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Background: The adenomatous polyposis coli (APC) locus on chromosome 5q21-22 shows frequent loss of heterozygosity (LOH) in esophageal carcinomas. However, the prevalence of truncating mutations in the APC gene in esophageal carcinomas is low. Because hypermethylation of promoter regions is known to affect several other tumor suppressor genes, we investigated whether the APC promoter region is hypermethylated in esophageal cancer patients and whether this abnormality could serve as a prognostic plasma biomarker.Methods: We assayed DNA from tumor tissue and matched plasma from esophageal cancer patients for hypermethylation of the promoter region of the APC gene. We used the maximal chi-square statistic to identify a discriminatory cutoff value for hypermethylated APC DNA levels in plasma and used bootstrap-like simulations to determine the P: value to test for the strength of this association. This cutoff value was used to generate Kaplan-Meier survival curves. All P values were based on two-sided tests.Results: Hypermethylation of the promoter region of the APC gene occurred in abnormal esophageal tissue in 48 (92%) of 52 patients with esophageal adenocarcinoma, in 16 (50%) of 32 patients with esophageal squamous cell carcinoma, and in 17 (39.5%) of 43 patients with Barrett's metaplasia but not in matching normal esophageal tissues. Hypermethylated APC DNA was observed in the plasma of 13 (25%) of 52 adenocarcinoma patients and in two (6.3%) of 32 squamous carcinoma patients. High plasma levels of methylated APC DNA were statistically significantly associated with reduced patient survival (P =.016).Conclusion: The APC promoter region was hypermethylated in tumors of the majority of patients with primary esophageal adenocarcinomas. Levels of hypermethylated APC gene DNA in the plasma may be a useful biomarker of biologically aggressive disease in esophageal adenocarcinoma patients and should be evaluated as a potential biomarker in additional tumor types. [ABSTRACT FROM AUTHOR]

Background: Accurate pretreatment staging of esophageal cancer (EC) is important in the evaluation and comparison of results of different treatment modalities. Few studies using minimally invasive staging techniques for this purpose have been reported. We previously demonstrated the usefulness of the thoracoscopic/laparoscopic (Ts/Ls) technique in pretreatment staging of EC. This study was conducted to evaluate the impact of trimodality based on pretreatment Ts/Ls staging diagnosis on EC., Methods: A retrospective study was performed on 2 groups of EC patients. Group A (44 patients) underwent pretreatment Ts/Ls staging and had trimodality treatment. Preoperative therapy consisted of concurrent chemotherapy (5-FU + cisplatinum) and radiotherapy. Group B (33 patients) underwent surgery alone. The study focused on stratified comparison of patterns of recurrence and survival in different pretreatment surgical T, N, and TNM stage categories., Results: The 3-year disease free survival of Group A was 40.8% with a median survival of 32.0 months, it was 43.6% with a median survival of 23.6 months in Group B. The difference was not significant (p=0.87). There was no difference in recurrence pattern between the 2 groups. Patients with squamous cell carcinoma in Group A had no local recurrence during the follow-up period while those in Group B had a high local recurrence rate of 40% (p<0.005). When stratified by T factor, patients with locally advanced T stage (T3-4) in Group A had a lower distant recurrence rate than their counterpart patients in Group B (9.1 vs 38.5%, p=0.03), they had a better survival but the difference was not significant (3-year disease free survival: 41.7 vs 17.9%, p=0.14). There were no significant differences in recurrence pattern and survival in different N categories and TNM stages between 2 groups. Multivariate analysis showed that only pretreatment surgical N status was an independent prognostic factor for the whole group (p=0.02)., Conclusions: Pretreatment Ts/Ls staging can provide accurate staging information for EC patients. Trimodality treatment was successful in local control for patients with squamous cell carcinoma. It was effective in reducing distant recurrence and might prolong survival in patients with advanced T stages. Pretreatment lymph node status was the most important prognosticator regardless of treatment modality. Pretreatment pathological staging should be included in the future clinical trials on multimodality treatments in EC patients.

