Perioperative benefit and outcome of thoracic epidural in esophageal surgery: a clinical review.

Surgery for esophageal cancer is a highly stressful and painful procedure, and a significant amount of analgesics may be required to eliminate perioperative pain and blunt the stress response to surgery. Proper management of postoperative pain has invariably been shown to reduce the incidence of postoperative complications and accelerate recovery. Neuraxial analgesic techniques after major thoracic and upper abdominal surgery have long been established to reduce respiratory, cardiovascular, metabolic, inflammatory, and neurohormonal complications.The aim of this review is to evaluate and discuss the relevant clinical benefits and outcome, as well as the possibilities and limits of thoracic epidural anesthesia/analgesia (TEA) in the setting of esophageal resections. A comprehensive search of original articles was conducted investigating relevant literature on MEDLINE, Cochrane reviews, Google Scholar, PubMed, and EMBASE from 1985 to July2017. The relationship between TEA and important endpoints such as the quality of postoperative pain control, postoperative respiratory complications, surgical stress-induced immunosuppression, the overall postoperative morbidity, length of hospital stay, and major outcomes has been explored and reported. TEA has proven to enable patients to mobilize faster, cooperate comfortably with respiratory physiotherapists and achieve satisfactory postoperative lung functions more rapidly. The superior analgesia provided by thoracic epidurals compared to that from parenteral opioids may decrease the incidence of ineffective cough, atelectasis and pulmonary infections, while the associated sympathetic block has been shown to enhance bowel blood flow, prevent reductions in gastric conduit perfusion, and reduce the duration of ileus. Epidural anesthesia/analgesia is still commonly used for major 'open' esophageal surgery, and the recognized advantages in this setting are soundly established, in particular as regards the early recovery from anesthesia, the quality of postoperative pain control, and the significantly shorter duration of postoperative mechanical ventilation. However, this technique requires specific technical skills for an optimal conduction and is not devoid of risks, complications, and failures.

Genetic risk of subsequent esophageal cancer in lymphoma and breast cancer long-term survival patients: a pilot study.

The occurrence of a second primary esophageal carcinoma (EC) in long-term cancer survivors may represent a late effect of previous radio-chemotherapeutic treatment. To identify the genetic factors that could increase this risk, we analyzed nine variants within ERCC1, XPD, XRCC1 and XRCC3 DNA repair pathway genes, and GSTP1, TP53 and MDM2 genes in 61 patients who received radio-chemotherapy for a prior lymphoma or breast cancer; 29 of them had a second primary EC. This cohort consists of 22 esophageal squamous cell carcinoma (ESCC) and 7 esophageal adenocarcinoma (EADC) patients. A validation cohort of 154 patients with sporadic EC was also included. The XPD Asp312Asn (rs1799793) was found to be associated with the risk of developing second primary ESCC (P=0.015). The resultant variant was also involved in the onset of sporadic ESCC (P=0.0018). To know in advance who among long-term cancer survivors have an increased risk of EC could lead to a more appropriate follow-up strategy.

Effect of preoperative chemoradiotherapy on outcome of patients with locally advanced esophagogastric junction adenocarcinoma-a pilot study.

