Clinicopathological factors predicting R0 resection and long-term survival after esophagectomy in patients with T4 esophageal cancer undergoing induction chemotherapy or chemoradiotherapy.

PURPOSE: To identify clinicopathological factors predicting R0 resection and long-term survival after esophagectomy in patients with T4 esophageal cancer following induction chemotherapy or chemoradiotherapy. METHODS: Of 48 patients with T4 esophageal cancer who underwent induction treatment, 30 underwent R0 esophagectomy. The factors predicting R0 resection and prognostic indicators were assessed in the 48 and 30 patients, respectively, using univariate and multivariate analyses. RESULTS: In the univariate analyses, the primary tumor response, improvement of dysphagia, the post-induction therapy Glasgow Prognostic Score, an early tumor response and the post-induction therapy serum albumin and C-reactive protein levels were significantly correlated with R0 resection. Multivariate logistic regression analyses revealed that the response status and improvement of dysphagia were independent predictors of R0 resection. The univariate analyses identified a yp-T classification (yp-T0/1 vs. yp-T2/3/4), yp-nodal status and the number of pathologically positive nodes post-therapy (≤ 1 vs. ≥ 2) as significant prognostic factors. The multivariate analysis revealed that the number of pathologically positive nodes was the only significant independent prognostic indicator. CONCLUSION: Patients showing an early tumor response to induction treatment and improvement of dysphagia may be appropriate candidates for esophagectomy, and individualized postoperative management strategies should be developed for patients with initially unresectable T4 esophageal cancer who have ≥ 2 positive nodes post-treatment.

Clinical and oncological effects of triplet chemotherapy followed by radical esophagectomy for resectable esophageal cancer associated with unfavorable prognostic factors.

PURPOSES: The purpose of this study was to evaluate the hypothesis that the survival of patients undergoing R0 resection after triplet chemotherapy for resectable esophageal cancer with unfavorable prognostic factors (Category 3) would be similar to that of patients undergoing esophagectomy for esophageal cancer without such factors (Category 1). METHODS: Patients with Category 3 tumors were assigned to receive triplet chemotherapy consisting of 5-fluorouracil, doxorubicin and nedaplatin (FAN) followed by radical esophagectomy. The outcomes of the bimodality treatment for Category 3 patients (n = 25) were compared with those of Category 1 patients (n = 41) in a prospective cohort study. RESULTS: Grade 3 or higher toxicity developed during chemotherapy in 32 % of the Category 3 patients, with no treatment-related deaths. No significant difference was detected in the surgery-related mortality and morbidity rates between the two groups. The recurrence-free survival was significantly worse in Category 3 than in Category 1 patients (p = 0.002), although the overall survival was not significantly different (p = 0.085) between the two groups in cases of R0 resection (5-year survival rates: 34.4 vs. 66.5 %). CONCLUSIONS: Although FAN chemotherapy followed by radical esophagectomy can be safely performed, this treatment modality may not have sufficient power to cure Category 3 disease.

Acute phlegmonous esophagitis as a rare but threatening complication of chemoradiotherapy: report of a case.

Phlegmonous infection involving the digestive tract has been reported to have a poor prognosis. However, the pathogenesis and clinical features of acute phlegmonous esophagitis have remained unclear due to the rarity of the disease. We herein report a case of acute phlegmonous esophagitis that showed a fulminant course during chemoradiotherapy for uterine cancer. The patient developed septic shock 10 h after postprandial nausea and vomiting, and a computed tomographic scan showed diffuse thickening of the esophageal wall. Severe leukopenia that was refractory to the administration of granulocyte colony-stimulating factor persisted during the first few days. The patient fortunately survived after intensive treatment. The acute phlegmonous esophagitis of the present case might have been evoked and worsened by chemoradiotherapy due to its emetic and myelosuppressive adverse effects, respectively. Although its incidence is extremely rare, acute phlegmonous esophagitis may occur as a life-threatening complication of chemoradiotherapy.

Induction chemotherapy or chemoradiotherapy followed by radical esophagectomy for T4 esophageal cancer: results of a prospective cohort study.