Purpose: The diagnosis of esophageal carcinoma has historically been associated with a poor prognosis. Recently, investigators have reported improved outcomes for this patient population with the use of trimodality therapy. These results have fueled the debate regarding which patients may benefit from this aggressive treatment course. This retrospective analysis was conducted in order to evaluate the importance of regional lymph node involvement, determined by surgical staging before the initiation of therapy., Patients and Materials: Between July 1991 and June 1999, 45 patients underwent surgical staging with thoracoscopy and/or laparoscopy followed by induction chemoradiation and surgical resection. All patients underwent consultation in our thoracic multidisciplinary clinic. Thoracoscopy included nodal sampling from American Thoracic Society levels 5, 6, 8, and 9 within the mediastinum. Laparoscopy included inspection of the liver and nodal sampling from the lesser curvature and the celiac axis. Preoperative chemoradiation consisted of two cycles of 5-fluorouracil (1000 mg/M2) and cisplatin (100 mg/M2) weeks 1 and 4 with 50.4 Gy. Radiotherapy was delivered at 1.8 Gy/fraction with 39.6 Gy being delivered to the large-field and 10.8 Gy to a small-field boost. The routine surgical procedure was an Ivor-Lewis esophagectomy performed 4 to 6 weeks after completion of induction therapy., Results: The median follow up was 24 months for all patients. The median overall survival was 23 months, with 1-, 2-, and 3-year survivals of 64%, 42%, and 34%, respectively. Thirty patients had pathological evidence of lymph node disease before therapy. The pathological complete response rate for the entire group was 51%. Node-positive patients had a path complete response rate of 14%, as compared with 59% for those who were NO. The median survival for these two groups was 15 months versus 35 months. Patients whose nodes were cleared by chemoradiation had a 3-year survival of 40%, whereas all patients with persistent nodal disease were dead by 2 years. Twenty-one patients have experienced recurrence of their disease. Thirteen patients had evidence of distant metastasis only, three local only, and five with both., Conclusion: Trimodality therapy offers patients with esophageal cancer an opportunity for long-term survival. Our experience has shown that minimally invasive pretreatment surgical staging provides useful information that can predict complete response and can help in the selection of appropriate patients for aggressive therapy.

Purpose: Patients presenting with apical sulcus tumors have historically been treated with preoperative radiotherapy followed by surgical resection. Since 1991, we have delivered an induction regimen consisting of combination chemotherapy and high-dose radiation in an attempt to improve tumor responses and increase survival for this patient population., Patients and Materials: This retrospective analysis consisted of 23 (13 men and 10 women) consecutive patients who completed trimodality therapy. The median age was 53 years. Histologies included adenocarcinoma (nine patients), squamous cell (five patients), large cell (three patients), and undifferentiated non-small cell lung carcinoma (six patients). Pretreatment stages were T3NO (14 patients), T3N2 (two patients), T3N3 (one patient), T4NO (five patients), and T4N2 (one patient). Preoperative therapy consisted of daily radiotherapy (median dose, 59.4 Gy) delivered at 1.8 Gy/day and concurrent combination chemotherapy consisting of either two cycles of cisplatin and etoposide or weekly carboplatin and paclitaxel. Surgical resection typically included lobectomy with chest wall resection., Results: All 23 patients were available for analysis of response and survival. The median follow-up was 53 months. The median number of days between completion of induction therapy and surgery was 56 days. Postoperative complications included prolonged atelectasis (two patients), pulmonary embolism (one patient), subarachnoid-pleural fistula (one patient), and deep vein thrombosis in the subclavian vein (one patient). The pathological complete response rate to induction therapy was 46% for the entire group. An additional 38% had evidence of tumor regression at the time of surgery. The 5-year disease-free and overall survivals were 36% and 49%, respectively. The median overall survival was 33 months. The median overall survival for those who achieved a pathological complete response has not been reached. Analysis of factors including age, sex, histology, differentiation, stage of disease, and radiation dose failed to identify any predictors of response or survival. CONCLUSION Concurrent chemotherapy and high-dose radiation can be safely delivered before surgery in patients presentingwith apical sulcus tumors. Our results compare favorably to other institutional series and support the further investigation of this approach in prospective trials.