BACKGROUND: To date, few studies of preoperative chemotherapy or chemoradiotherapy (crt) in gastroesophageal junction (gej) cancer have been statistically powered; indeed, gej tumours have thus far been grouped with esophageal or gastric cancer in phase iii trials, thereby generating conflicting results. METHODS: We studied 41 patients affected by locally advanced Siewert type i and ii gej adenocarcinoma who were treated with a neoadjuvant crt regimen [folfox4 (leucovorin-5-fluorouracil-oxaliplatin) for 4 cycles, and concurrent computed tomography-based three-dimensional conformal radiotherapy delivered using 5 daily fractions of 1.8 Gy per week for a total dose of 45 Gy], followed by surgery. Completeness of tumour resection (performed approximately 6 weeks after completion of crt), clinical and pathologic response rates, and safety and outcome of the treatment were the main endpoints of the study. RESULTS: All 41 patients completed preoperative treatment. Combined therapy was well tolerated, with no treatment-related deaths. Dose reduction was necessary in 8 patients (19.5%). After crt, 78% of the patients showed a partial clinical response, 17% were stable, and 5% experienced disease progression. Pathology examination of surgical specimens demonstrated a 10% complete response rate. The median and mean survival times were 26 and 36 months respectively (95% confidence interval: 14 to 37 months and 30 to 41 months respectively). On multivariate analysis, TNM staging and clinical response were demonstrated to be the only independent variables related to long-term survival. CONCLUSIONS: In our experience, preoperative chemoradiotherapy with folfox4 is feasible in locally advanced gej adenocarcinoma, but shows mild efficacy, as suggested by the low rate of pathologic complete response.

A multicenter phase II study of induction chemotherapy with FOLFOX-4 and cetuximab followed by radiation and cetuximab in locally advanced oesophageal cancer.

BACKGROUND: Preoperative chemoradiotherapy (CRT) improves the survival of patients with oesophageal cancer when compared with surgery alone. METHODS: We conducted a phase II, multicenter trial of FOLFOX-4 and cetuximab in patients with locally advanced oesophageal cancer (LAEC) followed by daily radiotherapy (180 cGy fractions to 5040 cGy) with concurrent weekly cetuximab. Cytokines levels potentially related to cetuximab efficacy were assessed using multiplex-bead assays and enzyme-linked immunosorbent assay at baseline, at week 8 and at week 17. Primary end point was complete pathological response rate (pCR). RESULTS: In all, 41 patients were enroled. Among 30 patients who underwent surgery, a pCR was observed in 8 patients corresponding to a rate of 27%. The most frequent grade 3/4 toxicity was skin (30%) and neutropenia (30%). The 36-month survival rates were 85 and 52% in patients with pathological CR or PR vs 38 and 33% in patients with SD or PD. CONCLUSIONS: Incorporating cetuximab into a preoperative regimen for LAEC is feasible; no correlation between cytokines changes and patient outcome was observed. Positron emission tomography/computed tomography study even if influenced by the small number of patients appears to be able to predict patients outcome both as early and late metabolic response.

The laparoscopic Heller-Dor operation remains an effective treatment for esophageal achalasia at a minimum 6-year follow-up.

BACKGROUND: The aim of this study was to investigate the long-term clinical outcome of the laparoscopic Heller Dor procedure for esophageal achalasia. METHODS: A total of 71 consecutive patients with a minimum 6 year follow-up were evaluated. These patients were seen at 1 and 6 months after the operation (at which time barium swallow, endoscopy, manometry, and pH monitoring were performed), and annually thereafter. A dedicated symptom score, that combined severity and frequency of symptoms was used. RESULTS: The median symptom score decreased from 22 (range, 9-29) preoperatively to 4 (range, 0-16) at last follow-up, (p < 0.01). During the follow-up period, 13 patients suffered symptom recurrence; seven of them (54%) had already been diagnosed at the 1-year follow-up. All of these patients were treated with complementary pneumatic dilations. Overall, at a minimum of 6- years after the operation, 81.7% of the patients were satisfied with the treatment and were able to eat normally. CONCLUSIONS: The long-term outcome of laparoscopic surgical treatment of esophageal achalasia is only slightly affected by the length of the follow-up and most of the symptomatic failures occur in the early period after the operation.

p53 alterations but no human papillomavirus infection in preinvasive and advanced squamous esophageal cancer in Italy.