BACKGROUND: We hypothesized that the survival rate of patients undergoing R0 esophagectomy after induction chemotherapy or chemoradiotherapy for unresectable T4 esophageal cancer (URT4) would be similar to that of patients undergoing esophagectomy for immediately resectable esophageal cancer with no unfavorable prognostic factors (RNU). METHODS: Between April 2002 and June 2012, 87 of 283 patients with esophageal cancer who presented at the University Hospital of the Ryukyus were enrolled in this prospective cohort study. Tumors were classified as RNU and URT4 in 44 and 43 of the 87 patients, respectively. Outcomes of treatment for URT4 patients were compared with those of RNU patients. RESULTS: The R0 resection rate (61 %) and in-hospital mortality rate (20 %) of URT4 patients were significantly poorer than those of RNU patients (98 and 2.3 %, respectively), although the morbidity rate was similar in the two groups (63 and 52 %, respectively). The 5-year survival rate (35 %) of URT4 patients was significantly poorer than that of RNU patients (67 %) in the intention-to-treat analysis. However, no significant difference was noted between the two survival curves for cases of R0 resection (5-year survival rate, 60 % vs. 69 %). Multivariate analysis revealed R status as the only significant independent prognostic factor for URT4 patients (P < 0.001; hazard ratio = 8.279). CONCLUSIONS: Satisfactory survival rates can be achieved if R0 resection is performed after induction treatment in patients with T4 esophageal cancer, although secondary radical esophagectomy is associated with a higher risk of in-hospital mortality.

Development of gastro-lymphatic fistula during chemoradiotherapy for advanced esophageal cancer: a case report.

This is a case report of a gastro-lymphatic fistula which appeared during chemoradiotherapy for advanced esophageal cancer. A 60-year-old male was referred to the University of the Ryukyus Hospital because of a 10 kg monthly weight loss and dysphagia. Computed tomography (CT) scans indicated thickened esophageal wall at the lower thoracic esophagus and a swollen lymph node attached to the lesser curvature of the stomach. Histological analysis of the biopsy specimen revealed poorly differentiated squamous cell carcinoma and the diagnosis was of advanced esophageal cancer. A combination of chemotherapy (nedaplatin and 5-fluorouracil) and radiotherapy was initiated. After radiotherapy (20 Gy), CT scans revealed that the swollen lymph node penetrated the gastric wall resulting in a gastro-lymphatic fistula. Although gastrostomy and intestinal fistula repair were performed for gastric decompression and tube feeding, respectively, the patient's general status did not improve and he died two months after interruption of his chemoradiotherapy. The results indicate that there may be some risks of gastro-lymphatic fistula in patients treated with concurrent chemoradiotherapy for advanced esophageal cancer when there are possible signs of involvement by CT scans.

Successful conservative management of a case of caustic esophagitis based on computed tomography assessment.

Case: We describe the case of a female patient who ingested approximately 100 mL of toilet bowl cleaner containing 9.5% hydrochloric acid in a suicide attempt. Upon admission for hematemesis and epigastric pain, she was alert and oriented with stable vital signs. Initial contrast-enhanced computed tomography (CT) demonstrated edematous changes with no evidence of upper gastrointestinal tract perforation. Endoscopy was not performed owing to the high risk of perforation. We managed this patient conservatively. Repeat contrast-enhanced CT revealed mediastinal emphysema on day 2, which resolved by day 6. The patient was subsequently discharged with no apparent strictures of the upper gastrointestinal tract. Outcome: Surgical interventions are frequently required following the ingestion of large amounts of highly concentrated hydrochloric acid; however, this patient was successfully managed conservatively. Conclusion: Contrast-enhanced CT is useful in the assessment of the respiratory and digestive systems and the prediction of potential complications.

Microsatellite instability in patients with gastric remnant cancer.