The objective was to evaluate the safety and effectiveness of endoscopic thoracic sympathectomy (ETS) for treatment of a variety of sympathetic disorders, including hyperhidrosis, splanchnic pain, reflex sympathetic dystrophy, and Raynaud upper extremity ischemia. Sixty-three ETS procedures were performed in 34 patients at the University of Maryland Medical System between March 1992 and August 1999 (14 male patients, 20 female patients; mean age 22 years). The indications for surgery were hyperhidrosis in 26 patients, upper extremity ischemia in 3 patients, splanchnic pain and reflex sympathetic dystrophy in 2 patients each, and facial blushing in 1 patient. Preoperative symptoms resolved completely or improved significantly in 97.1% (33/34) of patients. One patient with left reflex sympathetic dystrophy had symptoms that recurred shortly after surgery. There were no major complications; one patient with hyperhidrosis reported significant compensatory hyperhidrosis. These findings suggest that ETS is a safe and effective procedure for treatment of a variety of sympathetic disorders. Its application for hyperhidrosis is very effective, and its treatment of splanchnic pain, reflex sympathetic dystrophy, and Raynaud syndrome are rewarding. With increasing experience, ETS should become established in the repertoire of the thoracic surgeon.

One trial has suggested improved survival with preoperative chemotherapy and radiation therapy with acceptable morbidity and mortality. Other studies have not demonstrated apparent improvement in survival, although the protocols are somewhat different. Longer follow-up is needed in these preliminary studies, and well-designed, prospective, multicenter randomized trials are necessary in the future. These studies should compare identical CRT and surgery regimens and identify a group of esophageal patients that might benefit from preoperative chemotherapy or radiation therapy. In order to evaluate the results of future trials without bias and to determine which group of esophageal patients will benefit from preoperative CRT, pretreatment, accurate TNM staging by CT and EUS combined with pathologic LN staging when possible will be crucial in future trimodality therapy trials for esophageal cancer. The investigation of biologic molecular markers to predict chemoradiation sensitivity and prognosis deserves careful exploration. Unfortunately, those patients without a response do not benefit from the preoperative chemotherapy but still may suffer the associated toxicity. These patients may have a much higher risk of postoperative fatal complications including respiratory failure, bone marrow suppression, and sepsis. It has been shown that CR patients in the chemotherapy/surgery group survive longer than nonresponders; it would be helpful to find useful molecular biomarkers to identify chemotherapy-sensitive patients before the preoperative chemotherapy is employed. Several pilot trials are underway using chemotherapy sensitivity testing on the endoscopic biopsy specimen before the chemotherapy is applied.

Accurate pretreatment staging for patients with esophageal cancer (EC) is becoming increasingly important in the evaluation and comparison of different treatment modalities. Noninvasive staging methods are imperfect in detecting lymph node metastasis in patients with EC. Surgical staging with the thoracoscopic/laparoscopic (Ts/Ls) technique may provide accurate staging information that is useful for evaluating and comparing the results of clinical trials of preoperative chemotherapy and radiotherapy. It can be used to confirm or exclude suspicious distant metastasis found by other staging methods. Pretreatment (lymph node) biopsies obtained by Ts/Ls staging allow further molecular biologic analysis to detect occult lymph node metastasis for more accurate lymph node staging. Since 1992, we have used Ts/Ls staging for EC in 111 patients. We found that Ts/Ls is a promising method for staging lymph nodes in EC patients. A recent study showed that pretreatment surgical lymph node staging can predict response and survival for EC patients receiving trimodality treatment (ie, radiation, chemotherapy, and surgery). The information obtained with surgical staging now offers us the opportunity to optimize therapy to specific patient groups based on the extent of disease at the time of initial presentation. Nevertheless, unlike the practice of mediastinoscopy in lung cancer patients, Ts/Ls staging in EC patients remains an academic interest rather than a clinical practice. The concept of accurate pretreatment staging of EC remains to be realized and accepted in the clinical community.

Noninvasive staging of esophageal cancer (EC) is often inaccurate, and this fact has compromised clinical trials of treatment for EC. Prognostic evaluation might allocate chemotherapy and radiation more appropriately. Thoracoscopy and laparoscopy has recently shown promising results, and molecular analysis of the recovered tissue may further improve staging accuracy.