Geographic differences in exposure to suspected carcinogens have been identified in esophageal carcinogenesis, and both p53 alterations and human papillomavirus (HPV) infection have been reported in esophageal squamous carcinoma (ESC) from high-risk areas, including China and South Africa. The status of p53 alterations and HPV infection in ESC has not been determined in northern Italy, where the incidence of ESC is low. Formalin-fixed paraffin-embedded esophageal samples containing normal, dysplastic, and carcinomatous tissue from 18 patients were examined for p53 protein accumulation with immunohistochemistry, p53 mutation (exons 5-8) with PCR-single-strand conformation polymorphism analysis and DNA sequencing, and HPV infection with PCR using general primers to amplify the L1 gene. Accumulation of p53 protein was observed in both precancerous and carcinomatous lesions. p53 mutations were rare in dysplastic lesions but were detected in 9 of 18 carcinomas, a finding consistent with reports from other geographic areas. Examination of the p53 mutation spectrum revealed no hot spot mutation. In contrast, HPV was not found in any of these 18 cases. This is consistent with the findings from other low ESC risk areas in which HPV infection may not play a crucial role in esophageal oncogenesis, whereas the high risk of ESC in China and South Africa may be attributed to frequent HPV infection.

p53 overexpression in the multistep process of esophageal carcinogenesis.

The timing of p53 mutation in the multistep process of esophageal carcinogenesis is still under debate. We tested p53 expression in 16 samples of low-grade and 29 samples of high-grade esophageal dysplasia (ED) coexisting with esophageal squamous cancer (ESC) in 31 patients who underwent total esophagectomy. In normal mucosa, a positive immunoreaction was detected in 10 of 31 cases, always restricted to the lower half of the epithelial thickness. We detected p53-positive nuclei in 11 of 16, 23 of 29, and 23 of 31 samples of low-grade ED, high-grade ED, and ESC, respectively. Cases exhibiting positive staining in dysplastic samples also demonstrated positive immunoreaction in the carcinomatous tissue. Immunoreactivity in cancer cells was never found in the absence of positive dysplastic nuclei. A significantly higher score of immunoreactive nuclei was detected in high-grade versus low-grade and in low-grade compared with normal mucosa. These data suggest that p53 mutation may represent an early event in esophageal oncogenesis.

Esophagovisceral anastomotic leak. A prospective statistical study of predisposing factors.

An esophagovisceral anastomotic leak is a life-threatening postoperative complication, especially in the mediastinum. Of the 242 patients who underwent intrathoracic esophagogastric anastomosis for esophageal carcinoma (182 patients) and adenocarcinoma of the cardia (60 patients) between January 1980 and June 1985, 14 (5.8%) had esophageal anastomotic leakage and two died (0.8%). Various clinical and biologic parameters and aspects of operative technique were studied prospectively and analyzed statistically to identify possible factors responsible for leaks. Both bivariate and multivariate statistical analysis with logistic regression showed that the following clinical and biologic factors do not influence anastomotic leakage: tumor stage, the curative or palliative purpose of resection, neoplastic permeation of anastomotic margins, total protein concentration below 5 gm/dl, albumin concentration below 3 gm/dl, patient's age, diabetes, high blood pressure, cirrhosis of the liver, and cardiac, respiratory, or renal diseases. Technical factors, on the contrary, were statistically significant and of great clinical importance: manual as opposed to mechanical suturing (chi 2 = 8.8, p = 0.013) and single-layer as opposed to double-layer suturing (chi 2 = 9.9, p = 0.043). The level of the anastomosis was found to be a further statistically significant factor: The incidence of leakage was greater when the anastomosis was located between the azygos vein and the lower pulmonary vein (chi 2 = 15.5, p = 0.004) than above the azygos vein or below the lower pulmonary vein.

Chylothorax complicating esophagectomy for cancer: a plea for early thoracic duct ligation.

