Ryokuhei Manda

The incremental effect of positron emission tomography on diagnostic accuracy in the initial staging of esophageal carcinoma

The purpose of the current study was to assess whether [18F]fluorodeoxyglucose positron emission tomography (FDG‐PET) provides incremental value (e.g., additional information on lymph node involvement or the presence of distant metastases) compared with computed tomography (CT) in patients with esophageal carcinoma.

Inactivation of the PTEN/MMAC1/TEP1 gene in human lung cancers

The PTEN/MMAC1/TEP1 gene has been isolated as a tumor suppressor gene that is altered in several types of human tumors including brain, breast, and prostate cancers. In the present study, we report PTEN/MMAC1/TEP1 alterations in human lung cancers. Intragenic homozygous deletions were detected in 6 (40%) of 15 small cell lung carcinoma (SCLC) cell lines and in 2 (8%) of 25 non–small cell lung carcinoma (NSCLC) cell lines. A nonsense mutation and a missense mutation were detected in 2 (8%) NSCLC cell lines. An intragenic homozygous deletion, a 1‐bp frameshift mutation, and a nonsense somatic mutation were also detected in three (6%) of 47 surgical specimens. All the lung tumors with PTEN/MMAC1/TEP1 mutations were homozygous for the mutant alleles. These findings suggest that PTEN/MMAC1/TEP1 plays a role as a tumor suppressor gene in the genesis and/or progression of human lung cancer. Genes Chromosomes Cancer 22:152–156, 1998.

Usefulness of positron emission tomography for assessing the response of neoadjuvant chemoradiotherapy in patients with esophageal cancer.

BACKGROUND In this study, we retrospectively assessed the performance of 18-F-fluorodeoxyglucose positron emission tomography (FDG-PET) compared with computed tomography (CT) and esophagography for assessing the response of advanced esophageal squamous cell carcinoma (SCC) to neoadjuvant chemoradiotherapy. METHODS We studied 10 patients with thoracic esophageal SCC who received neoadjuvant chemoradiotherapy followed by surgery. Tumor response was assessed by CT, endoscopy, esophagography and FDG-PET before and after neoadjuvant treatment. RESULTS Assessment of the rate of decrease in standardized uptake value (SUV) revealed a partial response (more than 50% decrease) in 5 (50%) of the patients, and assessment of length decrease of FDG uptake showed a partial response in 9 (90%) of the patients. Comparison of the histological response and the rate of decrease of various parameters revealed significant associations between histological response and tumor length (P <0.05), SUV after neoadjuvant therapy (P <0.05), and reduction in the extent of FDG uptake (P <0.01). However histological response was not significantly correlated with the rate of reduction of SUV, for both CT and esophagography. CONCLUSIONS FDG-PET may be of considerable value for predicting the pathologic response of esophageal SCC to neoadjuvant therapy. Despite assessment of SUV before neoadjuvant therapy, low FDG uptake after therapy and reduction in the extent of FDG uptake may provide a reliable assessment of the response to therapy.

Value of positron emission tomography in the diagnosis of recurrent oesophageal carcinoma

Positron emission tomography (PET) with [18F]fluorodeoxyglucose (FDG) might be useful for staging oesophageal squamous cell carcinoma (SCC). FDG‐PET may be more accurate than computed tomography (CT) in diagnosing lymph node metastasis. This retrospective study compared the ability of FDG‐PET and CT to diagnose recurrent oesophageal carcinoma.

Increased expression of c-Ski as a co-repressor in transforming growth factor-β signaling correlates with progression of esophageal squamous cell carcinoma