Background: P53 protein overexpression in esophageal cancer and its correlation with response and survival after chemoradiation was retrospectively investigated., Methods: Pretreatment and resection specimens were stained by automatic p53 immunohistochemical staining technique., Results: P53 was expressed in 84.0% of esophagoscopy (EGD) biopsies; 71.4% of patients with metastasis of thoracoscopy/laparoscopy lymph nodes (TS/LS LN) identified by hematoxylin/eosin (H/E) were p53 (+); 14.2% of patients with negative TS/LS LN by H/E were p53 (+). Eleven out of 18 patients with p53 (+) in pretreatment EGD remained p53 (+) after chemoradiation; 38.8% of these patients had a pathological complete response (pCR). The median survival of this group was 15 months. Of 4 patients with p53 (-) pretreatment EGD, all of those were still p53 (-) after chemoradiation; 75% of these patients had pCR. The median survival was 30 months. In patients with p53 (+) TS/LS LN, 23% had a pCR after chemoradiation with a median survival of 16 months. In patients with p53 (-) TS/LS LN, 50.0% had a pCR with a median survival of 31.5 months., Conclusions: P53 protein overexpression in pretreatment EGD and TS/LS LN may predict response to chemoradiation and survival in esophageal cancer patients.

Video-assisted thoracic surgery (VATS) may be used for resection of posterior mediastinal tumors to avoid thoracotomy and shorten hospital stay. Between October 1990 and June 1998, 23 patients had VATS resection of posterior neurogenic tumors. The 14 females and 9 males ranged in age from 14 months to 70 years, with a median of 35 years. Operation time ranged from 30 to 120 minutes (median, 83), and intraoperative complications were limited to minor problems as well as conversion to thoracotomy to enhance complete tumor resection in four cases. Tumor pathology included nerve sheath origin (20) and autonomic ganglia (3). There was only one malignant schwannoma. Tumor size ranged from 0.7 to 13 cm in diameter. Median chest tube days was 1 day (range, 1-4), and hospital stay was 2 days (range, 1-9). Postoperative complications included transient paresthesia (three cases), ileus (two cases), pleural effusion (one case), and transient intercostal pain (one case). Posterior neurogenic tumors may be resected safely using video-assisted techniques. Conversion to thoracotomy to enhance complete resection is both possible and encouraged. The use of VATS seems to decrease hospital stay and minimize postoperative complications. In posterior neurogenic tumors without tumor extension to the spinal canal, VATS has become our preferred method for resection.

Esophageal cancer is the fastest growing malignancy in the United States. Surgery remains the standard primary treatment but overall survival for all patients undergoing primary surgery is dismal. This is thought to be secondary to the advanced stage in many patients at the time of diagnosis. The presence or absence of metastatic lymph nodes is indeed the single most important prognosticator. Current preoperative staging includes computerized tomography, magnetic resonance imaging, and transesophageal ultrasound. The limitations of each of these techniques are well known. Preoperative thoracoscopy and laparoscopy staging is emerging as a safe, effective, and accurate way of staging patients with esophageal cancer. Moreover, it may become important in allocating treatment, as it may be used to individualize radiation therapy fields, or to allocate bimodality or trimodality therapy to patients in trials, depending on the results of pretreatment lymph node sampling. Future trials in esophageal cancer should consider the results of pretreatment pathologic staging in allocating patients to appropriate modalities of therapy.

Background: Pulmonary resection after high-dose thoracic irradiation is reported to be associated with a high morbidity and mortality, and has been considered to be prohibitive., Methods: We report safe pulmonary resection in 19 consecutive patients receiving neoadjuvant therapy that included greater than 59 Gy thoracic radiation. The mean thoracic radiation dose was 61.8 Gy (range 59.5-66.5) and mean age was 52 years (range 36-72 years). Cell type was adenocarcinoma (6), squamous (7), and other non-small cell lung cancer (NSCLC) (6). Sixteen of 19 patients received concurrent chemotherapy. Median time from end of treatment to surgical resection was 89 days (range 22-258 days). Surgical resection included 13 lobectomies and six pneumonectomies (four right, two left)., Results: A complete pathologic response was seen in 8 of 19 (42%) patients. Three patients required intraoperative transfusion of blood. Mean intensive care unit stay was 2.0 days (range 1-8 days), and mean length of stay (LOS) was 8.0 days (range 3-18 days). There were four postoperative complications; one bronchopulmonary fistula, one subarachnoid-pleural fistula, and 2 patients with prolonged atelectasis. There was no incidence of acute respiratory distress syndrome (ARDS) or operative mortality., Conclusions: Pulmonary resection, including pneumonectomy, after chemotherapy and high-dose thoracic radiation may be performed safely with a low rate of intraoperative and postoperative complications.