OBJECTIVE: Postoperative chylothorax remains an uncommon but potentially life-threatening complication of esophagectomy for cancer, and the ideal management is still controversial. The aim of the study was to compare the outcomes of patients treated nonoperatively with those of patients promptly undergoing reoperation. METHODS: From 1980 to 1998, 1787 esophagectomies for esophageal or cardia cancer were performed, and 19 (1.1%) patients had postoperative chylothorax. We analyzed type of operation, surgical approach, delay of diagnosis of chylothorax, daily chest tube output, type of management, major complications, death, hospital stay, and final outcome. RESULTS: Of the 19 patients with chylothorax, 11 were initially managed nonoperatively (group A): 4 (36%) patients had spontaneous resolution of chylothorax, and the other 7 required reoperation for the persistence of a high-volume output. There were three infectious complications and one postoperative death in this group. No reliable predictive criteria of successful versus unsuccessful nonoperative management could be found. The 8 most recent patients underwent early reoperation (group B). All patients recovered, and no major complications possibly related to chylothorax or hospital deaths were observed. They were discharged after a median of 22 days (range, 12-85 days) compared with a median of 36 days (range, 21-64 days) for patients of group A. CONCLUSIONS: Early thoracic duct ligation is the treatment of choice for chylothorax occurring after esophagectomy. Reoperation should be performed immediately after the diagnosis is made to avoid the complications related to nutritional and immunologic depletion caused by prolonged nonoperative treatment.

Interferon therapy of cryptogenic chronic active liver disease and its relationship to anti-HCV.

In a randomized controlled trial of Interferon (IFN) in 60 patients (30 treated and 30 controls) with cryptogenic chronic active liver disease, 70% of treated patients showed complete response, but a high rate of biochemical relapse (62%) was noted. In these cases, a second response to higher doses of IFN has been more difficult and less frequent. A response to IFN was found in 88.5% of anti-HCV positive treated patients and only in 25% of anti-HCV negative. We suggest that serum anti-HCV is a suitable test to predict the response to IFN.

Videothoracoscopic enucleation of esophageal leiomyoma.

A new thoracoscopic technique to enucleate esophageal leiomyomas is described. The procedure has been successfully performed in 3 patients. All patients benefited by this new surgical approach due to the decreased operative trauma, reduced postoperative pain, quick recovery, and minute skin scars. Although further clinical experience and longer periods of follow-up are needed to evaluate the full benefits and limits of this new access, the early results of the thoracoscopic approach are promising.

Single-layered cervical esophageal anastomoses: a prospective study of two suturing techniques.

We carried out a prospective, randomized study over a 1-year period to compare the efficacy of a single layer of continuous absorbable monofilament (Maxon) with that of a single layer of interrupted Polyglactin sutures (Vicryl) in the performance of cervical esophagogastric anastomoses. Forty-two consecutive patients with carcinoma of the esophagus or cardia, in whom the stomach was transposed through the mediastinal route after esophagectomy, were enrolled in the study. There were 21 patients in each group. There was no hospital mortality. One asymptomatic anastomotic leak and two early anastomotic strictures requiring dilation occurred in patients in whom an interrupted technique was employed. The continuous technique required significantly less operative time (p < 0.0001), and the cost of the suture material was reduced markedly. We conclude that either a continuous or an interrupted monolayer esophagogastric anastomosis can give satisfactory results after esophagectomy for cancer, provided that the vascular supply to the gastric fundus is maintained adequately. The continuous technique has the advantages of being time-saving, cheaper, and easier to perform and to teach.

Push-through intubation: effective palliation in 409 patients with cancer of the esophagus and cardia.

Between 1980 and 1989, 355 patients with cancer of the esophagus and 54 with cancer of the cardia underwent push-through intubation because of advanced tumor stage or medical contraindications to tumor resection. In 36 other patients (8.1%), the attempt at transtumoral intubation failed. The hospital mortality rate after intubation was 3.4%. The following complications were observed: hemorrhage in 2.0% of the patients, esophageal perforation in 4.9%, tube dislodgment in 12.7%, and tube obstruction in 4.4%. Early resumption of semisolid oral feeding was possible in 80% of the discharged patients. The actuarial 1-year survival rate was 7.7% and the median survival, 3.9 months. In conclusion, push-through intubation represents a valid therapeutic choice, which is indicated mainly for patients with a long, infiltrating, and circumferential stricture of the thoracic esophagus or cardia that is inoperable and for patients with an esophagorespiratory or esophagomediastinal fistula.