Transforming growth factor‐β (TGF‐β) regulates cell growth inhibition, and inactivation of the TGF‐β signaling pathway contributes to tumor development. In our previous study, altered expression of TGF‐β, TGF‐β‐specific receptors and Smad4 was shown to correlate with tumor progression in esophageal squamous cell carcinoma (SCC). These components, however, were maintained normally in some patients with esophageal SCC. In our study, the mechanism by which aggressive esophageal SCC maintains these components was investigated, with particular emphasis on the participation of c‐Ski and SnoN as transcriptional co‐repressors in TGF‐β signaling. Immunohistochemistry for c‐Ski and SnoN was carried out on surgical specimens obtained from 80 patients with esophageal SCC. The expression of c‐Ski and SnoN was also studied in 6 established cell lines derived from esophageal SCC and compared to an immortalized human esophageal cell line by Western blotting. High levels of expression of c‐Ski, detected immunohistologically, were found to correlate with depth of invasion (p = 0.0080) and pathologic stage (p = 0.0447). There was, however, no significant correlation between expression of SnoN and clinicopathologic characteristics. A significant correlation between c‐Ski and TGF‐β expression was observed. Moreover, in patients with TGF‐β negative expression, the survival rates of patients with c‐Ski positive expression were significantly lower than those of patients with c‐Ski negative expression (p = 0.0486). c‐Ski was expressed at a high level in 5 of 6 cell lines derived from esophageal SCC compared to immortalized esophageal keratinocytes. Furthermore, the cyclin‐dependent kinase (CDK) inhibitor, p21 that was up‐regulated by TGF‐β signaling was expressed at a low level in the 5 cell lines. The expression of c‐Ski protein as a transcriptional co‐repressor in TGF‐β signaling seems to be correlated with tumor progression of esophageal SCC.

Pretreatment evaluation of combined HIF‐1α, p53 and p21 expression is a useful and sensitive indicator of response to radiation and chemotherapy in esophageal cancer

Tumor hypoxia has been known to be associated with resistance to radiation and chemotherapy (CRT). Hypoxia‐inducible factor‐1α (HIF‐1α), a transcription factor induced by hypoxic condition, plays a major role in the pleiotropic response observed under hypoxic conditions. It encodes proteins that play key roles in critical development and physiologic processes, including angiogenesis, glucose transport and erythropoiesis. On the other hand, cell cycle‐ and apoptosis‐control genes p53 and p21 may play major roles in the tumor response to cytotoxic agents such as radiation and chemotherapy. Previous reports have suggested that the regulation of p53 and p21 is HIF‐1‐dependent. Our aim was to evaluate the expression of the HIF‐1α, p53 and p21 proteins by immunohistochemistry in biopsy specimens of esophageal squamous cell carcinoma, which were obtained endoscopically from 65 patients before CRT, and then determine whether the levels of expression of these proteins predicted the clinical effectiveness of CRT in individual cancers. Also, to assess the relationship between expression of these proteins and cell death and cellular proliferation activity, we evaluated Ki67 expression and the apoptosis index (TUNEL). HIF‐1α expression in esophageal cancer was significantly and negatively related to the response to CRT, independently of p53 and p21 expression. Interestingly, 44.4% (12/27) of the HIF‐1α‐negative group showed a complete response to therapy. There was no significant correlation between the expression of HIF‐1α, p53 and p21 and proliferation and apoptosis. HIF‐1α overexpression may predict resistance to CRT and may be a helpful guide in choosing between therapeutic strategies, such as intensive combined modality therapy vs. palliative therapy. Combined immunohistochemical evaluation of HIF‐1α, p53 and p21 protein expression at the pretreatment biopsy is a very useful and powerful indicator of sensitivity to CRT in human esophageal cancer. Our data also indicate the importance of having a clear grasp of the degree of hypoxia (HIF‐1α) of a tumor, rather than its cellular character (proliferation and apoptosis), to indicate the likely impact of CRT.

Sentinel lymph nodes with technetium‐99m colloidal rhenium sulfide in patients with esophageal carcinoma

The authors assessed the detection of sentinel lymph nodes in patients with esophageal squamous cell carcinoma (SCC) using technetium‐99m colloidal rhenium sulfide. They studied whether an analysis of sentinel lymph nodes using cytokeratin (CK) immunohistochemistry increased the accuracy of staging.

Plasma Level of Transforming Growth Factor β1 Measured from the Azygos Vein Predicts Prognosis in Patients with Esophageal Cancer