Background: Aggressive routine surgical staging is necessary to evaluate patients to be treated on cooperative oncology protocols. Less than 1% of lung cancer patients in the United States are currently being treated in a clinical trial. Only with results from large, prospective trials can the questions of neoadjuvant and adjuvant therapy be answered., Methods: An outline describing the schema of preoperative patient evaluation, surgical staging, and the definition of surgical staging and resection procedures appropriate for patients considered for cooperative group protocol is presented. Current Cancer and Leukemia Group B (CALGB) protocols are used in the discussion as examples of this systematic approach., Conclusions: Over the next few years, it will be important to enter the maximum number of patients into combined modality studies to identify the role of neoadjuvant treatment in lung cancer. Entry of patients into protocols will also make their pathological specimens and clinical information available for basic science research related to treatment results. Adherence to a logical sequence of patient evaluation as outlined above will optimize patient care, as well as accrual to cooperative group studies.

The results of single modality treatment for esophageal cancer have been poor because of a high rate of local recurrence and distant metastasis. This is probably caused by the prevalence of advanced esophageal cancer at the time of diagnosis; only 3% of patients have Stage I disease, and most of them (80%) are Stage III or IV when they become symptomatic. The most frequently involved metastasis sites are lymph nodes (73%), lung (52%), and liver (47%). Neoadjuvant preoperative chemotherapy, radiotherapy, and combined chemoradiation have been added to the treatment of this disease to enhance local control, increase resectability rate, and improve disease-free survival. The results of recent trials are discussed.

Study Objective: The presence of pleural adhesions may render video-assisted thoracoscopic surgery (VATS) difficult or impossible. The aim of this study was to assess the value of chest CT in the detection of pleural adhesions prior to VATS., Design: Prospective study of the accuracy of chest CT in detecting pleural adhesions prior to VATS., Setting: Tertiary-referra; teaching hospital and Veterans Administration hospital., Patients: Between July 1994 and March 1995, 63 consecutive patients undergoing 64 VATS procedures were evaluated with chest CT prior to surgery., Measurements and Results: Preoperative scans were interpreted by consensus of two pulmonary radiologists prior to surgery. Suspected pleural adhesions and other findings related to the pleura were recorded on a form given to the surgeon prior to VATS. The surgeon confirmed or excluded each suspected adhesion during VATS, and documented any other lesions not identified preoperatively. Patient-by-patient and lesion-by-lesion analyses were performed. Pleural adhesions were correctly identified by CT in 28 of 39 cases (sensitivity, 71%) and excluded in 18 of 25 cases (specificity, 72%). On a lesion-by-lesion basis, 73 adhesions were identified during VATS, of which only 28 were identified prospectively at CT. There were 45 missed adhesions and 20 adhesions that were suggested falsely (sensitivity, 38%; specificity, 46%). Eighteen pleural spaces were correctly identified as being free of pleural adhesions., Conclusions: CT is moderately sensitive and specific for preoperative identification of pleural adhesions in patients undergoing VATS but its accuracy is poorer for individual lesions.

Whereas many patients with esophageal carcinoma present with what appears to be localized disease, cure rates with surgical resection alone remain low. Although surgical resection, where feasible, affords patients the best chance of cure, the primary tumor has often invaded local tissues or structures, and occult micrometastases often exist at the time of presentation. In an effort to improve treatment results, various combinations of surgery, radiotherapy, and chemotherapy have been used. The results of combined modality therapy are reviewed in this article. The importance of accurate pretreatment staging is discussed, and ongoing prospective randomized trials are reviewed.

Numerous applications of video-assisted thoracic surgery (VATS) in the management of diseases of the esophagus for structural, functional, benign, and malignant conditions have been reported. Indications and techniques for the use of VATS in the assessment and treatment of esophageal disease are discussed in this article. The need for careful evaluation of the safety, efficacy, and cost-effectiveness of these techniques is emphasized.