BACKGROUND: About 2% of patients who undergo partial distal gastrectomy for gastroduodenal diseases develop gastric remnant cancer 10 to 30 years after the gastrectomy. It is important in clinical practice to determine a molecular marker to identify patients susceptible to gastric remnant cancer.METHODS: We investigated nine gastric remnant cancers (from nine individuals who had gastrectomies for primary gastric cancer or gastroduodenal ulcer) for microsatellite instability (MSI) at six loci, using the polymerase chain reaction (PCR). A control group of ten patients with sporadic gastric cancers in the upper third of the stomach was also similarly analyzed.RESULTS: MSI was demonstrated in eight of nine cancers from the individuals who had had primary gastric cancer or gastroduodenal ulcer (88.9%) compared with two of ten cancers from the individuals with sporadic gastric cancer in the upper third of the stomach (20%).CONCLUSION: These results suggest that one or more MSI is associated with remnant gastric cancer after gastrectomy.

Barrett's adenocarcinoma associated with acquired eventration of the diaphragm.

We report a rare case of Barrett's adenocarcinoma asso-ciated with acquired eventration of the diaphragm in a 71-year-old woman. She initially developed dysphagia and epigastric discomfort in May, 1997. On July 9, she was referred to our Department of Surgery at the Ryukyus University Hospital for thorough examination and treatment. Esophageal adenocarcinoma and eventration of the diaphragm were revealed by exhaustive examinations, including chest X-ray, computed tomography, and magnetic resonance imaging, and proximal gastrectomy with reconstruction of jejunal interposition was performed, on August 8. Histologically, the tumor revealed that the adenocarcinoma arose from short-segment Barrett's esophagus (SSBE). It thus appears that eventration of the diaphragm may induce SSBE and Barrett's adenocarcinoma. We therefore recommend that periodic examinations of the esophagus and stomach be performed in patients with eventration of the diaphragm. Barrett's adenocarcinoma associated with acquired eventration of the diaphragm is reported. Patients with eventration of the diaphragm should undergo periodic examinations of the esophagus and stomach.

Analysis of microsatellite instability, K-ras gene mutation and p53 protein overexpression in intrahepatic cholangiocarcinoma.

BACKGROUND/AIMS: Genetic alterations are considered to play an important role in both the carcinogenesis and biological behavior of human malignancies. However, the clinical implications of intrahepatic cholangiocarcinoma are poorly understood. We investigated the microsatellite instability, K-ras gene mutations and p53 protein overexpression and their correlation with clinicopathological features to elucidate the clinical implications of genetic alterations in intrahepatic cholangiocarcinoma. METHODOLOGY: In twenty-three cases of surgically treated intrahepatic cholangiocarcinoma, microsatellite instability was examined by a PCR-SSCP analysis and K-ras gene mutation by a PCR-RFLP analysis, p53 protein overexpression by immunohistochemistry. We evaluated the correlation between genetic alterations and clinicopathological features. RESULTS: Microsatellite instability was observed in one case (4.7%), K-ras gene mutation in 9 (39.1%) and positive staining for p53 protein in 5 (21.7%). The incidence of K-ras gene mutations in hilar type intrahepatic cholangiocarcinoma (6 of 8, 75.0%) was significantly higher than that in peripheral type intrahepatic cholangiocarcinoma (3 of 15, 20.0%) (P < 0.05). Furthermore, the incidence of K-ras gene mutations in patients with lymph node metastasis (58.3%) tended to be higher than that in patients without lymph node metastasis (18.2%). The patients with K-ras gene mutations showed a statistically significant worse survival rate than those without such mutations (P < 0.05). No statistically significant correlations were observed between the p53 overexpression and clinicopathological features. CONCLUSIONS: These data suggest that K-ras gene mutations may be involved in the carcinogenesis of intrahepatic cholangiocarcinoma, especially in hilar type intrahepatic cholangiocarcinoma, and thus may be correlated with aggressive biological behavior.

Recent changes and the future roles of esophageal cancer surgery.

