REG Iα activates c-Jun through MAPK pathways to enhance the radiosensitivity of squamous esophageal cancer cells.

Identification of the key molecules that mediate susceptibility to anticancer treatments would be highly desirable. Based on clinical and cell biological studies, we recently proposed that regenerating gene (REG) Iα may be such a molecule. In the present study, we hypothesized that REG Iα increases radiosensitivity through activation of mitogen-activated protein kinase (MAPK) pathways. To test that idea, we transfected TE-5 and TE-9 squamous esophageal cancer cells with REG Iα and examined its involvement in MAPK signaling and its effect on susceptibility to radiotherapy. We found that REG Iα-expressing cells showed increased expression of c-Jun messenger RNA (mRNA) and phospho-c-Jun protein mediated via the c-Jun N-terminal kinase (JNK) pathway and extracellular signal-regulated kinase (ERK) pathway, as well as increased radiosensitivity. Immunohistochemical analysis confirmed the activation of c-Jun in tumors expressing REG Iα. Collectively, these findings suggest that REG Iα activates c-Jun via the JNK and ERK pathway, thereby enhancing radiosensitivity.

Tumoral CRP expression in thoracic esophageal squamous cell cancers is associated with poor outcomes.

PURPOSE: Cancer cells reportedly produce C-reactive protein (CRP) locally within tumors. The aim of this study was to determine whether tumoral CRP is associated with clinical outcome and recurrence in thoracic esophageal squamous cell cancer. METHODS: The subjects included 73 Japanese patients with thoracic esophageal squamous cell cancer (pathological Stage IIA-IV) that had not been treated preoperatively with either chemotherapy or radiotherapy. Tumoral CRP expression in resected specimens of tumor tissue was assessed by immunohistochemistry. The survival rate following surgery, the rates and patterns of recurrence, and the serum CRP levels before treatment and at recurrence were analyzed in patients with and without tumoral CRP expression. RESULTS: Fifty-nine percent of the study participants (43/73) were positive for tumoral CRP expression, and the remaining 41% (30/73) were negative. No significant difference in clinicopathological factors was observed between the tumoral CRP-positive and CRP-negative groups; however, patients expressing tumoral CRP showed significantly poorer survival and recurrence rates. A multivariate analysis showed that tumoral CRP expression was an independent factor contributing to the likelihood of a poor outcome. CONCLUSION: Tumoral CRP is associated with a poor outcome in thoracic esophageal squamous cell cancer. Tumoral CRP could therefore be an important target for the treatment of this disease.

IGFBP3 and BAG1 enhance radiation-induced apoptosis in squamous esophageal cancer cells.

Identification of reliable markers of radiosensitivity and the key molecules that enhance the susceptibility of esophageal cancer cells to anticancer treatments would be highly desirable. To identify molecules that confer radiosensitivity to esophageal squamous carcinoma cells, we assessed the radiosensitivities of the TE-5, TE-9 and TE-12 cloneA1 cell lines. TE-12 cloneA1 cells showed significantly greater susceptibility to radiotherapy at 5 and 10Gy than either TE-5 or TE-9 cells. Consistent with that finding, 24h after irradiation (5Gy), TE-12 cloneA1 cells showed higher levels of caspase 3/7 activity than TE-5 or TE-9 cells. When we used DNA microarrays to compare the gene expression profiles of TE-5 and TE-12 cloneA1 cells, we found that the mRNA and protein expression of insulin-like growth factor binding protein 3 (IGFBP3) and Bcl-2-associated athanogene 1 (BAG1) was five or more times higher in TE-12 cloneA1 cells than TE-5 cells. Conversely, knocking down expression of IGFBP3 and BAG1 mRNA in TE-12 cloneA1 cells using small interfering RNA (siRNA) significantly reduced radiosensitivity. These data suggest that IGFBP3 and BAG1 may be key markers of radiosensitivity that enhance the susceptibility of squamous cell esophageal cancer to radiotherapy. IGFBP3 and BAG1 may thus be useful targets for improved and more individualized treatments for patients with esophageal squamous cell carcinoma.

Interleukin-2 -330T>G genetic polymorphism associates with prognosis following surgery for thoracic esophageal squamous cell cancer.

