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.

A CRP genetic polymorphism associated with the tumoral expression of CRP in esophageal cancer.

C-reactive protein (CRP) produced locally within esophageal cancer is associated with the prognosis and the rate of recurrence. CRP genetic polymorphisms reportedly affect serum CRP concentrations; however, there are no reports of an association between genetic polymorphisms and tumoral CRP expression. This study enrolled 73 Japanese patients classified with Stage IIA-IV thoracic esophageal squamous cell cancer, and also investigated their CRP genetic polymorphisms using DNA extracted from their peripheral blood. The study then assessed the association between CRP genetic polymorphisms and tumoral CRP expression. The results revealed a significant association between the CRP 1846C>T genetic polymorphism and tumoral CRP expression. This finding suggests that tumoral CRP production controlled by CRP genetics significantly influences tumor behavior.

Interleukin-6 -634G>C genetic polymorphism is associated with prognosis following surgery for advanced thoracic esophageal squamous cell carcinoma.

OBJECTIVE: Systemic and/or local interleukin-6 (IL-6) reportedly plays an active role in the progression and prognosis of thoracic esophageal squamous cell carcinoma (TESCC). We assessed the associations between IL-6 and IL-6 receptor (IL-6R) genetic polymorphisms, tumoral IL-6 expression and survival rates following surgery. METHODS: The study participants were 63 Japanese patients treated between 2003 and 2008 for T2-T4 advanced TESCC using curative esophagectomy without neoadjuvant treatment. We investigated IL-6 -634G>C (rs1800796) and IL-6R 48892A>C (rs8192284, Asp358Ala) genetic polymorphisms using DNA from peripheral blood samples. In addition, tumoral IL-6 expression was investigated immunohistochemically in resected specimens, and serum IL-6 was measured using a human IL-6 immunoassay. RESULTS: There was a significant difference in survival between patients with the IL-6 -634G/G+G/C genotype and those with the C/C genotype, such that their 5-year overall survival rates were 42 and 72%, respectively. By contrast, the IL-6R 48892A /C genotype and tumoral IL-6 expression had no significant effect on survival among patients. Univariate and multivariate analyses revealed that IL-6 -634G>C polymorphism was an independent prognostic factor with a hazard ratio of 3. CONCLUSIONS: IL-6 -634G>C genetic polymorphism may be a predictive prognostic factor in patients receiving esophagectomy for TESCC.

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.

[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.

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.

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.

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.

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.