An esophagectomy remains the mainstay treatment for esophageal cancer, and an R0 resection is the most important type of surgery performed with a curative intent. Although a transthoracic esophagectomy is thought to offer better chance for cure in comparison to a transhiatal esophagectomy, the superiority of the former procedure over the latter has not been demonstrated by randomized clinical trials (RCTs). An extended esophagectomy with a three-field lymphadenectomy is a type of esophagectomy with the highest quality of tumor clearance and the capability of prolonging patient survival, but it is contraindicated for patients with 5 or more positive nodes, with simultaneous metastasis to three anatomic compartments, with cervical metastasis from lower esophageal cancer, and with intramural metastasis, because of the absence of survival benefits in these cases. An esophagectomy performed by thoracoscopy and laparoscopy techniques is feasible, however, such an esophagectomy combined with a systematic lymphadenectomy may not qualify as minimally invasive because of the equivalent morbidity rates to an open radical esophagectomy. Whether adjuvant chemotherapy with or without radiotherapy can effectively improve patient survival remains controversial, because only two of 15 RCTs of such adjuvant therapy so far reported have demonstrated a positive survival impact in comparison to surgery alone. The recent increased use of definitive chemoradiotherapy suggests the potential need to perform a salvage esophagectomy because the presence of local persistent or recurrent disease is common after this treatment. The development of a safe and effective salvage esophagectomy should thus be urgently established.

Prognostic significance of simultaneous presence of histological and immunohistochemical metastasis to lymph nodes in patients with esophageal cancer.

PURPOSE: Presence of simultaneous pathological and immunohistochemical nodal metastasis (pNM and iNM, respectively) and/or other clinical factors may be reliable prognostic predictors of survival in esophageal cancer patients who have undergone multidisciplinary treatment. METHODS: Univariate and multivariate analysis of the data collected from 77 patients who had undergone R0 esophagectomy was performed to determine the significance of presence of iNM or pNM, presence of simultaneous pNM, and other clinical factors as prognostic indicators in patients who had (n = 40) and had not (n = 37) undergone preoperative treatment. RESULTS: Presence of pNM was found to be a significant prognostic predictor in patients who had undergone preoperative treatment, presence of iNM in patients who had not undergone preoperative treatment, and presence of simultaneous pNM and iNM in both patient groups. Multivariate analysis indicated that the sole prognostic predictor for patients who had undergone preoperative treatment was presence of simultaneous pNM and iNM while that of patients who had not undergone preoperative treatment was clinical T category. CONCLUSION: Assessment of simultaneous presence of pNM and iNM may facilitate highly accurate prediction of survival in esophageal cancer patients undergoing R0 esophagectomy, regardless of whether they have undergone preoperative treatment.

Radical radiotherapy for superficial esophageal cancer: impact of clinical N stage on survival.

AIM: To retrospectively analyze the results of radical radiotherapy for patients with superficial esophageal cancer (SEC). PATIENTS AND METHODS: Forty-eight patients with SEC were reviewed. The median dose of external beam radiotherapy was 66 Gy (range, 30 to 70 Gy). Intraluminal brachytherapy was used in 10 patients, and 15 patients (31%) underwent chemotherapy. The median follow-up period was 28 months (range, 4 to 116 months). RESULTS: Sixteen patients had recurrence (11 patients: in-field local recurrence; 3 patients: regional lymph node recurrence; 2 patients: distant metastasis), and the 5-year local control (LC) rate was 74.2%. The 5-year overall survival and disease-free survival (DFS) rates were 44.5% and 48.6%, respectively. Patients with clinical N1 disease (5-year DFS: 0%) had significantly poorer DFS than patients with clinical N0 disease (5-year DFS: 51%, p=0.019). CONCLUSION: Radical radiotherapy yielded relatively favorable LC rates in patients with SEC, and clinical N stage was a significant prognostic factor for DFS.

Clinical significance of HIF-1alpha expression in patients with esophageal cancer treated with concurrent chemoradiotherapy.