BACKGROUND: Key molecules in the T helper (Th)1 and Th2 pathways underlie differential responses to the progression and surgical treatment of cancer. We investigated the relationship between Th1/Th2 cytokine polymorphism and prognosis in patients with thoracic esophageal squamous cell cancer. MATERIALS AND METHODS: The study participants were 159 Japanese patients treated for thoracic esophageal squamous cell cancer with curative esophagectomy at Akita University Hospital. We determined the associations between prognosis following esophagectomy and genetic polymorphisms in Th1 cytokines (interleukin [IL]-2, Interferon-γ, IL-12ß), and Th2 cytokines (IL-4, IL-10). RESULTS: IL-2 -330T>G genetic polymorphism was significantly associated with prognosis after esophagectomy. Univariate and multivariate analyses using a Cox proportional hazards model revealed that patients carrying the IL-2 -330G/G genotype had a significantly poorer prognosis than those carrying the T/G or T/T genotype. However, IL-2 -330T>G polymorphism was not associated with preoperative serum IL-2 levels. Moreover, interferon-γ, IL-12ß, IL-4, and IL-10 genetic polymorphisms were not associated with prognosis after esophagectomy for thoracic esophageal squamous cell cancer. CONCLUSIONS: It is suggested that IL-2 -330T>G genetic polymorphism may be a predictive factor for prognosis in patients receiving esophagectomy for thoracic esophageal squamous cell cancer.

[A case of recurrent malignant melanoma of esophagus responsive to combined chemotherapy, radiotherapy and cellular immunotherapy].

Treatment of primary malignant melanoma of the esophagus remains challenging. We treated a 53-year-old man with pT4N2M0, Stage IVa malignant melanoma of the esophagus with esophagectomy followed by adjuvant chemotherapy. Six months later, computed tomography revealed a 12 cm disseminated tumor of the mesenterium, multiple peritoneal dissemination, and a large amount of ascites. We administered chemotherapy consisting of dacarbazine combined with cisplatin and nimustine, and radiotherapy(50 Gy)was applied to the disseminated mesenteric tumor. At another clinic, the patient was administered synchronous cellular immunotherapy consisting of dendritic cells pulsed with autologous tumor lysates and lymphokine-activated killer cells. The mesenteric tumor was extremely responsive to this trimodal treatment. Because recurrence occurred later within the left orbita muscle, we added 50 Gy of radiation to prevent blindness. The patient responded to this treatment and survived another 6 months with high quality of life. It is difficult to treat advanced malignant melanoma of the esophagus, and patient prognosis is extremely poor. In this patient, the recurrent tumors responded well to trimodal therapy consisting of chemotherapy, radiotherapy and cellular immunotherapy.

Regenerating gene I regulates interleukin-6 production in squamous esophageal cancer cells.

Regenerating gene (REG) I plays important roles in cancer cell biology. The purpose of this study was to determine whether REG I affects cytokine production in cancer cells. We transfected TE-5 and TE-9 squamous esophageal cancer cells with REG Ialpha and Ibeta and examined its effects on cytokine expression. We found that transfecting TE-5 and TE-9 cells with REG I Ialpha and Ibeta led to significantly increased expression of interleukin (IL)-6 mRNA and protein, but it had little or no effect on expression of IL-2, IL-4, IL-5, IL-10, IL-12, IL-13, IL-17A, interferon-gamma, tumor necrosis factor-alpha, granulocyte-colony stimulating factor or transforming growth factor-beta1. The elevated IL-6 expression seen in REG Ialpha transfectants was silenced by small interfering RNA-mediated knockdown. These finding suggest that REG I may act through IL-6 to exert effects on squamous esophageal cancer cell biology.

CRP genetic polymorphism is associated with lymph node metastasis in thoracic esophageal squamous cell cancer.

BACKGROUND: Lymph node involvement is the most important prognostic factor in thoracic esophageal cancer. A more accurate molecular technique for diagnosing lymph node metastasis and a better understanding of the molecular mechanisms governing lymph node metastasis would be highly desirable. The purpose of this study is to examine the association between inflammation-related genetic polymorphisms and lymph node metastasis. METHODS: The study participants were 113 Japanese patients undergoing curative surgery for thoracic esophageal squamous cell cancer. DNA was extracted from blood samples and genetic polymorphisms in C-reactive protein (CRP), tumor necrosis factor (TNF)-alpha and -beta, interferon (IFN)-gamma, transforming growth factor (TGF)- beta, interleukin (IL)-1beta, IL-1 receptor antagonist, IL-2, IL-4, IL-6, IL-6 receptor, IL-10, and IL-12beta were investigated using the polymerase chain reaction-restriction fragment length polymorphism method. We then assessed the association between inflammation-related genes and lymph node metastasis. RESULTS: For CRP 1846C>T polymorphism, the frequency of the 1846T/T genotype was significantly higher in patients with lymph node metastasis (P = 0.0043), and the odds ratio (3.040) derived from logistic regression models indicated that the 1846T/T genotype significantly increases the likelihood of lymph node metastasis. In submucosal cancer, the utility of CRP 1846C>T polymorphism for predicting lymph node involvement was superior to usual methods (computed tomography and ultrasonography), with positive and negative predictive values of 69% and 75%, respectively. CONCLUSIONS: These findings suggest that CRP polymorphism is a potentially effective predictor of lymph node metastasis and may thus be useful for deciding on treatment strategy.