Surgical and endoscopic palliation of esophageal carcinoma.

We reviewed the records of 732 patients with advanced esophageal carcinoma to determine the efficacy of palliative therapy. Palliative resection was performed in 156 patients. Hospital mortality was 9.6%, 1-year survival was 29.1%, and median survival was 7.8 months. Excellent or good palliative results were obtained in 78% of operative survivors. Bypass procedures were performed in 49 patients: hospital mortality was 20.4%, with a median survival of 6.2 months. Excellent or good palliative results were obtained in 71% of operative survivors. Intubation of the tumor was performed in 254 patients. Thirty-day mortality was 10.2%, and median survival was 4.0 months. No patient received excellent palliation. Neodymium:yttrium-aluminum-garnet laser therapy or photodynamic therapy was performed in 50 patients. No procedure-related deaths were recorded, and median survival was 4.1 months. Excellent or good results were obtained in 83% of patients. Lesser procedures were performed in 106 patients, and 117 had only staging examinations. Although surgical palliation of esophageal cancer with resection or bypass provides good results, the cost is high. Improvements in palliative results require reduction in operative mortality, increased accuracy of preoperative staging, continuing use of laser therapy, and increased use of chemotherapy alone or in combination with radiotherapy and operation.

Anomalous transcripts and allelic deletions of the FHIT gene in human esophageal cancer.

The fragile histidine triad (FHIT) gene is localized on chromosome 3p14 and spans the common fragile site FRA3B. Even though its role in carcinogenesis is still unclear, this gene is frequently inactivated by carcinogen-induced intragenic deletions in many types of cancers, and FHIT abnormal transcripts are found in many primary tumors and tumor-derived cell lines. We evaluated FHIT gene involvement in 39 esophageal carcinomas (18 adenocarcinomas [AC¿, 21 squamous cell carcinomas [SCC]) by both reverse transcriptase-polymerase chain reaction (RT-PCR) amplification and loss of heterozygosity analysis (LOH). Thirty cases (77%) displayed either aberrant FHIT transcripts (12 cases) and/or LOH (24 cases); among these, only 6 samples displayed both aberrant transcripts and LOH, thus suggesting that the two events are probably independent. Moreover, LOH was significantly higher in SCC (80%) than in AC (44%), and because most of our patients are heavy smokers and/or alcohol consumers, these results suggest that the FHIT gene might be a common target for carcinogens also in the esophagus.

Esophageal cancer: a European perspective.

A survey was conducted among a group of European surgeons in order to investigate current attitudes and strategies in the management of squamous cell carcinoma of the esophagus. The survey consisted of a questionnaire mailed to surgeons in eight different countries with extensive clinical experience and scientific interest in the field. Eight questionnaires including the data of 6146 operated patients were available for analysis. A consensus emerged among the panelists that protocols of induction therapy should be routinely used in patients with locally advanced disease, especially in supracarinal tumors. Four of the surgeons advocated bilateral neck dissection in these patients. A progressive improvement in survival over the past three decades was noted. After 1990, the postoperative mortality rate was 6.2% after surgery alone and 9.7% after chemoradiation therapy followed by surgery. The 5-year survival rate after a complete resection was 38.5%. In the opinion of the panelists, esophagectomy remains the "gold standard" of therapy and should be regarded as an integral component of the treatment plan for patients with squamous cell carcinoma.

Epidermal growth-factor receptors and erbb2 protein expression in esophageal cancer and normal mucosa.