Purpose: Transforming growth factor (TGF)-β regulates cell growth inhibition. When tumor cells lose their sensitivity to TGF-β growth inhibition, the excess TGF-β that results may act on tumor cells to facilitate tumor development. Previously, we have shown that an elevated systemic TGF-β1 level is not related to tumor progression in esophageal cancer (Y. Fukai et al., Int J Cancer 2003;104:161–6). We considered that systemic inflammation or chronic disease, in addition to the tumor, may influence the plasma TGF-β level. Therefore, we examined the hypothesis that the plasma TGF-β level measured from the azygos vein would independently predict tumor progression and prognosis in patients with esophageal cancer. Experimental Design: Fifty-seven plasma samples were obtained intraoperatively from the azygos vein in patients with esophageal cancer. ELISA was used to quantify the plasma TGF-β1 levels, which were correlated with pathological features and patient survival. Results: The mean plasma TGF-β1 level measured from the azygos vein of esophageal cancer patients was 5.09 ± 0.48 ng/ml (mean ± SE). The survival rates of patients with a high TGF-β1 level (defined as a level above the 4.6 ng/ml level of normal controls) in the azygos vein were significantly lower than those of patients with a low TGF-β1 level (P = 0.0317). Moreover, the TGF-β1 level in the azygos vein was an independent prognostic factor for overall survival (P = 0.0474). Conclusions: The level of plasma TGF-β1 measured from the azygos vein is an independent predictor in patients with esophageal cancer and may reflect tumor progression more specifically because the azygos vein is responsible for venous return from the esophagus.

Surgical Treatment for Esophageal Cancer

Esophageal cancer is one of the most difficult malignancies to cure. The prognosis remains unsatisfactory despite significant advances in surgical techniques and perioperative management. The optimal treatment strategy for localized esophageal cancer has not yet been established. Surgical resection remains the mainstay of treatment for esophageal cancer, and curative resection is the most important surgery. Extended esophagectomy with three-field lymphadenectomy provides the highest quality of tumor clearance and prolongation of patient survival. There has been intense effort in developing novel strategies to treat patients with resectable esophageal cancer. Various combined-modality approaches have been attempted to improve treatment outcomes. Definitive chemoradiotherapy has an impact on long-term survival in patients with resectable esophageal cancer. Accordingly, there are three main combined-modality approaches: esophagectomy with adjuvant chemotherapy or chemoradiotherapy; primary definitive chemoradiotherapy with or without salvage esophagectomy, and preoperative chemoradiotherapy followed by planned esophagectomy. Recently, owing to the remarkable advances in optical technology, minimally invasive esophagectomy using endoscopic instruments has been introduced into esophageal cancer surgery. This article reviews recent changes in the treatment of esophageal cancer surgery, and considers the role of esophagectomy.

Prediction of hematogenous recurrence in patients with esophageal carcinoma

OBJECTIVES Despite recent advances in diagnosis and treatment of esophageal carcinoma, the future risk of hematogenous recurrence is still unpredictable. To identify risk factors of hematogenous recurrence in esophageal carcinoma, we used pathological and immunohistochemical analysis to examine relationships among clinical outcomes, clinicopathological features, and E-cadherin expression. METHODS Subjects were 102 patients with thoracic esophageal cancer who had undergone curative esophagectomy without preoperative treatment. We used univariate and multivariate logistic regression analyses to examine the relationship among clinical outcomes, clinicopathological features, and E-cadherin expression. RESULTS There was no significant relationship between E-cadherin expression and clinicopathological features at operation. However, the survival rates of patients with E-cadherin-negative tumors were significantly lower than those of patients with E-cadherin-weak and E-cadherin-positive tumors (P < 0.01). Disease recurrence had occurred in 49 (48.0%), with hematogenous recurrence in 29 (28.4%), of the 102 patients at the time of analysis. Metastasis occurred in liver in 14 patients, lung in 13, bone in 6, and brain in 2. Comparisons of hematogenous recurrences and clinicopathological features by multivariate regression analyses revealed significant associations between hematogenous recurrences; particularly in liver and lung metastasis and negative E-cadherin expression. With regard to the associations between the organ with the recurrence and the number of positive nodes; hematogenous recurrence, equal to or higher than lymphatic recurrence, was more likely to have occurred in patients with high numbers of positive nodes. Interestingly, with regard to the sites of positive nodes, liver metastasis was closely correlated with lymph node metastasis in the mid-thoracic as opposed to the abdominal region. Further, lung metastasis was most likely to occur in patients with cervical lymph node metastasis. CONCLUSIONS Esophageal carcinoma with negative E-cadherin expression tended to be associated with hematogenous recurrence, particularly with liver and lung metastasis. Hematogenous recurrences were significantly associated with high numbers and the site of positive nodes, as well as with lymphatic recurrence.