Lung Cancer Surgery in Partial Anomalous Pulmonary Venous Connection Patients.

We report pulmonary resections for lung cancers in 2 patients with partial anomalous pulmonary venous connection (PAPVC) identified preoperatively. In case 1, right upper lobectomy was performed as the definitive operation for both lung cancer and PAPVC in the same lobe. In case 2, because lung cancer and PAPVC existed in different lobes, cardiac catheterization was performed to evaluate the need for correction of the PAPVC. Then, left lower lobectomy was safely performed without correcting the PAPVC located in the left upper lobe. The treatment plan for patients with PAPVC who require pulmonary resection should be carefully considered.

[S-1 chemotherapy for cancer of the gastric tube used for esophageal reconstruction following surgery for esophageal cancer].

We used S-1 chemotherapy to treat 5 patients with cancer of the gastric tube used for esophageal reconstruction through the posterior mediastinal route following surgery for esophageal cancer. The response rate was 40%, the median survival 15 months, and 3 patients still survive. In those 3 patients, the gastric tube cancer was at a resectable stage, but the patients elected to have chemotherapy instead. One patient has survived 21 months after responding completely to 2 cycles of combined chemotherapy with S-1 and cisplatin. Another has survived 15 months after partially respondingto S-1 chemotherapy. And the third has survived 46 months after endoscopic treatment, radiation therapy and S-1 chemotherapy. S-1 chemotherapy thus appears to be an effective treatment for cancer of the gastric tube after surgery for esophageal cancer.

Metabolic Rather than Pathological Response to Preoperative Chemoradiotherapy Is a Stronger Predictor of Survival in cStage IIB-IV Esophageal Cancer.

AIM: We investigated which is the stronger predictor, pathological response or metabolic response, for survival outcome in patients treated with neoadjuvant chemoradiotherapy (NACRT) plus esophagectomy for thoracic esophageal squamous cell carcinoma (TESCC). PATIENTS AND METHODS: Fifty consecutive patients with cStage IIB-IV TESCC were enrolled. We analyzed the pathological response and metabolic response (fractional decrease in tumor maximum standardized uptake value) to NACRT. Independent prognostic factors predictive of 3-year survival were investigated using univariate and multivariate analyses. RESULTS: Among the 50 patients, 10 (20%) showed a pathological complete response (in both tumor and lymph nodes) and 36 (72%) showed grade 2-3 pathological response. Univariate analysis showed that age, gender, cT stage, pathological response and metabolic response to be significant prognostic factors. A subsequent multivariate analysis confirmed metabolic response and gender to be significant prognostic factors. CONCLUSION: Metabolic response for NACRT was an independent prognostic factor and a more powerful predictor of survival compared to pathological response.

Status of involved lymph nodes and direction of metastatic lymphatic flow between submucosal and t2-4 thoracic squamous cell esophageal cancers.

BACKGROUND: Three-field lymph node dissection for thoracic esophageal cancer is associated with high morbidity and reduced quality of life after surgery. Consequently, minimized lymphadenectomy would be desirable, if appropriate. In the present study, we retrospectively analyzed the status of involved nodes and the direction of metastatic lymphatic flow from tumors into involved nodes to determine whether submucosal squamous cell esophageal cancers are potential candidates for minimized lymphadenectomy. METHODS: We enrolled 199 patients who received esophagectomy with extensive lymph node dissection between 1989 and 2005 and retrospectively analyzed their prognoses, distribution of solitary metastatic lymph nodes, and the direction of metastatic lymphatic flow from the tumor, taking into consideration tumor location and depth. RESULTS: Of these patients with submucosal cancers, 83% had 1 or 2 involved nodes, and their esophageal cancer-specific 5-year survival rate was 66%. Solitary lymph node metastasis did not occur in neck lymph nodes in lower thoracic submucosal esophageal cancers, and the direction of metastatic lymphatic flow from the tumor was almost always in one direction. By contrast, T2-4 cancers with 2-4 involved nodes had bidirectional metastatic lymphatic flow from the tumor. CONCLUSIONS: There was a difference in the status of lymph node metastasis and the direction of metastatic lymphatic flow from tumors into involved nodes between submucosal and T2-4 thoracic squamous cell esophageal cancers. This analysis may be useful for developing an approach to minimized lymphadenectomy for thoracic esophageal cancers.