The epidermal growth factor receptor (EGFr) and the erbB2 protein (p185) concentrations were assessed in 31 esophageal cancer specimens and in the corresponding normal mucosa, in order to investigate the possible links with the main clinical and pathological parameters. Detectable and high affinity EGFr was found in 27/31 cancer and in 18/31 normal tissue samples. EGFr concentrations were not significantly different between cancer and normal tissue, although a trend toward higher levels in cancer was found. No relationships were found with histologic type, tumor bulk, lymph node status, pathologic stage, ploidy and type of surgical resection. A significant negative correlation between EGFr levels and overall survival was found. Detectable levels of p185 were found in all the tissues examined, but the expression was higher in adenocarcinoma than in squamous cell carcinoma samples. The EGFr role in malignant transformation still has to be established, but the determination could be of clinical use. As for p185, its role in the onset of esophageal cancer could be confined to the subgroup of the adenocarcinomas.

TAF test in primary esophageal carcinoma: comparison with other tumor markers.

An ELISA method for the determination of circulating specific HSV-TAA antibodies has recently become available (TAF test). The presence of TAF was tested in serum of 154 patients with primary esophageal carcinoma, collected in three institutions. The overall TAF-test positivity rate was 57.1%, being significantly lower in stage IV than in stage III patients. The concordance rate between TAF and CEA, ferritin, TPA, SCC and TATI was low, suggesting that TAF is probably independent of the other tumor markers evaluated. The clinical role of TAF-test determination in patients with esophageal carcinoma is currently under evaluation.

Tumor markers in squamous cell carcinoma of esophagus: immunometric assay in cytosol and membrane fraction.

Carcinoembryonic antigen (CEA), tissue polypeptide antigen (TPA), ferritin, and the monoclonal antibody-detected tumor-associated antigens CA19.9 and CA50 were measured by radioimmunoassay in tissue fractions of carcinoma and normal esophageal mucosa from 59 patients with untreated primary squamous cell carcinoma of the esophagus. Tumor markers were measured in cytosol (118 samples) and in a membrane-enriched fraction (32 samples). CEA, TPA and ferritin were detected in almost all the cytosol samples evaluated, CA19.9 and CA50 in 66% and 50% of cases respectively. Ferritin was significantly higher in carcinoma than in normal mucosa. The cytosol concentrations of CEA, TPA, CA19.9 and CA50 were not significantly different in carcinoma and normal tissue. Concentrations of CEA, CA19.9 and CA50 in the membrane fraction tended to be higher in normal tissue than in carcinoma, whereas the cytosol-to-membrane ratio was significantly higher in carcinoma. For CEA, CA19.9 and CA50, the phenotypic pattern of the malignant transformation seems to involve a different intracellular distribution rather than a quantitative change. No correlations were found between tissue and serum concentrations of the tumor markers, the former being related to the phenotypic characteristics of the tumor, the latter to the tumor burden.

Role of acid and bile reflux in development of specialised intestinal metaplasia in distal oesophagus.

BACKGROUND: Barrett's oesophagus is defined as specialised intestinal metaplasia in the distal oesophagus, regardless of extension. AIM: To study distal oesophagus function, and acid and bile exposure in patients with Long Segment (>3 cm), Short Segment (1 to 2 cm) and Ultra-short Segment (<1 cm) Barrett's Oesophagus, and in patients with gastro-oesophageal reflux disease without intestinal metaplasia. PATIENTS: Study population comprised 17 patients with Long, 8 with Short, 9 with Ultra-Short Segment Barrett's oesophagus, 32 with reflux disease and 12 healthy volunteers. METHODS: Patients were evaluated by manometry and by 24-hour pH and bile monitoring. RESULTS: Patients with intestinal metaplasia had greater acid exposure of the distal oesophagus than healthy volunteers. Patients with Long Segment Barrett's oesophagus had a longer history of symptoms, worse lower oesophageal sphincter pressures and longer bile and acid exposure than the other patients. Long Segment Barrett's oesophagus was predicted by low oesophageal pressure and increased bile exposure, age and male sex. CONCLUSION: Acid exposure in the distal oesophagus is probably the aetiological factor behind intestinal metaplasia, but a severely damaged antireflux barrier and bile in the refluxate are necessary for Long Segment Barrett's Oesophagus to develop.