AIM: We investigated whether hypoxia-inducible factor-1α (HIF-1 α) expression in pretreatment biopsies of esophageal cancer is predictive of clinical outcome in patients with esophageal cancer undergoing concurrent chemoradiotherapy (CRT). PATIENTS AND METHODS: A total of 25 patients were reviewed. Radiotherapy was administered to total doses of 40-66.6 Gy (median: 66.6 Gy) with a single fraction of 1.8-2 Gy. Cisplatin (80 mg/m2 on day 1) and 5-fluorouracil (800 mg/m2 on days 2-6) were administered concurrently with radiotherapy, every 3-4 weeks to a total of 1-2 courses. Tissue samples from esophageal cancer were obtained from all 25 patients by biopsy before concurrent CRT, and semiquantitative analyses of HIF-1α expression were performed using immunohistochemical staining. RESULTS: High HIF-1α expression was observed in 11 out of 25 patients (42.7%), and HIF-1α expression was significantly correlated with initial response to CRT (p=0.0027). Patients with high HIF-1α expression had significantly poorer local control (LC) (5-year LC: 42.7%) than those with low expression (5-year LC: 72.5%; p=0.0322). Patients with high HIF-1α expression also had significantly lower recurrence-free survival (RFS) (5-year RFS: 18.2%) compared to those with low HIF-1α expression (5-year RFS: 39.8%; p=0.0009), and on multivariate analysis, HIF-1α (p=0.001) and number of chemotherapy courses (p=0.010) were independent prognostic factors for RFS. CONCLUSION: HIF-1α expression is significantly correlated with initial response to concurrent CRT, and is predictive of RFS for patients with esophageal cancer receiving concurrent CRT.

Clinical significance of GLUT-1 expression in patients with esophageal cancer treated with concurrent chemoradiotherapy.

This study aimed to investigate whether glucose transporter-1 (GLUT-1) expression in a pretreatment esophageal cancer biopsy was predictive of clinical outcomes in patients with esophageal cancer undergoing concurrent chemoradiotherapy (CRT). A total of 25 patients with esophageal cancer treated with concurrent CRT were reviewed. Radiotherapy was administered up to total doses of 40-66.6 Gy (median 66.6 Gy) with a single fraction of 1.8-2 Gy. Regarding chemotherapy, cisplatin (80 mg/m(2) on day 1) and 5-fluorouracil (800 mg/m(2) on days 2-6) were used concurrently with radiotherapy, every 3-4 weeks for a total of 1-2 courses. Tissue samples from esophageal carcinoma were obtained from the 25 patients by biopsy prior to concurrent CRT, and a semiquantitative analysis of GLUT-1 expression was performed using immunohistochemical staining. High GLUT-1 expression was observed in 7 of 25 (28%) patients, and GLUT-1 expression was significantly correlated with clinical T stage (p=0.0454), clinical N stage (p=0.0324) and initial response to CRT (p=0.0185). Patients with a high GLUT-1 expression had significantly poorer local control (LC) (5-year LC 28.6%) than those with a low expression (5-year LC 73.4%, p<005). Multivariate analysis revealed that GLUT-1 and the number of chemotherapy courses were independent prognostic factors for LC. Patients with a high GLUT-1 expression had significantly lower recurrence-free survival (RFS) compared to those with a low GLUT-1 expression (p=0.0405). Multivariate analysis revealed that GLUT-1, the number of chemotherapy courses and clinical M stage were independent prognostic factors for RFS. GLUT-1 expression was significantly correlated with clinical T stage, clinical N stage and initial response to concurrent CRT, and was predictive of LC and RFS for patients with esophageal cancer treated with concurrent CRT.

Primary malignant melanoma of the esophagus arising from a melanotic lesion: report of a case.

We herein report a case of primary esophageal malignant melanoma in which the development from a preceding benign melanotic lesion and the growing process of the tumor were chronologically observed by serial endoscopic examinations. Biopsy specimens repeatedly taken from the tumor failed to identify the presence of malignant melanoma. A positron emission tomography scan and gross changes of the tumor endoscopically observed were useful for detecting the presence of malignant transformation. The patient eventually died of generalized metastatic disease soon after undergoing an esophagectomy. An early diagnosis may therefore be crucial for improving the treatment outcome of esophageal malignant melanoma. Therefore, esophageal melanotic lesions should be carefully followed up even if biopsy specimens repeatedly show no malignancy.