Interferon-gamma 874A>T genetic polymorphism is associated with infectious complications following surgery in patients with thoracic esophageal cancer.

BACKGROUND: Cytokines play a major role in the organization of orchestrated responses to infections, and there is an emerging consensus that cytokine gene polymorphisms mediate individual variations in cytokine expression. Our aim in this study was to assess whether cytokine polymorphisms were associated with infectious complications following esophagectomy in a Japanese population. METHODS: The study participants were Japanese patients treated with transthoracic esophagectomy without neoadjuvant treatment. DNA was extracted from blood samples, and genetic polymorphisms for interferon (INF)-gamma, tumor necrosis factor-alpha and -beta, transforming growth factor-beta1, interleukin (IL)-1beta, IL-1 receptor antagonist, IL-2, IL-6, IL-6 receptor, IL-10, and IL-12beta were investigated using the polymerase chain reaction-restriction fragment length polymorphism method. We then assessed the association between gene polymorphisms and postoperative infection. RESULTS: Of the 110 patients studied, 18 (16%) developed a postoperative infection (pneumonia, 14 patients; pyothorax, 5; intraabdominal abscess, 1; neck abscess, 1; sepsis, 2). Although the characteristics of patients who developed postoperative infections did not differ, analysis of the genotypes using the Fisher exact test revealed a significantly (P = .0215) greater incidence of postoperative infections among those carrying the INF-gamma 874 (rs2430561) A/A and A/T genotypes. Moreover, univariate and multivariate logistic regression models showed patients carrying the INF-gamma 874A/T genotype were significantly more likely to develop postoperative infectious complications (odds ratio>3.4). CONCLUSION: Our findings suggest that the IFN-gamma 874A>T polymorphism is potentially predictive of the likelihood that patients undergoing esophagectomy for thoracic esophageal cancer will develop postoperative infections. This polymorphism may therefore have important clinical relevance and should be considered when treatment regimens are designed.

C-reactive protein 1059G>C genetic polymorphism influences serum C-reactive protein levels after esophagectomy in patients with thoracic esophageal cancer.

BACKGROUND: Little is known about how C-reactive protein (CRP) genetic polymorphisms influence the rise in serum CRP levels seen after surgery. The purpose of this study was to assess the association between CRP polymorphisms and acute-phase serum CRP levels after esophagectomy for thoracic esophageal cancer. STUDY DESIGN: We enrolled 110 patients who underwent curative esophagectomy without neoadjuvant treatment between 2003 and 2008. Using peripheral blood samples collected from the patients, polymorphisms for CRP, tumor necrosis factor, interferon-gamma, tumor growth factor-beta1, interleukin (IL)-1beta, IL-1 receptor antagonist, IL-2, IL-4, IL-6, IL-6 receptor, IL-10, and IL-12beta were all investigated to determine which, if any, affect postoperative serum CRP levels and clinical outcomes. RESULTS: Although preoperative serum CRP levels did not differ, 12 hours after esophagectomy, serum CRP levels were significantly higher in patients carrying the CRP 1059G/G genotype than in those with the 1059G/C genotype (111 +/- 35 mg/L versus 78 +/- 17 mg/L; p = 0.0266), and after 36 hours CRP levels remained higher in those with the 1059G/G genotype (217 +/- 63 mg/L versus 140 +/- 51 mg/L; p = 0.0020). Logistic regression models revealed that patients carrying the CRP 1059G/G genotype had a significantly higher likelihood of a postesophagectomy increase in serum CRP, although the CRP 1059G>C genetic polymorphism had no effect on clinical outcomes. None of the other cytokine genetic polymorphisms influenced postoperative serum CRP levels. CONCLUSIONS: Our findings suggest that the CRP 1059G>C genetic polymorphism is 1 determinant of serum CRP levels after major surgery.