of VEGF. We also found a negative correlation between the ADC of the tumours and the amount of VEGF (r = 0.538, P = 0.026).ConclusionOur results indicated that the ADC value may be a novel prognostic factor and contribute to the treatment of oesophageal cancer.Key Points• Magnetic resonance apparent diffusion coefficient values inversely indicate tumour stromal collagen • There is also negative correlation between ADCs and vascular endothelial growth factor • ADC values may contribute to the treatment of oesophageal cancer.

Prognostic significance of CYFRA 21-1 in patients with esophageal squamous cell carcinoma

BACKGROUND CYFRA 21-1 has been reported as a useful tumor marker for esophageal carcinoma, but little information was reported about the clinicopathologic importance of CYFRA 21-1. The aim of this study was to analyze the clinicopathologic and prognostic significance of preoperative CYFRA 21-1 in patients with esophageal squamous cell carcinoma. STUDY DESIGN The CYFRA 21-1 levels were measured before surgery by enzyme-linked immunosorbent assays in 157 patients with primary esophageal squamous cell carcinomas using 3.5 ng/mL as the upper limit of normal. All patients underwent radical surgical procedures without any preoperative therapy. The association between the clinicopathologic factors assessed and the CYFRA 21-1 level was determined. The CYFRA 21-1 values were monitored after surgery in 45 available patients. The prognostic values were determined by multivariate analysis using Coxs proportional hazards model. RESULTS Thirty-one of the 157 patients (19.7%) had high CYFRA 21-1 levels (> or =3.5 ng/mL). CYFRA 21-1 levels were significantly increased in patients with large tumors (> or =40 mm, p = 0.009), deep tumors (T2-T4, p = 0.003), and node-positive tumors (p = 0.003). CYFRA 21-1 levels significantly decreased after surgery (p < 0.001). A high CYFRA 21-1 level before surgery was an independent prognostic factor for survival (p = 0.043). CONCLUSIONS A high CYFRA 21-1 level is associated with tumor progression and poor survival in patients with esophageal squamous cell carcinoma.

Role of Perfusion CT in Assessing Tumor Blood Flow and Malignancy Level of Gastric Cancer

Background/Aims: Intratumoral hemodynamics or tumor perfusion is useful in understanding the pathological background of the cancer. A parameter for a non-invasive, preoperative assessment of tumor perfusion has yet to be developed. Methods: The study included 50 patients who underwent surgery for gastric cancer. Perfusion computed tomography (P-CT) was performed using a 16-row multidetector CT, and tumor blood flow (ml/min/100 g tissue) values were measured. We compared blood flow with histopathological characteristics and evaluated its correlation with microvessel density and tumor stromal density and calculated the ratio of vessels and stromal tissue. Results: There was a significant decrease in blood flow in advanced tumor depth, peritoneal dissemination and undifferentiated subtypes. Cases with Lauren’s diffuse type carcinoma were found to have decreased blood flow compared to the mixed or intestinal type. As for the stromal structure, despite the lack of correlation with microvessel density, blood flow significantly decreased with increased stromal density. Conclusions: Decreased blood flow value acquired from P-CT may reflect a progressive state of gastric cancer. The pathological background for this relation involves the tumor stroma. Tumor perfusion decreased as the stage and malignant character of the tumor advanced, and therefore P-CT could be a better strategy to estimate the malignancy level of cancer.

Presence of Serum p53 Antibodies is Associated with Decreased In Vitro Chemosensitivity in Patients with Esophageal Cancer

Abstract Resistance to chemotherapy remains a serious problem inhibiting the successful treatment of advanced esophageal cancer. A number of studies have revealed that p53 genetic alteration and protein overexpression can predict chemosensitivity. Furthermore, p53 protein overexpression in cancer tissues has been found to induce serum p53 antibodies (p53-Abs). This study was conducted to examine whether analysis of serum p53 Abs could predict the chemosensitivity of esophageal cancer. Serum analysis of p53 antibodies was performed by enzyme-linked immunosorbent assay in 19 patients with esophageal squamous cell carcinoma preoperatively, then surgically resected specimens were stained immunohistochemically for p53 protein expression. Tumor tissues were also analyzed for chemosensitivity by the histoculture drug response assay (HDRA) using cis-dichlorodiammineplatinum(II) (CDDP), 5-fluorouracil (5-FU), and adriamycin (ADM). Serum p53-Abs were present in 47% (9/19) of the patients and immunohistochemical analysis revealed overexpression of p53 protein in 42% (8/19) of the tumors. The presence of serum p53 antibodies was significantly correlated with p53 immunoreactivity (P = 0.005). The inhibition index of patients positive for p53-Abs was significantly lower than that of patients negative for p53-Abs (P < 0.001). This tendency was also observed in the inhibition index to 5-FU. The presence of serum p53-Abs was associated with decreased in vitro chemosensitivity to CDDP and 5-FU. Thus, the detection of serum p53-Abs is suggested to be useful for predicting chemosensitivity in patients with esophageal cancer.

Surgical advantages of gastric SMTs by laparoscopy and endoscopy cooperative surgery.

BACKGROUND/AIMS The treatment of gastric submucosal tumors (SMTs) is strictly surgical and enucleation of the tumor or wedge resection of the stomach is efficient to achieve R0 resection. Laparoscopic and endoscopic cooperative surgery (LECS) can be safely performed with adequate cutting lines. This study describes the initial 16 cases treated by LECS and evaluates the advantages by LECS for gastric SMTs retrospectively. METHODOLOGY Sixteen patients with gastric SMT underwent LECS from June 2007 to December 2010, their surgical data, clinical characteristics and surgical specimens of SMTs were compared. The surgical specimens of 9 gastric SMTs treated by laparoscopic wedge resection (LWR) were compared as a control. RESULTS The median (range) length of operation time, blood loss, hospital stay after surgery were minutes 172 (115- 220), <5mL (<5-115) and 10 days (6-17), respectively. The median (range) ratio of the longest diameter of the tumor divided by the longest diameter of the surgical specimen in LECS and LWR were 0.86 (0.625-1.0) and 0.69 (0.44-1.0), respectively (p=0.0189, Wilcoxon rank sum test). CONCLUSIONS LECS minimizes the surgical specimen while still providing sufficient surgical margins to successfully cure gastric SMTs.